トップ›研究者一覧›石田竜弘

研究者を探す

研究者にアプローチする
更新情報を通知する

石田竜弘

徳島大学

プロフィール
教育活動
研究活動
社会活動
リサーチマップ・
Jグローバル
KAKEN
注目研究

研究者総覧で最新データを確認する

2024年12月4日更新

職名: 教授
電話: 088-633-7260
電子メール: ishida@tokushima-u.ac.jp
学歴: 1993/4: 徳島大学大学院博士前期課程入学
1995/4: 徳島大学大学院薬学研究科博士後期課程入学
1998/3: 徳島大学大学院薬学研究科薬品科学専攻博士後期課程修了
学位: 博士(薬学) (徳島大学) (1998年3月)
職歴・経歴: 1995/4: 日本学術振興会特別研究員(DC1)
1998/4: カナダ·アルバータ州立大学医歯学部博士研究員
2000/4: 徳島大学講師，薬学部
2014/10: 東北大学学際科学フロンティア研究所・客員教授

専門分野・研究分野: 生物薬剤学 (Biopharmaceutics)

研究者総覧で最新データを確認する

2024年12月4日更新

専門分野・研究分野: 生物薬剤学 (Biopharmaceutics)
担当経験のある授業科目: コアDDS講義 (学部)
先端医療薬学 (学部)
医療系分野における知的財産学概論 (大学院)
医薬品安全性学特論 (大学院)
卒業研究 (学部)
卒業研究1 (学部)
卒業研究2 (学部)
基礎医療薬学 (学部)
専攻公開ゼミナール (大学院)
応用医療薬学 (学部)
疾病学1 (学部)
疾病学2 (学部)
疾病学3 (学部)
育薬共通演習 (大学院)
臨床薬物動態学特論 (大学院)
薬剤学1 (学部)
薬剤学2 (学部)
薬剤学実習 (学部)
薬学演習 (大学院)
薬学科学特論Ⅰ (大学院)
薬学英語2 (学部)
薬学課題研究 (大学院)
薬科学演習1 (大学院)
薬科学特別研究 (大学院)
製剤学 (学部)
指導経験: 1人 (修士)

研究者総覧で最新データを確認する

2024年12月4日更新

専門分野・研究分野: 生物薬剤学 (Biopharmaceutics)

研究テーマ: リポソームを用いたdrug delivery systemの開発に関する研究 (リポソーム (liposomes), 薬物送達システム (drug delivery system), 癌治療 (cancer therapy), 虚血 (ischemia), 薬物速度論 (pharmacokinetics))

著書

Emam Emam Abdallah Sherif, Elhewan Emam Elsadek Emam Ali Nehal, Taro Shimizu and Tatsuhiro Ishida :
Liposomes Methods and Protocols (3rd Edition), --- The Post-insertion Method for the Preparation of PEGylated Liposomes ---,
Springer, Feb. 2023.

(要約): PEGylation is a crucial process for decorating the surface of liposomes with polyethylene glycol (PEG) for clinical use. This process endows the liposomes extended circulation time and improved stability in vivo. The post-insertion method is one of the well-established techniques for PEGylation. This method requires only one-step incubation to accomplish the transfer of PEGylated lipids from PEGylated lipid-based micelles into the membranes of preformed liposomes.
(キーワード): リポソーム (liposomes) / Polyethylene Glycols / Micelles
(出版サイトへのリンク): ● Publication site (DOI): 10.1007/978-1-0716-2954-3_14
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 36781759; ● Summary page in Scopus @ Elsevier: 2-s2.0-85147899423

(DOI: 10.1007/978-1-0716-2954-3_14, PubMed: 36781759, Elsevier: Scopus) 清水太郎, 石田竜弘 :
中分子医薬品やDDSに対する免疫応答,
株式会社シーエムシー出版, 2022年3月. 田島健次, 松島得雄, 小瀬亮太, 藤田彩華, 甲野裕之, 安藤英紀, 石田竜弘 :
ナノフィブリル化バクテリアセルロースの生産とその応用,
株式会社エヌ·ティー·エス, 2021年11月. 清水太郎, 石田竜弘 :
タンパクやナノ粒子に対するPEG修飾の有用性と免疫系に与える影響,
株式会社技術情報協会, 2021年8月. Elhewan Emam Elsadek Emam Ali Nehal, Lila Selim Ahmed Ali Abu Amr and Tatsuhiro Ishida :
Immunogenicity against PEGylated proteins, in Polymer-protein conjugates: From PEGylation and beyond (Chapter 5),
Elsevier Inc., Nov. 2019. 田島健次, 小瀬亮太, 石田竜弘, 松島得雄 :
発酵ナノセルロースの大量生産とその応用,
南江堂, 東京, 2019年2月. Lila Selim Ahmed Ali Abu Amr, J Szebeni. and Tatsuhiro Ishida :
Accelerated blood clearance phenomenon and complement activation-related pseudoallergy: two sides of the same coin,
Pan Stanford Publishing, Jan. 2019. Lila Selim Ahmed Ali Abu Amr and Tatsuhiro Ishida :
Anti-PEG immunity against PEGylated therapeutics.,
Pan Stanford Publishing, Jan. 2019. Lila Selim Ahmed Ali Abu Amr and Tatsuhiro Ishida :
The accelerated blood clearance (ABC) phenomenon of PEGylated nanocarriers.,
Pan Stanford Publishing, Jan. 2019. Lila Selim Ahmed Ali Abu Amr and Tatsuhiro Ishida :
Anti-PEG IgM production via a PEGylated nano-carrier system for nucleic acid delivery,
Springer, Jan. 2019. Lila Selim Ahmed Ali Abu Amr and Tatsuhiro Ishida :
Immune response to PEGylated nanomedicines: Impact of IgM Response,
The Springer International Publishing AG, Jun. 2018. Lila Selim Ahmed Ali Abu Amr, Taro Shimizu and Tatsuhiro Ishida :
PEGylation and anti-PEG antibodies.,
Pan Stanford Publishing, Jan. 2018. 石田竜弘 :
ドラッグデリバリーシステム(DDS,薬物送達システム),
南江堂, 2017年3月. 石田竜弘, 安藤英紀 :
ドラッグデリバリーシステム(DDS),
京都廣川書店, 2015年. Lila Selim Ahmed Ali Abu Amr, Tatsuhiro Ishida and T Allen :
Liposomal nanomedicine,
World Scientific, Oct. 2014. 石田竜弘, 際田弘志 :
腫瘍内微小環境の能動的制御に基づくDDSの開発とがん治療への応用,
株式会社シーエムシー出版, 2013年6月. Masako Ichihara, Naoto Moriyoshi, Lila Selim Ahmed Ali Abu Amr, Tatsuhiro Ishida and Hiroshi Kiwada :
Anti-PEG IgM production via a PEGylated nano-carrier system for nucleic acid delivery.,
Springer, Jun. 2012.

(要約): For the systemic application of nucleic acids such as plasmid DNA and small interfering RNA, safe and efficient carriers that overcome the poor pharmacokinetic properties of nucleic acids are required. A cationic liposome that can formulate lipoplexes with nucleic acids has significant promise as an efficient delivery system in gene therapy. To achieve in vivo stability and long circulation, most lipoplexes are modified with PEG (PEGylation). However, we reported that PEGylated liposomes lose their long-circulating properties when they are injected repeatedly at certain intervals in the same animal. This unexpected and undesirable phenomenon is referred to as the accelerated blood clearance (ABC) phenomenon. Anti-PEG IgM produced in response to the first dose of PEGylated liposomes has proven to be a major cause of the ABC phenomenon. Therefore, in a repeated dosing schedule, the detection of anti-PEG IgM in an animal treated with PEGylated lipoplex could be essential to predict the occurrence of the ABC phenomenon. This chapter introduces a method for the evaluation of serum anti-PEG IgM by a simple ELISA procedure, and describes some precautions associated with this method.
(キーワード): Animals / DNA / Drug Carriers / Enzyme-Linked Immunosorbent Assay / Horseradish Peroxidase / Immunoglobulin M / Liposomes / Male / Mice / Mice, Inbred BALB C / Nanostructures / Polyethylene Glycols / RNA, Small Interfering
(出版サイトへのリンク): ● Publication site (DOI): 10.1007/978-1-62703-140-0_4
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 23070762; ● Search Scopus @ Elsevier (PMID): 23070762; ● Search Scopus @ Elsevier (DOI): 10.1007/978-1-62703-140-0_4

(DOI: 10.1007/978-1-62703-140-0_4, PubMed: 23070762) 秋田英万, 石田竜弘 :
新しい剤形:ドラッグデリバリーシステム,
南江堂, 2011年12月. Lila Selim Ahmed Ali Abu Amr, Tatsuhiro Ishida and Hiroshi Kiwada :
Cationic liposomes and tumour vasculature targeting: a therapeutic approach that has potential for solid tumours.,
Souto, E.B. (Ed.), i-Smithers - Creative Publishing Solutions, Aug. 2011. Yusuke Doi, Tatsuhiro Ishida and Hiroshi Kiwada :
Breaking the barriers to tumor-targeting via nanocarrier-based drug delivery to the tumor microenvironment.,
Nova Science Publishers, 2010. Jose Mario Barichello, Tatsuhiro Ishida and Hiroshi Kiwada :
Complexation of siRNA and pDNA with cationic liposomes: The important aspects in lipoplex preparation.,
A chapter, Liposomes, Methods Mol. Biol., 2010.

(要約): In the last two decades, cationic liposomes have been investigated as vehicles for nucleic acids [plasmid DNA (pDNA) and small interfering RNA (siRNA)] delivery in vitro and in vivo. The formation of cationic liposomes-nucleic acids complexes, termed lipoplexes, depends on a number of experimental variables. The quality of the nucleic acid and the cationic liposome as well as the selection of diluents for diluting the concentrated stocks strongly affect the resulting lipoplexes and their efficiency of gene-expression or gene-silencing effect following transfection. In addition, the molar ratio of cationic lipid nitrogen (N) to siRNA or pDNA phosphate (P) (N/P ratio) influences the final characteristics of the lipoplexes, such as size, surface zeta potential, and reproducibility, thereby reflecting their efficiency following transfection. The methods presented in this chapter could be helpful to obtain reliable and reproducible lipoplexes and experimental results.
(キーワード): Cations / DNA / Gene Silencing / HeLa Cells / Humans / Liposomes / Plasmids / RNA, Small Interfering / Transfection
(出版サイトへのリンク): ● Publication site (DOI): 10.1007/978-1-60327-360-2_32
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 20072901; ● Search Scopus @ Elsevier (PMID): 20072901; ● Search Scopus @ Elsevier (DOI): 10.1007/978-1-60327-360-2_32

(DOI: 10.1007/978-1-60327-360-2_32, PubMed: 20072901) Tatsuhiro Ishida and Hiroshi Kiwada :
Synergistic antitumor activity of metronomic dosing chemotherapy in combination with liposomal anticancer drug.,
Nova Science Publishers, Apr. 2009. Tatsuhiro Ishida and Hiroshi Kiwada :
Unexpected reactions by in vivo application of PEGylated liposomes.,
Springer Science + Business Media, New York, USA, 2009. 石田竜弘, 際田弘志 :
第10章医学薬学でのリポソーム応用 1節リポソームと細胞の相互作用,
株式会社エヌ·ティー·エス, 東京, 2005年6月. 石田竜弘, 際田弘志 :
第10章医学薬学でのリポソーム応用 3節長期血中滞留性リポソーム,
株式会社エヌ·ティー·エス, 東京, 2005年6月.

論文

Eiichiro Kaneko, Haruto Tsujisaki, Masashi Fujiwara, Hidenori ANDO, Yasushi Sato, Tatsuhiro Ishida, Hirofumi Tani and Kenji Tajima :
Application of bacterial-derived long cellulose nanofiber to suspension culture of mammalian cells as a shear protectant,
International Journal of Biological Macromolecules, Vol.280, No.3, 135938, 2024.

(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijbiomac.2024.135938
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1016/j.ijbiomac.2024.135938

(DOI: 10.1016/j.ijbiomac.2024.135938) Mazaya Najmina, Shingo Kobayashi, Rena Shimazui, Haruka Takata, Mayuka Shibata, Kenta Ishibashi, Hiroshi Kamizawa, Akihiro Kishimura, Yoshihito Shiota, Daichi Ida, Taro Shimizu, Tatsuhiro Ishida, Yoshiki Katayama, Masaru Tanaka and Takeshi Mori :
A Stealthiness Evaluation of Main Chain Carboxybetaine Polymer Modified into Liposome,
Pharmaceutics, Vol.16, No.10, 1271, 2024.

(出版サイトへのリンク): ● Publication site (DOI): 10.3390/pharmaceutics16101271
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.3390/pharmaceutics16101271

(DOI: 10.3390/pharmaceutics16101271) Taiki Hori, Taro Shimizu, Hidenori ANDO, Naoto Okada, Hiroki Yamagami, Saya Yasui, Minae Hosoki, Akihiro Tojima, Toshiki Otoda, Tomoyuki Yuasa, Ken-ichi Aihara, Makoto Takishita, Sumiko Yoshida, Masahiro Abe, Tatsuhiro Ishida and Shingen Nakamura :
Humoral immune response against SARS-CoV-2 and polyethylene glycol elicited by anti-SARS-CoV-2 mRNA vaccine, and effect of pre-existing anti-polyethylene glycol antibody in patients with hematological and autoimmune diseases.,
Heliyon, Vol.10, No.10, e31489, 2024.

(要約): The effects of vaccination are modified by hematological and autoimmune diseases and/or treatment. Anti-SARS-CoV-2 mRNA vaccine contains polyethylene glycol (PEG), it is largely unknown whether PEG influences the effects of vaccination or induces a humoral response. This study examined whether anti-PEG antibodies before vaccination (pre-existing) influenced the acquisition of SARS-CoV-2 antibodies and evaluated the relationship between the development of anti-SARS-CoV-2 antibodies and anti-PEG antibodies after SARS-CoV-2 vaccination in hematological and autoimmune diseases. Anti-SARS-CoV-2 antibody IgG, anti-PEG IgG, and IgM titers were evaluated in patients with hematological and autoimmune diseases after the second dose of BNT162B2. Anti-PEG IgG and IgM titers were also measured before vaccination to examine changes after vaccination and the relationship with vaccine efficacy. In patients with hematological (n = 182) and autoimmune diseases (n = 96), anti-SARS-CoV-2 and anti-PEG antibody titers were evaluated after a median of 33 days from 2nd vaccination. The median anti-SARS-CoV-2 antibody titers were 1901 AU/mL and 3832 AU/mL in patients with hematological and autoimmune disease, respectively. Multiple regression analysis showed that age and days from 2nd vaccination were negatively associated with anti-SARS-CoV-2 antibody titers. Anti-CD20 antibody treatment was negatively correlated with anti-SARS-CoV-2 antibody titers in hematological disease, and C-reactive protein (CRP) was positively correlated with anti-SARS-CoV-2 antibody titers in autoimmune disease. Baseline anti-PEG antibody titers were significantly higher in patients with autoimmune disease but were not correlated with anti-SARS-CoV-2 antibody titers. Patients with increased anti-PEG IgG acquired higher anti-SARS-CoV-2 antibody titers in patients with autoimmune disease. Anti-SARS-CoV-2 antibody acquisition was suboptimal in patients with hematological disease, but both anti-SARS-CoV-2 antibody and anti-PEG IgG were acquired in patients with autoimmune disease, reflecting robust humoral immune response. Pre-existing anti-PEG antibody titers did not affect anti-SARS-CoV-2 antibody acquisition.
(徳島大学機関リポジトリ): ● Metadata: 119625
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.heliyon.2024.e31489
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 38813140; ● Search Scopus @ Elsevier (PMID): 38813140; ● Search Scopus @ Elsevier (DOI): 10.1016/j.heliyon.2024.e31489

(徳島大学機関リポジトリ: 119625, DOI: 10.1016/j.heliyon.2024.e31489, PubMed: 38813140) Takeru Hirai, Mayumi Ikeda-Imafuku, Nanami Tasaka, Chuang Tuan Giam Victor, Xian Ming, Tatsuhiro Ishida, Takaaki Akaike and Yu Ishima :
Human hair keratin responds to oxidative stress via reactive sulfur and supersulfides,
Advances in Redox Research, Vol.10, 100091, 2024.

(徳島大学機関リポジトリ): ● Metadata: 119211
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.arres.2023.100091
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1016/j.arres.2023.100091

(徳島大学機関リポジトリ: 119211, DOI: 10.1016/j.arres.2023.100091) Gaballa A Sherif, Taro Shimizu, Haruka Takata, Hidenori ANDO, Ibrahim Mohamed, Emam Emam Abdallah Sherif, Nana Amorim Cristina Matsuo, Yuri Kim, Naguib W Youssef, Mady M Fatma, Khaled A Khaled and Tatsuhiro Ishida :
Impact of anti-PEG IgM induced via the topical application of a cosmetic product containing PEG derivatives on the antitumor effects of PEGylated liposomal antitumor drug formulations in mice,
Molecular Pharmaceutics, Vol.21, No.2, 622-632, 2024.

(要約): Poly(ethylene glycol) (PEG) is used in many common products, such as cosmetics. PEG, however, is also used to covalently conjugate drug molecules, proteins, or nanocarriers, which is termed PEGylation, to serve as a shield against the natural immune system of the human body. Repeated administration of some PEGylated products, however, is known to induce anti-PEG antibodies. In addition, preexisting anti-PEG antibodies are now being detected in healthy individuals who have never received PEGylated therapeutics. Both treatment-induced and preexisting anti-PEG antibodies alter the pharmacokinetic properties, which can result in a subsequent reduction in the therapeutic efficacy of administered PEGylated therapeutics through the so-called accelerated blood clearance (ABC) phenomenon. Moreover, these anti-PEG antibodies are widely reported to be related to severe hypersensitivity reactions following the administration of PEGylated therapeutics, including COVID-19 vaccines. We recently reported that the topical application of a cosmetic product containing PEG derivatives induced anti-PEG immunoglobulin M (IgM) in a mouse model. Our finding indicates that the PEG derivatives in cosmetic products could be a major cause of the preexistence of anti-PEG antibodies in healthy individuals. In this study, therefore, the pharmacokinetics and therapeutic effects of Doxil (doxorubicin hydrochloride-loaded PEGylated liposomes) and oxaliplatin-loaded PEGylated liposomes (Liposomal l-OHP) were studied in mice. The anti-PEG IgM antibodies induced by the topical application of cosmetic products obviously accelerated the blood clearance of both PEGylated liposomal formulations. Moreover, in C26 tumor-bearing mice, the tumor growth suppressive effects of both Doxil and Liposomal l-OHP were significantly attenuated in the presence of anti-PEG IgM antibodies induced by the topical application of cosmetic products. These results confirm that the topical application of a cosmetic product containing PEG derivatives could produce preexisting anti-PEG antibodies that then affect the therapeutic efficacy of subsequent doses of PEGylated therapeutics.
(キーワード): Mice / Humans / Animals / Liposomes / Drug Compounding / COVID-19 Vaccines / Immunoglobulin M / Polyethylene Glycols / Neoplasms / Doxorubicin
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.molpharmaceut.3c00774
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 38273445; ● CiNii @ 国立情報学研究所 (CRID): 1360301163936245376; ● Summary page in Scopus @ Elsevier: 2-s2.0-85184304070

(DOI: 10.1021/acs.molpharmaceut.3c00774, PubMed: 38273445, CiNii: 1360301163936245376, Elsevier: Scopus) Taro Shimizu, Lila S Abu Amr, Yuka Kitayama, Ryo Abe, Haruka Takata, Hidenori ANDO, Yu Ishima and Tatsuhiro Ishida :
Peritoneal B Cells Play a Role in The Production of Anti-Polyethylene Glycol (PEG) IgM Against Intravenously Injected siRNA-PEGylated Liposome Complexes,
Biological & Pharmaceutical Bulletin, Vol.47, No.2, 469-477, 2024.

(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b23-00733
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.b23-00733

(DOI: 10.1248/bpb.b23-00733) Mayumi Ikeda-Imafuku, Tatsuya Fukuta, Chuang Tuan Giam Victor, Tomohiro Sawa, Toru Maruyama, Masaki Otagiri, Tatsuhiro Ishida and Yu Ishima :
Acute kidney injury caused by rhabdomyolysis is ameliorated by serum albumin-based supersulfides donors through antioxidative pathways,
Pharmaceuticals, Vol.17, No.1, 128, 2024.

(要約): Oxidative stress is responsible for the onset and progression of various kinds of diseases including rhabdomyolysis-induced acute kidney injury (AKI). Antioxidants are, therefore, thought to aid in the recovery of illnesses linked to oxidative stress. Supersulfide species have been shown to have substantial antioxidative activity; however, due to their limited bioavailability, few supersulfide donors have had their actions evaluated in vivo. In this study, human serum albumin (HSA) and N-acetyl-L-cysteine polysulfides (NACSn), which have polysulfides in an oxidized form, were conjugated to create a supersulfide donor. HSA is chosen to be a carrier of NACSn because of its extended blood circulation and high level of biocompatibility. In contrast to a supersulfide donor containing reduced polysulfide in HSA, the NACSn-conjugated HSAs exhibited stronger antioxidant activity than HSA and free NACSn without being uptaken by the cells in vitro. The supersulfide donor reduced the levels of blood urea nitrogen and serum creatinine significantly in a mouse model of rhabdomyolysis-induced AKI. Supersulfide donors significantly reduced the expression of oxidative stress markers in the kidney. These results indicate that the developed supersulfide donor has the therapeutic effect on rhabdomyolysis-induced AKI.
(徳島大学機関リポジトリ): ● Metadata: 119400
(出版サイトへのリンク): ● Publication site (DOI): 10.3390/ph17010128
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 38256961; ● CiNii @ 国立情報学研究所 (CRID): 1050582385450085504; ● Search Scopus @ Elsevier (PMID): 38256961; ● Search Scopus @ Elsevier (DOI): 10.3390/ph17010128

(徳島大学機関リポジトリ: 119400, DOI: 10.3390/ph17010128, PubMed: 38256961, CiNii: 1050582385450085504) Hiromi Sakai, Tomoko Kure, Naoko Kobayashi, Tadashi Ito, Yasushi Yamada, Tetsuya Yamada, Rina Miyamoto, Takahito Imaizumi, Jiro Ando, Takaomi Soga, Yasuo Osanai, Makoto Ogawa, Taro Shimizu, Tatsuhiro Ishida and Hiroshi Azuma :
Absence of Anaphylactic Reactions to Injection of Hemoglobin-vesicles (Artificial Red Cells) to Rodents,
ACS Omega, Vol.9, No.1, 1904-1915, 2024.

(要約): The safety and efficacy of hemoglobin vesicles (HbVs) as artificial oxygen carriers encapsulating a purified and concentrated Hb solution in liposomes have been studied extensively. The HbV surface, modified with PEG by incorporating a PEG-conjugated phospholipid, is beneficial for storage and biocompatibility. However, it might be possible that interaction of PEG and the pre-existing anti-PEG antibody in the bloodstream causes acute adverse reaction. This study used two sets of experiments with rats and guinea pigs to ascertain whether the anti-PEG antibody generated by the PEG-modified HbV injection can induce anaphylactic reactions. SD rats received repeated intravenous injection of HbV at a dose rate of 16 or 32 mL/kg three times. Not anti-PEG IgG but anti-PEG IgM was detected. Nevertheless, no anaphylactic reaction occurred. Guinea pigs were used to study the presence of active systemic anaphylaxis further after injections of the PEG-modified liposomes used for HbV. The animals were sensitized by three repeated subcutaneous injections of PEG-modified liposomes (PEG-liposome) along with adjuvant at 1 week intervals. For comparison, unmodified liposomes (liposome) and 10 times excessively PEG-modified liposomes with ionizable lipid (10PEG-DODAP-liposome) were used. Inclusion of PEG modification induced not only anti-PEG IgM but also anti-PEG IgG. Three weeks after the final injection, intravenous injection of both PEG-liposome and liposome (1 mL/kg) induced no anaphylactic reaction. However, the injection of 10PEG-DODAP-liposome showed one lethal anaphylaxis case and one mild anaphylaxis case. Antisera obtained from the animal sensitized as described above were inoculated (0.05 mL) intradermally into fresh guinea pigs. The presence of passive cutaneous anaphylaxis was evaluated after intravenous injections (1 mL/kg) of three liposomes with Evans blue. No dye leakage was detected at any inoculated skin point for PEG-liposome or liposome, but a slight leakage was detected in one inoculated skin point for 10PEG-DODAP-liposome. These results indicate the absence of acute allergic reactions at repeated injections of HbVs despite the anti-PEG antibody induction. Not all the PEG-modified liposomes show anaphylaxis, and it may depend on the amount of PEGylated phospholipid and lipid composition of PEG-modified liposomes.
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acsomega.3c08641
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 38222647; ● Summary page in Scopus @ Elsevier: 2-s2.0-85181159256

(DOI: 10.1021/acsomega.3c08641, PubMed: 38222647, Elsevier: Scopus) 横山宏司, 儘田光和, 髙田春風, 清水太郎, 安藤英紀, 石田竜弘 :
マクロゴール4000の関連する全身性紅斑を呈した女児例,
小児科, Vol.64, No.11, 1196-1199, 2023年.

(出版サイトへのリンク): ● Publication site (DOI): 10.18888/sh.0000002763
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1390579686915245568; ● Search Scopus @ Elsevier (DOI): 10.18888/sh.0000002763

(DOI: 10.18888/sh.0000002763, CiNii: 1390579686915245568) Kengo Yasuda, Hitoshi Maeda, Ryo Kinoshita, Yuki Minayoshi, Yuki Mizuta, Yuka Nakamura, Shuhei Imoto, Koji Nishi, Keishi Yamasaki, Mina Sakuragi, Teruya Nakamura, Mayumi Ikeda-Imafuku, Yasunori Iwao, Yu Ishima, Tatsuhiro Ishida, Yasuko Iwakiri, Masaki Otagiri, Hiroshi Watanabe and Toru Maruyama :
Encapsulation of an Antioxidant in Redox-Sensitive Self-Assembled Albumin Nanoparticle for the Treatment of Hepatitis,
ACS Nano, Vol.17, No.17, 16668-16681, 2023.

(要約): Hepatitis is an inflammation of the liver caused by the inadequate elimination of reactive oxygen species (ROS) derived from Kupffer cells. Edaravone is clinically used as an antioxidant but shows poor liver distribution. Herein, we report on the design of a Kupffer cell-oriented nanoantioxidant based on a disulfide cross-linked albumin nanoparticle containing encapsulated edaravone (EeNA) as a therapeutic for the treatment of hepatitis. Since the edaravone is bound to albumin, this results in a soluble and stable form of edaravone in water. Exchanging the intramolecular disulfide bonds to intermolecular disulfide bridges of albumin molecules allowed the preparation of a redox responsive albumin nanoparticle that is stable in the blood circulation but can release drugs into cells. Consequently, EeNA was fabricated by the nanoscale self-assembly of edaravone and albumin nanoparticles without the additives that are contained in commercially available edaravone preparations. EeNA retained its nanostructure under serum conditions, but the encapsulated edaravone was released efficiently under intracellular reducing conditions in macrophages. The EeNA was largely distributed in the liver and subsequently internalized into Kupffer cells within 60 min after injection in a concanavalin-A-induced hepatitis mouse. The survival rate of the hepatitis mice was significantly improved by EeNA due to the suppression of liver necrosis and oxidative stress by scavenging excessive ROS. Moreover, even through the postadministration, EeNA showed an excellent hepatoprotective action as well. In conclusion, EeNA has the potential for use as a nanotherapeutic against various types of hepatitis because of its Kupffer cell targeting ability and redox characteristics.
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acsnano.3c02877
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 37579503; ● Summary page in Scopus @ Elsevier: 2-s2.0-85169045394

(DOI: 10.1021/acsnano.3c02877, PubMed: 37579503, Elsevier: Scopus) Haruka Takata, Taro Shimizu, Rina Yamade, Nehal Ali Emam Elsadek Emam Elhewan, Sherif Abdallah Emam Emam, Hidenori ANDO, Yu Ishima and Tatsuhiro Ishida :
Anti-PEG IgM production induced by PEGylated liposomes as a function of administration route,
Journal of Controlled Release, Vol.360, 285-292, 2023.

(要約): Modifying the surface of nanoparticles with polyethylene glycol (PEG) is a commonly used approach for improving the in vitro stability of nanoparticles such as liposomes and increasing their circulation half-lives. We have demonstrated that, in certain conditions, an intravenous (i.v.) injection of PEGylated liposomes (PEG-Lip) induced anti-PEG IgM antibodies, which led to rapid clearance of second doses in mice. SARS-CoV-2 vaccines, composed of mRNA-containing PEGylated lipid nanoparticles, have been widely administered as intramuscular (i.m.) injections, so it is important to determine if PEGylated formulations can induce anti-PEG antibodies. If the favorable properties that PEGylation imparts to therapeutic nanoparticles are to be widely applicable this should apply to various routes of administration. However, there are few reports on the effect of different administration routes on the in vivo production of anti-PEG IgM. In this study, we investigated anti-PEG IgM production in mice following i.m., intraperitoneal (i.p.) and subcutaneous (s.c.) administration of PEG-Lip. PEG-Lip appeared to induce anti-PEG IgM by all the tested routes of administration, although the lipid dose causing maximum responses varied. Splenectomy attenuated the anti-PEG IgM production for all routes of administration, suggesting that splenic immune cells may have contributed to anti-PEG IgM production. Interestingly, in vitro experiments indicated that not only splenic cells but also cells in the peritoneal cavity induced anti-PEG IgM following incubation with PEG-Lip. These observations confirm previous experiments that have shown that measurable amounts of PEG-Lip administered i.p., i.m. or s.c. are absorbed to some extent into the blood circulation, where they can be distributed to the spleen and/or peritoneal cavity, and are recognized by B cells, triggering anti-PEG IgM production. The results obtained in this study have important implications for developing efficient PEGylated nanoparticular delivery system.
(キーワード): Mice / Animals / Humans / Polyethylene Glycols / Liposomes / COVID-19 Vaccines / Immunoglobulin M / COVID-19 / SARS-CoV-2
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2023.06.027
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 37355210; ● Search Scopus @ Elsevier (PMID): 37355210; ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2023.06.027

(DOI: 10.1016/j.jconrel.2023.06.027, PubMed: 37355210) Hidenori ANDO, Kiyoshi Eshima and Tatsuhiro Ishida :
A polyethylene glycol-conjugate of deoxycytidine analog, DFP-14927, produces potential antitumor effects on pancreatic tumor-xenograft murine models via inducing G2/M arrest,
European Journal of Pharmacology, Vol.950, 175758, 2023.

(要約): A deoxycytidine analog is a potential agent for the treatment of several cancers, which includes poorly prognostic pancreatic cancer. We previously developed deoxycytidine analog DFP-10917, and long-term/low-dose infusions of this analog has produced antitumor effects in leukemia cancer- and ovarian cancer-xenograft models. DFP-10917 is now undergoing clinical Phase III study in the United States for the treatment of patients with relapsed or refractory acute myeloid leukemia. PEG-drug conjugation has become a promising technique to improve the pharmacokinetic and pharmacodynamic properties of anti-cancer drugs. In the present study, we synthesized a novel PEG-drug conjugate of DFP-10917, referred to hereafter as DFP-14927, using a 4-armed CTPEG system to endow the DFP-10917 drug with favorable long-circulating properties that maximize its utility and antitumor efficacy. Intravenous injection of the synthesized DFP-14927 returned encouraging antitumor effects in a Panc-1 human pancreatic tumor- and a BxPC-3 human pancreatic tumor-xenograft models. These effects were comparable to that of free DFP-10917 as well as to that of gemcitabine, which is considered a standard in the treatment of pancreatic cancer. In vitro studies revealed that DFP-14927 inhibits cell division on human pancreatic cancer cell lines via arrest of the G2/M phase in the cell cycle, which is consistent with the effects of free DFP-10917. Intravenous administration of the newly synthesized DFP-14927 has induced G2/M arrest in human pancreatic tumor-xenograft murine models, which represents an improvement in the pharmacokinetics of DFP-10917. DFP-14927 could be an alternative for patients who cannot accept prolonged or continuous infusions of DFP-10917.
(キーワード): Female / Humans / Animals / Mice / Disease Models, Animal / Apoptosis / Heterografts / Cell Line, Tumor / G2 Phase Cell Cycle Checkpoints / Deoxycytidine / Pancreatic Neoplasms / Xenograft Model Antitumor Assays
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ejphar.2023.175758
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 37121563; ● Search Scopus @ Elsevier (PMID): 37121563; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ejphar.2023.175758

(DOI: 10.1016/j.ejphar.2023.175758, PubMed: 37121563) Taro Shimizu, Takaaki Matsuzaki, Shoishiro Fukuda, Chihiro Yoshioka, Yuna Shimazaki, Shunsuke Takese, Katsuhiro Yamanaka, Takashi Nakae, Masaki Ishibashi, Hidetoshi Hamamoto, Hidenori ANDO, Yu Ishima and Tatsuhiro Ishida :
Ionic liquid-based transcutaneous peptide antitumor vaccine; therapeutic effect in a mouse tumor model,
The AAPS Journal, Vol.25, No.2, 27, 2023.

(要約): Traditional vaccinations need to be injected with needles, and since some people have a strong aversion to needles, a needle-free alternative delivery system is important. In this study, we employed ionic liquids (ILs) for transcutaneous delivery of cancer antigen-derived peptides to obtain anticancer therapeutic effects in a needle-free manner. ILs successfully increased the in vitro skin permeability of a peptide from Wilms tumor 1 (WT1), one of the more promising cancer antigens, plus or minus an adjuvant, resiquimod (R848), a toll-like receptor 7 agonist. In vivo studies demonstrated that concomitant transcutaneous delivery of WT1 peptide and R848 by ILs induced WT1-specific cytotoxic T lymphocyte (CTL) in mice, resulting in tumor growth inhibition in Lewis lung carcinoma-bearing mice. Interestingly, administrating R848 in ILs before WT1 peptides in ILs increased tumor growth inhibition effects compared to co-administration of both. We found that the prior application of R848 increased the infiltration of leukocytes in the skin and that subsequent delivery of WT1 peptides was more likely to induce WT1-specific CTL. Furthermore, sequential immunization with IL-based formulations was applicable to different types of peptides and cancer models without induction of skin irritation. IL-based transcutaneous delivery of cancer antigen-derived peptides and adjuvants, either alone or together, could be a novel approach to needle-free cancer therapeutic vaccines.
(キーワード): Animals / Mice / Ionic Liquids / Neoplasms / Vaccines, Subunit / Adjuvants, Immunologic / Cancer Vaccines / Disease Models, Animal
(出版サイトへのリンク): ● Publication site (DOI): 10.1208/s12248-023-00790-w
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 36805860; ● Search Scopus @ Elsevier (PMID): 36805860; ● Search Scopus @ Elsevier (DOI): 10.1208/s12248-023-00790-w

(DOI: 10.1208/s12248-023-00790-w, PubMed: 36805860) Mohamed Ibrahim, Taro Shimizu, Hidenori ANDO, Yu Ishima, Helmy Omar Elgarhy, A Hatem Sarhan, K Amal Hussein and Tatsuhiro Ishida :
Investigation of anti-PEG antibody response to PEG-containing cosmetic products in mice,
Journal of Controlled Release, Vol.354, 260-267, 2023.

(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2023.01.012
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2023.01.012

(DOI: 10.1016/j.jconrel.2023.01.012) Ayano Sawa-Aihara, Katsuji Hattori, Goshi Nagao, Yoshihisa Yamada and Tatsuhiro Ishida :
Potential efficacy of proteasome inhibitor, Delanzomib, for the treatment of renal fibrosis,
Biological & Pharmaceutical Bulletin, Vol.46, No.2, 279-285, 2023.

(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b22-00713
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.b22-00713

(DOI: 10.1248/bpb.b22-00713) Naoto Okada, Taro Shimizu, Hidenori ANDO, Shingen Nakamura, Mitsuhiro Goda, Masahiro Abe, Takashi Kitahara, Tatsuhiro Ishida and Keisuke Ishizawa :
Clinical impact of anti-polyethylene glycol (PEG) antibody in haematological patients administered PEGylated-granulocyte colony-stimulating factor,
Clinical Pharmacology in Drug Development, Vol.12, No.8, 826-831, 2023.

(要約): Polyethylene glycol (PEG) is a polymer covalently attached to proteins to improve their half-life and efficacy. We previously reported that the PEGylated granulocyte colony-stimulating factor (PEG-G-CSF) is immunogenic, which could adversely impact drug efficacy and safety in animal models. Here, we analyzed the relationship between anti-PEG antibody titers and the clinical impact of PEG-G-CSF in 19 hematological patients. A gradual decrease of anti-PEG antibody titers from baseline was observed after PEG-G-CSF administration. Of the 19 participants, 10 were assessed for noninfectious fever after the first administration of PEG-G-CSF and three experienced this reaction. The receiver operating characteristic curve revealed that the cut-off values of pretreated anti-PEG IgM and IgG titers for noninfectious fever were set at 5.0 and 96.6 U/mL, respectively. All patients who experienced noninfectious fever had anti-PEG antibody titers above this cut-off value (P = .033). An enzyme-linked immunosorbent assay revealed that some anti-PEG antibodies in patients with anti-PEG antibody titers above the cut-off value reacted with the PEGylated liposome. These results indicate the reactivity of the anti-PEG antibodies to PEGylated therapeutics observed in hematologic patients and the possibility of the relationship between high titers of anti-PEG antibodies and the development of adverse events after PEG-G-CSF administration.
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/cpdd.1225
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 36708147; ● Search Scopus @ Elsevier (PMID): 36708147; ● Search Scopus @ Elsevier (DOI): 10.1002/cpdd.1225

(DOI: 10.1002/cpdd.1225, PubMed: 36708147) Kohki Tachibana, Kohshi Kusumoto, Mai Ogawa, Hidenori ANDO, Taro Shimizu, Yu Ishima, Tatsuhiro Ishida and Keiichiro Okuhira :
FTY720 reduces lipid accumulation by upregulating ABCA1 through liver X receptor and sphingosine kinase 2 signaling in macrophages,
International Journal of Molecular Sciences, Vol.23, 14617, 2022.

(徳島大学機関リポジトリ): ● Metadata: 118017
(出版サイトへのリンク): ● Publication site (DOI): 10.3390/ijms232314617
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.3390/ijms232314617

(徳島大学機関リポジトリ: 118017, DOI: 10.3390/ijms232314617) Hiroshi Azuma, Toraji Amano, Naoya Kamiyama, Naofumi Takehara, Maki Jingu, Harumi Takagi, Osamu Sugita, Naoko Kobayashi, Tomoko Kure, Taro Shimizu, Tatsuhiro Ishida, Masanori Matsumoto and Hiromi Sakai :
First-in-human Phase 1 trial of artificial red blood cells, hemoglobin vesicles, developed as a transfusion alternative,
Blood Advances, Vol.6, No.21, 5711-5715, 2022.

(徳島大学機関リポジトリ): ● Metadata: 117961
(出版サイトへのリンク): ● Publication site (DOI): 10.1182/bloodadvances.2022007977
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 35939788; ● Search Scopus @ Elsevier (PMID): 35939788; ● Search Scopus @ Elsevier (DOI): 10.1182/bloodadvances.2022007977

(徳島大学機関リポジトリ: 117961, DOI: 10.1182/bloodadvances.2022007977, PubMed: 35939788) Yu Ishima, Nio Yamazaki, V Chuang, Taro Shimizu, Hidenori ANDO and Tatsuhiro Ishida :
A maleimide-terminally modified PEGylated liposome induced the accelerated blood clearance independent of the production of anti-PEG IgM antibodies,
Biological & Pharmaceutical Bulletin, Vol.45, No.10, 1518-1524, 2022.

(キーワード): liposome / polyethylene glycol / accelerated blood clearance / maleimide / complement activation
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b22-00389
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1390856583390911232; ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.b22-00389

(DOI: 10.1248/bpb.b22-00389, CiNii: 1390856583390911232) 異島優, 小田切優樹, 石田竜弘 :
アルブミンのボリスルフィドによる新たな生体恒常性維持機構,
人工血液, Vol.30, 59-64, 2022年. Hidenori ANDO, Ai Ikeda, Maho Tagami, Nana Matsuo, Taro Shimizu, Yu Ishima, K Eshima and Tatsuhiro Ishida :
Oral administration of sodium bicarbonate can enhance the therapeutic outcome of Doxil® via neutralizing the acidic tumor microenvironment,
Journal of Controlled Release, Vol.350, 414-420, 2022.

(要約): The pH of the tumor microenvironment in solid tumors is reported to be more acidic than that of normal tissues. The pH is controlled by over-expression of several transporters that are associated with the progression, angiogenesis, and metastasis of solid tumors. Antitumor effects of weak-base anticancer agents, such as doxorubicin (DXR), could be reduced in an acidic environment because of increases in the ionized form of the drug under these conditions, reducing its membrane penetrability. In our previous studies, we demonstrated that oral administration of sodium bicarbonate (NaHCO) can neutralize the acidic tumor microenvironment and enhance the effects of small molecule anticancer drugs. However, it is not known whether or not increasing the tumor pH by oral administration of NaHCO leads to enhanced antitumor effects of lipidic nanoparticle formulations of weak-base anticancer drugs, such as Doxil®. In this study, we investigated the antitumor efficacy of Doxil® in combination with oral administration of NaHCO in a Colon26 tumor-bearing mouse model. NaHCO clearly enhanced the tumor-growth inhibitory effect of Doxil® without exacerbating any systemic side effects. In vitro studies indicated that high levels of DXR were internalized into cells at neutral pH. These studies demonstrate that the neutralization of acidic tumor microenvironment by an oral administration of NaHCO could be a promising approach to enhance the therapeutic outcomes of Doxil®.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2022.08.031
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 35988781; ● Search Scopus @ Elsevier (PMID): 35988781; ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2022.08.031

(DOI: 10.1016/j.jconrel.2022.08.031, PubMed: 35988781) Yoshino Kawaguchi, Taro Shimizu, Hidenori ANDO, Yu Ishima and Tatsuhiro Ishida :
Development of a nanocarrier-based splenic B cell-targeting system for loading antigens in vitro,
Biological & Pharmaceutical Bulletin, Vol.45, No.7, 926-933, 2022.

(徳島大学機関リポジトリ): ● Metadata: 117224
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b22-00222
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.b22-00222

(徳島大学機関リポジトリ: 117224, DOI: 10.1248/bpb.b22-00222) Taro Shimizu, Yoshino Kawaguchi, Hidenori ANDO, Yu Ishima and Tatsuhiro Ishida :
Development of an antigen delivery system for a B cell-targeted vaccine as an alternative to dendritic cell-targeted vaccines,
Chemical & Pharmaceutical Bulletin, Vol.70, No.5, 341-350, 2022.

(出版サイトへのリンク): ● Publication site (DOI): 10.1248/cpb.c22-00047
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1248/cpb.c22-00047

(DOI: 10.1248/cpb.c22-00047) Takaki Nakajima, Kazuya Nagano, Yuka Fukuda, Yu Ishima, Hiroko Shibata, Ryo Isaka, Tian-Qi Zhang, Yuya Haga, Kazuma Higashisaka, Hirofumi Tsujino, Tatsuhiro Ishida, Akiko Ishii-Watabe and Yasuo Tsutsumi :
Subvisible particles derived by dropping stress enhance anti-PEG antibody production and clearance of PEGylated proteins in mice,
Journal of Pharmaceutical Sciences, Vol.111, No.5, 1363-1369, 2022.

(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.xphs.2022.01.023
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1016/j.xphs.2022.01.023

(DOI: 10.1016/j.xphs.2022.01.023) Ryota Sumitomo, Cheng-long Huang, Hidenori ANDO, Tatsuhiro Ishida, Hiroyuki Cho and Hiroshi Date :
Wnt2b and Wnt5a expressions are highly associated with M2 TAMs in non-small-cell lung cancer,
Oncology Reports, Vol.48, No.5, 189, 2022.

(要約): Tumor-associated macrophages (TAMs), particularly M2 macrophages, promote tumor progression, while genes encode a family of multi-functional glycoproteins that serve an important role in tumorigenesis. Immunohistochemical studies were performed to evaluate Wnt2b and Wnt5a expression in tumor and stromal cells in M2 and M1 TAMs and Ki-67 proliferation index in 160 consecutive patients with resected non-small cell lung cancer (NSCLC). Overall, 52 tumors (32.5%) were classified as tumoral Wnt2b-high (Wnt2b-positive tumor cells >30%) and 95 (59.4%) as stromal Wnt2b-high (Wnt2b-positive stromal cells >30%), while 75 (46.9%) were classified as tumoral Wnt5a-high (Wnt5a-positive tumor cells >30%) and 63 (39.4%) as stromal Wnt5a-high (Wnt5a-positive stromal cells >28%). The density of M2 TAMs was significantly higher in the tumoral (P=0.0024) and stromal Wnt2b-high groups (P=0.0054). The density of M2 TAMs was also significantly higher in the tumoral (P=0.0005) and stromal Wnt5a-high groups (P=0.0486). By contrast, no difference in stromal or islet M1 TAM density was observed in relation to tumoral or stromal Wnt2b or Wnt5a status. Furthermore, Ki-67 proliferation index was significantly higher in the tumoral (P=0.0121) and stromal Wnt2b-high (P=0.0019) and tumoral Wnt5a-high (P=0.0088) groups. Overall survival rate was significantly lower in the Wnt2b-high (P=0.0437), Wnt5a-high (P=0.0106) and M2 TAM-high (P=0.0060) groups. Wnt2b and Wnt5a expression in tumor and stromal cells may induce M2 TAMs to produce more aggressive behavior during tumor progression in NSCLC.
(キーワード): Carcinoma, Non-Small-Cell Lung / Glycoproteins / Humans / Immunohistochemistry / Ki-67 Antigen / Lung Neoplasms / Tumor-Associated Macrophages / Wnt Proteins / Wnt-5a Protein
(出版サイトへのリンク): ● Publication site (DOI): 10.2139/ssrn.4088768
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 36102318; ● Search Scopus @ Elsevier (PMID): 36102318; ● Search Scopus @ Elsevier (DOI): 10.2139/ssrn.4088768

(DOI: 10.2139/ssrn.4088768, PubMed: 36102318) Kazuya Nakamura, Keisuke Aihara and Tatsuhiro Ishida :
Importance of process parameters influencing the mean diameters of siRNA-containing lipid nanoparticles (LNPs) on the in vitro activity of prepared LNPs,
Biological & Pharmaceutical Bulletin, Vol.45, No.4, 497-507, 2022.

(要約): Genetic drugs have the potential to treat a variety of diseases. Recently, lipid nanoparticles (LNPs) have attracted much attention among drug delivery systems for genetic drugs. LNPs have been practically used in small interfering RNA (siRNA) drugs and mRNA vaccines. Although LNPs are generally prepared by mixing nucleic acids in acidic aqueous buffer and lipid excipients in alcohol (i.e., ethanol), it is not well understood which process parameters in the LNPs formation affect the physicochemical properties and the functionality of LNPs. In this study, we used siRNA-containing LNPs as a model, and evaluated the effect that aqueous solution parameters (buffering agent type, salt concentration, and pH) and mixing parameters (ratio, speed, and temperature) exert on the physicochemical properties and in vitro gene-knockdown activity of LNPs. Among such parameters, the type of buffering agent, salt concentration (ionic strength), pH in acidic aqueous buffer, as well as the mixing ratio and speed significantly affected the mean particle diameter and in vitro gene-knockdown activity of LNPs. A strong correlation between the mean particle diameters and their in vitro gene-knockdown activities was observed. These observations suggest that the process parameters influencing the mean LNPs diameter are likely to be important in the formation of LNPs and also that these correlate with in vitro gene-knockdown activity. Because LNP systems are being further developed for future clinical applications of genetic drugs, information regarding the LNPs manufacturing process is of utmost importance. The results observed in this study will be useful for the manufacturing of optimal LNPs.
(キーワード): Lipids / Liposomes / Nanoparticles / RNA, Small Interfering
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b21-01016
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 35370275; ● Search Scopus @ Elsevier (PMID): 35370275; ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.b21-01016

(DOI: 10.1248/bpb.b21-01016, PubMed: 35370275) Marwa Sayed El, Taro Shimizu, Lila Selim Ahmed Ali Abu Amr, Elhewan Emam Elsadek Emam Ali Nehal, Emam Emam Abdallah Sherif, Eman Alaaeldin, Amal Kamal, Hatem Sarhan, Hidenori ANDO, Yu Ishima and Tatsuhiro Ishida :
A mouse model for studying the effect of blood anti-PEG IgMs levels on the in vivo fate of PEGylated liposomes,
International Journal of Pharmaceutics, Vol.615, 121539, 2022.

(要約): The presence of anti-polyethylene glycol (PEG) antibodies in the systemic circulation might have potential implications for the therapeutic activity of PEGylated products in vivo in the clinic. In order to study the effect of pre-existing anti-PEG antibodies on the in vivo fate and the therapeutic efficiency of PEGylated therapeutics, we developed a BALB/c mouse model by virtue of the intraperitoneal (i.p.) inoculation of hybridoma cells (HIK-M09 and HIK-M11), secreting monoclonal anti-PEG IgM, mimicking the presence of pre-existing anti-PEG antibodies in the blood. In the model, the titers of anti-PEG IgM in the blood increased as a function of hybridoma cells numbers and time after i.p. inoculation. The in vivo levels of anti-PEG IgM decreased in a dose-dependent manner, following i.v. administration of empty PEGylated liposomes. C26 tumor-bearing mice with measurable levels of anti-PEG IgM, receiving i.v. injection of DiR-labeled empty PEGylated liposomes, showed lower levels of liposomal tumor accumulation and higher levels of liver and spleen accumulation, compared to C26 tumor-bearing mice without measurable anti-PEG IgM. This specifies that the presence of anti-PEG IgM in the murine circulation induced accelerated blood clearance of PEGylated liposomes and reduced their tumor accumulation. The biodistribution and antitumor efficacy of commercially available doxorubicin (DXR)-containing PEGylated liposomes, Doxil®, were scrutinized in the anti-PEG IgM mouse model. In C26 tumor-bearing mice having circulating anti-PEG IgM, at 24 h after injection almost no DXR was observed in blood and tumor, and increased DXR accumulation was observed in spleen and liver, compared to tumor-bearing mice with no circulating anti-PEG IgM. The antitumor efficacy of Doxil® was significantly compromised in the C26 tumor-bearing mice in the presence of anti-PEG IgM. These results demonstrate that the anti-PEG IgM mouse model could be a useful prognostic indicator for the therapeutic effectiveness of different formulations of PEGylated therapeutics in pre-clinical studies.
(キーワード): Animals / Immunoglobulin M / Liposomes / Mice / Mice, Inbred BALB C / Polyethylene Glycols / Tissue Distribution
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2022.121539
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 35124114; ● Search Scopus @ Elsevier (PMID): 35124114; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ijpharm.2022.121539

(DOI: 10.1016/j.ijpharm.2022.121539, PubMed: 35124114) M Mostafa Mahmoud, Elhewan Emam Elsadek Emam Ali Nehal, Emam Emam Abdallah Sherif, Hidenori ANDO, Taro Shimizu, H Abdelkader, Yu Ishima, U Aly Farghaly, A H Sarhan and Tatsuhiro Ishida :
Using Bio-Layer Interferometry to evaluate anti-PEG antibody-mediated complement activation,
Biological & Pharmaceutical Bulletin, Vol.45, No.1, 129-135, 2022.

(要約): The purpose of this study was to develop a Bio-layer interferometry (BLI) system that could be an alternative approach for the direct evaluation of anti-polyethylene glycol (PEG) immunoglobulin M (IgM)-mediated complement activation of the accelerated blood clearance (ABC) phenomenon. Complement activation is well known to play an important role in the clearance of PEGylated and non-PEGylated nanomedicines following intravenous injection. This complement system is also thought to be responsible for the ABC phenomenon wherein repeated injections of PEGylated products are bound by anti-PEG antibodies. This study used three different sources of anti-PEG antibodies: HIK-M09 monoclonal antibodies (mAbs); HIK-M11 mAbs; and antiserum containing polyclonal anti-PEG IgMs. 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-n-[methoxy (polyethylene glycol)-2000] (mPEG-DSPE) was immobilized as an antigen on aminopropyl silane biosensor chips of BLI. All anti-PEG IgMs in the sources increased the signals (thickness of the layer around the sensor tip) regarding binding of anti-PEG antibodies to PEG on the chips. In all anti-PEG IgM sources, further increases in the signals were observed when incubated in naïve mouse serum, which is a complement source, but not in heat inactivated (56 °C, 30 min) mouse serum, which abolishes complement activity. These findings show that the complement activation mediated via anti-PEG IgMs, which occurred on the sensor chips, was detected via BLI analysis. The complement activation induced by all anti-PEG IgM sources was confirmed via conventional enzyme-linked immunosorbent assay (ELISA), which is the conventional mode for detection of complement activation. Our study results show that BLI is a simple alternative method for the detection of complement activation.
(キーワード): Animals / Complement Activation / Immunoglobulin M / Interferometry / Liposomes / Mice / Polyethylene Glycols
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b21-00772
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 34980774; ● CiNii @ 国立情報学研究所 (CRID): 1390290617368317184; ● Summary page in Scopus @ Elsevier: 2-s2.0-85123166599

(DOI: 10.1248/bpb.b21-00772, PubMed: 34980774, CiNii: 1390290617368317184, Elsevier: Scopus) Rie Ando-Matsuoka, Hidenori ANDO, Lila Selim Ahmed Ali Abu Amr, Noriyuki Maeda, Taro Shimizu, Yu Ishima and Tatsuhiro Ishida :
I.p.-injected cationic liposomes are retained and accumulate in peritoneally disseminated tumors,
Journal of Controlled Release, Vol.341, 524-532, 2022.

(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2021.12.004
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2021.12.004

(DOI: 10.1016/j.jconrel.2021.12.004) Keisuke Mogi, Ikumi Kamiya, Aimi Makino, Ayaka Hirao, Reina Abe, Yusuke Doi, Taro Shimizu, Hidenori ANDO, Katsuya Morito, Kentaro Takayama, Tatsuhiro Ishida and Kazuki Nagasawa :
Liposomalization of oxaliplatin exacerbates the non-liposomal formulation-induced decrease of sweet taste sensitivity in rats,
Journal of Pharmaceutical Sciences, Vol.110, No.12, 3937-3945, 2021.

(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.xphs.2021.07.004
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1016/j.xphs.2021.07.004

(DOI: 10.1016/j.xphs.2021.07.004) Eisaku Ohashi, Sangita Karanjit, Atsushi Nakayama, Kohei Takeuchi, Sherif E Emam, Hidenori ANDO, Tatsuhiro Ishida and Kosuke Namba :
Efficient construction of the hexacyclic ring core of palau'amine: the pK_a concept for proceeding with unfavorable equilibrium reactions,
Chemical Science, Vol.12, 2021.

(徳島大学機関リポジトリ): ● Metadata: 116279
(出版サイトへのリンク): ● Publication site (DOI): 10.1039/D1SC03260G
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1039/D1SC03260G

(徳島大学機関リポジトリ: 116279, DOI: 10.1039/D1SC03260G) Kazuyuki Saito, Taro Shimizu, Katsue Suzuki-Inoue, Tatsuhiro Ishida and Yoshiaki Wada :
Aseptic meningitis after vaccination of the BNT162b2 mRNA COVID19 vaccine,
Neurological Sciences, 2021.

(出版サイトへのリンク): ● Publication site (DOI): 10.1007/s10072-021-05543-1
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1007/s10072-021-05543-1

(DOI: 10.1007/s10072-021-05543-1) Ryo Kinoshita, Yu Ishima, Victor T.G. Chuang, Hiroshi Watanabe, Taro Shimizu, Hidenori ANDO, Keiichiro Okuhira, Masaki Otagiri, Tatsuhiro Ishida and Toru Maruyama :
The therapeutic effect of HSA dimer-doxorubicin complex against human pancreatic tumour,
Pharmaceutics, Vol.13, No.8, 1209, 2021.

(徳島大学機関リポジトリ): ● Metadata: 116618
(出版サイトへのリンク): ● Publication site (DOI): 10.3390/pharmaceutics13081209
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.3390/pharmaceutics13081209

(徳島大学機関リポジトリ: 116618, DOI: 10.3390/pharmaceutics13081209) Hidenori ANDO, Takashi Mochizuki, Amr Abu Ali Ahmed Selim Lila, Shunsuke Akagi, Kenji Tajima, Kenji Fujita, Taro Shimizu, Yu Ishima, Tokuo Matsushima, Takatomo Kusano and Tatsuhiro Ishida :
Doxorubicin embedded into nanofibrillated bacterial cellulose (NFBC) produces a promising therapeutic outcome for peritoneally metastatic gastric cancer in mice models via intraperitoneal direct injection,
Nanomaterials, Vol.11, 1697, 2021.

(徳島大学機関リポジトリ): ● Metadata: 116603
(出版サイトへのリンク): ● Publication site (DOI): 10.3390/nano11071697
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.3390/nano11071697

(徳島大学機関リポジトリ: 116603, DOI: 10.3390/nano11071697) Emam Emam Abdallah Sherif, Elhewan Emam Elsadek Emam Ali Nehal, Lila Selim Ahmed Ali Abu Amr, Haruka Takata, Yoshino Kawaguchi, Taro Shimizu, Hidenori ANDO, Yu Ishima and Tatsuhiro Ishida :
Anti-PEG IgM production and accelerated blood clearance phenomenon after the administration of PEGylated exosomes in mice,
Journal of Controlled Release, Vol.334, 327-334, 2021.

(要約): Recently, there is an increasing interest in exosomes or extracellular vesicles as potential candidates for delivering RNAs, proteins, genes, and anticancer agents. Engineering of exosome properties is rapidly evolving as a means of expanding exosome applications. PEGylation of exosomes is a technique used to improve their in vivo stability, circulation half-lives, and sometimes to allow the binding targeting ligands to the exosome exterior. According to FDA guidelines for the development of PEGylated proteins, immunological responses to PEGylated molecules and particles should be examined. In this study, we prepared PEGylated exosomes and investigated the production of anti-PEG IgM antibodies after single i.v. injections in mice. In addition, we monitored blood concentrations and tumor accumulation of a second dose of PEGylated exosomes administered after the initial dose. Single injections of PEGylated exosomes in mice induced anti-PEG IgM production in a T cell-dependent manner. The anti-PEG IgM production decreased when the injection dose of PEGylated exosomes was further increased. Anti-PEG IgM induced by injection of PEGylated exosomes decreased blood concentrations of a second dose of PEGylated exosomes and suppressed their tumor accumulation in a C26 murine colorectal cancer model. Initial injection doses of either PEGylated liposomes or PEGylated ovalbumin (PEG-OVA), both of them induced anti-PEG IgM production, also decreased the blood concentration of PEGylated exosomes. Interestingly, anti-PEG IgM induced by injection of PEGylated exosomes did not affect the blood concentration of PEG-OVA. These results imply the importance of monitoring anti-PEG IgM when repeat PEGylated exosome doses are required and/or when PEGylated exosomes are used together with other PEGylated therapeutics.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2021.05.001
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 33957196; ● Summary page in Scopus @ Elsevier: 2-s2.0-85105280797

(DOI: 10.1016/j.jconrel.2021.05.001, PubMed: 33957196, Elsevier: Scopus) Milad Reda Qelliny, Taro Shimizu, Nehal Ali Emam Elsadek Emam Elhewan, Sherif Abdallah Emam Emam, Haruka Takata, Zeinab M. A. Fathalla, Amal K. Hussein, Khaled A. Khaled, Hidenori ANDO, Yu Ishima and Tatsuhiro Ishida :
Incorporating gangliosides into PEGylated cationic liposomes that complexed DNA attenuates anti-PEG antibody production, but not anti-DNA antibody production in mice,
Molecular Pharmaceutics, Vol.18, No.6, 2406-2415, 2021.

(要約): Gangliosides (glycosphingolipids) reduce antibody production by inhibiting B-cell receptor (BCR) signaling. We have shown that a copresentation of gangliosides and polyethylene glycol (PEG) on the same liposomes suppresses anti-PEG IgM production in mice. In addition, we recently observed that pDNA incorporated in PEGylated cationic liposomes (PCLs) induces anti-DNA IgM, which could be a hurdle to the development of efficient gene delivery systems. Therefore, the focus of this study was to determine if the copresentation of gangliosides and DNA on the same PCL would suppress antibody production against DNA. PCLs including DNA induced both anti-PEG IgM production and anti-DNA IgM production. The extent of anti-PEG and anti-DNA IgM production was likely dependent on the immunogenicity of the complexed DNA. Treatment of clodronate-containing liposomes, which causes a depletion of phagocytic cells, suppressed anti-PEG IgM production from PCLs that did not include DNA but failed to suppress anti-PEG IgM production from PCLs that complexed DNA (PCLD). Both anti-PEG IgM and anti-DNA IgM was induced in T-cell-deficient nude mice as well as in normal mice following treatment with PCLs and PCLD, respectively. These results indicate that phagocytic cells contribute to anti-PEG IgM production but not to anti-DNA IgM production, while T-cells do not contribute to any form of antibody production. The copresentation of gangliosides and DNA significantly reduced anti-PEG IgM production but unfortunately did not reduce anti-DNA IgM production. It appears that the immunosuppressive effect of gangliosides, presumably via the CD22 signaling pathway, is limited only to anti-PEG immunity.
(キーワード): Animals / Antibody Formation / Cations / Clodronic Acid / DNA / Gangliosides / Gene Transfer Techniques / Genetic Therapy / Immunoglobulin M / Liposomes / Male / Mice / Phagocytes / Plasmids / Polyethylene Glycols
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.molpharmaceut.1c00255
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 33896187; ● Search Scopus @ Elsevier (PMID): 33896187; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.molpharmaceut.1c00255

(DOI: 10.1021/acs.molpharmaceut.1c00255, PubMed: 33896187) Hidenori ANDO, Yuta Murakami, Kiyoshi Eshima and Tatsuhiro Ishida :
A novel polyethylene glycol (PEG)-drug conjugate of Venetoclax, a Bcl-2 inhibitor, for treatment of acute myeloid leukemia (AML),
Cancer Reports, Vol.5, No.3, e1485, 2021.

(要約): Venetoclax (VTX) is an anticancer drug. It is a selective Bcl-2 inhibitor that is clinically used for the treatment of patients with lymphomas and leukemias. Treatment with VTX, however, is accompanied by severe adverse events such as tumor lysis syndrome and neutropenia, because VTX readily binds to serum proteins, which results in poor pharmacokinetics and poor tumor tissue concentration. To avoid such adverse events, VTX is administered using a daily or weekly ramp-up schedule that is cumbersome in clinical situations. To overcome these shortcomings, we prepared a novel polyethylene glycol (PEG)-drug conjugate of VTX (PEG-VTX) and evaluated its cytotoxic effects on acute myeloid leukemia (AML) both in vitro and in vivo. VTX and 4-armed PEG derivatives were covalently attached through an amide bond linker. In a series of in vitro studies, PEG-VTX selectively induced potent growth inhibition of MV4-11 human AML cells via the inducement of Bcl-2-mediated apoptosis. PEG-VTX had the effect of free VTX, presumably due to the protease-mediated release of VTX from the conjugates. In in vivo studies with AML tumor-xenograft mice models, intravenous PEG-VTX promoted sufficient tumor growth suppression. Compared with a regimen of oral free VTX, the intravenous regimen in those studies used a VTX dosage that was 15-30 times smaller for an OCI-AML-2 xenograft model and a dosing regimen that was less frequent for an MV4-11 xenograft model. The most important development, however, was the absence of weight loss related to severe side effects throughout the treatments. An increase in water solubility and the resultant hydrodynamic size of VTX via PEGylation improved the pharmacokinetics of VTX by avoiding protein interactions and lessening the extravasation from blood. The result was an increase in tumor accumulation and a decrease in the nonspecific distribution of VTX. The results of this study suggest that PEG-VTX could be an alternative therapeutic option for the safe and effective treatment of patients with AML.
(キーワード): Animals / Antineoplastic Agents / Bridged Bicyclo Compounds, Heterocyclic / Humans / Leukemia, Myeloid, Acute / Mice / Polyethylene Glycols / Sulfonamides
(徳島大学機関リポジトリ): ● Metadata: 116506
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/cnr2.1485
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 34173723; ● Search Scopus @ Elsevier (PMID): 34173723; ● Search Scopus @ Elsevier (DOI): 10.1002/cnr2.1485

(徳島大学機関リポジトリ: 116506, DOI: 10.1002/cnr2.1485, PubMed: 34173723) Hidenori ANDO, Sherif Abdallah Emam Emam, Yoshino Kawaguchi, Taro Shimizu, Yu Ishima, Kiyoshi Eshima and Tatsuhiro Ishida :
Increasing tumor extracellular pH by an oral alkalinizing agent improves antitumor responses of anti-PD-1 antibody: Implication of relationships between serum bicarbonate concentrations, urinary pH, and therapeutic outcomes,
Biological & Pharmaceutical Bulletin, Vol.44, No.6, 844-852, 2021.

(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b21-00076
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.b21-00076

(DOI: 10.1248/bpb.b21-00076) Naoki Hirakawa, Yu Ishima, Ryo Kinoshita, Ryuto Nakano, Chuang Tuan Giam Victor, Hidenori ANDO, Taro Shimizu, Keiichiro Okuhira, Toru Maruyama, Masaki Otagiri and Tatsuhiro Ishida :
Reduction-responsive and Multi-drug Deliverable Albumin Nanoparticles: an antitumor drug to Abraxane® against Human Pancreatic Tumor-Bearing Mice,
ACS Applied Bio Materials, Vol.4, No.5, 4302-4309, 2021.

(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acsabm.1c00110
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1021/acsabm.1c00110

(DOI: 10.1021/acsabm.1c00110) Haruka Takata, Taro Shimizu, Yoshino Kawaguchi, Hiro Ueda, Nehal Ali Emam Elsadek Emam Elhewan, Hidenori ANDO, Yu Ishima and Tatsuhiro Ishida :
Nucleic acids delivered by PEGylated cationic liposomes in systemic lupus erythematosus-prone mice: a possible exacerbation of lupus nephritis in the presence of pre-existing anti-nucleic acid antibodies,
International Journal of Pharmaceutics, Vol.601, 120529, 2021.

(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2021.120529
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1016/j.ijpharm.2021.120529

(DOI: 10.1016/j.ijpharm.2021.120529) Maichi Hama, Yu Ishima, Chuang V, Hidenori ANDO, Taro Shimizu and Tatsuhiro Ishida :
Evidence for delivery of Abraxane® via a denatured-albumin transport system,
ACS Applied Materials & Interfaces, Vol.13, No.17, 19736-19744, 2021.

(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acsami.1c03065
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1021/acsami.1c03065

(DOI: 10.1021/acsami.1c03065) Shunsuke Akagi, Hidenori ANDO, Kenji Fujita, Taro Shimizu, Yu Ishima, Kenji Tajima, Tokuo Matsushima, Takatomo Kusano and Tatsuhiro Ishida :
Therapeutic efficacy of a paclitaxel-loaded nanofibrillated bacterial cellulose (PTX/NFBC) formulation in a peritoneally disseminated gastric cancer xenograft model,
International Journal of Biological Macromolecules, Vol.174, 494-501, 2021.

(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijbiomac.2021.01.201
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1016/j.ijbiomac.2021.01.201

(DOI: 10.1016/j.ijbiomac.2021.01.201) Taro Shimizu, Yuki Watanabe, Hidenori ANDO, Yu Ishima and Tatsuhiro Ishida :
Lymphoid follicle antigen (Ag) delivery and enhanced rodent humoral immune responses mediated by Ag-containing PEGylated liposomes,
Vaccine, Vol.39, No.7, 1131-1139, 2021.

(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.vaccine.2021.01.008
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1016/j.vaccine.2021.01.008

(DOI: 10.1016/j.vaccine.2021.01.008) Hidenori ANDO, Kiyoshi Eshima and Tatsuhiro Ishida :
Neutralization of acidic tumor microenvironment (TME) with daily oral dosing of sodium potassium citrate (K/Na Citrate) increases therapeutic effect of anti-cancer agent in pancreatic cancer xenograft mice model,
Biological & Pharmaceutical Bulletin, Vol.44, No.2, 266-270, 2021.

(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b20-00825
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.b20-00825

(DOI: 10.1248/bpb.b20-00825) Taro Shimizu, Mizuki Awata, Lila Selim Ahmed Ali Abu Amr, Chihiro Yoshioka, Yoshino Kawaguchi, Hidenori ANDO, Yu Ishima and Tatsuhiro Ishida :
Complement activation induced by PEG enhances humoral immune responses against antigens encapsulated in PEG-modified liposomes,
Journal of Controlled Release, Vol.329, 1046-1053, 2021.

(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2020.10.033
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2020.10.033

(DOI: 10.1016/j.jconrel.2020.10.033) Takuma Takayama, Taro Shimizu, Lila Selim Ahmed Ali Abu Amr, Yuki Kanazawa, Hidenori ANDO, Yu Ishima and Tatsuhiro Ishida :
Adjuvant antitumor immunity contributes to the overall antitumor effect of PEGylated liposomal doxorubicin (Doxil®) in C26 tumor-bearing immunocompetent mice,
Pharmaceutics, Vol.12, No.10, 990, 2020.

(徳島大学機関リポジトリ): ● Metadata: 116247
(出版サイトへのリンク): ● Publication site (DOI): 10.3390/pharmaceutics12100990
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.3390/pharmaceutics12100990

(徳島大学機関リポジトリ: 116247, DOI: 10.3390/pharmaceutics12100990) Takuya Suzuki, Yuta Suzuki, Taro Hihara, Kenji Kubara, Keita Kondo, Kenji Hyodo, Kazuto Yamazaki, Tatsuhiro Ishida and Hiroshi Ishihara :
PEG shedding-rate-dependent blood clearance of PEGylated lipid nanoparticles in mice: faster PEG shedding attenuates anti-PEG IgM production,
International Journal of Pharmaceutics, Vol.588, 119792, 2020.

(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2020.119792
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1016/j.ijpharm.2020.119792

(DOI: 10.1016/j.ijpharm.2020.119792) Shota Fuimoto, Naoki Muguruma, Michiyasu Nakao, Hidenori ANDO, Takanori Kashihara, Yoshihiko Miyamoto, Koichi Okamoto, Shigeki Sano, Tatsuhiro Ishida, Yasushi Sato and Tetsuji Takayama :
Indocyanine green-labeled dasatinib as a new fluorescent probe for molecular imaging of gastrointestinal stromal tumors.,
Journal of Gastroenterology and Hepatology, Vol.36, No.5, 1253-1262, 2020.

(要約): It is difficult to differentiate gastrointestinal stromal tumors (GISTs) from other subepithelial lesions under gastrointestinal endoscopy. Because most GISTs express tyrosine kinase receptor c-KIT, fluorescence-labeled c-KIT-specific tyrosine kinase inhibitors seem to be useful agents for molecular imaging of GIST. We aimed to develop a near-infrared fluorescent imaging technology for GIST targeting c-KIT using the novel fluorescent probe indocyanine green-labeled dasatinib (ICG-dasatinib) and to investigate the antitumor effect of ICG-dasatinib on GIST cells. Indocyanine green-labeled dasatinib was synthesized by labeling linker-induced dasatinib with ICG derivative 3-indocyanine-green-acyl-1,3-thiazolidine-2-thione. Human GIST cell lines GIST-T1 and GIST-882M were incubated with ICG-dasatinib and observed by fluorescent microscopy. GIST cells were incubated with ICG-dasatinib, unlabeled dasatinib, or imatinib, and cell viabilities were evaluated. Subcutaneous GIST model mice or orthotopic GIST model rats were intravenously injected with ICG-dasatinib and observed using an IVIS Spectrum. Strong fluorescent signals of ICG-dasatinib were observed in both GIST cell lines in vitro. IC50 values for ICG-dasatinib, unlabeled dasatinib, and imatinib were 13.9, 1.17, and 16.2 nM in GIST-T1 and 26.6, 3.63, and 47.6 nM in GIST-882M cells, respectively. ICG-dasatinib accumulated in subcutaneous xenografts in mice. Fluorescent signals were also observed in liver and gallbladder, indicating biliary excretion; however, fluorescence intensity of tumors was significantly higher than that of intestine after washing. Strong fluorescent signals were observed in orthotopic xenografts through the covering normal mucosa in rats. Indocyanine green-labeled dasatinib could visualize GIST cells and xenografted tumors. The antitumor effect of ICG-dasatinib was preserved to the same degree as imatinib.
(出版サイトへのリンク): ● Publication site (DOI): 10.1111/jgh.15281
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32989784; ● Search Scopus @ Elsevier (PMID): 32989784; ● Search Scopus @ Elsevier (DOI): 10.1111/jgh.15281

(DOI: 10.1111/jgh.15281, PubMed: 32989784) Elhewan Emam Elsadek Emam Ali Nehal, Emam Emam Abdallah Sherif, Lila Selim Ahmed Ali Abu Amr, Taro Shimizu, Hidenori ANDO, Yu Ishima and Tatsuhiro Ishida :
Pegfilgrastim (PEG-G-CSF) induces anti-polyethylene glycol (PEG) IgM via a T cell-dependent mechanism,
Biological & Pharmaceutical Bulletin, Vol.43, No.9, 1393-1397, 2020.

(要約): Protein-based therapeutics are beginning to be widely used in various clinical settings. Conjugation of polyethylene glycol (PEGylation) to protein therapeutics improves their circulation half-lives in the body. However, we and other groups observed that the initial dose of some PEGylated protein-based therapeutics may induce anti-PEG antibodies (primarily immunoglobulin M (IgM)), resulting in the accelerated clearance of a second dose. The mechanism behind the induction of anti-PEG IgM by PEGylated protein-based therapeutics is still unclear. In this study, we found that Pegfilgrastim (PEG-G-CSF, the PEGylated form of the recombinant human granulocyte colony-stimulating factor) induced anti-PEG IgM in mice when administered via either intravenous or subcutaneous administration. However, the anti-PEG IgM induction is diminished both in athymic nude mice lacking T cells and in splenectomized mice. In addition, anti-PEG IgM production was significantly diminished in the cyclophosphamide-treated mice depleted of B-cells. These results indicate that anti-PEG IgM production by Pegfilgrastim occurs in spleen in a T cell-dependent manner, which differs from anti-PEG IgM induced by PEGylated liposomes. However, B cells, both marginal zone and follicular, are essential for anti-PEG IgM production in both PEGylated preparations.
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b20-00345
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32879214; ● Search Scopus @ Elsevier (PMID): 32879214; ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.b20-00345

(DOI: 10.1248/bpb.b20-00345, PubMed: 32879214) Takaaki Ryujin, Taro Shimizu, Ryo Miyahara, Daisuke Asai, Rena Shimazui, Takuma Yoshikawa, Akihiro Kishimura, Takeshi Mori, Tatsuhiro Ishida and Yoshiki Katayama :
Blood retention and antigenicity of polycarboxybetaine-modified liposomes,
International Journal of Pharmaceutics, Vol.586, 119521, 2020.

(要約): Zwitterionic polycarboxybetaines (PCBs) have gained attention as alternative stealth polymers whose liposomal formulation and protein conjugates were reported not to elicit anti-polymer antibodies. Here, we studied the blood retention and antigenicity of liposomes modified with PCBs focusing on their chemical structures and doses. We compared PCBs with either 1 or 3 (PCB1 or PCB3) spacer carbons between the carboxylate and ammonium groups. PCB3-modified liposomes had a short blood retention, whereas PCB1-modified liposomes demonstrated extended blood retention that was somewhat superior to PEGylated liposome. This confirmed the excellent non-fouling nature of PCB1 reported previously. Interestingly, PCB1-liposome as well as PCB3-liposome elicited specific IgMs toward each PCB. The dose-dependent production of specific IgMs to PCB-liposomes was similar to that of PEGylated liposome, i.e., high doses of PCB-liposomes reduced the production of specific IgMs, termed immunological tolerance. These results indicate the importance of investigating the effect of dose to clarify the existence of antigenicity of stealth polymers.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2020.119521
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32561308; ● Summary page in Scopus @ Elsevier: 2-s2.0-85086721197

(DOI: 10.1016/j.ijpharm.2020.119521, PubMed: 32561308, Elsevier: Scopus) A Nguyen, Hidenori ANDO, R Böttger, K K Viswanadham, E Rouhollahi, Tatsuhiro Ishida and S Li :
Utilization of Click Chemistry to Study the Effect of Poly(ethylene) Glycol Molecular Weight on the Self-Assembly of PEGylated Gambogic Acid Nanoparticles for the Treatment of Rheumatoid Arthritis,
Biomaterials Science, Vol.8, No.16, 4626-4637, 2020.

(要約): Many small-molecule drugs exhibit poor aqueous solubility, and various approaches have been developed to improve their solubility and delivery. Chemical conjugation of an insoluble drug to a hydrophilic polymer can promote the self-assembly into nanoparticles (NPs) to increase the apparent solubility and improve the pharmacokinetics of the drug. However, majority of the reports in the field disclose only one composition of the conjugate, while accumulating evidence suggests that structure-activity relationship (SAR) studies must be conducted to identify an optimal construct. In this study, we employed a click chemistry platform to robustly conjugate short-chain methoxypolyethylene glycol (mPEG) of three different molecular weights to a small molecule anti-inflammatory drug, gambogic acid (GA), and studied the SAR. NPs formed with mPEG550 and mPEG5000, referred to as NP-550 and NP-5000, respectively, had larger mean diameters (130.0 ± 16.9 nm and 143.0 ± 0.1 nm, respectively) and higher critical micellar concentrations (CMCs, 9.5 μg mL-1 and 10.5 μg mL-1, respectively) compared to NPs formed with mPEG2000 (NP-2000, mean diameter = 97.8 ± 5.0 nm and CMC = 6.6 μg mL-1). NP-2000 and NP-5000 did not cause significant hemolytic toxicity, whereas NP-550 and free GA induced 90% and 60% hemolysis, respectively. NP-2000 was selected for further studies due to its improved safety, small size and low CMC. In cultured inflammatory macrophages, NP-2000 exhibited activity comparable to free GA in suppressing tumor necrosis factor-α. In mice, NP-2000 showed 185-fold improved drug exposure compared to free GA after intraperitoneal delivery. Treatment with free GA showed little anti-inflammatory activity compared to vehicle control in a murine model of rheumatoid arthritis. In contrast, NP-2000 significantly reduced the paw inflammation by 27% from day 15 to day 29. NP-2000 showed no visible signs of toxicity in mice, while free GA elicited significant irritation at the injection site. Our work emphasizes the importance of performing SAR studies for developing an optimal drug-polymer conjugate for self-assembly into NPs. We also demonstrate a unique application of click chemistry to robustly synthesize a small library of conjugates for the SAR study.
(出版サイトへのリンク): ● Publication site (DOI): 10.1039/d0bm00711k
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32700691; ● Search Scopus @ Elsevier (PMID): 32700691; ● Search Scopus @ Elsevier (DOI): 10.1039/d0bm00711k

(DOI: 10.1039/d0bm00711k, PubMed: 32700691) Elhewan Emam Elsadek Emam Ali Nehal, Eri Hondoh, Taro Shimizu, Haruka Takata, Lila Selim Ahmed Ali Abu Amr, Emam Emam Abdallah Sherif, Hidenori ANDO, Yu Ishima and Tatsuhiro Ishida :
Impact of pre-existing or induced anti-PEG IgM on the pharmacokinetics of peginterferon alfa-2a (Pegasys®) in mice,
Molecular Pharmaceutics, Vol.17, No.8, 2964-2970, 2020.

(要約): PEGylation had been used successfully to improve the circulation half-lives and some physicochemical properties of protein therapeutics. However, anti-polyethylene glycol (anti-PEG) antibodies, either pre-existing or treatment-induced, can negatively affect the pharmacokinetics and pharmacological efficacy of PEGylated proteins. We have examined anti-PEG immune responses in mice for peginterferon alfa-2a (Pegasys), a clinically approved PEGylated protein therapeutic, at both the recommended dose (equivalent to 3 μg/kg in mice) and at higher doses (150 μg/kg) for single or repeated subcutaneous (s.c.) administrations. The effect of treatment-induced anti-PEG IgM on serum concentrations of Pegasys, following repeated administrations, was evaluated. In addition, the effect of pre-existing anti-PEG IgM elicited by a different PEGylated protein, PEG-OVA, on the systemic clearance of Pegasys, was investigated. At a s.c. dose of 3 μg/kg, single injections of Pegasys barely elicited anti-PEG immune responses. Four repeated doses of 150 μg/kg Pegasys elicited anti-PEG IgM production, depending on dose frequency, and triggered the rapid clearance of subsequent doses. In addition, anti-PEG-IgM produced in response to prior administration of PEG-OVA caused a rapid blood clearance of Pegasys. Our results, therefore, underscore the importance of screening for both pre-existing and treatment-induced anti-PEG antibodies in patients prior to and during treatment with PEGylated protein drugs.
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.molpharmaceut.0c00366
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32519877; ● Search Scopus @ Elsevier (PMID): 32519877; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.molpharmaceut.0c00366

(DOI: 10.1021/acs.molpharmaceut.0c00366, PubMed: 32519877) M Sayed M El, Haruka Takata, Taro Shimizu, Yoshino Kawaguchi, Lila Selim Ahmed Ali Abu Amr, Elhewan Emam Elsadek Emam Ali Nehal, E Alaaeldin, Yu Ishima, Hidenori ANDO, A Kamal, A H Sarhan and Tatsuhiro Ishida :
Hepatosplenic phagocytic cells indirectly contribute to anti-PEG IgM production in the accelerated blood clearance (ABC) phenomenon against PEGylated liposomes: Appearance of an unexplained mechanism in the ABC phenomenon,
Journal of Controlled Release, Vol.323, 102-109, 2020.

(要約): The accelerated blood clearance (ABC) phenomenon, caused in large degree via in vivo anti-PEG IgM production, is one of obstacles for development of PEGylated liposome and protein formulations, due to decreased efficiency and/or side effects such as anaphylaxis upon repeat administrations. We have shown in murine ABC models that splenectomy suppressed the level of anti-PEG IgM production induced by PEGylated liposomes, indicating that murine splenic B cells play an important role in its production. However, splenectomy did not completely inhibit production of anti-PEG IgM, suggesting that other cells may contribute to its production in the ABC phenomenon. In this study, we examined the contribution of hepatosplenic phagocytic cells to anti-PEG IgM production and clearance of PEGylated liposomes during the ABC phenomenon. Depletion of hepatosplenic phagocytic cells by pretreatment of mice with clodronate-containing non-PEGylated liposomes suppressed anti-PEG IgM production to a considerable degree, without a change in the number of splenic B cells, and attenuated the enhanced clearance of second dose of PEGylated liposomes. These results suggest that hepatosplenic phagocytic cells, in addition to splenic B cells, contribute to the production of anti-PEG IgM and the ABC phenomenon against PEGylated liposomes. The mechanism whereby splenic B cells interact with hepatosplenic phagocytic cells to produce anti-PEG IgM, upon administration of an initial dose of PEGylated liposomes remains to be elucidated.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2020.04.011
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32278827; ● Summary page in Scopus @ Elsevier: 2-s2.0-85083399688

(DOI: 10.1016/j.jconrel.2020.04.011, PubMed: 32278827, Elsevier: Scopus) Nehal Ali Emam Elsadek Emam Elhewan, Amr Abu Ali Ahmed Selim Lila, Sherif Abdallah Emam Emam, Taro Shimizu, Haruka Takata, Hidenori ANDO, Yu Ishima and Tatsuhiro Ishida :
Pegfilgrastim (PEG-G-CSF) induces anti-PEG IgM in a dose dependent manner and causes the accelerated blood clearance (ABC) phenomenon upon repeated administration in mice,
European Journal of Pharmaceutics and Biopharmaceutics, Vol.152, 56-62, 2020.

(要約): Pegfilgrastimis a recombinant PEGylated human granulocyte colony-stimulating factor (G-CSF) analog filgrastim (trade names Neulasta® or G-Lasta®) that stimulates the production of white blood cells (neutrophils). It is employed as an alternative to filgrastim (G-CSF) for chemotherapy-induced neutropenia in patients due to its longer half-life. In clinical settings, PEG-G-CSF is administered to cancer patients via both the s.c. and i.v. routes. In a murine study, we showed that, regardless of administration route, initial doses of PEG-G-CSF above 0.06 mg/kg elicited anti-PEG immune response in a dose-dependent manner. I.v. administration elicited higher levels of anti-PEG IgM than the s.c. route. Initial doses of PEG-G-CSF (6 mg/kg) that were high enough to trigger production of anti-PEG IgM, did not trigger the accelerated clearance of a lower subsequent dose (0.06 mg/kg) that was similar to i.v. clinical doses of PEG-G-CSF, but when the subsequent dose of PEG-G-CSF was raised to (6 mg/kg), the initial dose triggered the accelerated clearance of the second dose via an anti-PEG IgM-mediated complement activation. Similar observations were noted when an increased PEG-OVA dose was given as the second dose, indicating that pre-existing and/or treatment-induced anti-PEG antibodies might compromise the therapeutic activity and/or reduce tolerance of other PEGylated formulations. To the best of our knowledge, this is the first report to suggest the induction of the ABC phenomenon upon repeated injections of pegfilgrastim. In the clinic, cancer patients, receiving multiple cycles of chemotherapy, receive multiple cycles of pegfilgrastim to avoid infections and substantial morbidity. The ABC phenomenon to pegfilgrastim appears to be the cause of loss of clinical benefit of sequential treatments with pegfilgrastim in patients.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ejpb.2020.04.026
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32376372; ● Search Scopus @ Elsevier (PMID): 32376372; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ejpb.2020.04.026

(DOI: 10.1016/j.ejpb.2020.04.026, PubMed: 32376372) Yukiko Oh, Hitomi Niijima, Yuta Kawahara, Tomomi Hayase, Taro Shimizu, Tatsuhiro Ishida and Akira Morimoto :
An immediate hypersensitivity reaction induced by PEGylated recombinant factor VIII,
Haemophilia, 2020.

(出版サイトへのリンク): ● Publication site (DOI): 10.1111/hae.14048
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1111/hae.14048

(DOI: 10.1111/hae.14048) Ryo Koba, Hayato Fujita, Maiko Nishibori, Kiyoshi Saeki, Kinuko Nagayoshi, Yoshihiko Sadakari, Shuntaro Nagai, Oki Sekizawa, Kiyofumi Nitta, Tatsuya Manabe, Takashi Ueki, Tatsuhiro Ishida, Yoshinao Oda and Masafumi Nakamura :
Quantitative evaluation of the intratumoral distribution of platinum in oxaliplatin-treated rectal cancer: In situ visualization of platinum via synchrotron radiation X-ray fluorescence spectrometry,
International Journal of Cancer, Vol.146, No.9, 2498-2509, 2020.

(要約): Oxaliplatin (l-OHP), a platinum-based drug, is a key chemotherapeutic agent for colorectal cancer (CRC), but drug resistance and toxic effects have been major limitations of its use. Synchrotron radiation X-ray fluorescence spectrometry (SR-XRF) is a rapid, nondestructive technique for monitoring the distribution of metals and trace elements in cells or tissue samples. We applied SR-XRF to visualize the distribution of platinum and other elements in 30 rectal cancer specimens resected from patients who received l-OHP-based preoperative chemotherapy and quantified platinum concentration in the tumor epithelium and stroma, respectively, using calibration curves. The platinum concentration in rectal cancer tissue ranged 2.85-11.44 ppm, and the detection limit of platinum was 1.848 ppm. In the tumor epithelium, the platinum concentration was significantly higher in areas of degeneration caused by chemotherapy than in nondegenerated area (p < 0.001). Conversely, in the tumor stroma, the platinum concentration was significantly higher in patients with limited therapeutic responses than in those with strong therapeutic responses (p < 0.001). Furthermore, multivariate analysis illustrated that higher platinum concentration in the tumor stroma was an independent predictive factor of limited histologic response (odds ratio; 19.99, 95% confidence interval; 2.04-196.37, p = 0.013). This is the first study to visualize and quantify the distribution of platinum in human cancer tissues using SR-XRF. These results suggest that SR-XRF analysis may contribute to predicting the therapeutic effect of l-OHP-based chemotherapy by quantifying the distribution of platinum.
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/ijc.32592
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31344279; ● Summary page in Scopus @ Elsevier: 2-s2.0-85070929282

(DOI: 10.1002/ijc.32592, PubMed: 31344279, Elsevier: Scopus) Hidenori ANDO, Noriko Saito-Tarashima, Lila Selim Ahmed Ali Abu Amr, Nozomi Kinjoh, Taro Shimizu, Yu Ishima, Noriaki Minakawa and Tatsuhiro Ishida :
A unique gene-silencing approach, using an intelligent RNA expression device (iRed), results in minimal immune stimulation when given by local intrapleural injection in malignant pleural mesothelioma,
Molecules, Vol.25, No.7, 1725, 2020.

(要約): We have recently introduced an intelligent RNA expression device (iRed), comprising the minimum essential components needed to transcribe short hairpin RNA (shRNA) in cells. Use of iRed efficiently produced shRNA molecules after transfection into cells and alleviated the innate immune stimulation following intravenous injection. To study the usefulness of iRed for local injection, the engineered iRed encoding luciferase shRNA (Luc iRed), complexed with cationic liposomes (Luc iRed/liposome-complexes), was intrapleurally injected into an orthotopic mesothelioma mouse model. Luc iRed/liposome-complexes markedly suppressed the expression of a luciferase marker gene in pleurally disseminated mesothelioma cells. The suppressive efficiency was correlated with the expression level of shRNA within the mesothelioma cells. In addition, intrapleural injection of iRed/liposome-complexes did not induce IL-6 production in the pleural space and consequently in the blood compartment, although plasmid DNA (pDNA) or dsDNA (the natural construct for iRed) in the formulation did. Local delivery of iRed could augment the in vivo gene silencing effect without eliciting pronounced innate immune stimulation. Our results might hold promise for widespread utilization of iRed as an RNAi-based therapeutic for intracelial malignant cancers.
(徳島大学機関リポジトリ): ● Metadata: 115605
(出版サイトへのリンク): ● Publication site (DOI): 10.3390/molecules25071725
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32283709; ● Summary page in Scopus @ Elsevier: 2-s2.0-85083281974

(徳島大学機関リポジトリ: 115605, DOI: 10.3390/molecules25071725, PubMed: 32283709, Elsevier: Scopus) Yu Ishima, Ai Minomo, Chuang Tuan Giam Victor, Tetsuya Fukuda, Kohshi Kusumoto, Keiichiro Okuhira, Yoshiaki Suwa, Hiroshi Watanabe, Tatsuhiro Ishida, Hiroshi Morioka, Toru Maruyama and Masaki Otagiri :
Albumin domain mutants with enhanced Aβ binding capacity identified by phage display analysis for application in various peripheral Aβ elimination approaches of Alzheimer's disease treatment,
IUBMB life, Vol.72, No.4, 641-651, 2020.

(要約): Deposition of amyloid protein, particularly Aβ , is a major contributor to the onset of Alzheimer's disease (AD). However, almost no deposition of Aβ in the peripheral tissues could be found. Human serum albumin (HSA), the most abundant protein in the blood, has been reported to inhibit amyloid formation through binding Aβ, which is believed to play an important role in the peripheral clearance of Aβ. We identified the Aβ binding site on HSA and developed HSA mutants with high binding capacities for Aβ using a phage display method. HSA fragment 187-385 (Domain II) was found to exhibit the highest binding capacity for Aβ compared with the other two HSA fragments. To elucidate the sequence that forms the binding site for Aβ on Domain II, a random screening of Domain II display phage biopanning was constructed. A number of mutants with higher Aβ binding capacities than the wild type were identified. These mutants exhibited stronger scavenging abilities than the wild type, as revealed via in vitro equilibrium dialysis of Aβ experiments. These findings provide useful basic data for developing a safer alternative therapy than Aβ vaccines and for application in plasma exchange as well as extracorporeal dialysis.
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/iub.2203
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31794135; ● Summary page in Scopus @ Elsevier: 2-s2.0-85076101146

(DOI: 10.1002/iub.2203, PubMed: 31794135, Elsevier: Scopus) Tasuku Torao, Miyuki Mimura, Yasufumi Ohshima, Kohki Fujikawa, Mahadi Hasan, Tatsuharu Shimokawa, Naoshi Yamazaki, Hidenori ANDO, Tatsuhiro Ishida, Tatsuya Fukuta, Tamotsu Tanaka and Kentaro Kogure :
Characteristics of unique endocytosis induced by weak current for cytoplasmic drug delivery,
International Journal of Pharmaceutics, Vol.576, 119010, 2020.

(徳島大学機関リポジトリ): ● Metadata: 114728
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2019.119010
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1016/j.ijpharm.2019.119010

(徳島大学機関リポジトリ: 114728, DOI: 10.1016/j.ijpharm.2019.119010) Emam Emam Abdallah Sherif, Lila Selim Ahmed Ali Abu Amr, Elhewan Emam Elsadek Emam Ali Nehal, Hidenori ANDO, Taro Shimizu, Keiichiro Okuhira, Yu Ishima, M Mahdy, E Ghazy and Tatsuhiro Ishida :
Cancer cell-type tropism is one of crucial determinants for the efficient systemic delivery of cancer cell-derived exosomes to tumor tissues,
European Journal of Pharmaceutics and Biopharmaceutics, Vol.145, 27-34, 2019.

(要約): Exosomes are gaining increasing attention as drug delivery vehicles due to their low toxicity and ability to functionally transfer biological cargos between cells. However, the therapeutic applicability of exosomes is partially hampered by a lack of cell-type specificity. In this study, therefore, we investigated the impact of cell-type tropism on the in vivo systemic delivery of exosomes to tumor tissues. Exosomes derived from murine colorectal cancer cells (C26) (C26-Exos) and murine melanoma cells (B16BL6) (B16BL6-Exos) were collected. In vitro cellular uptake of either autologous (C26) or allogeneic (B16BL6) exosomes by C26 tumor cells was determined. In vivo tumor accumulation of each type of exosomes in mice bearing C26 tumors was monitored with an in vivo imaging system (IVIS). In in vitro studies, autologous C26-Exos were more efficiently taken up by C26 cancer cells, compared to allogeneic B16BL6-Exos. For in vivo studies, exosomes were modified with surface polyethylene glycol (PEG) to improve their circulation lifetimes. Although both types of PEGylated exosomes accumulated in C26-tumor tissue, autologous exosomes were preferentially accumulated within C26-tumor tissue compared to allogeneic exosomes. The increased tumor accumulation of autologous PEGylated exosomes was accompanied by the preferential uptake of exosomes by not only C26-tumor cells but also tumor-associated immune cells. This study implies that cancer cell-type tropism is an important factor in the achievement of tumor cell targeting with cancer cell-derived exosomes.
(キーワード): Animals / Cell Line, Tumor / Colorectal Neoplasms / Drug Delivery Systems / Exosomes / Male / Melanoma / Mice / Mice, Inbred BALB C / Polyethylene Glycols / Tropism
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ejpb.2019.10.005
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31629787; ● Summary page in Scopus @ Elsevier: 2-s2.0-85073758566

(DOI: 10.1016/j.ejpb.2019.10.005, PubMed: 31629787, Elsevier: Scopus) Hidenori ANDO, M Fukushima, K Eshima, Taichi Hasui, Taro Shimizu, Yu Ishima, C Huang, H Wada and Tatsuhiro Ishida :
A novel intraperitoneal therapy for gastric cancer with DFP-10825, a unique RNAi therapeutic targeting thymidylate synthase, in peritoneally disseminated xenograft model,
Cancer Medicine, Vol.8, No.17, 7313-7321, 2019.

(要約): In advanced gastric cancer, peritoneal dissemination is a life-threatening mode of metastasis. Since the treatment options with conventional chemotherapy remain limited, any novel therapeutic strategy that could control such metastasis would improve the outcome of treatment. We recently developed a unique RNA interference therapeutic regimen (DFP-10825) consisting of short hairpin RNA against thymidylate synthase (TS shRNA) and cationic liposomes. The treatment with DFP-10825 has shown remarkable antitumor activity in peritoneally disseminated human ovarian cancer-bearing mice via intraperitoneal administration. In this study, we expanded DFP-10825 to the treatment of peritoneally disseminated gastric cancer. DFP-10825 was administered intraperitoneally into mice with intraperitoneally implanted human gastric cancer cells (MKN45 or NCI-N87). Antitumor activity and host survival benefits were monitored. Intraperitoneal distribution of fluorescence-labeled DFP-10825 was monitored in this MKN45 peritoneally disseminated mouse model. Intraperitoneal injection of DFP-10825 suppressed tumor growth in two peritoneally disseminated cancer models (MKN45 and NCI-N87) and increased the survival time of the MKN45 model without severe side effects. Throughout the treatment regimen, no significant body weight loss was associated with the administration of DFP-10825. Interestingly, after intraperitoneal injection, fluorescence-labeled DFP-10825 retained for more than 72 hours in the peritoneal cavity and selectively accumulated in disseminated tumors. Intraperitoneal injection of DFP-10825 demonstrated effective antitumor activity without systemic severe adverse effects via the selective delivery of RNAi molecules into disseminated tumors in the peritoneal cavity. Our current study indicates that DFP-10825 could become an alternative option to improve the outcomes of patients with peritoneally disseminated gastric cancer.
(徳島大学機関リポジトリ): ● Metadata: 115036
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/cam4.2598
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31609087; ● Search Scopus @ Elsevier (PMID): 31609087; ● Search Scopus @ Elsevier (DOI): 10.1002/cam4.2598

(徳島大学機関リポジトリ: 115036, DOI: 10.1002/cam4.2598, PubMed: 31609087) 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
PEG修飾リポソームに対する免疫応答,
人工血液, Vol.27, 37-43, 2019年. S Ichimizu, H Watanabe, H Maeda, K Hamasaki, K Ikegami, V Chuang, Ryo Kinoshita, K Nishida, Taro Shimizu, Yu Ishima, Tatsuhiro Ishida, T Seki, H Katsuki, S Futaki, M Otagiri and T Maruyama :
Cell-penetrating mechanism of intracellular targeting albumin: Contribution of macropinocytosis induction and endosomal escape,
Journal of Controlled Release, Vol.304, 156-163, 2019.

(要約): We recently developed a cell-penetrating drug carrier composed of albumin (HSA) combined with palmitoyl-cyclic-(D-Arg). While it is possible that the palmitoyl-cyclic-(D-Arg)/HSA enters the cell mainly via macropinocytosis, the mechanism responsible for the induction of macropinocytosis and endosomal escape remain unknown. We report herein that palmitoyl-cyclic-(D-Arg)/HSA might interact with heparan sulfate proteoglycan and the chemokine receptor CXCR4 followed by multiple activations of the PKC/PI3K/JNK/mTOR signaling pathways to induce macropinocytosis. This result was further confirmed by a co-treatment with 70 kDa dextran, a macropinocytosis marker. Using liposomes that mimic endosomes, the leakage of 5,6-carboxyfluorescein from liposome was observed in the presence of palmitoyl-cyclic-(D-Arg)/HSA only in the case of the anionic late endosome-like liposomes but not the neutral early endosome-like liposomes. Heparin largely inhibited this leakage, suggesting the importance of electrostatic interactions between palmitoyl-cyclic-(D-Arg)/HSA and the late-endosomal membrane. Immunofluorescence staining and Western blotting data indicated that the intact HSA could be transferred from endosomes to the cytosol. These collective data suggest that the palmitoyl-cyclic-(D-Arg)/HSA is internalized via macropinocytosis and intact HSA is released from the late endosomes to the cytoplasm before the endosomes fuse with lysosomes. Palmitoyl-cyclic-(D-Arg)/HSA not only functions as an intracellular drug delivery carrier but also as an inducer of macropinocytosis.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2019.05.015
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31082432; ● Summary page in Scopus @ Elsevier: 2-s2.0-85065581511

(DOI: 10.1016/j.jconrel.2019.05.015, PubMed: 31082432, Elsevier: Scopus) Hidenori ANDO, Lila Selim Ahmed Ali Abu Amr, M Fukushima, Rie Matsuoka, Taro Shimizu, Keiichiro Okuhira, Yu Ishima, C Huang, H Wada and Tatsuhiro Ishida :
A simplified method for manufacturing RNAi therapeutics for local administration,
International Journal of Pharmaceutics, Vol.564, 256-262, 2019.

(要約): RNA interference (RNAi) is one of the most promising strategies for cancer therapeutics. The successful translation of RNAi therapeutics to a clinic setting requires a delivery system that is efficient and simple to upscale. In this study, we devised a simple industrial method to manufacture lipoplex, which includes short hairpin RNA against the expression of thymidylate synthase (TS shRNA) - a key molecule for DNA biosynthesis. An aqueous solution of TS shRNA was gently mixed with either a precursor of cationic liposome (Presome DF-1) or a cationic lipid mixture in an o/w emulsion. This solution was subsequently lyophilized under optimal conditions to obtain either FD-lipoplex-1 or FD-lipoplex-2, respectively. With this method, a lipoplex in activated form was obtained via a simple "one-step" hydration with saline. Both forms of FD-lipoplex showed physicochemical properties comparable to those of conventional lipoplex. FD-lipoplexes stably retained TS shRNA within their formulations in the presence of tumor ascites fluid. Intraperitoneal treatment with either FD-lipoplex-1 or FD-lipoplex-2 provided a therapeutic level of efficacy comparable to that of conventional lipoplex in the treatment of a peritoneal disseminated gastric cancer mouse model. Collectively, established freeze-drying-based methods for RNAi-therapeutic preparation could realistically be used in a clinical setting for the treatment of patients with peritoneal disseminated cancer.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2019.04.054
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31015002; ● Summary page in Scopus @ Elsevier: 2-s2.0-85064496754

(DOI: 10.1016/j.ijpharm.2019.04.054, PubMed: 31015002, Elsevier: Scopus) Yusuke Doi, Taro Shimizu, Yu Ishima and Tatsuhiro Ishida :
Long-term storage of PEGylated liposomal oxaliplatin with improved stability and long circulation times in vivo,
International Journal of Pharmaceutics, Vol.564, 237-243, 2019.

(要約): Liposomal anticancer drugs have been developed with improved clinical effects and reduced side effects. We have developed a PEGylated liposomal formulation of oxaliplatin that has anticancer effects in animal models of colorectal cancer with a favorable toxicity profile. To move this formulation into clinical development, a formulation that is stable during long term storage is needed, which has similar pharmacokinetics and therapeutic activity against solid tumors to the original formulation. In this study, we found that PEGylated liposomal oxaliplatin showed no changes in particle size after long term storage (12 months at 2-8 °C), but phospholipid degradation had occurred. Hence, the stored formulation had compromised membrane integrity, resulting in decreased in vivo circulation times of the liposomes. To improve the stability during long-term storage, a screening study to obtain an appropriate stabilizer was carried out. The buffer 2-morpholinoethansulfonic acid (MES) attenuated not only phospholipid degradation but also oxaliplatin degradation, unlike most other excipients. After 12 months storage at 2-8 °C in the presence of MES only slight degradation of phospholipids in PEGylated liposomal oxaliplatin occurred, resulting in similar in vivo pharmacokinetic profiles of the encapsulated oxaliplatin to the original formulation. Long term stability of PEGylated liposomal oxaliplatin was achieved by addition of MES, resulting in long circulation half-lives in vivo, a property which would be expected to lead to increased suppression of tumor growth and reduced side effects. Our formulation may now be suitable for clinical development.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2019.04.042
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31002935; ● Summary page in Scopus @ Elsevier: 2-s2.0-85064481198

(DOI: 10.1016/j.ijpharm.2019.04.042, PubMed: 31002935, Elsevier: Scopus) Haruka Kawahara, Naoki Miyashita, Kohki Tachibana, Yusuke Tsuda, Kyohei Morimoto, Kouhei Tsuji, Akira Shigenaga, Akira Otaka, Tatsuhiro Ishida and Keiichiro Okuhira :
A photo-activatable peptide mimicking functions of apolipoprotein A-I,
Biological & Pharmaceutical Bulletin, Vol.42, No.6, 1019-1024, 2019.

(要約): Apolipoprotein A-I (apoA-I) plays a critical role in high-density lipoprotein (HDL) biogenesis, function and structural dynamics. Peptides that mimic apoA-I have a short amphipathic α-helical structure that can functionally recapitulate many of the same biologic properties of full-length apoA-I in HDL. Hence, they might be expected to have clinical applications in the reduction of atherosclerosis. However, nonspecific cellular efflux of cholesterol induced by apoA-I mimetic peptides might cause side effects that are, as yet, unidentified. In this study, we developed a photo-activatable peptide, 2F*, which is an 18 amino acid peptide mimicking apoA-I bearing an internal photocleavable caging group that is designed to assume an α-helical structure in response to a light stimulus and trigger efflux of cholesterol from cells. Without light irradiation, 2F* peptide showed a low tendency for the formation of α-helices, and therefore did not associate with lipids and failed to induce efflux of cholesterol. In addition, 2F* did not cause hemolysis under our experimental condition. Mass spectrometry indicated that, after light exposure, the caging group detached from 2F* and it assumed the α-helical structure in the presence of lipids, and enhanced cholesterol efflux from cells. Photo-activatable peptides such as 2F* that control cholesterol efflux following light stimulus may be useful for future atherosclerosis-reducing therapies.
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b19-00114
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31155576; ● Summary page in Scopus @ Elsevier: 2-s2.0-85067107514

(DOI: 10.1248/bpb.b19-00114, PubMed: 31155576, Elsevier: Scopus) Mayumi Ikeda, Yu Ishima, VTG Chuang, Maki Sakai, Hiroki Osafune, Hidenori ANDO, Taro Shimizu, Keiichiro Okuhira, H Watanabe, T Maruyama, M Otagiri, T Akaike and Tatsuhiro Ishida :
Distribution of Polysulfide in Human Biological Fluids and Their. Association with Amylase and Sperm Activities,
Molecules, Vol.24, No.9, 1689, 2019.

(要約): Intracellular polysulfide could regulate the redox balance via its anti-oxidant activity. However, the existence of polysulfide in biological fluids still remains unknown. Recently, we developed a quantitative analytical method for polysulfide and discovered that polysulfide exists in plasma and responds to oxidative stress. In this study, we confirmed the presence of polysulfide in other biological fluids, such as semen and nasal discharge. The levels of polysulfide in these biological fluids from healthy volunteers ( = 9) with identical characteristics were compared. Additionally, the circadian rhythm of plasma polysulfide was also investigated. The polysulfide levels detected from nasal discharge and seminal fluid were approximately 400 and 600 μM, respectively. No correlation could be found between plasma polysulfide and the polysulfide levels of tear, saliva, and nasal discharge. On the other hand, seminal polysulfide was positively correlated with plasma polysulfide, and almost all polysulfide contained in semen was found in seminal fluid. Intriguingly, saliva and seminal polysulfide strongly correlated with salivary amylase and sperm activities, respectively. These results provide a foundation for scientific breakthroughs in various research areas like infertility and the digestive system process.
(徳島大学機関リポジトリ): ● Metadata: 115606
(出版サイトへのリンク): ● Publication site (DOI): 10.3390/molecules24091689
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31052207; ● Summary page in Scopus @ Elsevier: 2-s2.0-85065659717

(徳島大学機関リポジトリ: 115606, DOI: 10.3390/molecules24091689, PubMed: 31052207, Elsevier: Scopus) 関陽介, 植野美彦, 澤田麻衣子, 石田竜弘 :
入学者選抜の評価を支援する分散評価システムの開発と導入 ―薬学部AO入試における書類審査での活用事例から―,
大学入試研究ジャーナル, No.29, 217-222, 2019年.

(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1523669554920042240

(CiNii: 1523669554920042240) Yu Ishima, Kaori Watanabe, Victor T. G. Chuang, Iyo Takeda, Teruo Kuroda, Wakano Ogawa, Hiroshi Watanabe, Yasunori Iwao, Tatsuhiro Ishida, Masaki Otagiri and Toru Maruyama :
S-Nitrosated alpha-1-acid glycoprotein exhibits antibacterial activity against multidrug-resistant bacteria strains and synergistically enhances the effect of antibiotics,
FASEB BioAdvances, Vol.1, No.3, 137-150, 2019.

(徳島大学機関リポジトリ): ● Metadata: 116302
(出版サイトへのリンク): ● Publication site (DOI): 10.1096/fba.1018
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32123826; ● Search Scopus @ Elsevier (PMID): 32123826; ● Search Scopus @ Elsevier (DOI): 10.1096/fba.1018

(徳島大学機関リポジトリ: 116302, DOI: 10.1096/fba.1018, PubMed: 32123826) Taro Shimizu, Lila Selim Ahmed Ali Abu Amr, Mizuki Awata, Yukiyo Kubo, Yu Mima, Yosuke Hashimoto, Hidenori ANDO, Keiichiro Okuhira, Yu Ishima and Tatsuhiro Ishida :
A cell assay for detecting anti-PEG immune response against PEG-modified therapeutics,
Pharmaceutical Research, Vol.35, No.11, 223, 2018.

(要約): Immunogenicity of PEGylated proteins and nanomedicines represents a potential impediment against their development and use in clinical settings. The purpose of this study is to develop a method for detecting anti-PEG immunity of PEGylated proteins and/or nanomedicines using flow cytometry. The binding of fluorescence-labeled mPEG-modified liposomes to HIK-G11 cells, PEG-specific hybridoma cells, or spleen cells was evaluated by flow cytometry for detecting immunogenicity of PEGylated therapeutics. The fluorescence-labeled methoxy PEG (mPEG)-modified liposomes were efficiently bound to HIK-G11 cells. Such staining with fluorescence-labeled mPEG-modified liposomes was significantly inhibited in the presence of either non-labeled mPEG-modified liposomes or mPEG-modified ovalbumin (OVA) but not polyglycerol-modified liposomes. In addition, we found that mPEG-modified liposomes, highly immunogenic, caused proliferation of PEG-specific cells, while hydroxyl PEG-modified liposomes, less immunogenic, scarcely caused. Furthermore, after intravenous injection of mPEG-modified liposomes, the percentage of PEG-specific cells in the splenocytes, as determined by flow cytometry, corresponded well with the production level of anti-PEG antibodies, as determined by ELISA. PEG-specific B cell assay we introduced may become a useful method to detect an anti-PEG immune response against PEGylated therapeutics and clarify the mechanism for anti-PEG immune responses.
(出版サイトへのリンク): ● Publication site (DOI): 10.1007/s11095-018-2505-3
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 30280273; ● Summary page in Scopus @ Elsevier: 2-s2.0-85054175366

(DOI: 10.1007/s11095-018-2505-3, PubMed: 30280273, Elsevier: Scopus) Taro Shimizu, Lila Selim Ahmed Ali Abu Amr, Yoshino Kawaguchi, Yuna Shimazaki, Yu Mima, Yosuke Hashimoto, Keiichiro Okuhira, G Storm, Yu Ishima and Tatsuhiro Ishida :
A novel platform for cancer vaccines: Antigen-selective delivery to splenic marginal zone B cells via repeated injections of PEGylated liposomes,
The Journal of Immunology, Vol.201, No.10, 2969-2976, 2018.

(要約): Treating cancer with vaccines has been a challenge. In this study, we introduce a novel Ag delivery platform for cancer vaccines that delivers an encapsulated Ag to splenic marginal zone B (MZ-B) cells via the aid of a PEGylated liposome (PL) system. Splenic MZ-B cells have recently attracted interest as alternative APCs. In mice, preimmunization with empty (no Ag encapsulation) PLs triggered the efficient delivery of a subsequent dose of Ag-containing PLs, injected 3 d later, to the spleen compared with a single dose of Ag-containing PLs. In addition, immunization with empty PLs allowed three subsequent sequential injections of OVA-PLs to efficiently induce a CTL response against OVA-expressing murine thymoma (EG7-OVA) cells and resulted in in vivo growth inhibition of subsequently inoculated EG7-OVA cells. However, these sequential treatments require repeated immunizations to achieve their antitumor effect. Therefore, to improve the antitumor effect of our novel vaccine system, an adjuvant, -galactosylceramide (GC), was incorporated into the OVA-PLs (GC/OVA-PLs). As expected, the incorporation of GC reduced the required number of immunizations with OVA-PLs to the point that a single immunization treatment with empty PLs and an injection of GC/OVA-PL efficiently triggered a potent CTL induction, resulting in a rejection of the development and a suppression of the growth of tumors that had already developed s.c. Results of this study indicate that a novel Ag delivery platform that grants efficient Ag delivery to splenic MZ-B cells shows promise as a therapeutic modality for conquering tumor growth and/or progression.
(出版サイトへのリンク): ● Publication site (DOI): 10.4049/jimmunol.1701351
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 30333124; ● Search Scopus @ Elsevier (PMID): 30333124; ● Search Scopus @ Elsevier (DOI): 10.4049/jimmunol.1701351

(DOI: 10.4049/jimmunol.1701351, PubMed: 30333124) T Mészáros, G Kozma, Taro Shimizu, Kohga Miyahara, K Turjeman, Tatsuhiro Ishida, Y Barenholz, R Urbanics and J Szebeni :
Involvement of complement activation in the pulmonary vasoactivity of polystyrene nanoparticles in pigs: Unique surface properties underlying alternative pathway activation and instant opsonization,
International Journal of Nanomedicine, Vol.13, 6345-6357, 2018.

(要約): It has been proposed that many hypersensitivity reactions to nanopharmaceuticals represent complement (C)-activation-related pseudoallergy (CARPA), and that pigs provide a sensitive animal model to study the phenomenon. However, a recent study suggested that pulmonary hypertension, the pivotal symptom of porcine CARPA, is not mediated by C in cases of polystyrene nanoparticle (PS-NP)-induced reactions. To characterize PS-NPs and reexamine the contribution of CARPA to their pulmonary reactivity in pigs. C activation by 200, 500, and 750 nm (diameter) PS-NPs and their opsonization were measured in human and pig sera, respectively, and correlated with hemodynamic effects of the same NPs in pigs in vivo. Physicochemical characterization of PS-NPs included size, ζ-potential, cryo-transmission electron microscopy, and hydrophobicity analyses. C activation in human serum was measured by ELISA and opsonization of PS-NPs in pig serum by Western blot and flow cytometry. Pulmonary vasoactivity of PS-NPs was quantified in the porcine CARPA model. PS-NPs are monodisperse, highly hydrophobic spheres with strong negative surface charge. In human serum, they caused size-dependent, significant rises in C3a, Bb, and sC5b-9, but not C4d. Exposure to pig serum led within minutes to deposition of C5b-9 and opsonic iC3b on the NPs, and opsonic iC3b fragments (C3dg, C3d) also appeared in serum. PS-NPs caused major hemodynamic changes in pigs, primarily pulmonary hypertension, on the same time scale (minutes) as iC3b fragmentation and opsonization proceeded. There was significant correlation between C activation by different PS-NPs in human serum and pulmonary hypertension in pigs. PS-NPs have extreme surface properties with no relevance to clinically used nanomedicines. They can activate C via the alternative pathway, entailing instantaneous opsonization of NPs in pig serum. Therefore, rather than being solely C-independent reactivity, the mechanism of PS-NP-induced hypersensitivity in pigs may involve C activation. These data are consistent with the "double-hit" concept of nanoparticle-induced hypersensitivity reactions involving both CARPA and C-independent pseudoallergy.
(キーワード): Animals / Complement Activation / Complement C3b / Drug Hypersensitivity / Humans / Immunologic Factors / Liposomes / Male / Nanoparticles / Polystyrenes / Pulmonary Circulation / Surface Properties / Swine
(徳島大学機関リポジトリ): ● Metadata: 115154
(出版サイトへのリンク): ● Publication site (DOI): 10.2147/IJN.S161369
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 30349254; ● Search Scopus @ Elsevier (PMID): 30349254; ● Search Scopus @ Elsevier (DOI): 10.2147/IJN.S161369

(徳島大学機関リポジトリ: 115154, DOI: 10.2147/IJN.S161369, PubMed: 30349254) Emam Emam Abdallah Sherif, Hidenori ANDO, Lila Selim Ahmed Ali Abu Amr, Taro Shimizu, Keiichiro Okuhira, Yu Ishima, M Mahdy, F Ghazy, I Sagawa and Tatsuhiro Ishida :
Liposome co-incubation with cancer cells secreted exosomes (extracellular vesicles) with different proteins expressions and different uptake pathways,
Scientific Reports, Vol.8, No.1, 14493, 2018.

(要約): We recently showed that in vitro incubation of cells with liposomes of varying compositions can increase exosome secretion and increase the yield of harvested exosomes (extracellular vesicles, EVs). This might foster their potential therapeutic implementations. In the current study, we investigated the surface proteins and the uptake of the harvested exosomes (EVs) to see if the incubation of cells with liposomes would change the biological properties of these exosomes (EVs). Interestingly, exosomes (EVs) induced by solid cationic liposomes lacked some major exosome marker proteins such as CD9, flotillin-1, annexin-A2 and EGF, and subsequently had lower levels of cellular uptake upon re-incubation with donor cancer cells. However, exosomes (EVs) induced under normal condition and by fluid cationic liposomes, displayed the entire spectrum of proteins, and exhibited higher uptake by the donor cancer cells. Although endocytosis was the major uptake pathway of exosomes (EVs) by tumor cells, endocytosis could occur via more than one mechanism. Higher exosome uptake was observed in donor B16BL6 cells than in allogeneic C26 cells, indicating that donor cells might interact specifically with their exosomes (EVs) and avidly internalize them. Taken together, these results suggest a technique for controlling the characteristics of secreted exosomes (EVs) by incubating donor cancer cells with liposomes of varying physiochemical properties.
(徳島大学機関リポジトリ): ● Metadata: 114955
(出版サイトへのリンク): ● Publication site (DOI): 10.1038/s41598-018-32861-w
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 30262875; ● Summary page in Scopus @ Elsevier: 2-s2.0-85054056121

(徳島大学機関リポジトリ: 114955, DOI: 10.1038/s41598-018-32861-w, PubMed: 30262875, Elsevier: Scopus) Emam Emam Abdallah Sherif, Hidenori ANDO, Lila Selim Ahmed Ali Abu Amr, Shinya Kobayashi, Taro Shimizu, Keiichiro Okuhira, Yu Ishima and Tatsuhiro Ishida :
Doxorubicin expands in vivo secretion of circulating exosome in mice,
Biological & Pharmaceutical Bulletin, Vol.41, No.7, 1078-1083, 2018.

(要約): Modulation of tumor immunity is a known factor in the antitumor activity of many chemotherapeutic agents. Exosomes are extracellular nanometric vesicles that are released by almost all types of cells, which includes cancer cells. These vesicles play a crucial role in tumor immunity. Many in vitro studies have reproduced the aggressive secretion of exosomes following treatment with conventional anticancer drugs. Nevertheless, how chemotherapeutic agents including nanomedicines such as Doxil affect the in vivo secretion of exosomes is yet to be elucidated. In this study, the effect of intravenous injection of either free doxorubicin (DXR) or liposomal DXR formulation (Doxil) on exosome secretion was evaluated in BALB/c mice. Exosomes were isolated from serum by using an ExoQuick™ kit. Free DXR treatment markedly increased serum exosome levels in a post-injection time-dependent manner, while Doxil treatment did not. Exosomal size distribution and marker protein expressions (CD9, CD63, and TSG101) were studied. The physical/biological characteristics of treatment-induced exosomes were comparable to those of control mice. Interestingly, splenectomy significantly suppressed the copious exosomal secretions induced by free DXR. Collectively, our results indicate that conventional anticancer agents induce the secretion of circulating exosomes, presumably via stimulating immune cells of the spleen. As far as we know, this study represents the first report indicating that conventional chemotherapeutics may induce exosome secretion which might, in turn, contribute partly to the antitumor effect of chemotherapeutic agents.
(キーワード): Animals / Antibiotics, Antineoplastic / Doxorubicin / Exocytosis / Exosomes / Injections, Intravenous / Male / Mice / Mice, Inbred BALB C / Models, Animal / Polyethylene Glycols / Spleen
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b18-00202
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29962402; ● Summary page in Scopus @ Elsevier: 2-s2.0-85049360539

(DOI: 10.1248/bpb.b18-00202, PubMed: 29962402, Elsevier: Scopus) Taro Shimizu, Lila Selim Ahmed Ali Abu Amr, Risako Fujita, Mizuki Awata, Munehira Kawanishi, Yosuke Hashimoto, Keiichiro Okuhira, Yu Ishima and Tatsuhiro Ishida :
A hydroxyl PEG version of PEGylated liposomes and its impact on anti-PEG IgM induction and on the accelerated clearance of PEGylated liposomes,
European Journal of Pharmaceutics and Biopharmaceutics, Vol.127, 142-149, 2018.

(要約): Surface decoration of liposomes with polyethylene glycol (PEG), PEGylation, is recognized as a method to bestow liposomes with a prolonged circulation time following intravenous administration. However, many reports have emphasized that a first dose of PEGylated liposomes (PL) elicits an anti-PEG IgM antibody response that can trigger a rapid systemic clearance of a second dose of PL via a phenomenon that is referred to as "accelerated blood clearance (ABC)." Such a phenomenon is usually observed with PL that has been modified with methoxy-PEG. In the current study, we introduced various functional groups, methoxy (OCH), amino (NH), carboxyl (COOH), and hydroxyl (OH), at the chain ends of PEG to investigate the effect on anti-PEG IgM induction. Among different PEG-modified liposomes, hydroxyl PEG-modified liposomes (PL-OH) efficiently attenuated the anti-PEG IgM response in vitro. In addition, PL-OH was less recognizable by anti-PEG IgM compared with other PLs. These findings raised the possibility that PL-OH could attenuate/abrogate elicitation of the ABC phenomenon. Nonetheless, upon repeated intravenous injection, PL-OH triggered the enhanced clearance of a subsequently injected second dose. Furthermore, in vitro studies have demonstrated that, as a complement activator, PL-OH is stronger than PL-OCH and induces further complement activation in the presence of anti-PEG IgM, which was the predominant contributor to the rapid clearance of a second dose of PL-OH. Our results suggest that the screening of complement activation by polymer-modified products in tandem with anti-polymer antibody production should be a prerequisite in the development of polymers that might enhance the therapeutic efficacy of nanocarriers.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ejpb.2018.02.019
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29462689; ● Summary page in Scopus @ Elsevier: 2-s2.0-85042257067

(DOI: 10.1016/j.ejpb.2018.02.019, PubMed: 29462689, Elsevier: Scopus) Emam Emam Abdallah Sherif, Hidenori ANDO, Lila Selim Ahmed Ali Abu Amr, Taro Shimizu, Masami Ukawa, Keiichiro Okuhira, Yu Ishima, A M Mahdy, S F Ghazy and Tatsuhiro Ishida :
A novel strategy to increase the yield of exosomes (extracellular vesicles) for an expansion of basic research,
Biological & Pharmaceutical Bulletin, Vol.41, No.5, 733-742, 2018.

(要約): Exosomes are tiny extracellular vesicles that are usually harvested in small quantities. Such small yield has been an obstacle for the expansion of the basic research regarding exosome analysis and applications in drug delivery. To increase exosome yield, we attempted to stimulate tumor cells via the addition of liposomes in vitro. Neutral, cationic-bare or PEGylated liposomes were incubated with four different tumor cell lines. The stimulatory effect of liposomal formulations on exosome secretion and cellular uptake propensity of the collected exosome by mother cells or different cells was evaluated. Both neutral and cationic-bare liposomes enhanced exosome secretion in a dose-dependent manner. Fluid cationic liposomes provided the strongest stimulation. Surprisingly, the PEGylation of bare liposomes diminished exosome secretion. Exosomes harvested in the presence of fluid cationic liposomes showed increased cellular uptake, but solid cationic liposomes did not. Our findings indicate that the physicochemical properties of liposomes determine whether they will act as a stimulant or as a depressant on exosome secretion from tumor cells. Liposomal stimulation may be a useful strategy to increase exosome yield, although further preparation to increase the purity of exosomes may be needed. In addition, fine-tuning of the biological properties of induced exosomes could be achieved via controlling the physicochemical properties of the stimulant liposomes.
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b17-00919
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29709910; ● Summary page in Scopus @ Elsevier: 2-s2.0-85046668949

(DOI: 10.1248/bpb.b17-00919, PubMed: 29709910, Elsevier: Scopus) Yuki Minayoshi, Hitoshi Maeda, Hiroki Yanagisawa, Keisuke Hamasaki, Yuki Mizuta, Kento Nishida, Ryo Kinoshita, Yuki Enoki, Tadasi Imafuku, Giam Victor Tuan Chuang, Tomoaki Koga, Yukiko Fujiwara, Motohiro Takeya, Kayoko Sonoda, Tomohiro Wakayama, Kazuaki Taguchi, Yu Ishima, Tatsuhiro Ishida, Yasuko Iwakiri, Motohiko Tanaka, Yutaka Sasaki, Hiroshi Watanabe, Masako Otagiri and Toru Maruyama :
Development of Kupffer cell targeting type-I interferon for the treatment of hepatitis via inducing anti-inflammatory and immunomodulatory actions,
Drug Delivery, Vol.25, No.1, 1067-1077, 2018.

(要約): Because of its multifaceted anti-inflammatory and immunomodulatory effects, delivering type-I interferon to Kupffer cells has the potential to function as a novel type of therapy for the treatment of various types of hepatitis. We report herein on the preparation of a Kupffer cell targeting type-I interferon, an albumin-IFNα2b fusion protein that contains highly mannosylated N-linked oligosaccharide chains, Man-HSA(D494N)-IFNα2b, attached by combining albumin fusion technology and site-directed mutagenesis. The presence of this unique oligosaccharide permits the protein to be efficiently, rapidly and preferentially distributed to Kupffer cells. Likewise IFNα2b, Man-HSA(D494N)-IFNα2b caused a significant induction in the mRNA levels of IL-10, IL-1Ra, PD-L1 in RAW264.7 cells and mouse isolated Kupffer cells, and these inductions were largely inhibited by blocking the interferon receptor. These data indicate that Man-HSA(D494N)-IFNα2b retained the biological activities of type-I interferon. Man-HSA(D494N)-IFNα2b significantly inhibited liver injury in Concanavalin A (Con-A)-induced hepatitis model mice, and consequently improved their survival rate. Moreover, the post-administration of Man-HSA(D494N)-IFNα2b at 2 h after the Con-A challenge also exerted hepato-protective effects. In conclusion, this proof-of-concept study demonstrates the therapeutic effectiveness and utility of Kupffer cell targeting type-I interferon against hepatitis via its anti-inflammatory and immunomodulatory actions.
(キーワード): Animals / Anti-Inflammatory Agents / B7-H1 Antigen / Cell Line / Hepatitis / Humans / Immunologic Factors / Interferon Type I / Interferon-alpha / Interleukin 1 Receptor Antagonist Protein / Interleukin-10 / Kupffer Cells / Liver / Male / Mannose / Mice / Mice, Inbred C57BL / Mice, Inbred ICR / RAW 264.7 Cells / Recombinant Proteins / Serum Albumin
(徳島大学機関リポジトリ): ● Metadata: 115087
(出版サイトへのリンク): ● Publication site (DOI): 10.1080/10717544.2018.1464083
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29688069; ● Summary page in Scopus @ Elsevier: 2-s2.0-85053734891

(徳島大学機関リポジトリ: 115087, DOI: 10.1080/10717544.2018.1464083, PubMed: 29688069, Elsevier: Scopus) 田島健次, 小瀬亮太, 石田竜弘, 松島得雄 :
発酵ナノセルロース(NFBC)の大量生産とその医療応用,
月刊バイオインダストリー, Vol.35, No.4, 55-63, 2018年. M Ikeda, Yu Ishima, R Kinoshita, V Chuang, N Tasaka, N Matsuo, H Watanabe, Taro Shimizu, Tatsuhiro Ishida, M Otagiri and T Maruyama :
A Novel S-Sulfhydrated Human Serum Albumin Preparation Suppresses Melanin Synthesis,
Redox Biology, Vol.14, 354-360, 2018.

(徳島大学機関リポジトリ): ● Metadata: 115707
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.redox.2017.10.007
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29040960; ● Summary page in Scopus @ Elsevier: 2-s2.0-85042682163

(徳島大学機関リポジトリ: 115707, DOI: 10.1016/j.redox.2017.10.007, PubMed: 29040960, Elsevier: Scopus) Hidenori ANDO, Lila Selim Ahmed Ali Abu Amr, Masao Tanaka, Yusuke Doi, Yasuko Terada, Naoto Yagi, Taro Shimizu, Keiichiro Okuhira, Yu Ishima and Tatsuhiro Ishida :
Intratumoral visualization of oxaliplatin within a liposomal formulation using X-ray fluorescence spectrometry,
Molecular Pharmaceutics, Vol.15, No.2, 403-409, 2018.

(要約): Microsynchrotron radiation X-ray fluorescence spectrometry (-SR-XRF) is an X-ray procedure that utilizes synchrotron radiation as an excitation source. -SR-XRF is a rapid, nondestructive technique that allows mapping and quantification of metals and biologically important elements in cell or tissue samples. Generally, the intratumor distribution of nanocarrier-based therapeutics is assessed by tracing the distribution of a labeled nanocarrier within tumor tissue, rather than by tracing the encapsulated drug. Instead of targeting the delivery vehicle, we employed -SR-XRF to visualize the intratumoral microdistribution of oxaliplatin (l-OHP) encapsulated within PEGylated liposomes. Tumor-bearing mice were intravenously injected with either l-OHP-containing PEGylated liposomes (l-OHP liposomes) or free l-OHP. The intratumor distribution of l-OHP within tumor sections was determined by detecting the fluorescence of platinum atoms, which are the main elemental components of l-OHP. The l-OHP in the liposomal formulation was localized near the tumor vessels and accumulated in tumors at concentrations greater than those seen with the free form, which is consistent with the results of our previous study that focused on fluorescent labeling of PEGylated liposomes. In addition, repeated administration of l-OHP liposomes substantially enhanced the tumor accumulation and/or intratumor distribution of a subsequent dose of l-OHP liposomes, presumably via improvements in tumor vascular permeability, which is also consistent with our previous results. In conclusion, -SR-XRF imaging efficiently and directly traced the intratumor distribution of the active pharmaceutical ingredient l-OHP encapsulated in liposomes within tumor tissue. -SR-XRF imaging could be a powerful means for estimating tissue distribution and even predicting the pharmacological effect of nanocarrier-based anticancer metal compounds.
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.molpharmaceut.7b00762
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29287147; ● Summary page in Scopus @ Elsevier: 2-s2.0-85041697937

(DOI: 10.1021/acs.molpharmaceut.7b00762, PubMed: 29287147, Elsevier: Scopus) Hidenori ANDO, Lila Selim Ahmed Ali Abu Amr, Munehira Kawanishi, Taro Shimizu, Keiichiro Okuhira, Yu Ishima and Tatsuhiro Ishida :
Reactivity of IgM antibodies elicited by PEGylated liposomes or PEGylated lipoplexes against auto and foreign antigens,
Journal of Controlled Release, Vol.270, 114-119, 2018.

(要約): Polyethylene glycol (PEG) is an attractive tool for the development of nanoparticle-based cancer therapy since it endows nanoparticles with extended-circulation properties. Nevertheless, recent reports have revealed that intravenous injection of either PEGylated liposomes (SLs) or PEGylated lipoplex (PLpx) could elicit an anti-PEG immunoglobulin (IgM) response in a T cell-independent (TI) manner that would substantially compromise the in vivo fate of PEGylated products upon repeated administration. In the same context, viral or bacterial infections trigger the production of polyreactive IgM that binds both self and foreign antigens. The polyreactivity of IgM elicited by SLs or PLpx, to bacteria and other polymers, however, is yet to be elucidated. In this study, the polyreactivity of IgM elicited by SLs or PLpx was challenged against different bacteria (TI antigens) and against synthetic polymer composed of repetitive structures (PVP-360 or FITC-dextran). Results demonstrated that anti-PEG IgM elicited by either SLs or PLpx showed no reactivity to various bacteria examined, while the IgM showed remarkable reactivity to both PVP-360 and FITC-dextran. In addition, interestingly, anti-PEG IgM elicited by either SLs or PLpx showed no antinuclear antibody-like immune reactivity, and, therefore, treatment with either SLs or PLpx was not expected to exacerbate autoimmune diseases such as systemic lupus erythematosus. Collectively, our findings could provide information supporting the safety of PEGylated nanoparticle-based pharmaceutics, particularly in patients with autoimmune diseases.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2017.12.002
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29217175; ● Summary page in Scopus @ Elsevier: 2-s2.0-85037534004

(DOI: 10.1016/j.jconrel.2017.12.002, PubMed: 29217175, Elsevier: Scopus) Sheuli Afroz, Ayano Yagi, Kouki Fujikawa, M. Motiur Rahman, Katsuya Morito, Tatsuya Fukuta, Shiro Watanabe, Kazunori Toida, Emi Kiyokage, Taro Shimizu, Tatsuhiro Ishida, Kentaro Kogure, Akira Tokumura and Tamotsu Tanaka :
Lysophosphatidic acid in medicinal herbs enhances prostaglandin E2 and protects against indomethacin-induced gastric cell damage in vivo and in vitro,
Prostaglandins & Other Lipid Mediators, Vol.135, 36-44, 2018.

(要約): Lysophosphatidic acid (LPA) is a bioactive phospholipid that induces diverse biological responses. Recently, we found that LPA ameliorates NSAIDs-induced gastric ulcer in mice. Here, we quantified LPA in 21 medicinal herbs used for treatment of gastrointestinal (GI) disorders. We found that half of them contained LPA at relatively high levels (40-240 μg/g) compared to soybean seed powder (4.6 μg/g), which we previously identified as an LPA-rich food. The LPA in peony (Paeonia lactiflora) root powder is highly concentrated in the lipid fraction that ameliorates indomethacin-induced gastric ulcer in mice. Synthetic 18:1 LPA, peony root LPA and peony root lipid enhanced prostaglandin E production in a gastric cancer cell line, MKN74 cells that express LPA abundantly. These materials also prevented indomethacin-induced cell death and stimulated the proliferation of MKN74 cells. We found that LPA was present in stomach fluids at 2.4 μM, which is an effective LPA concentration for inducing a cellular response in vitro. These results indicated that LPA is one of the active components of medicinal herbs for the treatment of GI disorder and that orally administered LPA-rich herbs may augment the protective actions of endogenous LPA on gastric mucosa.
(徳島大学機関リポジトリ): ● Metadata: 112025
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.prostaglandins.2018.01.003
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29462674; ● Summary page in Scopus @ Elsevier: 2-s2.0-85042401633

(徳島大学機関リポジトリ: 112025, DOI: 10.1016/j.prostaglandins.2018.01.003, PubMed: 29462674, Elsevier: Scopus) K Tanaka, M Shimoda, V Chuang, K Nishida, M Kawahara, Tatsuhiro Ishida, M Otagiri, T Maruyama and Yu Ishima :
Thioredoxin-Albumin Fusion Protein Prevents Copper enhanced Zinc-induced Neurotoxicity via Its Antioxidative activity,
International Journal of Pharmaceutics, Vol.535, No.1-2, 140-147, 2018.

(要約): Zinc (Zn) is a co-factor for a vast number of enzymes, and functions as a regulator for immune mechanism and protein synthesis. However, excessive Zn release induced in pathological situations such as stroke or transient global ischemia is toxic. Previously, we demonstrated that the interaction of Zn and copper (Cu) is involved in the pathogenesis of Alzheimer's disease and vascular dementia. Furthermore, oxidative stress has been shown to play a significant role in the pathogenesis of various metal ions induced neuronal death. Thioredoxin-Albumin fusion (HSA-Trx) is a derivative of thioredoxin (Trx), an antioxidative protein, with improved plasma retention and stability of Trx. In this study, we examined the effect of HSA-Trx on Cu/Zn-induced neurotoxicity. Firstly, HSA-Trx was found to clearly suppress Cu/Zn-induced neuronal cell death in mouse hypothalamic neuronal cells (GT1-7 cells). Moreover, HSA-Trx markedly suppressed Cu/Zn-induced ROS production and the expression of oxidative stress related genes, such as heme oxygenase-1. In contrast, HSA-Trx did not affect the intracellular levels of both Cu and Zn after Cu/Zn treatment. Finally, HSA-Trx was found to significantly suppress endoplasmic reticulum (ER) stress response induced by Cu/Zn treatment in a dose dependent manner. These results suggest that HSA-Trx counteracted Cu/Zn-induced neurotoxicity by suppressing the production of ROS via interfering the related gene expressions, in addition to the highly possible radical scavenging activity of the fusion protein. Based on these findings, HSA-Trx has great potential as a promising therapeutic agent for the treatment of refractory neurological diseases.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2017.11.012
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29122608; ● Summary page in Scopus @ Elsevier: 2-s2.0-85032951371

(DOI: 10.1016/j.ijpharm.2017.11.012, PubMed: 29122608, Elsevier: Scopus) 安藤英紀, 石田竜弘 :
放射光施設(SPring-8)における蛍光X線分析法を用いたオキサリプラチン腫瘍内分布解析,
薬剤学, Vol.78, No.1, 28-33, 2018年.

(出版サイトへのリンク): ● Publication site (DOI): 10.14843/jpstj.78.28
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1390001205741139840; ● Search Scopus @ Elsevier (DOI): 10.14843/jpstj.78.28

(DOI: 10.14843/jpstj.78.28, CiNii: 1390001205741139840) Kentaro Nishida, Misaki Kashiwagi, Shunsuke Shiba, Kiwamu Muroki, Akihiro Ohishi, Yusuke Doi, Hidenori ANDO, Tatsuhiro Ishida and Kazuki Nagasawa :
Liposomalization of oxaliplatin induces skin accumulation of it, but negligible skin toxicity,
Toxicology and Applied Pharmacology, Vol.337, 76-84, 2017.

(要約): Liposomalization causes alteration of the pharmacokinetics of encapsulated drugs, and allows delivery to tumor tissues through passive targeting via an enhanced permeation and retention (EPR) effect. PEGylated liposomal doxorubicin (Doxil(®), Lipo-DXR), a representative liposomal drug, is well-known to reduce cardiotoxicity and increase the anti-tumor activity of DXR, but to induce the hand-foot syndrome (HFS) as a result of skin DXR accumulation, which is one of its severe adverse effects. We have developed a new liposomal preparation of oxaliplatin (l-OHP), an important anti-tumor drug for treatment of colorectal cancer, using PEGylated liposomes (Lipo-l-OHP), and showed that Lipo-l-OHP exhibits increased anti-tumor activity in tumor-bearing mice compared to the original preparation of l-OHP. However, whether Lipo-l-OHP causes HFS-like skin toxicity similar to Lipo-DXR remains to be determined. Administration of Lipo-l-OHP promoted accumulation of platinum in rat hind paws, however, it caused negligible morphological and histological alterations on the plantar surface of the paws. Administration of DiI-labeled empty PEGylated liposomes gave almost the same distribution profile of dyes into the dermis of hind paws with DXR as in the case of Lipo-DXR. Treatment with Lipo-l-OHP, Lipo-DXR, DiI-labeled empty PEGylated liposomes or empty PEGylated liposomes caused migration of CD68(+) macrophages into the dermis of hind paws. These findings suggest that the skin toxicity on administration of liposomalized drugs is reflected in the proinflammatory characteristics of encapsulated drugs, and indicate that Lipo-l-OHP with a higher anti-cancer effect and no HFS may be an outstanding l-OHP preparation leading to an improved quality of life of cancer patients.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.taap.2017.10.006
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29054682; ● Summary page in Scopus @ Elsevier: 2-s2.0-85032786660

(DOI: 10.1016/j.taap.2017.10.006, PubMed: 29054682, Elsevier: Scopus) Mayumi Ikeda, Yu Ishima, Victor Chuang, Tsuyoshi Ikeda, Ryo Kinoshita, Hiroshi Watanabe, Tatsuhiro Ishida, Masaki Otagiri and Toru Maruyama :
Apoptosis induction of Poly-S-nitrosated human serum albumin in resistant solid tumor under hypoxia can be restored by phosphodiesterase 5 inhibition,
Nitric Oxide: Biology and Chemistry, Vol.69, 28-34, 2017.

(要約): Poly-S-nitrosated human serum albumin (Poly-SNO-HSA) delivered and accumulated nitric oxide (NO) in tumors and induces apoptosis. Tumor hypoxia is strongly associated with malignant progression and tumor resistance to therapy. In this study, we examined the cytotoxic effect of Poly-SNO-HSA under hypoxia on the murine colon 26 adenocarcinoma (C26) cells in vitro and in vivo. Under hypoxia, at about 4 times LD50 dose of Poly-SNO-HSA in vitro, the reactive oxygen species production was hindered but apoptotic cells were induced via cGMP pathway as the effect was suppressed by a soluble guanylate cyclase inhibitor, NS2028. The apoptosis induction effect of low dose Poly-SNO-HSA on C26 cells in vitro under hypoxia can be restored by a phosphodiesterase 5 (PDE5) inhibitor, vardenafil. In C26-bearing mice, Poly-SNO-HSA/vardenafil combination treatment significantly suppressed the tumor volume compared with Poly-SNO-HSA or vardenafil treatment alone. Furthermore, the core tumor tissues showed increased expression of caspase-3 than the non-core tissue. The expression of caspase-3 appeared to overlap with the hypoxic zone of tumor tissues. Similar results were also obtained when the experiments were repeated using Epimedium extract, a natural herbal supplement with PDE5 inhibition activity. In conclusion, Poly-SNO-HSA/PDE5 inhibitors combination therapy is a promising approach for enhancing the anticancer therapeutic effects of Poly-SNO-HSA against not only anti-cancer drug resistance but also hypoxic stress related solid tumor resistance.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.niox.2017.04.005
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28414103; ● Search Scopus @ Elsevier (PMID): 28414103; ● Search Scopus @ Elsevier (DOI): 10.1016/j.niox.2017.04.005

(DOI: 10.1016/j.niox.2017.04.005, PubMed: 28414103) Ryo Kinoshita, Yu Ishima, Victor T.G. Chuang, Hideaki Nakamura, Jun Fang, Hiroshi Watanabe, Taro Shimizu, Keiichiro Okuhira, Tatsuhiro Ishida, Hiroshi Maeda, Masaki Otagiri and Toru Maruyama :
Improved anticancer effects of albumin-bound paclitaxel nanoparticle via augmentation of EPR effect and albumin-protein interactions using S-Nitrosated Human Serum Albumin Dimer,
Biomaterials, Vol.140, 162-169, 2017.

(要約): In the latest trend of anticancer chemotherapy research, there were many macromolecular anticancer drugs developed based on enhanced permeability and retention (EPR) effect, such as albumin bound paclitaxel nanoparticle (nab- PTX, also called Abraxane). However, cancers with low vascular permeability posed a challenge for these EPR based therapeutic systems. Augmenting the intrinsic EPR effect with an intrinsic vascular modulator such as nitric oxide (NO) could be a promising strategy. S-nitrosated human serum albumin dimer (SNO-HSA Dimer) shown promising activity previously was evaluated for the synergistic effect when used as a pretreatment agent in nab-PTX therapy against various tumor models. In the high vascular permeability C26 murine colon cancer subcutaneous inoculation model, SNO-HSA Dimer enhanced tumor selectivity of nab-PTX, and attenuated myelosuppression. SNO-HSA Dimer also augmented the tumor growth inhibition of nab-PTX in low vascular permeability B16 murine melanoma subcutaneous inoculation model. Furthermore, nab-PTX therapy combined with SNO-HSA Dimer showed higher antitumor activity and improved survival rate of SUIT2 human pancreatic cancer orthotopic model. In conclusion, SNO-HSA Dimer could enhance the therapeutic effect of nab-PTX even in low vascular permeability or intractable pancreatic cancers. The possible underlying mechanisms of action of SNO-HSA Dimer were discussed.
(キーワード): Albumin-Bound Paclitaxel / Albumins / Animals / Antineoplastic Agents / Capillary Permeability / Cell Line, Tumor / Drug Synergism / Female / Humans / Male / Melanoma, Experimental / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / Neoplasms / Nitric Oxide / Nitroso Compounds / Paclitaxel / Pancreatic Neoplasms / Protein Multimerization / Serum Albumin, Human
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.biomaterials.2017.06.021
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28651144; ● Summary page in Scopus @ Elsevier: 2-s2.0-85021192830

(DOI: 10.1016/j.biomaterials.2017.06.021, PubMed: 28651144, Elsevier: Scopus) Lila Selim Ahmed Ali Abu Amr, Naoto Moriyoshi, Masakazu Fukushima, Cheng-long Huang, Hiromi Wada and Tatsuhiro Ishida :
Metronomic S-1 dosing and thymidylate synthase silencing have synergistic antitumor efficacy in a colorectal cancer xenograft model.,
Cancer Letters, Vol.400, 223-231, 2017.

(要約): Metronomic chemotherapy is currently considered an emerging therapeutic option in clinical oncology. S-1, an oral formulation of Tegafur (TF), a prodrug of 5-fluorouracil (5-FU), is designed to improve the antitumor activity of 5-FU in tandem with reducing its toxicity. Clinically, metronomic S-1 dosing has been approved for the standard first- and second-line treatment of metastatic or advanced stage of colorectal (CRC). However, expression of intratumor thymidylate synthase (TS), a significant gene in cellular proliferation, is associated with poor outcome to 5-FU-based chemotherapeutic regimens. In this study, therefore, we examined the effect of a combination of TS silencing by an RNA interfering molecule, chemically synthesized short hairpin RNA against TS (shTS), and 5-FU on the growth of human colorectal cancer cell (DLD-1) both in vitro and in vivo. The combined treatment of both shTS with 5-FU substantially inhibited cell proliferation in vitro. For in vivo treatments, the combined treatment of metronomic S-1 dosing with intravenously injected polyethylene glycol (PEG)-coated shTS-lipoplex significantly suppressed tumor growth, compared to a single treatment of either S-1 or PEG-coated shTS-lipoplex. In addition, the combined treatment increased the proportion of apoptotic cells in the DLD-1 tumor tissue. Our results suggest that metronomic S-1 dosing combined with TS silencing might represent an emerging therapeutic strategy for the treatment of patients with advanced CRC.
(キーワード): Administration, Metronomic / Animals / Antimetabolites, Antineoplastic / Apoptosis / Cell Line, Tumor / Cell Proliferation / Colorectal Neoplasms / Drug Combinations / Humans / Male / Mice, Inbred BALB C / Mice, Nude / Oxonic Acid / RNA Interference / RNAi Therapeutics / Tegafur / Thymidylate Synthase / Time Factors / Transfection / Tumor Burden / Xenograft Model Antitumor Assays
(徳島大学機関リポジトリ): ● Metadata: 115035
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.canlet.2016.11.005
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 27838412; ● Summary page in Scopus @ Elsevier: 2-s2.0-85007010070

(徳島大学機関リポジトリ: 115035, DOI: 10.1016/j.canlet.2016.11.005, PubMed: 27838412, Elsevier: Scopus) Taro Shimizu, Lila Selim Ahmed Ali Abu Amr, Miho Nishio, Yusuke Doi, Hidenori ANDO, Masami Ukawa, Yu Ishima and Tatsuhiro Ishida :
Modulation of antitumor immunity contributes to the enhanced therapeutic efficacy of liposomal oxaliplatin in mouse model,
Cancer Science, Vol.108, No.9, 1864-1869, 2017.

(要約): Immune modulation of the tumor microenvironment has been reported to participate in the therapeutic efficacy of many chemotherapeutic agents. Recently, we reported that liposomal encapsulation of oxaliplatin (l-OHP) within PEGylated liposomes conferred a superior antitumor efficacy to free l-OHP in murine colorectal carcinoma-bearing mice through permitting preferential accumulation of the encapsulated drug within tumor tissue. However, the contribution of the immune-modulatory properties of liposomal l-OHP and/or free l-OHP to the overall antitumor efficacy was not elucidated. In the present study, therefore, we investigated the effect of liposomal encapsulation of l-OHP within PEGylated liposomes on the antitumor immunity in both immunocompetent and immunodeficient mice. Liposomal l-OHP significantly suppressed the growth of tumors implanted in immunocompetent mice, but not in immunodeficient mice. In immunocompetent mice, liposomal l-OHP increased the tumor MHC-1 level and preserved antitumor immunity through decreasing the number of immune suppressor cells, including regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, which collectively suppress CD8(+) T cell-mediated tumor cells killing. In contrast, free l-OHP ruined antitumor immunity. These results suggest that the antitumor efficacy of liposomal l-OHP is attributed, on the one hand, to its immunomodulatory effect on tumor immune microenvironment that is superior to that of free l-OHP, and on the other hand, to its direct cytotoxic effect on tumor cells.
(徳島大学機関リポジトリ): ● Metadata: 112372
(出版サイトへのリンク): ● Publication site (DOI): 10.1111/cas.13305
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28643902; ● Search Scopus @ Elsevier (PMID): 28643902; ● Search Scopus @ Elsevier (DOI): 10.1111/cas.13305

(徳島大学機関リポジトリ: 112372, DOI: 10.1111/cas.13305, PubMed: 28643902) Alaaeldin Eman, Lila Selim Ahmed Ali Abu Amr, Hidenori ANDO, M Fukushima, C Huang, H Wada, H.A Sarhan, K.A Khaled and Tatsuhiro Ishida :
Co-administration of liposomal l-OHP and PEGylated TS shRNA-lipoplex: A novel approach to enhance anti-tumor efficacy and reduce the immunogenic response to RNAi molecules,
Journal of Controlled Release, Vol.255, 210-217, 2017.

(要約): Many therapeutic strategies have been applied in efforts to conquer the development and/or progression of cancer. The combination of chemotherapy and an RNAi-based approach has proven to be an efficient anticancer therapy. However, the feasibility of such a therapeutic strategy has been substantially restricted either by the failure to achieve the efficient delivery of RNAi molecules to tumor tissue or by the immunostimulatory response triggered by RNAi molecules. In this study, therefore, we intended to investigate the efficacy of using liposomal oxaliplatin (liposomal l-OHP) to guarantee the efficient delivery of RNAi molecules, namely shRNA against thymidylate synthase (TS shRNA) complexed with cationic liposome (TS shRNA-lipoplex), to solid tumors, and to suppress the immunostimulatory effect of RNAi molecules, TS shRNA, following intravenous administration. Herein, we describe how liposomal l-OHP enhanced the intra-tumor accumulation of TS shRNA-lipoplex and significantly reduced the immunostimulatory response triggered by TS shRNA. Consequently, such enhanced accumulation of TS shRNA-lipoplex along with the cytotoxic effect of liposomal l-OHP led to a remarkable tumor growth suppression (compared to mono-therapy) following systemic administration. Our results, therefore, may have important implications for the provision of a safer and more applicable combination therapy of RNAi molecules and anti-cancer agents that can produce a more reliable anti-tumor effect.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2017.04.040
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28461099; ● Search Scopus @ Elsevier (PMID): 28461099; ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2017.04.040

(DOI: 10.1016/j.jconrel.2017.04.040, PubMed: 28461099) Mayumi Ikeda, Yu Ishima, Akitomo Shibata, Victor T.G. Chuang, Tomohiro Sawa, Hideshi Ihara, Hiroshi Watanabe, Ming Xian, Yuya Ouchi, Taro Shimizu, Hidenori ANDO, Masami Ukawa, Tatsuhiro Ishida, T Akaike, M Otagiri and T Maruyama :
Quantitative determination of polysulfide in albumins, plasma proteins and biological fluid samples using a novel combined assays approach,
Analytica Chimica Acta, Vol.969, 18-25, 2017.

(要約): Hydrogen sulfide (H2S) signaling involves polysulfide (RSSnSR') formation on various proteins. However, the current lack of sensitive polysulfide detection assays poses methodological challenges for understanding sulfane sulfur homeostasis and signaling. We developed a novel combined assay by modifying Sulfide Antioxidant Buffer (SAOB) to produce an "Elimination Method of Sulfide from Polysulfide" (EMSP) treatment solution that liberates sulfide, followed with methylene blue (MB) sulfide detection assay. The combined EMSP-MB sulfide detection assay performed on low molecular weight sulfur species showed that sulfide was produced from trisulfide compounds such as glutathione trisulfide and diallyl trisulfide, but not from the thiol compounds such as cysteine, cystine and glutathione. In the case of plasma proteins, this novel combined detection assay revealed that approximately 14.7, 1.7, 3.9, 3.7 sulfide mol/mol released from human serum albumin, 1-anti-trypsin, 1-acid glycoprotein and ovalbumin, respectively, suggesting that serum albumin is a major pool of polysulfide in human blood circulation. Taken together with the results of albumins of different species, the liberated sulfide has a good correlation with cysteine instead of methionine, indicating the site of incorporation of polysulfide is cysteine. With this novel sulfide detention assay, approximately 8,000, 120 and 1100 M of polysulfide concentrations was quantitated in human healthy plasma, saliva and tear, respectively. Our promising polysulfide specific detection assay can be a very important tool because quantitative determination of polysulfide sheds light on the functional consequence of protein-bound cysteine polysulfide and expands the research area of reactive oxygen to reactive polysulfide species.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.aca.2017.03.027
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28411626; ● Summary page in Scopus @ Elsevier: 2-s2.0-85017155399

(DOI: 10.1016/j.aca.2017.03.027, PubMed: 28411626, Elsevier: Scopus) Takakuni Matsuda, Shogo Hiraoka, Hiroki Urashima, Ako Ogura and Tatsuhiro Ishida :
Preparation of an ultrafine rebamipide ophthalmic suspension with high transparency,
Biological & Pharmaceutical Bulletin, Vol.40, No.5, 665-674, 2017.

(要約): A 2% commercially available, milky-white, rebamipide micro-particle suspension is used to treat dry eyes, and it causes short-term blurring of the patient's vision. In the current study, to improve the transparency of a rebamipide suspension, we attempted to obtain a clear rebamipide suspension by transforming the rebamipide particles to an ultrafine state. In the initial few efforts, various rebamipide suspensions were prepared using a neutralizing crystallization method with additives, but the suspensions retained their opaque quality. However, as a consequence of several critical improvements in the neutralizing crystallization methods such as selection of additives for crystallization, process parameters during crystallization, the dispersion method, and dialysis, we obtained an ultrafine rebamipide suspension (2%) that was highly transparent (transmittance at 640 nm: 59%). The particle size and transparency demonstrated the fewest level of changes at 25°C after 3 years, compared to initial levels. During that period, no obvious particle sedimentation was observed. The administration of this ultrafine rebamipide suspension (2%) increased the conjunctival mucin, which was comparable to the commercially available micro-particle suspension (2%). The corneal and conjunctival concentration of rebamipide following ocular administration of the ultrafine suspension was slightly higher than that of the micro-particle suspension. The ultrafine rebamipide suspension (eye-drop formulation) with a highly transparent ophthalmic clearness should improve a patient's QOL by preventing even a shortened period of blurred vision.
(キーワード): Administration, Ophthalmic / Alanine / Animals / Anti-Ulcer Agents / Conjunctiva / 角膜 (cornea) / 結晶化 (crystallization) / 透析 (dialysis) / Male / Mucins / Ophthalmic Solutions / Particle Size / Quinolones / Rabbits / Suspensions / X線回折 (X-ray diffraction)
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b16-00962
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28458352; ● Summary page in Scopus @ Elsevier: 2-s2.0-85019212162

(DOI: 10.1248/bpb.b16-00962, PubMed: 28458352, Elsevier: Scopus) Yu Mima, Lila Selim Ahmed Ali Abu Amr, Taro Shimizu, Masami Ukawa, Hidenori ANDO, Yasuko Kurata and Tatsuhiro Ishida :
Ganglioside inserted into PEGylated liposome attenuates anti-PEG immunity,
Journal of Controlled Release, Vol.250, 20-26, 2017.

(要約): Despite the clinical introduction of a vast number of polyethylene glycol (PEG)-conjugated therapeutics, conjugated PEG is also known for an unfortunate inclination toward immunogenicity. Immunogenicity of PEG, manifested by the robust production of anti-PEG IgM, is known to compromise the therapeutic efficacy and/or reduce the tolerance of PEGylated therapeutics. In the present study, we inserted ganglioside into the membrane of PEGylated liposome (PL) to prepare ganglioside-modified PEGylated liposomes (G-PL), and investigated its efficacy in attenuating the anti-PEG IgM response against PL. A single intravenous injection of G-PL significantly attenuated the anti-PEG IgM production, compared with that of naïve PL. In addition, pretreatment with G-PL substantially alleviated the anti-PEG IgM response elicited by a subsequent dose of PL, presumably via inducing B cell tolerance, and as a consequence, this modification abrogated/attenuated the incidence of the rapid clearance of subsequently administrated PL. These results indicate that incorporating gangliosides in PEGylated liposome membrane not only prevents the immunogenicity of PEG but also induces the tolerance of B cells to subsequent doses of the immunogenic PL. Consequently, liposomal membrane modification with ganglioside might represent a promising approach to attenuating the immunogenicity of PEGylated liposomes while preserving their therapeutic efficacy, particularly upon repeated administration.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2017.01.040
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28179196; ● Summary page in Scopus @ Elsevier: 2-s2.0-85011965687

(DOI: 10.1016/j.jconrel.2017.01.040, PubMed: 28179196, Elsevier: Scopus) Yusuke Doi, Lila Selim Ahmed Ali Abu Amr, Haruna Matsumoto, Tomoko Okada, Taro Shimizu and Tatsuhiro Ishida :
Improvement of intratumor microdistribution of PEGylated liposome via tumor priming by metronomic S-1 dosing,
International Journal of Nanomedicine, Vol.11, 5573-5582, 2016.

(要約): The efficient delivery of nanocarrier-based cancer therapeutics into tumor tissue is problematic. Structural abnormalities, tumor vasculature heterogeneity, and elevated intratumor pressure impose barriers against the preferential accumulation of nanocarrier-based cancer therapeutics within tumor tissues and, consequently, compromise their therapeutic efficacy. Recently, we have reported that metronomic S-1, orally available tegafur formulation, dosing synergistically augmented the therapeutic efficacy of oxaliplatin (l-OHP)-containing PEGylated liposome without increasing the toxicity in animal model. However, the exact mechanism behind such synergistic effect was not fully elucidated. In this study, therefore, we tried to shed the light on the contributions of metronomic S-1 dosing to the enhanced accumulation and/or spatial distribution of PEGylated liposome within tumor tissue. Tumor priming with metronomic S-1 treatment induced a potent apoptotic response against both angiogenic endothelial cells and tumor cells adjacent to tumor blood vessels, resulting in enhanced tumor blood flow via transient normalization of tumor vasculature, along with alleviation of intratumor pressure. Such a change in the tumor microenvironment imparted by S-1 treatment allows efficient delivery of PEGylated liposome to tumor tissue and permits their deep penetration/distribution into the tumor mass. Such a priming effect of S-1 dosing can be exploited as a promising strategy to enhance the therapeutic efficacy of nanocarrier-based cancer therapeutics suffering from inadequate/heterogeneous delivery to tumor tissues.
(キーワード): Animals / Apoptosis / Cell Line, Tumor / Chemistry, Pharmaceutical / Drug Carriers / Drug Combinations / Drug Delivery Systems / Electron Spin Resonance Spectroscopy / Humans / Liposomes / Male / Mice / Mice, Inbred BALB C / Nanomedicine / Organoplatinum Compounds / Oxonic Acid / Perfusion / Polyethylene Glycols / Pressure / Tegafur / Tissue Distribution / Tumor Microenvironment
(徳島大学機関リポジトリ): ● Metadata: 115155
(出版サイトへのリンク): ● Publication site (DOI): 10.2147/IJN.S119069
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 27822036; ● Search Scopus @ Elsevier (PMID): 27822036; ● Search Scopus @ Elsevier (DOI): 10.2147/IJN.S119069

(徳島大学機関リポジトリ: 115155, DOI: 10.2147/IJN.S119069, PubMed: 27822036) Akitomo Shibata, Yu Ishima, Mayumi Ikeda, Hirokazu Sato, Tadashi Imafuku, Victor T. G. Chuang, Yuya Ouchi, Takaya Abe, Hiroshi Watanabe, Tatsuhiro Ishida, Masaki Otagiri and Toru Maruyama :
Human serum albumin hydropersulfide is a potent reactive oxygen species scavenger in oxidative stress conditions such as chronic kidney disease,
Biochemical and Biophysical Research Communications, Vol.479, No.3, 578-583, 2016.

(要約): Recently, hydropersulfide (RSSH) was found to exist in mammalian tissues and fluids. Cysteine hydropersulfide can be found in free cysteine residues as well as in proteins, and it has potent antioxidative activity. Human serum albumin (HSA) is the most abundant protein in mammalian serum. HSA possesses a free thiol group in Cys-34 that could be a site for hydropersulfide formation. HSA hydropersulfide of high purity as a positive control was prepared by treatment of HSA with Na2S. The presence of HSA hydropersulfide was confirmed by spectroscopy and ESI-TOFMS analysis where molecular weights of HSA hydropersulfide by increments of approximately 32 Da (Sulfur atom) were detected. The fluorescent probe results showed that Alexa Fluor 680 conjugated maleimide (Red-Mal) was a suitable assay and bromotrimethylammoniumbimane bromide appeared to be a selective reagent for hydropersulfide. The effect of oxidative stress related disease on the existence of albumin hydropersulfides was examined in rat 5/6 nephrectomy model of chronic kidney disease (CKD). Interestingly, the level of hydropersulfides in rat 5/6 nephrectomy model serum was decreased by a uremic toxin that increases oxidative stress in rat 5/6 nephrectomy model. Furthermore, we demonstrated that the levels of HSA hydropersulfide in human subjects were reduced in CKD but restored by hemodialysis using Red-Mal assay. We conclude that HSA hydropersulfide could potentially play an important role in biological anti-oxidative defense, and it is a promising diagnostic and therapeutic marker of oxidative diseases.
(キーワード): Adult / Aged / Aged, 80 and over / Animals / Female / Fluorescent Dyes / Free Radical Scavengers / Humans / Male / Middle Aged / 分子量 (molecular weight) / Oxidants / 酸化ストレス (oxidative stress) / Rats / Rats, Wistar / 活性酸素 (reactive oxygen species) / Renal Dialysis / Renal Insufficiency, Chronic / Serum Albumin / Spectrometry, Mass, Electrospray Ionization / Sulfhydryl Compounds / Sulfides
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.bbrc.2016.09.113
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 27666483; ● Summary page in Scopus @ Elsevier: 2-s2.0-84989831563

(DOI: 10.1016/j.bbrc.2016.09.113, PubMed: 27666483, Elsevier: Scopus) Lila Selim Ahmed Ali Abu Amr, M. Fukushima, C. Huang, H Wada and Tatsuhiro Ishida :
Systemically administered RNAi molecule sensitizes malignant pleural mesothelioma cells to pemetrexed therapy,
Molecular Pharmaceutics, Vol.13, No.11, 3955-3963, 2016.

(要約): Pemetrexed (PMX) is a key drug for the management of malignant pleural mesothelioma (MPM). However, its therapeutic efficacy is cruelly restricted in many clinical settings by the overexpression of thymidylate synthase (TS) gene. Recently, we emphasized the efficacy of locally administered shRNA designed against TS gene in enhancing the cytotoxic effect of PMX against orthotopically implanted MPM cells in tumor xenograft tumor model. Herein, we explored the efficiency of systemic, rather than local, delivery of TS RNAi molecule in sensitizing MPM cells to the cytotoxic effect of PMX. We here designed a PEG-coated TS shRNA-lipoplex (PEG-coated TS shRNA-lipoplex) for systemic injection. PEG modification efficiently delivered TS shRNA in the lipoplex to tumor tissue following intravenous administration as indicated by a significant suppression of TS expression level in tumor tissue. In addition, the combined treatment of PMX with systemic injection of PEG-coated TS shRNA-lipoplex exerted a potent antitumor activity in a s.c. xenograft tumor model, compared to a single treatment with either PMX or PEG-coated TS shRNA-lipoplex. Metastasis, or the spread, of mesothelioma substantially dedicates the effectiveness of treatment options. The systemic, in addition to local, delivery of tumor targeted anti-TS RNAi system we propose in this study might be an effective option to extend the clinical utility of PMX in treating malignant mesothelioma.
(徳島大学機関リポジトリ): ● Metadata: 115599
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.molpharmaceut.6b00728
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 27740765; ● Search Scopus @ Elsevier (PMID): 27740765; ● Search Scopus @ Elsevier (DOI): 10.1021/acs.molpharmaceut.6b00728

(徳島大学機関リポジトリ: 115599, DOI: 10.1021/acs.molpharmaceut.6b00728, PubMed: 27740765) Takuma Takayama, Masami Ukawa, Yuki Kanazawa, Hidenori ANDO, Taro Shimizu and Tatsuhiro Ishida :
Hydrodynamic tail vein injection as a simple tool for yielding extended transgene expression in solid tumors.,
Biological & Pharmaceutical Bulletin, Vol.39, No.9, 1555-1558, 2016.

(要約): Hydrodynamic tail vein injection was considered an in vivo transfection method that yields a higher level of gene expression mainly in the liver. This method has been applied to cancer gene therapy targeting both hepatic and non-hepatic cancers. However, intratumor transgene expression in non-hepatic tumors has not been well studied. In this study, we showed an extended transgene expression of -galactosidase (LacZ), a nonsecretory protein, in a subcutaneously implanted murine solid tumor following the hydrodynamic injection of plasmid DNA (LacZ pDNA). Our result may indicate that the hydrodynamic injection method is a powerful tool that can be used to gain transgene expression not only in the liver but also in solid tumors.
(キーワード): Animals / Cell Line, Tumor / DNA / Gene Expression / Gene Transfer Techniques / Genetic Therapy / Injections, Intravenous / Liver / Male / Mice / Mice, Inbred BALB C / Neoplasms / Plasmids / Tail / Transgenes / beta-Galactosidase
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b16-00283
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 27582335; ● Summary page in Scopus @ Elsevier: 2-s2.0-84984698994

(DOI: 10.1248/bpb.b16-00283, PubMed: 27582335, Elsevier: Scopus) Y Miwa, H Hamamoto and Tatsuhiro Ishida :
Lidocaine self-sacrificially improves the skin permeation of the acidic and poorly water-soluble drug etodolac via its transformation into an ionic liquid,
European Journal of Pharmaceutics and Biopharmaceutics, Vol.102, 92-100, 2016.

(要約): Poor transdermal penetration of active pharmaceutical ingredients (APIs) impairs both bioavailability and therapeutic benefits and is a major challenge in the development of transdermal drug delivery systems. Here, we transformed a poorly water-soluble drug, etodolac, into an ionic liquid in order to improve its hydrophobicity, hydrophilicity and skin permeability. The ionic liquid was prepared by mixing etodolac with lidocaine (1:1, mol/mol). Both the free drug and the transformed ionic liquid were characterized by differential scanning colorimetry (DSC), infrared spectroscopy (IR), and saturation concentration measurements. In addition, in vitro skin-permeation testing was carried out via an ionic liquid-containing patch (Etoreat patch). The lidocaine and etodolac in ionic liquid form led to a relatively lower melting point than either lidocaine or etodolac alone, and this improved the lipophilicity/hydrophilicity of etodolac. In vitro skin-permeation testing demonstrated that the Etoreat patch significantly increased the skin permeation of etodolac (9.3-fold) compared with an etodolac alone patch, although an Etoreat patch did not increase the skin permeation of lidocaine, which was consistent with the results when using a lidocaine alone patch. Lidocaine appeared to self-sacrificially improve the skin permeation of etodolac via its transformation into an ionic liquid. The data suggest that ionic liquids composed of approved drugs may substantially expand the formulation preparation method to meet the challenges of drugs which are characterized by poor rates of transdermal absorption.
(徳島大学機関リポジトリ): ● Metadata: 115101
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ejpb.2016.03.003
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 26945484; ● Search Scopus @ Elsevier (PMID): 26945484; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ejpb.2016.03.003

(徳島大学機関リポジトリ: 115101, DOI: 10.1016/j.ejpb.2016.03.003, PubMed: 26945484) Lila Selim Ahmed Ali Abu Amr, Chihiro Katoh, M Fukushima, C Huang, H Wada and Tatsuhiro Ishida :
Downregulation of thymidylate synthase by RNAi molecules enhances the antitumor effect of pemetrexed in an orthotopic malignant mesothelioma xenograft mouse model,
International Journal of Oncology, Vol.48, No.4, 1399-1407, 2016.

(要約): Malignant pleural mesothelioma (MPM) is an incurable cancer with an increasing incidence. Currently, pemetrexed (PMX)-based chemotherapy is the mainstay of chemotherapy for MPM, however, the outcome of PMX-based chemotherapy in patients with MPM is dismal. RNA interference (RNAi) technology has been considered as an effective tool to substantially enhance the therapeutic efficacy of chemotherapeutic agents in many preclinical and clinical settings. In this study, therefore, we investigated whether non-viral anti-thymidylate synthase RNAi embedded liposome (TS shRNA lipoplex) would effectively guide the downregulation of TS in human malignant mesothelioma MSTO-211H cells. Consequently, it enhanced the antitumor effect of PMX both in vitro and in vivo. TS shRNA effectively enhanced the in vitro cell growth inhibition upon treatment with PMX via downregulating TS expression in the MSTO-211H cell line. In in vivo orthotopic tumor model, the combined treatment of PMX and TS shRNA lipoplex efficiently combated the progression of orthotopic thoracic tumors and as a result prolonged mouse survival, compared to each single treatment. Our findings emphasize the pivotal relevance of RNAi as an effective tool for increasing the therapeutic efficacy of PMX, a cornerstone in the treatment regimens of MPM, and thereby, raising the possibility for the development of a novel therapeutic strategy, combination therapy of TS-shRNA and PMX, that can surpass many of the currently applied, but less effective, therapeutic regimens against lethal MPM.
(出版サイトへのリンク): ● Publication site (DOI): 10.3892/ijo.2016.3367
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 26847426; ● Search Scopus @ Elsevier (PMID): 26847426; ● Search Scopus @ Elsevier (DOI): 10.3892/ijo.2016.3367

(DOI: 10.3892/ijo.2016.3367, PubMed: 26847426) Masami Ukawa, Yukako Fujiwara, Hidenori ANDO, Taro Shimizu and Tatsuhiro Ishida :
Hepatic tumor metastases cause enhanced PEGylated liposome uptake by Kupffer cells,
Biological & Pharmaceutical Bulletin, Vol.39, No.2, 215-220, 2016.

(要約): Kupffer cells in livers bearing tumor metastases were found to have promoted tumor invasion and exacerbated the metastasis. This implies that the function of Kupffer cells might differ between animals bearing hepatic metastases and those that are healthy. Kupffer cells are considered responsible for the accumulation of liposomes in the liver. In this study, we hypothesized that the alteration in the function of Kupffer cells by hepatic metastasis would also affect the biodistribution of liposomes following intravenous administration. The hepatic accumulation and the blood concentration of PEGylated liposomes were compared between healthy mice and tumor-bearing mice. We noted that hepatic accumulation and elimination from the blood were significantly accelerated in tumor-bearing mice, indicating that our hypothesis was correct. In the tumor-bearing mice, the proportion of Kupffer cells taking up liposomes was significantly increased. Intravenous injection of oxaliplatin (l-OHP) containing PEGylated liposomes decreased the fraction of Kupffer cells, but this administration caused no injury to the hepatocytes. These results suggest that PEGylated liposomes containing l-OHP may have the potential to treat metastatic hepatic cancer-not only via the direct killing of the cancer cells but also via a reduction in tumor-supportive Kupffer cells.
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b15-00611
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 26830481; ● Summary page in Scopus @ Elsevier: 2-s2.0-84958964867

(DOI: 10.1248/bpb.b15-00611, PubMed: 26830481, Elsevier: Scopus) Noriko Saito-Tarashima, Hidenori ANDO, Takamitsu Kojima, Nozomi Kinjo, Yosuke Hashimoto, Kazuhiro Furukawa, Tatsuhiro Ishida and Noriaki Minakawa :
Gene silencing using 4'-thioDNA as an artificial template to synthesize short-hairpin RNA without inducing a detectable innate immune response,
Molecular Therapy. Nucleic Acids, Vol.5, e274, 2016.

(要約): The development of a versatile technique to induce RNA interference (RNAi) without immune stimulation in vivo is of interest as existing approaches to trigger RNAi, such as small interfering RNA (siRNA) and plasmid DNA (pDNA) expressing short hairpin RNA (shRNA), present drawbacks arising from innate immune stimulation. To overcome them, an intelligent shRNA expression device (iRed) designed to induce RNAi was developed. The minimum sequence of iRed encodes only the U6 promoter and shRNA. A series of iRed comprises a polymerase chain reaction (PCR)-amplified 4'-thioDNA in which any one type of adenine (A), guanine (G), cytosine (C), or thymine (T) nucleotide unit was substituted by each cognate 4'-thio derivatives, i.e., dSA iRed, dSG iRed, dSC iRed, and ST iRed respectively. Each modified iRed acted as a template to transcribe shRNA with RNAi activity. The highest shRNA yield was generated using dSC iRed that exerted gene silencing activity in an orthotopic mouse model of mesothelioma. Reducing the minimal structure required to transcribe shRNA and the presence of the 4'-thiomodification synergistically function to abrogate innate immune response induced by dsDNA. The iRed will introduce a new approach to induce RNAi without inducing a detectable innate immune response.
(徳島大学機関リポジトリ): ● Metadata: 110894
(出版サイトへのリンク): ● Publication site (DOI): 10.1038/mtna.2015.48
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 26730811; ● Summary page in Scopus @ Elsevier: 2-s2.0-84953792236

(徳島大学機関リポジトリ: 110894, DOI: 10.1038/mtna.2015.48, PubMed: 26730811, Elsevier: Scopus) N Eldin Essam, Lila Selim Ahmed Ali Abu Amr, Kazuyoshi Kawazoe, M H Elnahas, A M Mahdy and Tatsuhiro Ishida :
Encapsulation in a rapid-release liposomal formulation enhances the anti-tumor efficacy of pemetrexed in a murine solid mesothelioma-xenograft model,
European Journal of Pharmaceutical Sciences, Vol.81, 60-66, 2016.

(要約): We recently developed a PEG-coated liposome encapsulating the anti-folate drug pemetrexed (PMX). Such liposomal formulations have shown potent cytotoxic effects against malignant pleural mesothelioma (MPM) cells in vitro. In the present study, we investigated the pharmacokinetics, bio-distribution and in vivo anti-tumor efficacy of two liposomal PMX formulations with different drug release rates in a murine mesothelioma-xenograft model. Liposomes with different PMX release rates were prepared via manipulating liposomal membrane fluidity through incorporating either a solid-phase (HSPC) or a fluid-phase (POPC) phospholipid. Both liposomal PMX formulations showed prolonged plasma pharmacokinetics and were accumulated to a similar extent in tumors and other tissues, presumably, due to surface modification with polyethylene glycol (PEG). In a murine mesothelioma-xenograft model, interestingly, PMX encapsulated in a fast-release POPC liposome produced superior tumor growth suppression compared with either free PMX or PMX encapsulated in a slow-release HSPC liposome. Such in vivo anti-tumor efficacy was accomplished mainly by a potent induction of apoptosis within tumor tissue by the released PMX from POPC liposomes. Our results clearly emphasize the therapeutic efficacy of liposomal PMX over free PMX in conquering aggressive solid tumors such as malignant mesothelioma. A guarantee of the targeted delivery of PMX to tumor cells helps overcome some of the major shortcomings encountered with the use of free PMX.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ejps.2015.09.015
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 26415830; ● Search Scopus @ Elsevier (PMID): 26415830; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ejps.2015.09.015

(DOI: 10.1016/j.ejps.2015.09.015, PubMed: 26415830) Hiroyuki Nakamura, Lila Selim Ahmed Ali Abu Amr, Miho Nishio, Masao Tanaka, Hidenori ANDO, Hiroshi Kiwada and Tatsuhiro Ishida :
Intra-tumor distribution of PEGylated liposome upon repeated injection: No possession by prior dose,
Journal of Controlled Release, Vol.220, 406-413, 2015.

(要約): Liposomes have proven to be a viable means for the delivery of chemotherapeutic agents to solid tumors. However, significant variability has been detected in their intra-tumor accumulation and distribution, resulting in compromised therapeutic outcomes. We recently examined the intra-tumor accumulation and distribution of weekly sequentially administered oxaliplatin (l-OHP)-containing PEGylated liposomes. In that study, the first and second doses of l-OHP-containing PEGylated liposomes were distributed diversely and broadly within tumor tissues, resulting in a potent anti-tumor efficacy. However, little is known about the mechanism underlying such a diverse and broad liposome distribution. Therefore, in the present study, we investigated the influence of dosage interval on the intra-tumor accumulation and distribution of "empty" PEGylated liposomes. Intra-tumor distribution of sequentially administered "empty" PEGylated liposomes was altered in a dosing interval-dependent manner. In addition, the intra-tumor distribution pattern was closely related to the chronological alteration of tumor blood flow as well as vascular permeability in the growing tumor tissue. These results suggest that the sequential administrations of PEGylated liposomes in well-spaced intervals might allow the distribution to different areas and enhance the total bulk accumulation within tumor tissue, resulting in better therapeutic efficacy of the encapsulated payload. This study may provide useful information for a better design of therapeutic regimens involving multiple administrations of nanocarrier drug delivery systems.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2015.11.002
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 26548975; ● Summary page in Scopus @ Elsevier: 2-s2.0-84946716430

(DOI: 10.1016/j.jconrel.2015.11.002, PubMed: 26548975, Elsevier: Scopus) Hidenori ANDO, Sakiko Kobayashi, Lila Selim Ahmed Ali Abu Amr, N Eldin Essam, Chihiro Katoh, Taro Shimizu, Masami Ukawa, Kazuyoshi Kawazoe and Tatsuhiro Ishida :
Advanced therapeutic approach for the treatment of malignant pleural mesothelioma via the intrapleural administration of liposomal pemetrexed,
Journal of Controlled Release, Vol.220, 29-36, 2015.

(要約): Malignant pleural mesothelioma (MPM) is an aggressive cancer that proliferates in the pleural cavity. Pemetrexed (PMX) in combination with cisplatin is currently the approved standard care for MPM, but a dismal response rate persists. Recently, we prepared various liposomal PMX formulations using different lipid compositions and evaluated their in vitro cytotoxicity against human mesothelioma cells (MSTO-211H). In the present study, we investigated the in vivo therapeutic effect of our liposomal PMX formulations using an orthotopic MPM tumor mouse model. PMX encapsulated within either cholesterol-containing (PMX/Chol CL) or cholesterol-free (PMX/Non-Chol CL) cationic liposome was intrapleurally injected into tumor-bearing mice. PMX encapsulated in cholesterol-free liposomes (PMX/Non-Chol CL) drastically inhibited the tumor growth in the pleural cavity, while free PMX and PMX encapsulated in cholesterol-containing liposomes (PMX/Chol CL) barely inhibited the tumor growth. The enhanced in vivo anti-tumor efficacy of PMX/Non-Chol CL was credited, on the one hand, for prolonging the retention of cationic liposomes in the pleural cavity via their electrostatic interaction with the negatively charged membranes of tumor cells, but on the other hand, it was charged with contributing to a higher drug release from the "fluid" liposomal membrane following intrapleural administration. This therapeutic strategy of direct intrapleural administration of liposomal PMX, along with the great advances in CL-guided therapeutics, might be a promising therapeutic approach to conquering the poor prognosis for MPM.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2015.10.019
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 26476173; ● Summary page in Scopus @ Elsevier: 2-s2.0-84944717805

(DOI: 10.1016/j.jconrel.2015.10.019, PubMed: 26476173, Elsevier: Scopus) Taro Shimizu, Yu Mima, Yosuke Hashimoto, Masami Ukawa, Hidenori ANDO, Hiroshi Kiwada and Tatsuhiro Ishida :
Anti-PEG IgM and complement system are required for the association of second doses of PEGylated liposomes with splenic marginal zone B cells,
Immunobiology, Vol.220, No.10, 1151-1160, 2015.

(要約): The accelerated blood clearance (ABC) phenomenon makes it crucial to use PEGylated liposomes and micelles to deliver drugs. The ABC phenomenon is an immune response against an initial dose of PEGylated liposome, which causes subsequent doses to be rapidly cleared by macrophages in the liver. We recently found that in the early phase of the ABC phenomenon, subsequent doses of PEGylated liposomes were associated with splenic marginal zone (MZ)-B cells and were transported from the MZ to the follicle (FO). In this study, we investigated the underlying mechanisms behind the association of subsequent doses of PEGylated liposomes with MZ-B cells in the spleen. Serum factors, anti-PEG IgM and complement system, were crucial to the association of PEGylated liposomes with MZ-B cells, while the sensitization of MZ-B cells by the first dose of PEGylated liposomes was not significant. It was the complement receptors (CRs) on the MZ-B cells, rather than either the PEG-specific B-cell receptors or the IgM Fc receptors, that were the main contributors to the association between PEGylated liposomes and MZ-B cells. It appeared that anti-PEG IgM would bind to PEGylated liposomes and causes subsequent complement activation, resulting in the formation of immune complexes of PEGylated liposome-anti-PEG IgM-complement. The MZ-B cells then recognized these immune complexes via their CRs. Such an association via CRs might have triggered the transport of the immune complex by MZ-B cells to the FO in the spleen. The information obtained in this study might be useful in the development of an efficient antigen delivery system to usher PEGylated nanoparticles into FO dendritic cells.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.imbio.2015.06.005
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 26095176; ● Summary page in Scopus @ Elsevier: 2-s2.0-84937974851

(DOI: 10.1016/j.imbio.2015.06.005, PubMed: 26095176, Elsevier: Scopus) Munehira Kawanishi, Yosuke Hashimoto, Taro Shimizu, Ikuko Sagawa, Tatsuhiro Ishida and Hiroshi Kiwada :
Comprehensive analysis of PEGylated liposome-asscociated proteins relating to the accelerated blood clearance phenomenon by combination with shotgun analysis and conventional methods,
Biotechnology and Applied Biochemistry, Vol.62, No.4, 547-555, 2015.

(要約): PEGylated liposome, sterically stabilized by polyethylene glycol (PEG), results in reduced recognition of the liposome by the mononuclear phagocyte system. Recently, we reported regarding the accelerated blood clearance (ABC) phenomenon that PEGylated liposome is cleared very rapidly from blood circulation upon repeated injection. Anti-PEG IgM production and subsequent complement activation were crucial in causing the ABC phenomenon. However, there still remains the possibility that unknown plasma factors might affect the fate of PEGylated liposome that is subjected to the ABC phenomenon. A label-free approach to shotgun analysis is a great tool for characterizing proteins in a biological system. In this study, therefore, a shotgun analysis was employed to identify plasma protein bound on PEGylated liposome after the ABC phenomenon was induced in the mouse model. The analysis revealed that immunoglobulin and complement components (C1 and C3) are the major proteins. Subsequent analysis with enzyme-linked immunosorbent assay and Western blotting showed that the immunoglobulin was IgM and that the complement system was mainly activated via an anti-PEG IgM-mediated classical pathway. These results support our earlier assumptions-anti-PEG IgM and complement activation were the major causes of the ABC phenomenon. Our proposed analytical strategy would be expected to provide useful information for the development and design of the nanocarrier drug delivery system.
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/bab.1291
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 25196743; ● Summary page in Scopus @ Elsevier: 2-s2.0-84939520973

(DOI: 10.1002/bab.1291, PubMed: 25196743, Elsevier: Scopus) Yu Mima, Yosuke Hashimoto, Taro Shimizu, Hiroshi Kiwada and Tatsuhiro Ishida :
Anti-PEG IgM is a major contributor to the accelerated blood clearance of polyethylene glycol-conjugated protein,
Molecular Pharmaceutics, Vol.12, No.7, 2429-2435, 2015.

(要約): Limited therapeutic efficacy of polyethylene glycol-conjugated (PEGylated) protein drugs has been recently reported in animals and human following repeat injections. Since there are reports that an accelerated blood clearance (ABC) phenomenon is caused by repeated injection of PEGylated liposome, there is an assumption that PEGylated proteins lose their long circulating property when they are injected repeatedly due to the induction of anti-PEG antibody. Although induction of anti-PEG antibody by PEGylated protein has been reported, there is little evidence of accelerated blood clearance of PEGylated protein upon repeated injection. Herein, we investigated the blood concentration of PEGylated ovalbumin (PEG-OVA), a model PEGylated protein, upon its repeated injection. A single intravenous administration of PEG-OVA elicited an anti-PEG IgM response but not anti-PEG IgG response, while the administration did not elicit antibody against OVA. At 24 h postinjection of test PEG-OVA, although control mice showed 41.6% dose of PEG-OVA in blood, the mice pretreated with PEG-OVA showed rapid clearance of test PEG-OVA from blood and undetectable level of PEG-OVA. Interestingly, the anti-PEG IgM induced by PEGylated liposome did not affect the blood concentration of subsequent dose of PEG-OVA. Our result suggests that anti-PEG IgM is a major contributor to the accelerated blood clearance of PEG-conjugated protein, but the presence of anti-PEG IgM in blood circulation does not necessarily affect circulating property of entire PEGylated materials.
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/acs.molpharmaceut.5b00144
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 26070445; ● Summary page in Scopus @ Elsevier: 2-s2.0-84936758421

(DOI: 10.1021/acs.molpharmaceut.5b00144, PubMed: 26070445, Elsevier: Scopus) Noriko Saito-Tarashima, Tatsuya Sumitomo, Hidenori ANDO, Kazuhiro Furukawa, Tatsuhiro Ishida and Noriaki Minakawa :
Synthesis of DNA fragments containing 2-deoxy-4-selenonucleoside units using DNA polymerases: comparison of dNTPs with O, S and Se at the 4-position in replication Org,
Organic & Biomolecular Chemistry, Vol.13, No.25, 6949-6952, 2015.

(要約): 4'-SelenoDNA fragments were synthesized for the first time using 4'-selenothymidine triphosphate (SeTTP) by taking advantage of its bioequivalence against DNA polymerases. DNA fragments each with a homologous element (O, S or Se) at the 4'-position of the thymidine units were effectively amplified using KOD Dash DNA polymerase.
(出版サイトへのリンク): ● Publication site (DOI): 10.1039/c5ob00941c
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 26053864; ● Summary page in Scopus @ Elsevier: 2-s2.0-84934957265

(DOI: 10.1039/c5ob00941c, PubMed: 26053864, Elsevier: Scopus) Yosuke Hashimoto, Taro Shimizu, Lila Selim Ahmed Ali Abu Amr, Tatsuhiro Ishida and Hiroshi Kiwada :
Relationship between the concentration of anti-polyethylene glycol (PEG) in immunoglobulin M (IgM) and the intensity of the accelerated blood clearance (ABC) phenomenon against PEGylated liposomes in mice,
Biological & Pharmaceutical Bulletin, Vol.38, No.3, 417-424, 2015.

(要約): PEGylation, which is the surface modification of nanocarriers with polyethylene glycol (PEG), has increased the circulation time and reduced the immunogenic responses to nanocarriers. However, many reports have demonstrated that the intravenous injection of sterically stabilized PEGylated liposome (SL) causes an accelerated blood clearance (ABC) of subsequent doses via anti-PEG immunoglobulin M (IgM)-mediated complement activation. In the present study, the relationships between serum anti-PEG IgM concentration, the intensity of complement activation and the hepatic clearance of SL were quantitatively investigated for their role in the ABC phenomenon. Interestingly, with increasing serum anti-PEG IgM concentrations, the intensity of complement activation increased linearly, while the intensity of the hepatic clearance of SL was increased and then saturated. In addition, only 15-17% of anti-PEG IgM in blood circulation induced by SL at different doses was associated with a second dose SL. The present results indicate that it is the hepatic uptake of SL that is the limiting step in the ABC phenomenon, rather than the association of anti-PEG IgM to the SL and a subsequent complement activation.
(キーワード): anti-polyethylene glycol (PEG) / immunoglobulin M (IgM) / PEGylated liposome (SL) / accelerated blood clearance (ABC) phenomenon / complement activation
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b14-00653
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 25757923; ● CiNii @ 国立情報学研究所 (CRID): 1390282679608052736; ● Summary page in Scopus @ Elsevier: 2-s2.0-84937217183

(DOI: 10.1248/bpb.b14-00653, PubMed: 25757923, CiNii: 1390282679608052736, Elsevier: Scopus) N Eldin Essam, M H Elnahas, A M Mahdy and Tatsuhiro Ishida :
Liposomal pemetrexed: Formulation, characterization and in vitro cytotoxicity studies for effective management of malignant pleural mesothelioma,
Biological & Pharmaceutical Bulletin, Vol.38, No.3, 461-469, 2015.

(要約): Pemetrexed (PMX) is a newly developed multi-targeted anti-folate with promising clinical activity in many solid tumors including malignant pleural mesothelioma (MPM). However, PMX does not show sufficient anti-tumor activity in vivo when used alone either due to inefficient delivery of adequate concentrations to tumor tissue or dose-limiting side effects. In order to overcome these problems and to achieve potent anti-tumor activity, PMX was encapsulated into a liposomal delivery system. In the present study, various formulations of liposomal PMX were prepared. The effect of formulation parameters on the encapsulation efficiency of PMX within liposomes was evaluated. In addition, the influence of drug release rate on the in vitro cytotoxicity was investigated. Encapsulation of PMX within liposomes was remarkably increased by the incorporation of cholesterol within liposomal membranes and by increasing the total lipid concentration. Encapsulation efficiency was found to be unaffected by the type of phospholipid used or the inclusion of a cation lipid, DC-6-14. Interestingly, encapsulation of PMX within "fluid" liposomes was found to allow efficient release of PMX from liposomes resulting in a potent in vitro cytotoxicity against MPM MSTO-211H cell line. On the other hand, entrapment of PMX within "solid" liposomes substantially hindered PMX release from liposomes, and thus PMX failed to exert any in vitro cytotoxicity. These results suggest that encapsulation of PMX within "fluid" liposomes might represent a novel strategy to enhance the therapeutic efficacy of PMX while minimizing the side effect encountered by the non selective delivery of free PMX to various body tissues.
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b14-00769
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 25757929; ● Summary page in Scopus @ Elsevier: 2-s2.0-84936159744

(DOI: 10.1248/bpb.b14-00769, PubMed: 25757929, Elsevier: Scopus) Takuya Suzuki, Masako Ichihara, Kenji Hyodo, Eiichi Yamamoto, Tatsuhiro Ishida, Hiroshi Kiwada, Hiroshi Kikuchi and Hiroshi Ishihara :
Influence of dose and animal species on accelerated blood clearance of PEGylated liposomal doxorubicin,
International Journal of Pharmaceutics, Vol.476, 205-212, 2014.

(要約): We recently demonstrated that Doxil loses its long-circulating properties when injected repeatedly at doses below 2 mg/m(2) in dogs. In studies using other animal species, PEGylated liposomal doxorubicin has been reported not to induce the accelerated blood clearance (ABC) phenomenon. We investigated the issue of whether Doxil can elicit the ABC phenomenon in several species. In minipigs, the ABC phenomenon was induced at 2 mg/m(2). In other animal species, the ABC phenomenon was not observed at higher doses (>2 mg/m(2)), but was observed at much lower doses (0.2 mg/m(2)). The pharmacokinetic profile of a second dose of Doxil reflected the circulating anti-PEG IgM level induced by the first dose. The ABC phenomenon was not observed at the clinically recommended DXR dose (20 mg/m(2)) in any animal species. These results indicate that Doxil can cause the ABC phenomenon in all animals tested, the extent of induction was dependent on the first dose of Doxil, and a higher Doxil dose lessened the ABC phenomenon. The current study results suggest that a careful study design including selection of animal species is important for preclinical studies using PEGylated liposomal formulations even if they contain anticancer drugs that suppress the host immune response.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2014.09.047
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 25280884; ● Summary page in Scopus @ Elsevier: 2-s2.0-84907897464

(DOI: 10.1016/j.ijpharm.2014.09.047, PubMed: 25280884, Elsevier: Scopus) Yota Saito, Yosuke Hashimoto, Mai Arai, Noriko Saito-Tarashima, Tadashi Miyazawa, Kazuya Miki, Mayumi Takahashi, Kazuhiro Furukawa, Naoshi Yamazaki, Akira Matsuda, Tatsuhiro Ishida and Noriaki Minakawa :
Chemistry, properties, and in vitro and in vivo applications of 2'-O-methoxyethyl-4'-thioRNA, a novel hybrid type of chemically modified RNA.,
ChemBioChem, Vol.15, No.17, 2535-2540, 2014.

(要約): We report the synthesis, properties, and in vitro and in vivo applications of 2'-O-methoxyethyl-4'-thioRNA (MOE-SRNA), a novel type of hybrid chemically modified RNA. In its hybridization with complementary RNA, MOE-SRNA showed a moderate improvement of Tm value (+3.4 °C relative to an RNA:RNA duplex). However, the results of a comprehensive comparison of the nuclease stability of MOE-SRNA relative to 2'-O-methoxyethylRNA (MOERNA), 2'-O-methyl-4'-thioRNA (Me-SRNA), 2'-O-methylRNA (MeRNA), 4'-thioRNA (SRNA), and natural RNA revealed that MOE-SRNA had the highest stability (t1/2 >48 h in human plasma). Because of the favorable properties of MOE-SRNA, we evaluated its in vitro and in vivo potencies as an anti-microRNA oligonucleotide against miR-21. Although the in vitro potency of MOE-SRNA was moderate, its in vivo potency was significant for the suppression of tumor growth (similar to that of MOERNA).
(キーワード): Animals / Cell Proliferation / HeLa Cells / Humans / Mice / Mice, Inbred BALB C / Mice, Nude / MicroRNAs / Neoplasms / Nucleic Acid Conformation / RNA (RNA) / RNA Stability / Tumor Cells, Cultured
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/cbic.201402398
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 25314258; ● Summary page in Scopus @ Elsevier: 2-s2.0-84915745333

(DOI: 10.1002/cbic.201402398, PubMed: 25314258, Elsevier: Scopus) Yosuke Hashimoto, Lila Selim Ahmed Ali Abu Amr, Taro Shimizu, Tatsuhiro Ishida and Hiroshi Kiwada :
B cell-intrinsic toll-like receptor 7 is responsible for the enhanced anti-PEG IgM production following injection of siRNA-containing PEGylated lipoplex in mice,
Journal of Controlled Release, Vol.184, 1-8, 2014.

(要約): Recently, we reported that immunostimulatory siRNA-containing PEGylated lipoplex (PEGylated siRNA-lipoplex) activates the immune system, resulting in the enhanced production of anti-PEG IgM. However, the enhancing mechanism upon anti-PEG IgM production has not been fully elucidated. In this study, we employed toll-like receptor 7 knock out (TLR7 KO) mice, and showed how PEGylated siRNA-lipoplex activates the innate immune system through TLR7 and consequently enhances anti-PEG IgM production. In addition, we showed that SCID mice reconstituted with TLR7-deficient B cells failed to enhance anti-PEG IgM production following the injection of PEGylated siRNA-lipoplex, but that SCID mice reconstituted with wild type B cells did enhance anti-PEG IgM production. These results suggest that immune activation via B cell-intrinsic TLR7, but not other TLR7-expressing cells, contributes predominantly to an enhanced anti-PEG IgM production in response to the intravenous injection of PEGylated siRNA-lipoplexes. A strategy to evade B cell-intrinsic TLR7 activation by siRNA, such as chemical modification, may overcome immunological barriers to PEGylated liposome-based siRNA therapeutics.
(キーワード): Adoptive Transfer / Animals / B-Lymphocytes / Cytokines / Immunoglobulin M / Liposomes / Male / Membrane Glycoproteins / Mice, Inbred BALB C / Mice, Knockout / Mice, SCID / Polyethylene Glycols / RNA, Small Interfering / Spleen / Toll-Like Receptor 7
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2014.04.003
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 24727075; ● Summary page in Scopus @ Elsevier: 2-s2.0-84899502162

(DOI: 10.1016/j.jconrel.2014.04.003, PubMed: 24727075, Elsevier: Scopus) Yosuke Hashimoto, Yumi Uehara, Lila Selim Ahmed Ali Abu Amr, Tatsuhiro Ishida and Hiroshi Kiwada :
Activation of TLR9 by incorporated pDNA within PEG-coated lipoplex enhances anti-PEG IgM production,
Gene Therapy, Vol.21, No.6, 593-598, 2014.

(要約): Cationic liposome represents a promising alternative to viral vectors for the delivery of therapeutic genes. For in vivo use, surface modification of the liposome with polyethylene glycol (PEG) is frequently applied to achieve gene-expression in the targeted tissue. However, we have reported that PEG-coated liposomes have induced anti-PEG IgM, which has caused subsequent doses of PEG-coated liposome to be rapidly cleared from blood circulation, and the complexation of pDNA electrostatically associated with liposome surface has enhanced this antibody response. In this study, we investigated how a Toll-like receptor (TLR) might enhance anti-PEG IgM production. PEG-coated pDNA-lipoplex (PDCL) was injected into either wild type, MyD88 (all TLR adaptor protein, independent of TLR3) knock out (KO) or TLR9 KO mice, and the anti-PEG IgM production levels were detected. Attenuated anti-PEG IgM production following the injection of PDCL was observed in both MyD88 and TLR9 KO mice compared to wild type mice, probably due to the abolished induction of cytokines in both MyD88 and TLR9 KO mice. Our results suggest that TLR, exclusively TLR9, signaling plays a potential role in the enhanced anti-PEG IgM production following the injection of PDCL. This result may have important implications for the design and development of an efficient PEG-coated non-viral gene vector.
(キーワード): Animals / Antibodies, Anti-Idiotypic / Cytokines / Liposomes / Male / Mice, Inbred BALB C / Mice, Knockout / Myeloid Differentiation Factor 88 / Plasmids / Polyethylene Glycols / Signal Transduction / Splenectomy / Toll-Like Receptor 9
(出版サイトへのリンク): ● Publication site (DOI): 10.1038/gt.2014.32
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 24694537; ● Summary page in Scopus @ Elsevier: 2-s2.0-84902086530

(DOI: 10.1038/gt.2014.32, PubMed: 24694537, Elsevier: Scopus) Yosuke Hashimoto, Taro Shimizu, Yu Mima, Lila Selim Ahmed Ali Abu Amr, Tatsuhiro Ishida and Hiroshi Kiwada :
Generation, characterization and in vivo biological activity of two distinct monoclonal anti-PEG IgMs,
Toxicology and Applied Pharmacology, Vol.277, No.1, 30-38, 2014.

(要約): PEGylation, the attachment of polyethylene glycol (PEG) to nanocarriers and proteins, is a widely accepted approach to improving the in vivo efficacy of the non-PEGylated products. However, both PEGylated liposomes and PEGylated proteins reportedly trigger the production of specific antibodies, mainly IgM, against the PEG moiety, which possibly leads to a reduction in safety and therapeutic efficacy of the PEGylated products. In the present study, two monoclonal anti-PEG IgMs--HIK-M09 via immunization with an intravenous injection of PEGylated liposomes (SLs) and HIK-M11 via immunization with a subcutaneous administration of PEGylated ovalbumin (PEG-OVA) were successfully generated. The generated IgMs showed efficient reactivity to mPEG2000 conjugated to 1,2-distearoyl-sn-glycero-3-phospho-ethanolamine (DSPE), PEGylated liposome (SL) and PEG-OVA. It appears that HIK-M09 recognizes ethoxy (OCH2CH2) repeat units along with a terminal motif of PEG, while HIK-M11 recognizes only ethoxy repeat units of PEG. Such unique properties allow HIK-M09 to bind with dense PEG. In addition, their impact on the in vivo clearance of the PEGylated products was investigated. It was found that the generated ant-PEG IgMs induced a clearance of SL as they were intravenously administered with SL. Interestingly, the HIK-M11, generated by PEG-OVA, induced the clearance of both SL and PEG-OVA, while the HIK-M09, generated by SL, induced the clearance of SL only. We here revealed that the presence of serum anti-PEG IgM and the subsequent binding of anti-PEG IgM to the PEGylated products are not necessarily related to the enhanced clearance of the products. It appears that subsequent complement activation following anti-PEG IgM binding is the most important step in dictating the in vivo fate of PEGylated products. This study may have implications for the design, development and clinical application of PEGylated products and therapeutics.
(キーワード): Animals / Antibodies, Anti-Idiotypic / Antibodies, Monoclonal / Cell Line, Tumor / Complement Activation / Hybridomas / Liposomes / Male / Mice / Mice, Inbred BALB C / Ovalbumin / Phosphatidylethanolamines / Polyethylene Glycols / Rats, Wistar / Spleen
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.taap.2014.03.002
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 24632081; ● Summary page in Scopus @ Elsevier: 2-s2.0-84897940686

(DOI: 10.1016/j.taap.2014.03.002, PubMed: 24632081, Elsevier: Scopus) Takako Nakashima, N Sako, Takakuni Matsuda, N Uematsu, K Sakurai and Tatsuhiro Ishida :
Novel Submicronized Rebamipide Liquid with Moderate Viscosity: Significant Effects on Oral Mucositis in Animal Models,
Biological & Pharmaceutical Bulletin, Vol.37, No.4, 671-678, 2014.

(要約): This study aimed at developing a novel rebamipide liquid for an effective treatment of oral mucositis. The healing effects of a variety of liquids comprising submicronized rebamipide crystals were investigated using a rat cauterization-induced oral ulcer model. Whereas 2% rebamipide liquid comprising micro-crystals did not exhibit significant curative effect, 2% rebamipide liquids comprising submicronized crystals with moderate viscosities exhibited healing effects following intra-oral administration. The 2% and 4% optimized rebamipide liquids showed significant healing effects in the rat oral ulcer model (p<0.01). In addition, in the rat radiation-induced glossitis model, whereby the injury was caused to the tongue by exposing only around the rat's snout to a 15 Gy of X-irradiation, the 2% optimized rebamipide liquid significantly reduced the percent area of ulcerated injury (p<0.05). In conclusion, the submicronized rebamipide liquid with moderate viscosity following intra-oral administration showed better both healing effect in the rat oral ulcer model and preventive effect in the rat irradiation-induced glossitis model.
(キーワード): Administration, Oral / Alanine / Animals / Anti-Ulcer Agents / Cautery / Disease Models, Animal / Drug Carriers / Glossitis / Male / Nanoparticles / Oral Ulcer / Quinolones / Rats / Stomatitis / Viscosity / X-Rays
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b13-01006
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 24694614; ● Summary page in Scopus @ Elsevier: 2-s2.0-84898751899

(DOI: 10.1248/bpb.b13-01006, PubMed: 24694614, Elsevier: Scopus) Hiroyuki Nakamura, Yusuke Doi, Lila Selim Ahmed Ali Abu Amr, Ai Nagao, Tatsuhiro Ishida and Hiroshi Kiwada :
Sequential treatment of oxaliplatin-containing PEGylated liposome together with S-1 improves intratumor distribution of subsequent doses of oxaliplatin-containing PEGylated liposome,
European Journal of Pharmaceutics and Biopharmaceutics, Vol.87, No.1, 142-151, 2014.

(要約): We recently reported that combination therapy with metronomic S-1 dosing and oxaliplatin (l-OHP)-containing PEGylated liposomes improved antitumor activity in a murine colorectal tumor model. However, little is known about the mechanism underlying such improved therapeutic efficacy. Here we investigated the impact of combined treatment on biodistribution, tumor accumulation and intratumor distribution of test PEGylated liposomes and on the structure of tumor vasculature in a solid tumor. The combined treatment clearly enhanced tumor accumulation and intratumor distribution of a subsequent test dose of PEGylated liposome as a result of on the one hand prolonging blood circulation of test liposome and on the other hand the alteration in tumor microenvironment. The l-OHP-containing PEGylated liposomes contributed predominantly to the enhanced tumor accumulation and altered tumor distribution of test liposome. On the other hand, metronomic S-1 dosing contributed to the altered tumor distribution but not the tumor accumulation of test liposome. The antitumor effect of the combined treatment, reflected by the proportion of apoptotic cells in the tumor, was approximately equally accounted for by each of the two treatments, leading to a roughly additive effect. In conclusion, 1-OHP-containing PEGylated liposome together with S-1 enhanced intratumor influx, leading to improved antitumor activity of subsequently injected 1-OHP-containing PEGylated liposomes and/or S-1. This strategy we propose, which is clinically applicable, may overcome the problems related to the use of EPR effect-based nanocarrier systems.
(キーワード): Animals / Antineoplastic Agents / Apoptosis / Cell Line, Tumor / Colorectal Neoplasms / Drug Administration Schedule / Drug Carriers / Drug Combinations / Drug Therapy, Combination / Liposomes / Liver / Male / Mice, Inbred BALB C / Organoplatinum Compounds / Oxonic Acid / Polyethylene Glycols / Tegafur / Tissue Distribution
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ejpb.2013.12.007
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 24361534; ● Summary page in Scopus @ Elsevier: 2-s2.0-84901597347

(DOI: 10.1016/j.ejpb.2013.12.007, PubMed: 24361534, Elsevier: Scopus) Lila Selim Ahmed Ali Abu Amr, Yumi Uehara, Tatsuhiro Ishida and Hiroshi Kiwada :
Application of polyglycerol-coating to pDNA lipoplex for the evasion of the accelerated blood clearance (ABC) phenomenon in nucleic acid delivery.,
Journal of Pharmaceutical Sciences, Vol.103, No.2, 557-566, 2014.

(要約): Cationic liposomes (CLs) have shown promise as nonviral delivery systems. To achieve in vivo stability and long circulation, most liposomes are modified with hydrophilic polymer polyethylene glycol (PEG). However, we have reported that repeated administration of PEG-coated CLs containing plasmid DNA (pDNA; PEGylated lipoplexes) induces what is referred to as "the accelerated blood clearance (ABC) phenomenon" and, consequently, subsequently administered lipoplexes lose their prolonged circulation characteristics. Anti-PEG IgM produced in response to the first dose of PEG-coated pDNA-lipoplexes (PEG-DCL) has proven to be a major cause of the ABC phenomenon. In this study, to evade and/or attenuate this unexpected immune response, we modified the surface of a lipoplex with polyglycerol (PG)-derived lipid. The PG-coated pDNA-lipoplex (PG-DCL) attenuated the production of anti-polymer IgM, whereas PEG-coated pDNA-lipoplex (PEG-DCL) did not. In addition, a second dose of PG-DCL maintained the accumulation level in the tumor tissue of a tumor-bearing mouse model, comparable to that of the first dose, whereas the tumor accumulation level of a second dose of PEG-DCL was significantly compromised, compared with the first dose of PEG-DCL. Our results indicate that surface modification of lipoplex with PG represents a viable means for the attenuation, and/or evasion, of the ABC phenomenon that is encountered upon repeated administrations of nucleic acids containing PEG-coated nanocarriers.
(キーワード): Animals / Antimetabolites / B-Lymphocytes / Bromodeoxyuridine / Cell Proliferation / Cytokines / DNA / Drug Carriers / Drug Delivery Systems / Excipients / Fluorescent Dyes / Genetic Therapy / Glycerol / Immunoglobulin M / Liposomes / Male / Mice / Mice, Inbred BALB C / Neoplasm Transplantation / Plasmids / Polyethylene Glycols / Polymers / Rats / Rats, Wistar
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/jps.23823
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 24347396; ● Summary page in Scopus @ Elsevier: 2-s2.0-84895929589

(DOI: 10.1002/jps.23823, PubMed: 24347396, Elsevier: Scopus) Lila Selim Ahmed Ali Abu Amr, Masako Ichihara, Taro Shimizu, Tatsuhiro Ishida and Hiroshi Kiwada :
Ex-Vivo/In-Vitro Anti-Polyethylene Glycol (PEG) IgM Production From Murine Splenic B Cells Stimulated by PEGylated Liposome,
Biological & Pharmaceutical Bulletin, Vol.36, No.11, 1842-1848, 2013.

(要約): We have reported that PEGylated liposomes lose their long-circulating properties when injected twice into the same animal within a certain interval (the accelerated blood clearance (ABC) phenomenon). We assumed that this phenomenon was triggered via the abundant secretion of anti-polyethylene glycol (PEG) immunoglobulin M (IgM) in response to the first dose of PEGylated liposomes and that the spleen played an important role in the production of anti-PEG IgM. However, no direct evidence has yet confirmed this suspicion. In the current study, we verified, both in vitro and ex vivo, that spleen cells are indeed responsible for the production of anti-PEG IgM in response to PEGylated liposomes. In this study, spleen cells obtained from either naïve mice or mice pre-treated with PEGylated liposomes induced the production of anti-PEG IgM in a dose- and time-dependent manner, upon incubation with PEGylated liposomes. In addition, we confirmed that among the different fractions of splenic B cells, IgM-positive B cells, rather than CD45R-positive or CD19-positive splenic B cells, which are presumed to be the marginal zone B (MZB) cells, are the major cells producing anti-PEG IgM in the response to stimulation by PEGylated liposomes. These results may provide new insights into the mechanisms underlying the anti-PEG IgM production in response to the stimulation by PEGylated liposomes.
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b13-00562
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 24189428; ● Search Scopus @ Elsevier (PMID): 24189428; ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.b13-00562

(DOI: 10.1248/bpb.b13-00562, PubMed: 24189428) Takako Nakashima, N Uematsu, M Shibamori, K Sakurai, Tatsuhiro Ishida and Hiroshi Kiwada :
Establishment of an X-ray irradiation-induced glossitis model in rats: biphasic elevation of proinflammatory cytokines and chemokines,
The Journal of Pharmacology and Experimental Therapeutics, Vol.347, No.3, 660-668, 2013.

(要約): Oral mucositis is a frequent and serious side effect in patients who receive radiotherapy for head and neck cancer. The purpose of this study was to develop a noninvasive and quantitative model of oral mucositis in rats, investigate the pathophysiology, and evaluate the efficacy of pharmacological interventions. Rats received a single dose of 15 Gy of X-rays to the snout after shielding of the remainder of the rat body with lead plates to protect the body from irradiation (day 0). After irradiation, the macroscopic area of tongue injury gradually increased. The total area of injury and the ulcer-like area reached a maximum on day 7 and then gradually decreased until disappearance on day 28. Expression of proinflammatory cytokines and chemokines occurred transiently within 1-4 hours after irradiation and returned to a normal level at 24 hours. This expression was again observed from days 3 to 5 and increased significantly on day 7, which approximately coincided with the histologic severity of tissue damage. Subcutaneous administration of palifermin at 3 mg/kg per day for 3 consecutive days before irradiation completely prevented ulcer formation in this model. In conclusion, we established a novel model of glossitis in rats, induced by X-ray irradiation, in which biphasic elevations of expression of proinflammatory cytokines and chemokines could be monitored. This model is considered useful to investigate the pathophysiology of oral mucositis and evaluate the preventive effect of pharmacological interventions on oral mucositis induced by X-ray irradiation.
(キーワード): Animals / Chemokines / Cytokines / Fibroblast Growth Factor 7 / Gene Expression / Glossitis / Male / Mucositis / Radiation Injuries, Experimental / Radiation-Protective Agents / Rats / Rats, Sprague-Dawley / Real-Time Polymerase Chain Reaction / Tongue / X-Rays
(出版サイトへのリンク): ● Publication site (DOI): 10.1124/jpet.113.208405
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 24060545; ● Search Scopus @ Elsevier (PMID): 24060545; ● Search Scopus @ Elsevier (DOI): 10.1124/jpet.113.208405

(DOI: 10.1124/jpet.113.208405, PubMed: 24060545) Lila Selim Ahmed Ali Abu Amr, Kousuke Nawata, Taro Shimizu, Tatsuhiro Ishida and Hiroshi Kiwada :
Use of polyglycerol (PG), instead of polyethylene glycol (PEG), prevents induction of the accelerated blood clearance phenomenon against long-circulating liposomes upon repeated administration,
International Journal of Pharmaceutics, Vol.456, No.1, 235-242, 2013.

(要約): The accelerated blood clearance (ABC) phenomenon accounts for the rapid systemic clearance of PEGylated nanocarriers upon repeated administrations. IgM production against the polyethylene glycol (PEG) coating in PEGylated liposomes is now known to be responsible for such unexpected pharmacokinetical alterations. The ABC phenomenon poses a remarkable clinical challenge by reducing the therapeutic efficacy of encapsulated drugs and causing harmful effects due to the altered tissue distribution pattern of the drugs. In this study, we investigated the in vivo performance of liposomes modified with polyglycerol (PG) upon repeated injection, and the in vivo therapeutic efficacy of such liposomes when they encapsulated a cytotoxic agent, doxorubicin (DXR). Repeated injection of PEG-coated liposomes in rats induced the ABC phenomenon, while repeated injection of PG-coated liposomes did not. In addition, DXR-containing PG-coated liposomes showed antitumor activity that was superior to that of free DXR and similar to that of DXR-containing PEG-coated liposomes upon repeated administration. These results indicate that polyglycerol (PG) might represent a promising alternative to PEG via enhancing the in vivo performance of liposomes by not eliciting the ABC phenomenon upon repeated administration.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2013.07.059
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 23928149; ● Search Scopus @ Elsevier (PMID): 23928149; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ijpharm.2013.07.059

(DOI: 10.1016/j.ijpharm.2013.07.059, PubMed: 23928149) E Alaaeldin, Lila Selim Ahmed Ali Abu Amr, Naoto Moriyoshi, H Sarahan, A Khaled, Tatsuhiro Ishida and Hiroshi Kiwada :
The co-delivery of oxaliplatin abrogates the immunogenic response to PEGylated siRNA-lipoplex.,
Pharmaceutical Research, Vol.30, No.9, 2344-2354, 2013.

(要約): In vivo application of siRNA/PEGylated cationic liposome complex (lipoplex) is impeded by two main obstacles: cytokine responses and anti-PEG IgM responses to PEGylated siRNA-lipoplex. Here, we investigated whether co-administration of oxaliplatin (l-OHP) abrogates the cytokine release and anti-PEG IgM production by PEGylated siRNA-lipoplex. Free l-OHP was administered either simultaneously or 30 min prior to PEGylated siRNA-lipoplex administration, and cytokine response and anti-PEG IgM production were evaluated. In addition, the effect of the liposomal encapsulation of l-OHP on the immunogenic response of PEGylated siRNA-lipoplex was investigated. Simultaneous co-administration of free l-OHP with PEGylated siRNA-lipoplex caused a significant reduction in anti-PEG IgM production, along with an increase in the cytokine response. Free l-OHP injected prior to the lipoplex injection, however, successfully reduced cytokine release and anti-PEG IgM response. Platination of siRNA by simultaneously administered free l-OHP might facilitate the dissociation of double-stranded siRNA to single-stranded siRNA, resulting in the inducement of a potent immuno-stimulation of siRNA via endosomal toll-like receptors (TLRs). On the other hand, encapsulation of l-OHP into the siRNA-lipoplex resulted in a reduction of both anti-PEG IgM production and cytokine responses. Our results suggest that, besides the expected therapeutic efficacy of co-administration, encapsulation of l-OHP into the PEGylated siRNA-lipoplex has great potential for minimizing the immunostimulation of PEGylated siRNA-lipoplex, resulting in a safe, applicable, and compliant treatment regimen for sequential clinical administration.
(キーワード): Animals / Antineoplastic Agents / Cytokines / Immunoglobulin M / Liposomes / Male / Mice / Mice, Inbred BALB C / NF-kappa B / Organoplatinum Compounds / Polyethylene Glycols / RNA, Small Interfering
(出版サイトへのリンク): ● Publication site (DOI): 10.1007/s11095-013-1078-4
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 23673556; ● Search Scopus @ Elsevier (PMID): 23673556; ● Search Scopus @ Elsevier (DOI): 10.1007/s11095-013-1078-4

(DOI: 10.1007/s11095-013-1078-4, PubMed: 23673556) 石田竜弘, 際田弘志 :
腫瘍内微小環境の能動的制御に基づくsiRNAデリバリー技術の開発とがん治療への展開,
薬学雑誌, Vol.133, No.3, 379-386, 2013年.

(要約): Efficient systemic siRNA delivery to cells in the target tissue is a current critical challenge in the drug delivery field. Several studies have demonstrated that nanoparticles such as polyethylene glycol (PEG)-coated siRNA-lipoplexes may enhance the systemic delivery of siRNA to tumor. However, the disordered tumor microenvironment still poses a potential impediment with respect to the efficient delivery of PEG-coated siRNA-lipoplexes. We recently showed that metronomic S-1 dosing (daily oral administration) enhanced the accumulation of PEG-coated liposome containing anticancer drug in solid tumor tissue and thereby increased therapeutic efficacy in tumor-bearing mouse model. To extend this work, we tried to investigate the effect of metronomic S-1 dosing on the intratumoral accumulation of PEG-coated siRNA-lipoplex and, thereby, their therapeutic efficacy in solid tumor-bearing mouse model. Results showed that metronomic S-1 dosing improved systemic delivery of intravenously injected PEG-coated siRNA-lipoplexes into solid tumor tissue. In addition, the combined therapy of S-1 and PEG-coated siRNA-lipoplexes showed potent tumor growth suppressive effect. Our proposed strategy may pose a promising therapeutic one to conquer cancer progression with siRNA.
(キーワード): combination therapy / small interfering RNA / lipoplex / metronomic chemotherapy / S-1
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/yakushi.12-00239-5
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1390001206129003136; ● Search Scopus @ Elsevier (DOI): 10.1248/yakushi.12-00239-5

(DOI: 10.1248/yakushi.12-00239-5, CiNii: 1390001206129003136) Taro Shimizu, Tatsuhiro Ishida and Hiroshi Kiwada :
Transport of PEGylated liposomes from the splenic marginal zone to the follicle in the induction phase of the accelerated blood clearance phenomenon.,
Immunobiology, Vol.218, No.5, 725-732, 2013.

(要約): The accelerated blood clearance (ABC) phenomenon has been reported to enhance the clearance of PEGylated liposomes from the blood circulation when the liposomes are injected into the same animal repeatedly. We have shown that anti-PEG IgM production from splenic B cells is crucial in the ABC phenomenon. In this study, we describe the crucial role of marginal zone (MZ) B cells in the anti-PEG IgM production and recognition of PEGylated liposomes in the induction phase of ABC phenomenon. Suppression of the anti-PEG IgM production was correlated with the disappearance of IgM(high) cells in the MZ, particularly MZ-B cells, following cyclophosphamide (CPA)-treatment, confirming that splenic MZ-B cells are responsible for anti-PEG IgM production. The MZ-B cells stimulated by a first dose of PEGylated liposomes internalized the second dose of PEGylated liposomes in a PEG modification-dependent manner and transported the liposomes into the follicle (FO) region. To the best of our knowledge, this is the first report showing that PEGylated liposome is recognized by MZ-B cells and transported to the FO region like blood-borne antigens or immune complexes. It is likely that PEGylated liposomes are recognized as a TI-2 antigen by the first line of defense against life-threatening infections by blood-borne organisms. Our study may have implications for immunogenicity of synthesized polymer-grafted therapeutics including nanocarriers, nucleic acids and proteins.
(キーワード): Animals / Antigens, T-Independent / B-Lymphocytes / Biological Transport / Cyclophosphamide / Immunoglobulin M / Injections, Intravenous / Liposomes / Male / Metabolic Clearance Rate / Molecular Mimicry / Polyethylene Glycols / Rats / Rats, Wistar / Spleen
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.imbio.2012.08.274
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 22995937; ● Search Scopus @ Elsevier (PMID): 22995937; ● Search Scopus @ Elsevier (DOI): 10.1016/j.imbio.2012.08.274

(DOI: 10.1016/j.imbio.2012.08.274, PubMed: 22995937) K Ichikawa, T Asai, K Shimizu, S Yonezawa, T Urakami, H Miyauchi, H Kawashima, Tatsuhiro Ishida, Hiroshi Kiwada and N Oku :
Suppression of immune response by antigen-decorated liposomes encapsulating model agents: A novel strategy for the treatment of allergy.,
Journal of Controlled Release, Vol.167, No.3, 284-289, 2013.

(要約): A specific antigen-sensitized animal has antigen-specific immune cells that recognize the antigen. Therefore, an antigen-modified drug carrier would be recognized by the immune cells. When such a carrier encapsulates certain drugs, these drugs should be specifically delivered to the immune cells. To examine this strategy, ovalbumin (OVA) was used as model antigen, and mice were presensitized with 100 μg of OVA with Alum. For preparing OVA-modified liposomes (OVA-lipo), OVA was incubated with DSPE-PEG-NHS and resulting DSPE-PEG-OVA was inserted into liposomes. OVA-specific IgG was produced 6-fold higher by intravenous injection of OVA-lipo thrice (10 μg as OVA in each injection) in OVA-sensitized mice, than that by the injection of control liposomes, suggesting that OVA-lipo was recognized by the antigen-specific immune cells. Moreover, intra-splenic accumulation of OVA-lipo was observed in OVA-sensitized mice, but not in naive mice. To achieve the delivery of a drug to specific immune cells, OVA-lipo encapsulated low dose of doxorubicin (DOX) as a model drug (20 μg DOX/mouse, Ca. 1 mg/kg) was injected in the sensitized mice. The injection of OVA-lipo encapsulating DOX suppressed the production of IgE against OVA, suggesting that the specific delivery of the drug to immune cells responsible for OVA recognition was achieved and that these immune cells were removed by the drug treatment. This strategy would be useful for the fundamental treatment of allergy by the use of immunosuppressing agents.
(キーワード): Animals / Antibiotics, Antineoplastic / Antigens / Cholesterol / Doxorubicin / Female / Hypersensitivity / Immunoglobulin E / Immunoglobulin G / Kidney / Liposomes / Liver / Lung / Mice / Mice, Inbred BALB C / Myocardium / Ovalbumin / Phosphatidylcholines / Phosphatidylethanolamines / Polyethylene Glycols / Spleen
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2013.02.002
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 23419947; ● Search Scopus @ Elsevier (PMID): 23419947; ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2013.02.002

(DOI: 10.1016/j.jconrel.2013.02.002, PubMed: 23419947) Ai Nagao, Lila Selim Ahmed Ali Abu Amr, Tatsuhiro Ishida and Hiroshi Kiwada :
Abrogation of the accelerated blood clearance phenomenon by SOXL regimen: Promise for clinical application.,
International Journal of Pharmaceutics, Vol.441, No.1-2, 395-401, 2013.

(要約): We recently proposed an S-1 combined with oxaliplatin (SOXL) regimen, a combination treatment consisting of oral metronomic S-1 dosing and intravenous administration of oxaliplatin (l-OHP) containing PEGylated liposomes, which showed potent antitumor activity in vivo. PEGylated liposomes induce what is referred to as the "accelerated blood clearance (ABC) phenomenon" upon repeated administration and consequently lose their long-circulating characteristics. This phenomenon seems to pose an impediment for the clinical application and use of PEGylated liposomal formulations. In the present study, l-OHP-containing PEGylated liposomes in the SOXL regimen significantly attenuated the ABC phenomenon in a dose-dependent manner through suppression of the anti-PEG IgM response, which allowed an enhanced hepatic uptake of subsequently injected test PEGylated liposomes. In tumor-bearing mice, the abrogation of the ABC phenomenon restored intratumor accumulation of subsequently injected PEGylated liposomes. Consequently, the therapeutic efficacy of the SOXL regimen over the combination of the free form of the drugs was credited not only with the selective delivery of drugs to the tumor tissue but also with ensuring an adequate accumulation of subsequent doses within the tumor tissue. The SOXL regimen we proposed may hold promise as a safe and effective treatment regimen for advanced colorectal cancer.
(キーワード): Administration, Metronomic / Animals / Antineoplastic Combined Chemotherapy Protocols / Colonic Neoplasms / Colorectal Neoplasms / Dose-Response Relationship, Drug / Drug Combinations / Drug Delivery Systems / Liposomes / Liver / Male / Mice / Mice, Inbred BALB C / Organoplatinum Compounds / Oxonic Acid / Polyethylene Glycols / Tegafur / Tissue Distribution
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2012.11.015
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 23174409; ● Summary page in Scopus @ Elsevier: 2-s2.0-84872804670

(DOI: 10.1016/j.ijpharm.2012.11.015, PubMed: 23174409, Elsevier: Scopus) Takuya Suzuki, Masako Ichihara, Kenji Hyodo, Eiichi Yamamoto, Tatsuhiro Ishida, Hiroshi Kiwada, Hiroshi Ishihara and Hiroshi Kikuchi :
Accelerated blood clearance of PEGylated liposomes containing doxorubicin upon repeated administration to dogs.,
International Journal of Pharmaceutics, Vol.436, No.1-2, 636-643, 2012.

(要約): The accelerated blood clearance phenomenon involving anti-PEG IgM production has been recognized as an important issue for the design and development of PEGylated liposomes. Here, we show that empty PEGylated liposomes and Doxil, PEGylated liposomes containing doxorubicin, both caused anti-PEG IgM production and thereby a rapid clearance of the second and/or third dose of Doxil in Beagle dogs in a lipid-dose, inverse-dependent manner. It appears that the pharmacokinetic profile of the second and third administration of Doxil reflected the presence of anti-PEG IgM circulating in the blood. Doxil plus an excess amount of empty PEGylated liposomes rather enhanced the production of anti-PEG IgM compared to Doxil of the same doxorubicin dose. During sequential administration, increasing the lipid dose of Doxil in each dose by the addition of empty PEGylated liposomes strongly attenuated the magnitude of the ABC phenomenon during the effectuation phase of a second and third dose of Doxil. Our results suggest that the pre-clinical study of anti-cancer drug-containing PEGylated liposomes with dogs must be carefully designed and performed with monitoring of the anti-PEG IgM and liposomal drugs circulating in the blood.
(キーワード): Animals / Antibiotics, Antineoplastic / Dogs / Doxorubicin / Immunoglobulin M / Liposomes / Male / Polyethylene Glycols / Rats / Rats, Wistar
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2012.07.049
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 22850293; ● Search Scopus @ Elsevier (PMID): 22850293; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ijpharm.2012.07.049

(DOI: 10.1016/j.ijpharm.2012.07.049, PubMed: 22850293) Lila Selim Ahmed Ali Abu Amr, N Eldin Essam, Masako Ichihara, Tatsuhiro Ishida and Hiroshi Kiwada :
Multiple administration of PEG-coated liposomal oxaliplatin enhances its therapeutic efficacy: a possible mechanism and the potential for clinical application.,
International Journal of Pharmaceutics, Vol.438, No.1-2, 176-183, 2012.

(要約): We previously developed a PEG-coated cationic liposome that enabled dual targeting delivery of oxaliplatin (l-OHP) to both tumor endothelial cells and tumor cells in a solid tumor. The targeted liposomal l-OHP formulation consequently elicited potent antitumor efficacy in a murine solid tumor model after 3 sequential injections. However, the probable mechanism(s) for this enhanced antitumor activity has not been fully elucidated. In the present study, therefore, the changes in tumor microenvironment induced by sequential administration of liposomal l-OHP were investigated, with emphasis on its impact to the intratumoral localization of the subsequently injected dose. In addition, the potential for anti-PEG IgM production upon repeated administration of liposomal l-OHP-containing PEGylated lipid was clearly revealed. Two sequential injections of liposomal l-OHP induced superior apoptotic activity in tumor tissue and thus resulted in broader intratumor distribution of the subsequent test dose of PEG-coated cationic liposomes, compared with a single injection of liposomal l-OHP. In addition, it was confirmed that repeated administration of liposomal l-OHP did not induce a significant anti-PEG IgM response, indicating that l-OHP encapsulated in PEG-coated liposomes was efficient in abrogating the ABC phenomenon. These results suggest that sequential treatment strategies with liposomal cytotoxic agents might be superior to mono-treatment strategies in achieving alterations in the tumor microenvironment and maintaining/restoring the pharmacokinetics of the formulation, and, therefore, would result in substantial therapeutic efficacy.
(キーワード): Animals / Antineoplastic Agents / Apoptosis / Cell Line, Tumor / Immunoglobulin M / Liposomes / Male / Mice / Mice, Inbred C57BL / Neoplasms / Organoplatinum Compounds / Polyethylene Glycols / Tissue Distribution / Treatment Outcome
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2012.08.030
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 22944302; ● Search Scopus @ Elsevier (PMID): 22944302; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ijpharm.2012.08.030

(DOI: 10.1016/j.ijpharm.2012.08.030, PubMed: 22944302) Taro Shimizu, Masako Ichihara, Yasuo Yoshioka, Tatsuhiro Ishida, Shinsaku Nakagawa and Hiroshi Kiwada :
Intravenous administration of polyethylene glycol-coated (PEGylated) proteins and PEGylated adenovirus elicits an anti-PEG immunoglobulin M response.,
Biological & Pharmaceutical Bulletin, Vol.35, No.8, 1336-1342, 2012.

(要約): A single intravenous administration of polyethylene glycol-coated (PEGylated) bovine serum albumin (BSA) and ovalbumin (OVA) elicited an anti-PEG immunoglobulin M (IgM) response, similar to that from PEGylated liposomes, although the administration did not elicit specific neutralizing antibodies to BSA and OVA. A cross-reactivity was observed between anti-PEG IgMs elicited by PEG-BSA and PEGylated liposomes. The anti-PEG IgM level induced by PEGylated proteins (BSA and OVA) reached the maximum at day 5 following intravenous injection. This production pattern was consistent with that induced by PEGylated liposomes. Splenectomy suppressed the anti-PEG IgM response against PEG-BSA and PEGylated liposomes. These observations relating PEG-BSA and PEGylated liposomes indicate that PEGylated proteins might promote the immune responses against PEG with a mechanism similar to that of PEGylated liposomes. In addition, a single intravenous administration of PEGylated adenovirus (PEG-Ad) also elicited an anti-PEG IgM response in a PEG-modification ratio dependent manner. To the best of our knowledge, this is the first report showing that an intravenous administration can elicit an anti-PEG IgM response against PEGylated substances. It appears that anti-PEG IgMs can be produced by the systemic administration of a PEGylated substance and may limit the efficacy of PEGylated substances such as proteins, Ad vector and nanoparticles, due to a cross-reactivity seen in some patients. The immunogenicity of PEGylated substances is usually tested against those very substances, rather than against covalently attached PEG. Our study suggests that the PEG immunogenicity of PEGylated therapeutic agents and particles merits further investigation.
(キーワード): Adenoviridae / Animals / Cattle / Immunoglobulin M / Injections, Intravenous / リポソーム (liposomes) / Male / Ovalbumin / Polyethylene Glycols / Rats / Rats, Wistar / Serum Albumin / Splenectomy
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b12-00276
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 22863934; ● CiNii @ 国立情報学研究所 (CRID): 1390001204632293632; ● Search Scopus @ Elsevier (PMID): 22863934; ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.b12-00276

(DOI: 10.1248/bpb.b12-00276, PubMed: 22863934, CiNii: 1390001204632293632) Lila Selim Ahmed Ali Abu Amr, Haruna Matsumoto, Yusuke Doi, Hiroyuki Nakamura, Tatsuhiro Ishida, Hiroshi Kiwada and Hiroshi Kiwada :
Tumor type dependent vascular permeability constitutes a potential impediment to the therapeutic efficacy of liposomal oxaliplatin.,
European Journal of Pharmaceutics and Biopharmaceutics, Vol.81, No.3, 524-531, 2012.

(要約): The delivery of anticancer agents to solid tumors is problematic. Nanomolecular drug carriers represent an attractive alternative strategy for efficient anticancer drug delivery to tumor tissue, because they appear to target tumors and have limited toxicity in normal tissue. However, inadequate and heterogeneous distribution of nanocarriers in tumor tissue is a major impediment for their efficient use in clinical cancer therapy. In the present study, we examined the effect of tumor type on the intratumor accumulation and distribution of polyethylene glycol (PEG)-coated liposomes using in vivo mouse models of three cancer cell lines: colon adenocarcinoma (C26), Lewis lung carcinoma (LLC), and B16BL6 melanoma (B16BL6). The tumor growth inhibition and the apoptotic response of oxaliplatin (l-OHP) encapsulated in the PEG-coated liposomes were tumor type dependent and correlated with a tendency toward tumor accumulation and intratumor distribution of PEG-coated liposome, in contrast to in vitro cytotoxicity of l-OHP. A potent antitumor effect observed in both C26 and LLC tumor-bearing mice was attributed to the enhanced extravasation with subsequent preferential accumulation of PEG-coated liposomes through tumor vasculature with high permeability. Our results suggest that the permeability of tumor vasculature constitutes a potential impediment to tumor localization and thereby to the antitumor efficacy of PEG-coated liposomal anticancer drugs.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ejpb.2012.04.010
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 22554766; ● Search Scopus @ Elsevier (PMID): 22554766; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ejpb.2012.04.010

(DOI: 10.1016/j.ejpb.2012.04.010, PubMed: 22554766) Jose Mario Barichello, Shinji Kizuki, Tatsuaki Tagami, Soares Alberto Lira Luiz, Hiroshi Kikuchi, Tatsuhiro Ishida and Hiroshi Kiwada :
Agitation during lipoplex formation harmonizes the interaction of siRNA to cationic liposomes.,
International Journal of Pharmaceutics, Vol.430, No.1-2, 359-365, 2012.

(要約): We recently demonstrated that agitation during lipoplex formation (vorLTsiR) improves the gene knockdown effect of siRNA because the resultant decrease in lipoplex size leads to an enhanced uptake by cells. In furthering this line of research, the present study was focused on the interaction of siRNA to cationic liposomes during lipoplex preparation. A fluorescence resonance energy transfer (FRET) study indicated that the application of agitation in the presence of siRNA effectively reorganized positively charged lipids (DC-6-14 and DOPE) in an order that effectively promoted further electrostatic interaction between the negatively charged phosphate backbone of siRNA and the positively charged lipids in the cationic liposome membrane. A circular dichroism (CD) study indicated that the agitation did not bring about a change in the A-form helix of siRNA, therefore the interactions between the lateral anionic groups of siRNA - responsible for the characteristic bands of the A-form helix - and cationic liposomes were effectively promoted. Factorial design coupled with response surface methodology was used to statistically analyze the influence of vortex speed and time and siRNA dose on the in vitro gene knockdown effects of siRNA-lipoplex that were spontaneously formulated (spoLTsiR) along with that formulated under agitation (vorLTsiR). The analysis indicated that vortex speed plays the most important role in enhancing the gene knockdown effect of siRNA among the three variables, although all three are important. It was concluded that the high energy transmitted by applying agitation during lipoplex formation harmonized the interaction of siRNA to positively charged lipids (DC-6-14 and DOPE) in cationic liposomes, resulting in a superior gene knockdown efficacy of vorLTsiR compared to spoLTsiR. Our study suggests that the preparation procedure is one of the critical factors in producing the enhanced gene knockdown effect of siRNA.
(キーワード): Cations / Circular Dichroism / Ethanolamines / Factor Analysis, Statistical / Fluorescence Resonance Energy Transfer / Gene Knockdown Techniques / HeLa Cells / Humans / Liposomes / Luciferases / Motion / Myristates / Nucleic Acid Conformation / Phosphatidylethanolamines / RNA Interference / RNA, Small Interfering / Time Factors / Transfection
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2012.04.006
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 22525078; ● Search Scopus @ Elsevier (PMID): 22525078; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ijpharm.2012.04.006

(DOI: 10.1016/j.ijpharm.2012.04.006, PubMed: 22525078) Tatsuaki Tagami, Lila Selim Ahmed Ali Abu Amr, Mariko Matsunaga, Naoto Moriyoshi, Hiroyuki Nakamura, Kazuya Nakamura, Takuya Suzuki, Yusuke Doi, Tatsuhiro Ishida and Hiroshi Kiwada :
Improved intratumoral delivery of PEG-coated siRNA-lipoplexes by combination with metronomic S-1 dosing in a murine solid tumor model,
Drug Delivery and Translational Research, Vol.2, No.2, 77-86, 2012.

(出版サイトへのリンク): ● Publication site (DOI): 10.1007/s13346-012-0059-1
(文献検索サイトへのリンク): ● Summary page in Scopus @ Elsevier: 2-s2.0-84864774906

(DOI: 10.1007/s13346-012-0059-1, Elsevier: Scopus) Lila Selim Ahmed Ali Abu Amr, Tomoko Okada, Yusuke Doi, Masako Ichihara, Tatsuhiro Ishida and Hiroshi Kiwada :
Combination therapy with metronomic S-1 dosing and oxaliplatin-containing PEG-coated cationic liposomes in a murine colorectal tumor model: Synergy or antagonism?,
International Journal of Pharmaceutics, Vol.426, 263-270, 2012.

(要約): Combination therapy with 2 or more drugs with different mechanisms of action has been considered a promising strategy for the effective treatment of advanced and metastatic cancers. However, the rational design of combination therapy represents a potential prerequisite for its effectiveness. Recently, we showed that the combination of oral metronomic S-1 dosing with oxaliplatin (l-OHP)-containing PEG-coated "neutral" liposomes exerted excellent antitumor activity. In addition, we recently designed a PEG-coated "cationic" liposome for dual-targeting delivery of l-OHP to tumor endothelial cells and tumor cells in a solid tumor. This targeted liposomal l-OHP formulation showed efficient antitumor activity in a murine tumor model, compared with l-OHP-containing PEG-coated "neutral" liposomes. In the present study, we investigated the issue of whether metronomic S-1 dosing with l-OHP-containing PEG-coated "cationic" liposomes creates synergy. Unfortunately, metronomic S-1 dosing resulted in impaired delivery of PEG-coated "cationic" liposomes into tumor tissue, presumably by decreasing the binding sites on tumor blood vessels available for the liposomes. The anticipated cytotoxic synergistic effect of the combination treatment was not achieved. Instead, the combination treatment showed lower antitumor efficacy than l-OHP-containing PEG-coated "cationic" liposomes alone. These results suggest that the combined treatment of S-1 and l-OHP-containing PEG-coated "cationic" liposomes seems to be antagonistic rather than synergistic.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2012.01.046
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 22310465; ● Search Scopus @ Elsevier (PMID): 22310465; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ijpharm.2012.01.046

(DOI: 10.1016/j.ijpharm.2012.01.046, PubMed: 22310465) Tatsuaki Tagami, Takuya Suzuki, Mariko Matsunaga, Kazuya Nakamura, Naoto Moriyoshi, Tatsuhiro Ishida and Hiroshi Kiwada :
Anti-angiogenic therapy via cationic liposome-mediated systemic siRNA delivery.,
International Journal of Pharmaceutics, Vol.422, No.1-2, 280-289, 2012.

(要約): siRNA has been touted as a therapeutic molecule against genetic diseases, which include cancers. But several challenging issues remain in order to achieve efficient systemic siRNA delivery and a sufficient therapeutic effect for siRNA in vivo. Cationic liposome shows promise as a carrier for nucleic acids, as it can selectively bind to angiogenic tumor blood vessels. In this way, anti-angiogenic therapy via cationic liposome-mediated systemic siRNA delivery could be achieved in cancer therapy. In the present study, we proved our assumption by preparing various kinds of polyethylene glycol (PEG)-coated siRNA/cationic liposome complexes (siRNA-lipoplexes) and screening the avidity of these siRNA-lipoplexes upon angiogenic tumor blood vessels by means of a murine dorsal air sac (DAS) model. The lipoplex, having a lipid composition of DC-6-14/POPC/CHOL/DOPE/mPEG(2000)-DSPE=20/30/30/20/5 (molar ratio) and a charge ratio of cationic liposome and siRNA=3.81 (+/-), showed a higher binding index to newly formed blood vessels. Systemic injection with the lipoplex containing siRNA for the Argonaute2 gene (apoptosis-inducible siRNA) resulted in significant anti-tumor effect without severe side effects in mice with Lewis lung carcinoma. Our results indicate that the PEGylated cationic liposome-mediated systemic delivery of cytotoxic siRNA achieves anti-angiogenesis, resulting in the suppression of tumor growth.
(キーワード): Air Sacs / Animals / Argonaute Proteins / Carcinoma, Lewis Lung / Cations / Cell Cycle Checkpoints / Cell Proliferation / Cholesterol / Ethanolamines / Genetic Therapy / Lipids / Liposomes / Male / Mice / Myristates / Neovascularization, Pathologic / Neovascularization, Physiologic / Phosphatidylcholines / Phosphatidylethanolamines / Polyethylene Glycols / RNA Interference / RNA, Small Interfering / Time Factors / Transfection / Tumor Burden
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2011.10.059
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 22101286; ● Search Scopus @ Elsevier (PMID): 22101286; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ijpharm.2011.10.059

(DOI: 10.1016/j.ijpharm.2011.10.059, PubMed: 22101286) Kazuya Nakamura, Lila Selim Ahmed Ali Abu Amr, Mariko Matsunaga, Yusuke Doi, Tatsuhiro Ishida and Hiroshi Kiwada :
A double-modulation strategy in cancer treatment with a chemotherapeutic agent and siRNA.,
Molecular Therapy, Vol.19, No.11, 2040-2047, 2011.

(要約): 5-Fluorouracil (5-FU) is broadly considered the drug of choice for treating human colorectal cancer (CRC). However, 5-FU resistance, mainly caused by the overexpression of antiapoptotic proteins such as Bcl-2, often leads ultimately to treatment failure. We here investigated the effect of Bcl-2 gene silencing, using small interfering RNA (siRNA) (siBcl-2), on the efficacy of 5-FU in CRC. Transfection of siBcl-2 by a Lipofectamine2000/siRNA lipoplex effectively downregulated Bcl-2 expression in the DLD-1 cell line (a CRC), resulting in significant cell growth inhibition in vitro upon treatment with 5-FU. For in vivo treatments, S-1, an oral formulation of Tegafur (TF), a prodrug of 5-FU, was used to mimic 5-FU infusion. The combined treatment of polyethylene glycol (PEG)-coated siBcl-2-lipoplex and S-1 showed superior tumor growth suppression in a DLD-1 xenograft model, compared to each single treatment. Surprisingly, daily S-1 treatment enhanced the accumulation of PEG-coated siBcl-2-lipoplex in tumor tissue. We propose a novel double modulation strategy in cancer treatment, in which chemotherapy enhances intratumoral siRNA delivery and the delivered siRNA enhances the chemosensitivity of tumors. Combination of siRNA-containing nanocarriers with chemotherapy may compensate for the limited delivery of siRNA to tumor tissue. In addition, such modulation strategy may be considered a promising therapeutic approach to successfully managing 5-FU-resistant tumors.
(キーワード): Animals / Antineoplastic Agents / Apoptosis / Cell Line, Tumor / Cell Survival / Combined Modality Therapy / Drug Combinations / Gene Knockdown Techniques / Gene Silencing / Gene Therapy / Genes, bcl-2 / Humans / Male / Mice / Mice, Inbred BALB C / Mice, Nude / Neoplasms / Oxonic Acid / RNA, Small Interfering / Tegafur / Xenograft Model Antitumor Assays
(出版サイトへのリンク): ● Publication site (DOI): 10.1038/mt.2011.174
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21878904; ● Search Scopus @ Elsevier (PMID): 21878904; ● Search Scopus @ Elsevier (DOI): 10.1038/mt.2011.174

(DOI: 10.1038/mt.2011.174, PubMed: 21878904) Tatsuaki Tagami, Takuya Suzuki, Kiyomi Hirose, Jose Mario Barichello, Naoshi Yamazaki, Tomohiro Asai, Naoto Oku, Tatsuhiro Ishida and Hiroshi Kiwada :
Argonaute2 is a potential target for siRNA-based cancer therapy for HT1080 human fibrosarcoma.,
Drug Delivery and Translational Research, Vol.1, No.4, 277-288, 2011.

(出版サイトへのリンク): ● Publication site (DOI): 10.1007/s13346-011-0025-3
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1007/s13346-011-0025-3

(DOI: 10.1007/s13346-011-0025-3) Atsushi Saito, Hiroaki Shimizu, Yusuke Doi, Tatsuhiro Ishida, Miki Fujimura, Takashi Inoue, Hiroshi Kiwada and Teiji Tominaga :
Immunoliposomal drug delivery system targeting lectin-like oxidized low density lipoprotein receptor 1 for carotid plaque lesion in rats.,
Journal of Neurosurgery, Vol.115, No.4, 720-727, 2011.

(要約): Targeted drug delivery with immunoliposomes has been applied to various in vivo animal models and is newly focused as a novel therapeutic target. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX1) is a potent regulator of systemic atherosclerosis, and the authors focused on its effect on carotid plaques. The authors developed a LOX1-targeted liposomal rho-kinase inhibitor and examined the therapeutic effect on carotid intimal hypertrophy in rats. LOX1-targeted rho-kinase inhibitor fasudil-containing liposomes, composed of hydrogenated soy phosphatidylcholine/cholesterol/PEG(2000)-DSPE, were prepared by conjugating anti-LOX1 antibodies on the surface and by remote loading of fasudil. Carotid intimal hypertrophy was induced by balloon injury, and the drugs were intravenously administered on Day 3 postinjury. The rats were divided into 4 groups: nontreatment, treatment with intravenous fasudil (2 mg), treatment with liposomal fasudil (2 mg), and treatment with LOX1-targeted liposomal fasudil (2 mg). The authors compared intimal hypertrophy, atherosclerotic factor, and matrix metalloproteinase-9 expression among groups. DiI-labeled LOX1-targeted liposomes were prominently observed in the lesions on Day 7 after the surgery. The intimal thickness was significantly reduced in the LOX1-targeted liposomal fasudil-treated group (mean 81.6 ± 13.9 m) compared with the other groups (no treatment 105.4 ± 16.8 m; fasudil treatment 102.4 ± 20.0 m; and liposomal fasudil treatment 102.8 ± 22.2 m; p = 0.046). Matrix metalloproteinase-9 expression was also significantly reduced in the LOX1-targeted liposomal fasudil group. Liposomes conjugated with anti-LOX1 antibody effectively reached carotid artery lesions, and liposomal rho-kinase significantly inhibited intimal hypertrophy. The new liposomal drug delivery system targeting LOX1 may become a therapeutic strategy for atherosclerotic diseases.
(キーワード): 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Animals / Carotid Artery Diseases / Carotid Artery, Common / Drug Delivery Systems / Liposomes / Male / Plaque, Atherosclerotic / Rats / Rats, Sprague-Dawley / Scavenger Receptors, Class E
(出版サイトへのリンク): ● Publication site (DOI): 10.3171/2011.5.JNS10227
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21682565; ● Search Scopus @ Elsevier (PMID): 21682565; ● Search Scopus @ Elsevier (DOI): 10.3171/2011.5.JNS10227

(DOI: 10.3171/2011.5.JNS10227, PubMed: 21682565) Jose Mario Barichello, Shinji Kizuki, Tatsuaki Tagami, Tomohiro Asai, Tatsuhiro Ishida, Hiroshi Kikuchi, Naoto Oku and Hiroshi Kiwada :
Agitation during lipoplex formation improves the gene knockdown effect of siRNA.,
International Journal of Pharmaceutics, Vol.410, No.1-2, 153-160, 2011.

(要約): The successful delivery of therapeutic siRNA to the designated target cells and their availability at the intracellular site of action are crucial requirements for successful RNAi therapy. In the present study, we focused on the siRNA-lipoplex preparation procedure and its effect on the gene-knockdown efficiency of siRNA in vitro. Agitation (vortex-mixing) during siRNA-lipoplex (vor-LTsiR) preparation and its effect on the gene-knockdown efficiency of stably expressed cell GFP was investigated, and their efficiency was compared with that of spontaneously formed lipoplex (spo-LTsiR). A dramatic difference in size between lipoplexes was observed at the N/P ratio of 7.62 (siRNA dose of 30 nM), even though both lipoplexes were positively charged. With the siRNA dose of 30 nM, vor-LTsiR accomplished a 50% gene-knockdown, while spo-LTsiR managed a similar knockdown effect at the 120 nM level, suggesting that the preparation procedure remarkably affects the gene-knockdown efficacy of siRNA. The uptake of vor-LTsiR was mainly via clathrin-mediated endocytosis, whereas that of spo-LTsiR was via membrane fusion. In addition, by inhibiting clathrin-mediated endocytosis, the gene-knockdown efficiency was significantly lowered. The size of the lipoplex, promoted by the preparation procedure, is likely to define the entry pathway, resulting in an increased amount of siRNA internalized in cells and an enhanced gene-knockdown efficacy. The results of the present study definitively show that a proper siRNA-lipoplex preparation procedure makes a significant contribution to the efficiency of cellular uptake, and thereby, to the gene-knockdown efficiency of siRNA.
(キーワード): Cations / Cell Line, Tumor / Clathrin / Endocytosis / Gene Knockdown Techniques / Gene Silencing / Humans / Lipids / Liposomes / RNA, Small Interfering
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2011.03.001
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21392562; ● Search Scopus @ Elsevier (PMID): 21392562; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ijpharm.2011.03.001

(DOI: 10.1016/j.ijpharm.2011.03.001, PubMed: 21392562) Masako Ichihara, Taro Shimizu, Ami Imoto, Yuki Hashiguchi, Yumi Uehara, Tatsuhiro Ishida and Hiroshi Kiwada :
Anti-PEG IgM response against PEGylated liposomes in mice and rats.,
Pharmaceutics, Vol.3, No.1, 1-11, 2011.

(出版サイトへのリンク): ● Publication site (DOI): 10.3390/pharmaceutics3010001
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.3390/pharmaceutics3010001

(DOI: 10.3390/pharmaceutics3010001) Tatsuaki Tagami, Yumi Uehara, Naoto Moriyoshi, Tatsuhiro Ishida and Hiroshi Kiwada :
Anti-PEG IgM production by siRNA encapsulated in a PEGylated lipid nanocarrier is dependent on the sequence of the siRNA.,
Journal of Controlled Release, Vol.151, No.2, 149-154, 2011.

(要約): We recently reported that the prolonged circulation property of PEGylated cationic liposomes containing nucleic acids disappears, if the second dose is injected within a few days later, due to the production of anti-PEG IgM. This accelerated blood clearance is a concern for treating diseases which require repeated treatment with a PEGylated formulation containing nucleic acids. In this study, we investigated the effect of encapsulation of siRNA in a recently introduced PEGylated lipid nanocarrier for which the term "wrapsome" (PEGylated wrapsome, PEG-WS) was proposed as well as the sequence of the encapsulated siRNA on anti-PEG IgM production. siRNA encapsulated in PEG-WS produced little anti-PEG IgM relative to siRNA in conventional PEGylated lipoplexes. The sequence of siRNA in the PEG-WL dramatically affected the anti-PEG IgM production; a potent immune stimulatory siRNA induced a higher anti-PEG IgM production. Such enhanced effect was abrogated by incorporation of 2'-O-methyl (2'-OMe) uridine into the sequence of siRNA, probably via inhibiting cytokine induction such as IL-6 and TNF-. Our results strongly indicate that the use of an encapsulation-type lipid nanocarrier with a low immuno-stimulatory siRNA may allow repeated dosing of siRNA containing PEGylated formulations without the induction of a strong immune reaction against PEG and thus may advance synthetic siRNA into a broad range of therapeutic applications.
(キーワード): Animals / Base Sequence / Drug Carriers / Immunoglobulin M / Liposomes / Male / Mice / Nanocapsules / Nanoparticles / Polyethylene Glycols / RNA, Small Interfering
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2010.12.013
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21223988; ● Search Scopus @ Elsevier (PMID): 21223988; ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2010.12.013

(DOI: 10.1016/j.jconrel.2010.12.013, PubMed: 21223988) Yusuke Doi, Tomoko Okada, Haruna Matsumoto, Masako Ichihara, Tatsuhiro Ishida and Hiroshi Kiwada :
Combination therapy of metronomic S-1 dosing with oxaliplatin-containing PEG-coated liposome improves antitumor activity in a murine colorectal tumor model.,
Cancer Science, Vol.101, No.11, 2470-2475, 2010.

(要約): Metronomic chemotherapy has been advocated recently as a novel chemotherapeutic regimen. Polyethylene glycol (PEG)-coated liposomes are well known to accumulate in solid tumors by virtue of the highly permeable angiogenic blood vessels characteristic for growing tumor tissue, the so-called "enhanced permeability and retention (EPR) effect". To expand the range of applications and investigate the clinical value of the combination strategy, the therapeutic benefit of metronomic S-1 dosing in combination with oxaliplatin (l-OHP)-containing PEG-coated liposomes was evaluated in a murine colon carcinoma-bearing mice model. S-1 is an oral fluoropyrimidine formulation and metronomic S-1 dosing is a promising alternative to infused 5-FU in colorectal cancer therapy. Therefore, the combination of S-1 with l-OHP may be an alternative to FOLFOX (infusional 5-FU/leucovorin (LV) in combination with l-OHP), which is a first-line therapeutic regimen of a colorectal carcinoma. The combination of oral metronomic S-1 dosing with intravenous administration of liposomal l-OHP formulation exerted excellent antitumor activity without severe overlapping side-effects, compared with either metronomic S-1 dosing, free l-OHP or liposomal l-OHP formulation alone or metronomic S-1 dosing plus free l-OHP. We confirmed that the synergistic antitumor effect is due to prolonged retention of l-OHP in the tumor on account of the PEG-coated liposomes, presumably via alteration of the tumor microenvironment caused by the metronomic S-1 treatment. The combination regimen proposed here may be a breakthrough in treatment of intractable solid tumors and an alternative to FOLFOX in advanced colorectal cancer therapy with acceptable tolerance and preservation of quality of life (QOL).
(キーワード): Animals / Antineoplastic Combined Chemotherapy Protocols / Cell Line, Tumor / Colorectal Neoplasms / Disease Models, Animal / Dose-Response Relationship, Drug / Drug Combinations / Drug Synergism / Humans / Liposomes / Male / Mice / Mice, Inbred BALB C / Organoplatinum Compounds / Oxonic Acid / Polyethylene Glycols / Tegafur / Treatment Outcome / Tumor Burden
(出版サイトへのリンク): ● Publication site (DOI): 10.1111/j.1349-7006.2010.01678.x
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 20731663; ● Search Scopus @ Elsevier (PMID): 20731663; ● Search Scopus @ Elsevier (DOI): 10.1111/j.1349-7006.2010.01678.x

(DOI: 10.1111/j.1349-7006.2010.01678.x, PubMed: 20731663) T Ishihara, T Maeda, H Sakamoto, N Takasaki, M Shigyo, Tatsuhiro Ishida, Hiroshi Kiwada, Y Mizushima and T Mizushima :
Evasion of the accelerated blood clearance phenomenon by coating of nanoparticles with various hydrophilic polymers.,
Biomacromolecules, Vol.11, No.10, 2700-2706, 2010.

(要約): The accelerated blood clearance (ABC) phenomenon is induced upon repeated injections of poly(ethylene glycol) (PEG)-coated colloidal carriers. It is essential to suppress this phenomenon in a clinical setting because the pharmacokinetics must be reproducible. In this study, we evaluated the induction of the ABC phenomenon using nanoparticles coated with various hydrophilic polymers instead of PEG. Nanoparticles encapsulating prostaglandin E1 were prepared by the solvent diffusion method from a blend of poly(lactic acid) (PLA) and block copolymers consisting of various hydrophilic polymers and PLA. Coating of nanoparticles with poly(N-vinyl-2-pyrrolidone) (PVP), poly(4-acryloylmorpholine), or poly(N,N-dimethylacrylamide) led to extended residence of the nanoparticles in blood circulation in rats, although they had a shorter half-life than the PEG-coated nanoparticles. The ABC phenomenon was not induced upon repeated injection of PVP-coated nanoparticles at various time intervals, dosages, or frequencies, whereas it was elicited by PEG-coated nanoparticles. In addition, anti-PVP IgM antibody, which is estimated to be one of the crucial factors for induction of the ABC phenomenon, was not produced after injection of PVP-coated nanoparticles. These results suggest that the use of PVP, instead of PEG, as a coating material for colloidal carriers can evade the ABC phenomenon.
(キーワード): Animals / Blood Circulation Time / Drug Carriers / Enzyme-Linked Immunosorbent Assay / Hydrophobic and Hydrophilic Interactions / Immunoglobulin M / Injections, Intravenous / Male / Metabolic Clearance Rate / Nanoparticles / Polymers / Polyvinyls / Pyrrolidines / Rats / Rats, Wistar
(出版サイトへのリンク): ● Publication site (DOI): 10.1021/bm100754e
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 20795699; ● Search Scopus @ Elsevier (PMID): 20795699; ● Search Scopus @ Elsevier (DOI): 10.1021/bm100754e

(DOI: 10.1021/bm100754e, PubMed: 20795699) Y Eto, Y Yoshioka, Tatsuhiro Ishida, X Yao, T Morishige, S Narimatsu, H Mizuguchi, Y Mukai, N Okada, Hiroshi Kiwada and S Nakagawa :
Optimized PEGylated adenovirus vector reduces the anti-vector humoral immune response against adenovirus and induces a therapeutic effect against metastatic lung cancer.,
Biological & Pharmaceutical Bulletin, Vol.33, No.9, 1540-1544, 2010.

(要約): Application of adenovirus vectors (Adv) in metastatic cancer treatment is limited. We previously demonstrated that covalent conjugation of polyethleneglycol (PEG) to Adv enhances therapeutic effects and decreases toxic side-effects after systemic administration, but the level of immune response to PEGylated Adv (PEG-Ad) was not examined. Here, we examined the effect of PEGylation of Adv on the production of anti-Adv antibodies and antitumor response. We constructed a set of PEG-Ad using 5-kDa PEG, with modification rates of 30%, 45% and 90%. After systemic administration of Advs to rats, we examined the level of anti-Adv immunoglobulin (Ig)G and IgM in serum. The levels of anti-Adv IgG and anti-Adv IgM in rats treated with unmodified Adv were higher than those in control group. Rats treated with PEG-Ad that had a 90% modification rate showed lower level of anti-Adv IgG and anti-Adv IgM than those treated with unmodified Adv, whereas rats treated with PEG-Ad that had a 30% or 45% modification rate showed a similar level of anti-Adv IgG and IgM to those treated with unmodified Adv. Systemic administration of PEG-Ad that had a 90% modification rate, and expressed tumor necrosis factor-alpha, significantly reduced the number of metastatic colonies in the lung compared to unmodified Adv, with negligible side effects. These results suggest that systemic administration of PEG-Ad with an appropriate PEG modification rate has the potential to reduce the production of antibodies against Adv and increase the therapeutic response against metastatic cancer.
(キーワード): Adenoviridae / Animals / Antibodies, Viral / Antiviral Agents / Female / Gene Therapy / Genetic Vectors / HEK293 Cells / Humans / Lung Neoplasms / Male / Melanoma, Experimental / Mice / Mice, Inbred C57BL / Polyethylene Glycols / Rats / Rats, Wistar
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.33.1540
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 20823571; ● Search Scopus @ Elsevier (PMID): 20823571; ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.33.1540

(DOI: 10.1248/bpb.33.1540, PubMed: 20823571) Hiroyuki Yamazaki, Masateru Miyake, Naoki Kamada, Toru Nishibayashi, Tadashi Mukai, Masaaki Odomi, Tatsuhiro Ishida and Hiroshi Kiwada :
Co-administration of tacrolimus suppresses pharmacokinetic modulation of multiple subcutaneously administrated human interferon-alpha in beagle dogs.,
Drug Metabolism and Pharmacokinetics, Vol.25, No.2, 149-154, 2010.

(要約): Specific antibody production is an important issue in crossover pharmacokinetic (PK) studies of protein-based formulations. We recently reported that intravenous co-administration of tacrolimus with multiple human interferon-alpha (h-IFN) administrations successfully suppressed the production of anti-h-IFN antibodies in rats. Since crossover PK studies are preferentially carried out using larger animals such as dogs or monkeys that are capable of accepting the same dosage formulations as those for clinical use, we extended our study of co-administration of tacrolimus with multiple h-IFN administrations to beagle dogs in the present study. Beagle dogs were subcutaneously administered 0.5 million IU/kg of h-IFN once a week for 4 weeks. In some experiments, tacrolimus at 0.01 or 0.1 mg/kg was intravenously co-administered at the same time as the h-IFN administration. Co-administration of the lower dose of tacrolimus (0.01 mg/kg) failed to suppress the anti-h-IFN IgG responses, while co-administration of the higher dose (0.1 mg/kg) successfully suppressed these responses. Moreover, co-administration of tacrolimus had little effect on the serum creatinine concentrations, suggesting that multiple administrations of tacrolimus at the concentrations examined did not cause severe renal disorders. Taken together, the present data confirm that co-administration of tacrolimus is a promising way to assess crossover PK studies of human or humanized proteinic formulations in beagle dogs.
(キーワード): Animals / Dogs / Drug Interactions / Humans / Injections, Subcutaneous / Interferon-alpha / Tacrolimus
(出版サイトへのリンク): ● Publication site (DOI): 10.2133/dmpk.25.149
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 20460820; ● Search Scopus @ Elsevier (PMID): 20460820; ● Search Scopus @ Elsevier (DOI): 10.2133/dmpk.25.149

(DOI: 10.2133/dmpk.25.149, PubMed: 20460820) H Koide, T Asai, K Hatanaka, S Akai, T Ishii, E Kenjo, Tatsuhiro Ishida, Hiroshi Kiwada, H Tsukada and N Oku :
T cell-independent B cell response is responsible for ABC phenomenon induced by repeated injection of PEGylated liposomes.,
International Journal of Pharmaceutics, Vol.392, No.1-2, 218-223, 2010.

(要約): Repeated injection of polyethyleneglycol-modified (PEGylated) liposomes causes a rapid clearance of them from the bloodstream, this phenomenon is called accelerated blood clearance (ABC). In the present study, we focused on the immune system responsible for the ABC phenomenon. PEGylated liposomes were preadministered to BALB/c mice and [(3)H]-labeled ones were then administered to them 3 days after the preadministration. Consistent with our previous results, the preadministration with PEGylated liposomes triggered the rapid clearance of [(3)H]-labeled PEGylated liposomes from the bloodstream, but that with PEGylated liposomes encapsulating doxorubicin (Dox) did not. In addition, we found that the ABC phenomenon was observed when a mixture of free Dox and PEGylated liposomes was preadministered. These data indicate that immune cells responsible for the ABC phenomenon might be selectively damaged by the Dox encapsulated in PEGylated liposomes. The ABC phenomenon was also observed in BALB/c nu/nu mice, but not in BALB/c SCID mice. The amount of anti-PEG IgM antibody induced by the stimulation with the PEGylated liposomes was significantly increased in the BALB/c nu/nu mice, but not in the BALB/c SCID ones. These data indicate that a T cell-independent B cell response would play a significant role in the ABC phenomenon. Furthermore, the present study suggests that PEGylated liposomes might be recognized by B cells as a thymus-independent type 2 (TI-2) antigen. The present study provides important information for the future development of liposomal medicines.
(キーワード): Animals / Antigens, T-Independent / B-Lymphocytes / Dose-Response Relationship, Drug / Doxorubicin / Immunoglobulin M / Injections, Intravenous / Liposomes / Male / Metabolic Clearance Rate / Mice / Mice, Inbred BALB C / Mice, SCID / Polyethylene Glycols / T-Lymphocytes / Tissue Distribution
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2010.03.022
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 20227473; ● Search Scopus @ Elsevier (PMID): 20227473; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ijpharm.2010.03.022

(DOI: 10.1016/j.ijpharm.2010.03.022, PubMed: 20227473) Tatsuaki Tagami, Kazuya Nakamura, Taro Shimizu, Naoshi Yamazaki, Tatsuhiro Ishida and Hiroshi Kiwada :
CpG motifs in pDNA-sequences increase anti-PEG IgM production induced by PEG-coated pDNA-lipoplexes.,
Journal of Controlled Release, Vol.142, No.2, 160-166, 2010.

(要約): Gene therapy is largely dependent on the development of efficient delivery vehicles. To prolong their circulating time, PEGylation of the surface of a delivery vehicle is frequently applied. However, we have reported previously that anti-PEG IgM produced by intravenous injection of PEG-coated liposome is responsible for enhanced clearance of second dose PEG-coated liposomes, which is known as the "accelerated blood clearance (ABC) phenomenon." A similar phenomenon has been observed with PEG-coated pDNA-lipoplexes (PDCLs) upon their repeated injection. But the effect of the sequence of pDNA in PDCLs on inducing the ABC phenomenon has not been thoroughly investigated. Here, we focus on CpG motifs in pDNA, which are known to have a potent immune-stimulatory activity. PDCLs with non-CpG pDNA (PNDCL) diminished the anti-PEG IgM response, resulting in significant accumulation of a second dose in tumor tissue, comparable to that of a single injection, but not in enhanced accumulation in liver. In addition, PDCL induced proliferation of IgM(+) splenic cells including B cells. These results suggest that the CpG motif is a major cause of the induction of the ABC phenomenon when PDCLs are repeatedly injected. Immunogenicity is a relevant point of concern for non-viral delivery systems. Our results indicate that the use of non-CpG pDNA may allow meaningful repeated dosing of pDNA formulations without the induction of a strong immune reaction and thus may have important implications for therapeutic use of liposomal formulations of nucleic acids.
(キーワード): Animals / B-Lymphocytes / Cell Proliferation / CpG Islands / DNA / Immunoglobulin M / Liposomes / Male / Mice / Mice, Inbred BALB C / Mice, Nude / Polyethylene Glycols
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2009.10.017
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19850094; ● Search Scopus @ Elsevier (PMID): 19850094; ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2009.10.017

(DOI: 10.1016/j.jconrel.2009.10.017, PubMed: 19850094) Lila Selim Ahmed Ali Abu Amr, Yusuke Doi, Kazuya Nakamura, Tatsuhiro Ishida and Hiroshi Kiwada :
Sequential administration with oxaliplatin-containing PEG-coated cationic liposomes promotes a significant delivery of subsequent dose into murine solid tumor.,
Journal of Controlled Release, Vol.142, No.2, 167-173, 2010.

(要約): Recently, we designed a PEG-coated cationic liposome to achieve dual targeting delivery of l-OHP to both tumor endothelial cells and tumor cells in a solid tumor. The targeted liposomal l-OHP formulation showed an efficient antitumor activity in a murine tumor model after three sequential liposomal l-OHP injections. This led us to assume that prior dosing with liposomes might enhance the intra-tumoral accumulation of a subsequent dose, and hence improve the therapeutic efficacy of entrapped l-OHP. The present study shows that while a single liposomal l-OHP injection does not enhance tumor accumulation of subsequent test-PEG-coated cationic liposomes, two sequential injections of liposomal l-OHP do. Cumulative cytotoxic effects of l-OHP delivered by PEG-coated cationic liposomes led to deep diffusion of a subsequent dose of liposomal l-OHP in solid tumor presumably as a result of the enlarged intra-tumoral interstitial space. Our study suggests that sequential injections of a targeted liposomal anticancer drug is of significant clinical and practical importance in enhancing the delivery of adequate quantities of anticancer agents into intractable solid tumors, and thereby may achieve a significant anticancer efficacy.
(キーワード): Animals / Antineoplastic Agents / Carcinoma, Lewis Lung / Cations / Liposomes / Male / Mice / Mice, Inbred C57BL / Neoplasms / Organoplatinum Compounds / Polyethylene Glycols
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2009.10.020
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19861140; ● Search Scopus @ Elsevier (PMID): 19861140; ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2009.10.020

(DOI: 10.1016/j.jconrel.2009.10.020, PubMed: 19861140) Tsutomu Ishihara, Miho Takeda, Haruka Sakamoto, Ayumi Kimoto, Chisa Kobayashi, Naoko Takasaki, Kanae Yuki, Ken-ichiro Tanaka, Mitsuko Takenaga, Rie Igarashi, Taishi Maeda, Naoki Yamakawa, Yoshinari Okamoto, Masami Otsuka, Tatsuhiro Ishida, Hiroshi Kiwada, Yutaka Mizushima and Tohru Mizushima :
Accelerated blood clearance phenomenon upon repeated injection of PEG-modified PLA-nanoparticles.,
Pharmaceutical Research, Vol.26, No.10, 2270-2279, 2009.

(要約): We recently developed prostaglandin E(1) (PGE(1))-encapsulated nanoparticles, prepared with a poly(lactide) homopolymer (PLA, Mw = 17,500) and monomethoxy poly(ethyleneglycol)-PLA block copolymer (PEG-PLA) (NP-L20). In this study, we tested whether the accelerated blood clearance (ABC) phenomenon is observed with NP-L20 and other PEG-modified PLA-nanoparticles in rats. The plasma levels of PGE(1) and anti-PEG IgM antibody were determined by EIA and ELISA, respectively. Second injections of NP-L20 were cleared much more rapidly from the circulation than first injections, showing that the ABC phenomenon was induced. This ABC phenomenon, and the accompanying induction of anti-PEG IgM antibody production, was optimal at a time interval of 7 days between the first and second injections. Compared to NP-L20, NP-L33s that were prepared with PLA (Mw = 28,100) and have a smaller particle size induced production of anti-PEG IgM antibody to a lesser extent. NP-L20 but not NP-L33s gave rise to the ABC phenomenon with a time interval of 14 days. NP-L33s showed a better sustained-release profile of PGE(1) than NP-L20. This study revealed that the ABC phenomenon is induced by PEG-modified PLA-nanoparticles. We consider that NP-L33s may be useful clinically for the sustained-release and targeted delivery of PGE(1).
(キーワード): Animals / Blood Circulation Time / Metabolic Clearance Rate / Nanoparticles / Particle Size / Polyethylene Glycols / Rats / Rats, Wistar / Time Factors
(出版サイトへのリンク): ● Publication site (DOI): 10.1007/s11095-009-9943-x
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19633820; ● Search Scopus @ Elsevier (PMID): 19633820; ● Search Scopus @ Elsevier (DOI): 10.1007/s11095-009-9943-x

(DOI: 10.1007/s11095-009-9943-x, PubMed: 19633820) Hiroyuki Yamazaki, Masateru Miyake, Toru Nishibayashi, Tadashi Mukai, Masaaki Odomi, Tatsuhiro Ishida and Hiroshi Kiwada :
Effect of co-administration of tacrolimus on the pharmacokinetics of multiple subcutaneous administered interferon-alpha in rats.,
Pharmaceutical Research, Vol.26, No.8, 1832-1837, 2009.

(要約): Repeated administration of exogenous proteinic compounds triggers the production of specific antibodies. This reaction is limits not only pharmacokinetic studies in animal but also development of human or humanized proteins as drugs. We investigated the effect of co-administration of tacrolimus on pharmacokinetic of human interferon-alpha (h-IFN) following multiple subcutaneous administration in rats. h-IFN was administered at a dose of 5 million IU/kg. For some experiments, tacrolimus was also either subcutaneously or intravenously injected in rats at a dose of 0.001 or 0.5 mg/kg as well as with administration of h-IFN. Multiple administration of h-IFN without co-administration of tacrolimus induced IgG response at 2 or 3 weeks following first administration in the short dosing interval (daily, once per 3 days, or once per a week), irrespective of the dosing interval. Both intravenous and subcutaneous administration of tacrolimus (0.5 mg/kg) with multiple h-IFN injections successfully suppressed IgG response against h-IFN. Interestingly, in lower doses (0.001 mg/kg), intravenous co-administration of tacrolimus showed much stronger suppressive effect than subcutaneous co-administration. Intravenous co-administration of tacrolimus (0.001 mg/kg) may be a promising way to assess crossover pharmacokinetic study of human or humanized proteinic formulations with multiple dosing schedules in an experimental animal.
(キーワード): Animals / Drug Interactions / Enzyme-Linked Immunosorbent Assay / Humans / Immunosuppressive Agents / Injections, Subcutaneous / Interferon-alpha / Male / Rats / Rats, Sprague-Dawley / Tacrolimus
(出版サイトへのリンク): ● Publication site (DOI): 10.1007/s11095-009-9892-4
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19415469; ● Search Scopus @ Elsevier (PMID): 19415469; ● Search Scopus @ Elsevier (DOI): 10.1007/s11095-009-9892-4

(DOI: 10.1007/s11095-009-9892-4, PubMed: 19415469) Tatsuaki Tagami, Kazuya Nakamura, Taro Shimizu, Tatsuhiro Ishida and Hiroshi Kiwada :
Effect of siRNA in PEG-coated siRNA-lipoplex on the anti-PEG IgM production.,
Journal of Controlled Release, Vol.137, No.3, 234-240, 2009.

(要約): For efficient delivery of small interfering RNA (siRNA) in vivo, it is important to control the blood circulation of the delivery vehicle. Surface modification of the siRNA/cationic liposome complex (siRNA-lipoplex) with polyethylene glycol (PEG) is expected to enhance circulation time in blood. However, we have recently reported that anti-PEG IgM production after the first injection of PEG-coated liposome is responsible for a reduction in the blood circulation of the second dose of the liposome, which is known as the accelerated blood clearance (ABC) phenomenon. It is unknown whether a PEG-coated siRNA-lipoplex (PSCL) can cause the ABC phenomenon and anti-PEG IgM production. In this study, an anti-PEG IgM response to PSCL was detected and was inversely related to the PSCL dose. Interestingly, the anti-PEG IgM response was significantly lower for PSCL than it was for PEG-coated naked cationic liposomes (PCL). The studies with splenectomized mice and nude mice indicated that anti-PEG IgM production was closely related to an interaction of PSCL and PCL with the spleen, which is associated with a T cell-independent mechanism. In addition, PSCL induced apoptosis on IgM-expressing splenic cells more strongly than PCL did, which suggests that accumulation in the spleen and the apoptotic effect of PEG-coated substances on splenic B cells could affect the potency of anti-PEG IgM production.
(キーワード): Animals / Apoptosis / B-Lymphocytes / Dose-Response Relationship, Immunologic / Immunoglobulin G / Immunoglobulin M / Liposomes / Male / Mice / Mice, Inbred BALB C / Mice, Nude / Polyethylene Glycols / RNA, Small Interfering / Spleen / Splenectomy
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2009.04.006
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19361546; ● Search Scopus @ Elsevier (PMID): 19361546; ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2009.04.006

(DOI: 10.1016/j.jconrel.2009.04.006, PubMed: 19361546) Tatsuhiro Ishida, Emi Shiraga and Hiroshi Kiwada :
Synergistic antitumor activity of metronomic dosing of cyclophosphamide in combination with doxorubicin-containing PEGylated liposomes in a murine solid tumor model.,
Journal of Controlled Release, Vol.134, No.3, 194-200, 2009.

(要約): Cyclophosphamide (CPA) and doxorubicin (DXR)-containing sterically stabilized liposomes (DXR-SL) have a proven clinical activity. We propose that a metronomic CPA dosing schedule enhances accumulation of DXR-SL in solid tumors, because it causes apoptosis in the endothelial cells of the growing tumor vasculature and thereby may increase the permeability of the tumor microvessels. To establish the validity of this hypothesis we investigated the therapeutic benefits of metronomic CPA dosing (p.o.) combined with DXR-SL (i.v.) in a Lewis lung carcinoma, subcutaneously growing in C57BL/6 mouse. The metronomic CPA dosing clearly promoted accumulation and subsequent deep diffusion of SL in the solid tumor as a result of rather a transient increase in the density of CD31(+)-microvessels, which shows high permeability to SL. It appears that the enhancing effect of metronomic CPA dosing is strongly dependent on the dose of CPA as well as on the time at which the treatment was initiated. Our study indicates that the use of metronomic chemotherapy combined with nanocarriers may be of significant clinical and practical importance in treating intractable solid tumors.
(キーワード): Administration, Oral / Animals / Antineoplastic Combined Chemotherapy Protocols / Carcinoma, Lewis Lung / Cell Line, Tumor / Cyclophosphamide / Dose-Response Relationship, Drug / Doxorubicin / Drug Administration Schedule / Drug Synergism / Injections, Intravenous / Male / Mice / Mice, Inbred C57BL / Neovascularization, Pathologic / Polyethylene Glycols / Treatment Outcome / Xenograft Model Antitumor Assays
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2008.11.019
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19095022; ● Search Scopus @ Elsevier (PMID): 19095022; ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2008.11.019

(DOI: 10.1016/j.jconrel.2008.11.019, PubMed: 19095022) Lila Selim Ahmed Ali Abu Amr, Shinji Kizuki, Yusuke Doi, Takuya Suzuki, Tatsuhiro Ishida and Hiroshi Kiwada :
Oxaliplatin encapsulated in PEG-coated cationic liposomes induces significant tumor growth suppression via a dual-targeting approach in a murine solid tumor model.,
Journal of Controlled Release, Vol.137, No.1, 8-14, 2009.

(要約): We recently designed a PEG-coated cationic liposome targeted to angiogenic vessels and showed, in a murine dorsal air sac model, potent anti-angiogenic activity of an oxaliplatin (l-OHP) formulation of this liposome. In the present study, we extended the l-OHP formulation to a murine tumor-xenograft model. Following three injections, l-OHP containing PEG-coated cationic liposomes showed substantial tumor growth suppression and increased survival time of tumor-bearing mice without apparent side effects, compared with other l-OHP containing PEG-coated neutral liposomes and free l-OHP. In vivo imaging showed a preferential tumor accumulation and a broader distribution of PEG-coated cationic liposomes, compared with PEG-coated neutral liposomes. In addition, PEG-coated cationic liposomes delivered larger amounts of l-OHP into the tumor tissue than other l-OHP formulations, correlating with its antitumor efficiency. In vitro studies indicated that PEG-coated cationic liposomes were internalized not only by tumor cells but also by endothelial cells, and consequently its l-OHP formulation displayed higher cytotoxicity towards both cell types as compared with l-OHP containing PEG-coated neutral liposomes. In summary, l-OHP containing PEG-coated cationic liposomes induced significant tumor growth suppression, presumably by delivering encapsulated l-OHP into both tumor endothelial cells and tumor cells. Such dual targeting approach, i.e. vascular-targeting and tumor-targeting with a single liposomal l-OHP formulation, may have great potential for overcoming some major limitations in conventional chemotherapy.
(キーワード): Angiogenesis Inhibitors / Animals / Carcinoma, Lewis Lung / Cations / Coated Materials, Biocompatible / Dosage Forms / Drug Carriers / Drug Delivery Systems / Excipients / Liposomes / Male / Mice / Mice, Inbred C57BL / Neovascularization, Pathologic / Organoplatinum Compounds / Polyethylene Glycols / Xenograft Model Antitumor Assays
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2009.02.023
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19285528; ● Search Scopus @ Elsevier (PMID): 19285528; ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2009.02.023

(DOI: 10.1016/j.jconrel.2009.02.023, PubMed: 19285528) Yoshimasa Isakari, Shinji Sogo, Tatsuhiro Ishida, Takuma Kawakami, Toshihide Ono, Takao Taki and Hiroshi Kiwada :
Gene expression analysis during platelet-like particle production in phorbol myristate acetate-treated MEG-01 cells.,
Biological & Pharmaceutical Bulletin, Vol.32, No.3, 354-358, 2009.

(要約): A comprehensive gene-expression analysis during platelet (PLT) production from megakaryocytes may give important information on genes involved in the PLT production process. However, the low abundance of primary megakaryocytes makes the gene expression analysis difficult. Therefore, we employed MEG-01 cells, a human megakaryocytic cell line, and confirmed that the cell line produces PLT-like particles by treatment with phorbol myristate acetate (PMA). After treatment of MEG-01 cells with PMA for 8 or 24 h, comprehensive gene expression analysis was carried out using a microarray and Reverse Transcription-Polymerase Chain Reaction (RT-PCR). From the microarray analysis, 141 genes were up-regulated (>2-fold) and 164 genes were down-regulated (<1/2-fold). However, known PLT-related genes were not included in the up- or down-regulated genes. On the other hand, RT-PCR analysis detected increased expression of beta1-tubulin, CD62P, gpIbalpha and gpIII, which are related to PLT function and megakaryocyte differentiation, following PMA treatment for 24 h. These results indicate that the MEG-01 cell may be an alternative model system to study the process of human PLT production from megakaryocytes. The gene-expression analysis might be a powerful tool for identifying genes related to PLT production, if the experimental conditions are optimized.
(キーワード): Blood Platelets / Cell Line / Gene Expression Profiling / Humans / Megakaryocytes / Oligonucleotide Array Sequence Analysis / Reverse Transcriptase Polymerase Chain Reaction / Tetradecanoylphorbol Acetate
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.32.354
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19252277; ● Search Scopus @ Elsevier (PMID): 19252277; ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.32.354

(DOI: 10.1248/bpb.32.354, PubMed: 19252277) Lila Selim Ahmed Ali Abu Amr, Takuya Suzuki, Yusuke Doi, Tatsuhiro Ishida and Hiroshi Kiwada :
Oxaliplatin targeting to angiogenic vessels by PEGylated cationic liposomes suppresses the angiogenesis in a dorsal air sac mouse model.,
Journal of Controlled Release, Vol.134, No.1, 18-25, 2009.

(要約): Oxaliplatin (trans-l-diaminocyclohexane oxalatoplatinum, l-OHP) is a third-generation platinum analogue with proven anti-tumor activity against many tumor cell lines, however it does not show sufficient anti-tumor activity in vivo when used alone. In order to overcome this problem and to achieve an anti-angiogenic therapy with l-OHP, the drug was encapsulated into PEG-coated cationic liposomes, which were designed to target the newly formed vessels, and its anti-angiogenic activity was evaluated in an in vivo mouse dorsal air sac (DAS) assay. For the DAS assay, chambers filled with tumor cells were implanted underneath the dorsal skin. l-OHP encapsulated in PEG-coated cationic liposomes (5 mg/kg mice) was intravenously injected once on day 1, 2, 3 or 4 after chamber implantation. On the fifth day after chamber implantation, animals were sacrificed and tumor-angiogenesis was evaluated. Liposome-encapsulated l-OHP completely suppressed angiogenesis in the skin when it was administered day 3 after chamber implantation. Under similar experimental conditions, neither l-OHP encapsulated in PEG-coated neutral liposomes, nor free l-OHP, nor "empty" (no drug containing) PEG-coated cationic liposomes showed such strong suppressive effect. The present study suggests that the liposomal formulation of l-OHP, which targeted to angiogenic vessels, has a remarkable in vivo anti-angiogenic activity and the formulation may become a promising novel approach to achieve anti-angiogenic therapy.
(キーワード): Air Sacs / Angiogenesis Inhibitors / Animals / Blood Vessels / Cell Line, Tumor / Erythrocytes / Liposomes / Male / Mice / Models, Animal / Neoplasms, Experimental / Neovascularization, Pathologic / Organoplatinum Compounds / Polyethylene Glycols
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2008.10.018
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19010364; ● Search Scopus @ Elsevier (PMID): 19010364; ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2008.10.018

(DOI: 10.1016/j.jconrel.2008.10.018, PubMed: 19010364) Tatsuaki Tagami, Kiyomi Hirose, Jose Mario Barichello, Tatsuhiro Ishida and Hiroshi Kiwada :
Global gene expression profiling in cultured cells is strongly influenced by treatment with siRNA-cationic liposome complexes.,
Pharmaceutical Research, Vol.25, No.11, 2497-2504, 2008.

(要約): The purpose of this study is to determine if the treatment with siRNA-lipoplexes significantly influences on global gene expression in the treated cells. We investigated global gene expression in a HT1080 cell line by a cDNA microarray. We also evaluated the effect of lipofection on global gene expression by determining the change of the expression of an exogenous gene, green fluorescence protein (GFP), and also determined treatment-related cytotoxicity. Treatment of the cells with either siRNA-lipoplexes or cationic liposomes altered the expression of approximately 2,500 genes. When lipoplexes containing non-specific siRNAs were used, GFP expression was enhanced. In this case the effect was independent on the dose and type of siRNA in the formulation. By contrast, when lipoplexes containing a specific siRNA against GFP was used, GFP expression was markedly diminished. These results clearly indicate that an efficient reduction of a targeted gene expression by a specific siRNA is accompanied by a significant alteration of the expression of numerous non-targeted genes. In addition, treatment-related cytotoxicity increased with siRNA- and cationic lipid-doses, but was not dependent on siRNA type. Non-specific effects of siRNA-lipoplexes may either enhance, attenuate or even fully mask the desired outcomes of siRNA-based biochemical studies and therapies.
(キーワード): Cell Line, Tumor / Cell Survival / Gene Expression Profiling / Green Fluorescent Proteins / Humans / Liposomes / Oligonucleotide Array Sequence Analysis / RNA, Small Interfering
(出版サイトへのリンク): ● Publication site (DOI): 10.1007/s11095-008-9663-7
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 18581204; ● Search Scopus @ Elsevier (PMID): 18581204; ● Search Scopus @ Elsevier (DOI): 10.1007/s11095-008-9663-7

(DOI: 10.1007/s11095-008-9663-7, PubMed: 18581204) Hiroyuki Koide, Tomohiro Asai, Kentaro Hatanaka, Takeo Urakami, Takayuki Ishii, Eriya Kenjo, Masamichi Nishihara, Masayuki Yokoyama, Tatsuhiro Ishida, Hiroshi Kiwada and Naoto Oku :
Particle size-dependent triggering of accelerated blood clearance phenomenon.,
International Journal of Pharmaceutics, Vol.362, No.1-2, 197-200, 2008.

(要約): A repeat-injection of polyethylene glycol-modified liposomes (PEGylated liposomes) causes a rapid clearance of them from the blood circulation in certain cases that is referred to as the accelerated blood clearance (ABC) phenomenon. In the present study, we examined whether polymeric micelles trigger ABC phenomenon or not. As a preconditioning treatment, polymeric micelles (9.7, 31.5, or 50.2 nm in diameter) or PEGylated liposomes (119, 261 or 795 nm) were preadministered into BALB/c mice. Three days after the preadministration [(3)H]-labeled PEGylated liposomes (127 nm) as a test dose were administered into the mice to determine the biodistribution of PEGylated liposomes. At 24h after the test dose was given, accelerated clearance of PEGylated liposomes from the bloodstream and significant accumulation in the liver was observed in the mice preadministered with 50.2-795 nm nanoassemblies (PEGylated liposomes or polymeric micelles). In contrast, such phenomenon was not observed with 9.7-31.5 nm polymeric micelles. The enhanced blood clearance and hepatic uptake of the test dose (ABC phenomenon) were related to the size of triggering nanoassemblies. Our study provides important information for developing both drug and gene delivery systems by means of nanocarriers.
(キーワード): Animals / Dose-Response Relationship, Drug / Liposomes / Male / Metabolic Clearance Rate / Mice / Mice, Inbred BALB C / Particle Size / Phospholipids / Polyethylene Glycols / Tissue Distribution
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2008.06.004
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 18586076; ● Search Scopus @ Elsevier (PMID): 18586076; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ijpharm.2008.06.004

(DOI: 10.1016/j.ijpharm.2008.06.004, PubMed: 18586076) Emi Shiraga, Jose Mario Barichello, Tatsuhiro Ishida and Hiroshi Kiwada :
A metronomic schedule of cyclophosphamide combined with PEGylated liposomal doxorubicin has a highly antitumor effect in an experimental pulmonary metastatic mouse model.,
International Journal of Pharmaceutics, Vol.353, No.1-2, 65-73, 2008.

(要約): Metronomic chemotherapy is a novel approach to the control of advanced cancer, as it appears to preferentially inhibit endothelial cell activity in the growing vasculature of tumors. Doxorubicin-containing sterically stabilized liposomes (DXR-SL) accumulate in large amounts in tumor tissue, resulting in enhanced antitumor effects of the encapsulated DXR. In the present study, it was hypothesized that metronomic chemotherapy may further augment the accumulation of DXR-SL, improving its therapeutic efficacy. This study tests the antitumor efficacy for the combination of a metronomic cyclophosphamide (CPA)-dosing schedule with sequential intravenous injections of DXR-SL in the treatment of lung metastatic B16BL6 melanoma-bearing mice. Three dosing schedules for the combination of metronomic CPA injections (s.c. 170 mg/kg every 6 days) plus either a low or a high dose of DXR-SL (i.v. 1 or 5 mg/kg every 6 days) were set: Schedule I, DXR-SL was given 3 days before the first CPA treatment; Schedule II, DXR-SL and CPA were given simultaneously; and, Schedule III, DXR-SL was given 3 days after the first CPA treatment. Lung weight and median survival time (MST) were evaluated. As expected, both the dosing schedule as well as the dose of DXR-SL improved therapeutic efficacy. Schedule I with the low DXR dose and Schedule II with the low or high DXR dose significantly increased MST, compared with regular metronomic CPA therapy. Under the dosing schedules (Schedule I with the low DXR dose and Schedule II with the high DXR), there was a strong relationship between increased MST and decreased lung weight. However, Schedule I with high DXR dose resulted in significantly lower lung weights, but did not increase MST, suggesting that chemotherapy may result in increased toxicity in some conditions. Although treatment regimens require optimization, the results of the present study may prove useful in further explorations of combining metronomic chemotherapy with liposomal anticancer drugs in the treatment of solid tumors.
(キーワード): Animals / Antineoplastic Combined Chemotherapy Protocols / Cell Line, Tumor / Cyclophosphamide / Doxorubicin / Drug Administration Schedule / Lung Neoplasms / Male / Melanoma, Experimental / Mice / Mice, Inbred C57BL / Polyethylene Glycols
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2007.11.020
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 18155369; ● Search Scopus @ Elsevier (PMID): 18155369; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ijpharm.2007.11.020

(DOI: 10.1016/j.ijpharm.2007.11.020, PubMed: 18155369) Kuniko Matsumura-Takeda, Tatsuhiro Ishida, Shinji Sogo, Yoshimasa Isakari, Takao Taki, Toshiki Sudo and Hiroshi Kiwada :
Lactoferrin inhibits platelet production from human megakaryocytes in vitro.,
Biological & Pharmaceutical Bulletin, Vol.31, No.4, 569-573, 2008.

(要約): The mechanism of megakaryopoiesis, proplatelet formation (PPF) and platelet (PLT) production is not fully elucidated. Lactoferrin (LF) has been reported to have many biological functions including cell proliferation and differentiation, and the LF receptor is present on megakaryocytic cells. In the present study, we examined the effect of human LF (hLF) on PLT production from primary megakaryocytes (MKs). At first, we developed a PLT production system derived from human CD34+ cells by thrombopoietin (TPO) stimulation. Because the number of proplatelets, PLTs and CD41+ MKs was remarkably increased after day 5, we employed the TPO-induced CD34+ cells on day 5. Then, the effect of hLF on PLT production from human primary MKs was examined. In the range of 3-30 micrg/ml, hLF significantly inhibited PLT production up to about 60%. However, it did not significantly change the intensity of CD41 expression in MKs and the ploidy of MKs. In addition, it did not inhibit MK progenitors. These results suggest that LF directly inhibits PLT production from matured MKs, but does not inhibit megakaryopoiesis, including proliferation/maturation processes.
(キーワード): Animals / Antigens, CD34 / Bone Marrow Cells / Cell Differentiation / Humans / Indicators and Reagents / Lactoferrin / Male / Megakaryocytes / Membrane Proteins / Mice / Mice, Inbred BALB C / Platelet Aggregation Inhibitors / Platelet Membrane Glycoprotein IIb / Ploidies / Stem Cells
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.31.569
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 18379042; ● Search Scopus @ Elsevier (PMID): 18379042; ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.31.569

(DOI: 10.1248/bpb.31.569, PubMed: 18379042) Tatsuhiro Ishida, Shuntarou Kashima and Hiroshi Kiwada :
The contribution of phagocytic activity of liver macrophages to the accelerated blood clearance (ABC) phenomenon of PEGylated liposomes in rats.,
Journal of Controlled Release, Vol.126, No.2, 162-165, 2008.

(要約): We earlier reported that PEGylated liposomes lose their long-circulating property when they are administered twice in the same animal within certain intervals. We recently proposed that anti-PEG IgM elicited by the first dose PEGylated liposomes selectively binds to the surface of a second dose, subsequently leading to substantial complement activation and complement-receptor mediated uptake of the second dose by hepatic Kupffer cells. In this study we found, by using a single-pass liver perfusion technique, that the first dose does not increase the intrinsic phagocytic activity of the Kupffer cells. It was also found that only serum obtained from rats that had received a first dose is able to enhance the hepatic uptake of test dose. The conditioned-serum-dependent hepatic uptake was completely abolished by pre-treatment of the serum at 56 degrees C for 30 min, which inhibits the complement activity. Conclusively, our results strongly support our earlier proposal that complement activation caused by anti-PEG IgM elicited by the first dose is a major cause of the initiation of the accelerated blood clearance of a subsequent dose PEGylated liposome in the ABC phenomenon.
(キーワード): Animals / Liposomes / Liver / Macrophages / Male / Metabolic Clearance Rate / Phagocytes / Polyethylene Glycols / Rats / Rats, Wistar
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2007.11.009
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 18160170; ● Search Scopus @ Elsevier (PMID): 18160170; ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2007.11.009

(DOI: 10.1016/j.jconrel.2007.11.009, PubMed: 18160170) Mario José Barichello, Noriko Yamakawa, Masatoshi Kisyuku, Hiroshi Handa, Taiki Shibata, Tatsuhiro Ishida and Hiroshi Kiwada :
Combined effect of liposomalization and addition of glycerol on the transdermal delivery of isosorbide 5-nitrate in rat skin.,
International Journal of Pharmaceutics, Vol.357, No.1-2, 199-205, 2008.

(要約): In this report, we investigated the combined effect of drug liposomalization and addition of glycerol on the transdermal delivery of isosorbide 5-nitrate (ISN) in rat abdominal skin in vitro. Occlusive application of both liposomal and aqueous ISN solution, with and without addition of 5% glycerol, showed that drug liposomalization and addition of glycerol has far-reaching implications for ISN permeation and accumulation in 4 and 8 weeks old rat abdominal skin. Using 8 weeks old rat abdominal skin, the optimal concentration of glycerol to be added to liposomal ISN was found to be 5%. The ISN mean values permeated through and accumulated in stripped 8 weeks old rat abdominal skin from those formulations described above were not significant different, which might indicate the combined effect of glycerol and liposomal ISN resides solely in the stratum corneum (SC). Based on previous reports, the enhancement effect of glycerol might be due to an increase in the SC hydration, and perhaps due to subtle changes in the lipid organization caused by penetration of liposomal lipids within the SC intercellular spaces. These data might provide evidence that glycerol action on SC is useful to facilitate skin permeation and accumulation of drugs formulated in liposome.
(キーワード): Administration, Cutaneous / Animals / Chemistry, Pharmaceutical / Drug Carriers / Glycerol / Isosorbide Dinitrate / Liposomes / Male / Rats / Rats, Wistar / Skin Absorption / Vasodilator Agents
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2008.01.052
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 18343610; ● Search Scopus @ Elsevier (PMID): 18343610; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ijpharm.2008.01.052

(DOI: 10.1016/j.ijpharm.2008.01.052, PubMed: 18343610) T Asai, Y Suzuki, S Matsushita, S Yonezawa, J Yokota, Y Katanasaka, Tatsuhiro Ishida, T Dewa, Hiroshi Kiwada, N Nango and N Oku :
Disappearance of the angiogenic potential of endothelial cells caused by Argonaute2 knockdown.,
Biochemical and Biophysical Research Communications, Vol.368, No.2, 243-248, 2008.

(要約): Argonaute2 (Ago2), a component protein of RNA-induced silencing complex, plays a central role in RNA interference. We focused on the involvement of Ago2 in angiogenesis. Human umbilical vein endothelial cells (HUVECs) stimulated with several growth factors such as vascular endothelial growth factor were used for angiogenesis assays. We applied polycation liposomes for transfection of small interfering RNA (siRNA) to determine the biological effects of siRNA for Ago2 (siAgo2) on HUVECs. The proliferation study indicated that siAgo2 significantly suppressed the growth of HUVECs compared with control siRNA. TUNEL staining showed a certain population of HUVECs treated with siAgo2 underwent apoptosis. Furthermore, the treatment with siAgo2 suppressed the tube formation of HUVECs and significantly reduced the length of the tubes. These present data demonstrate that siAgo2 inhibited indispensable events of angiogenesis in vitro. This is the first report suggesting that Ago2 is required for angiogenesis.
(キーワード): Apoptosis / Argonaute Proteins / Cell Line / Cell Proliferation / Endothelial Cells / Eukaryotic Initiation Factor-2 / Gene Silencing / Humans / Neovascularization, Physiologic
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.bbrc.2008.01.074
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 18222171; ● Search Scopus @ Elsevier (PMID): 18222171; ● Search Scopus @ Elsevier (DOI): 10.1016/j.bbrc.2008.01.074

(DOI: 10.1016/j.bbrc.2008.01.074, PubMed: 18222171) Tatsuhiro Ishida, Wang Xinyu, Taro Shimizu, Kousuke Nawata and Hiroshi Kiwada :
PEGylated liposomes elicit an anti-PEG IgM response in a T-cells independent manner.,
Journal of Controlled Release, Vol.122, No.3, 349-355, 2007.

(要約): We recently reported that intravenous injections of "empty" PEGylated liposomes without encapsulated or surface coupled proteins elicit a PEG-specific IgM response in rats. In the present study, simultaneous weak anti-PEG IgG and strong anti-PEG IgM responses were detected following intravenous injections of "empty" PEGylated liposomes. The pattern of immune response appears to differ from the classic primary response against T cell-dependent (TD) antigens. The anti-PEG IgM response was detected in T-cell deficient nude BALB/c mice following intravenous injection of "empty" PEGylated liposomes, suggesting that "empty" PEGylated liposomes initiate the immune response against PEG in a T cell-independent manner. In vitro splenic lymphocytes-proliferation assay indicated that TNP-LPS, a typical type 1 T cell-independent (TI) antigen (TI-1 antigen), significantly primed the proliferation, while TNP-Ficoll, a typical type 2 TI antigen (TI-2 antigen), and "empty" PEGylated liposomes did not prime any proliferation under these experimental conditions. In addition, in splenic marginal zone (MZ) B-cell-depleted rats, the anti-PEG IgM response was diminished, while the immune reactions against TNP-BSA (a TD antigen) and TNP-LPS (TI-1 antigen) were not diminished. These results demonstrate that "empty" PEGylated liposomes may promote the immune response against PEG as a result of priming the activation of MZ B cells, as TI-2 antigen promotes a specific IgM response. In conclusion, although the mechanistic details behind the immune reaction against "empty" PEGylated liposomes are not yet clear, the liposomes elicit an anti-PEG IgM response in a T cell-independent manner and appear to be a TI-2 antigen, and splenic MZ B cells may be essential for the immune response against "empty" PEGylated liposomes.
(キーワード): Animals / Antigens, T-Independent / Cell Proliferation / Cyclophosphamide / Immunoglobulin G / Immunoglobulin M / Injections, Intravenous / リポソーム (liposomes) / Male / Mice / Mice, Inbred BALB C / Mice, Nude / Polyethylene Glycols / Rats / Rats, Wistar / Spleen / Tリンパ球 (T lymphocytes)
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2007.05.015
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 17610982; ● Search Scopus @ Elsevier (PMID): 17610982; ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2007.05.015

(DOI: 10.1016/j.jconrel.2007.05.015, PubMed: 17610982) Hiroto Hatakeyama, Hidetaka Akita, Emi Ishida, Koichi Hashimoto, Hideo Kobayashi, Takanori Aoki, Junko Yasuda, Kenichi Obata, Hiroshi Kikuchi, Tatsuhiro Ishida, Hiroshi Kiwada and Hideyoshi Harashima :
Tumor targeting of doxorubicin by anti MT1-MMP antibody-modified PEG liposomes.,
International Journal of Pharmaceutics, Vol.342, No.1-2, 194-200, 2007.

(要約): Immunoliposomes are potent carriers for targeting of therapeutic drugs to specific cells. Membrane type-1 matrix metalloproteinase (MT1-MMP), which plays an important role in angiogenesis, is expressed on angiogenic endothelium cells as well as tumor cells. Then, the MT1-MMP might be useful as a target molecule for tumor and neovascularity. In the present study, we addressed a utility of antibodies against the MT1-MMP as a targeting ligand of liposomal anticancer drug. Fab' fragments of antibody against the MT1-MMP were modified at distal end of polyethylene glycol (PEG) of doxorubicin (DXR)-encapsulating liposomes, DXR-sterically stabilized immunoliposomes (DXR-SIL[anti-MT1-MMP(Fab')]). Modification with the antibody significantly enhanced cellular uptake of DXR-SIL[anti-MT1-MMP(Fab')] into the HT1080 cells, which highly express MT1-MMP, compared with the non-targeted liposomes (DXR-stealthliposomes (DXR-SL)), suggesting that MT1-MMP antibody (Fab') is a potent targeting ligand for the MT1-MMP expressed cells. In vivo systemic administration of DXR-SIL[anti-MT1-MMP(Fab')] into the tumor-bearing mice showed significant suppression of tumor growth compared to DXR-SL. This is presumably due to the active targeting of immunoliposomes for tumor and neovascularity. However, tumor accumulation of DXR-SIL[anti-MT1-MMP(Fab')] and DXR-SL were comparable, suggesting that both liposomal formulations accumulated in tumor via enhanced permeation and retention (EPR) effect, but not via targeting to the MT1-MMP expressed on both the endothelial and tumor cells. It appears that the enhanced antitumor activity of DXR-SIL[anti-MT1-MMP(Fab')] resulted from acceleration of cellular uptake of lioposomes owing to the incorporated antibody after extravasation from capillaries in tumor.
(キーワード): Animals / Antibiotics, Antineoplastic / Antibodies, Monoclonal / Doxorubicin / Drug Compounding / Drug Delivery Systems / Excipients / Immunochemistry / Immunoglobulin Fab Fragments / Liposomes / Male / Matrix Metalloproteinase 14 / Mice / Mice, Inbred BALB C / Neoplasms, Experimental / Polyethylene Glycols
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2007.04.037
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 17583453; ● Search Scopus @ Elsevier (PMID): 17583453; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ijpharm.2007.04.037

(DOI: 10.1016/j.ijpharm.2007.04.037, PubMed: 17583453) Kazutaka Atobe, Tatsuhiro Ishida, Emi Ishida, Kouichi Hashimoto, Hideo Kobayashi, Jyunko Yasuda, Takanori Aoki, Ken-ichi Obata, Hiroshi Kikuchi, Hidetaka Akita, Tomohiro Asai, Hideyoshi Harashima, Naoto Oku and Hiroshi Kiwada :
In vitro efficacy of a sterically stabilized immunoliposomes targeted to membrane type 1 matrix metalloproteinase (MT1-MMP).,
Biological & Pharmaceutical Bulletin, Vol.30, No.5, 972-978, 2007.

(要約): The poor selective cytotoxicity of anticancer drugs lead to dose-limiting adverse effects which compromise the clinical outcome. Solid tumors recruit new blood vessels to support their growth, and epitopes that are uniquely expressed on tumor cells and tumor endothelial cells (ECs) can function as targets for immunoliposomal anticancer drugs. Membrane type 1 matrix metalloproteinase (MT1-MMP), an important protein related to tumor growth and angiogenesis, is expressed on malignant tumor cells and is activated ECs. Selective delivery could be achieved by targeting MT1-MMP, as well as other angiogenic ECs. In this regard, an anti-MT1-MMP Fab' antibody was used to prepare a MT1-MMP targeted sterically stabilized immunoliposomes (SIL[anti-MT1-MMP(Fab')]). The binding and intracellular distribution of SIL[anti-MT1-MMP(Fab')] and a non-targeted sterically stabilized liposomes (SL) were examined using human fibrosarcoma HT-1080 cells. SIL[anti-MT1-MMP(Fab')] was taken up by the cells in a lipid concentration, temperature, and time dependent manner, ultimately accumulating in the lysosomes. The cytotoxicity of doxorubicin (DXR)-containing SIL[anti-MT1-MMP(Fab')] (DXR-SIL[anti-MT1-MMP(Fab')]) was significantly higher than that of DXR-containing SL. The cellular internalization of SIL[anti-MT1-MMP(Fab')] was inhibited by endocytosis inhibitors, suggesting that their internalization was mediated via clathrin- or caveolae-dependent endocytosis. Furthermore, the efficient binding of SIL[anti-MT1-MMP(Fab')] was observed on human umbilical vein endothelial cells (HUVEC). Based on these results, it would be expected that DXR-SIL[anti-MT1-MMP(Fab')] may achieve direct tumor cell kill and indirect tumor cell kill via the destruction of the tumor endothelium in vivo. This strategy may have the potential for overcoming some major limitations in conventional chemotherapy in vivo.
(キーワード): Antibodies, Monoclonal / Antineoplastic Agents / Cell Line, Tumor / Cell Survival / Doxorubicin / Drug Stability / Endothelial Cells / Flow Cytometry / Humans / Immunoglobulin Fab Fragments / Liposomes / Matrix Metalloproteinase 14 / Microscopy, Confocal
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.30.972
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 17473445; ● Search Scopus @ Elsevier (PMID): 17473445; ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.30.972

(DOI: 10.1248/bpb.30.972, PubMed: 17473445) Lap Thi Nguen, Kazutaka Atobe, Mari Jose Barichello, Tatsuhiro Ishida and Hiroshi Kiwada :
Complex formation with plasmid DNA increases the cytotoxicity of cationic liposomes.,
Biological & Pharmaceutical Bulletin, Vol.30, No.4, 751-757, 2007.

(要約): Cationic liposomes (CL) are one of the most widely studied non-viral vectors for gene delivery. It is well-known that CL induces cytotoxicity following lipofection. However, little is known regarding the mechanism involved in the cytotoxicity. In this study, the in vitro cytotoxicity of CL and its complex with pDNA (lipoplex) was investigated, and a part of the mechanism of induction as well. While free pDNA did not show any cytotoxicity, pDNA increased the cytotoxicity of CL via the formation of lipoplex. In addition, the lipoplex-induced cytotoxicity increased in a lipoplex dose-dependent manner, irrespective of the type of pDNA, cell line and the absence or presence of serum. An assay showed that apoptosis was largely induced by treatment with the lipoplex (lipofection), but not with CL alone, in the tested range of concentration of CL and pDNA. Furthermore, following treatment with lipoplexes, the cells exhibited the morphological features of apoptosis and DNA fragmentation. A cDNA microarray study showed that the lipofection up-regulated 45 genes related to apoptosis, transcription regulation and immune response. These results clearly indicate that pDNA in the lipoplex increases the cytotoxicity of CL as a result of inducing apoptosis. The fundamental principle for gene therapy is to deliver gene-based therapeutics to target cells for specific gene targeting with minimal cytotoxicity. Our results suggest the possibility that cytotoxicity induced by lipofection, accompanied by gene changes, could intrinsically exacerbate, attenuate or even mask the desired effects of gene-based therapy.
(キーワード): Animals / Apoptosis / Cations / Cell Line, Tumor / DNA / DNA Fragmentation / DNA, Complementary / Dose-Response Relationship, Drug / Gene Expression Profiling / Gene Expression Regulation / Gene Therapy / Genetic Vectors / Glioma / HeLa Cells / Humans / Liposomes / Melanoma, Experimental / Mice / Oligonucleotide Array Sequence Analysis / Plasmids / Rats / Transfection
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.30.751
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 17409515; ● Search Scopus @ Elsevier (PMID): 17409515; ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.30.751

(DOI: 10.1248/bpb.30.751, PubMed: 17409515) Tatsuaki Tagami, Mari Jose Barichello, Hiroshi Kikuchi, Tatsuhiro Ishida and Hiroshi Kiwada :
The gene-silencing effect of siRNA in cationic lipoplexes is enhanced by incorporating pDNA in the complex.,
International Journal of Pharmaceutics, Vol.333, No.1-2, 62-69, 2007.

(要約): Efficient delivery is a key issue in translating interference RNA technology into a feasible therapy. The efficiency of carrier systems used for this technology is commonly tested by co-transfection, i.e. simultaneous transfection with an exogenous gene and with the siRNA. Two approaches can be distinguished: (1) with the two transfectants in the same carrier complex (siRNA/pDNA/carrier) and (2) with the two transfectants in different carrier complexes (pDNA/carrier and siRNA/carrier). The process to prepare the nucleic acid(s)-carrier complexes and the transfection procedure may affect the effectiveness of the gene-silencing process. In this study, two preparation methods were compared, namely the co-preparation of an siRNA/pDNA/liposome lipoplex (Method I) and the separate preparation of an siRNA/liposome lipoplex and a pDNA/liposome lipoplex (Method II). siRNA in the lipoplex produced by Method I showed a stronger gene-silencing effect than that in the lipoplexes prepared by Method II. There was no significant difference between the two methods in the amount of siRNA delivered to cells. Cellular entry and intracellular trafficking of siRNA/pDNA/liposome lipoplex is likely to differ from those of the separate lipoplexes. When in Method II non-transcriptional pDNA was included in the complex with siRNA, the gene-silencing effect was significantly enhanced. If and to what extent the experimental design is suitable to quantify RNA interference remains to be demonstrated.
(キーワード): Animals / Cations / Cell Line, Tumor / Cholesterol / Cytoplasm / Ethanolamines / Genes, Reporter / Lipids / Liposomes / Luciferases, Firefly / Luciferases, Renilla / Melanoma, Experimental / Mice / Myristates / Particle Size / Phosphatidylethanolamines / Plasmids / RNA Interference / RNA, Small Interfering / Transfection
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2006.09.057
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 17097247; ● Search Scopus @ Elsevier (PMID): 17097247; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ijpharm.2006.09.057

(DOI: 10.1016/j.ijpharm.2006.09.057, PubMed: 17097247) Xinyu Wang, Tatsuhiro Ishida and Hiroshi Kiwada :
Anti-PEG IgM elicited by injection of liposomes is involved in the enhanced blood clearance of a subsequent dose of PEGylated liposomes.,
Journal of Controlled Release, Vol.119, No.2, 236-244, 2007.

(要約): Earlier we reported that PEGylated liposomes lose their long-circulating characteristic when they are administrated twice in the same animal with certain intervals (referred to as the accelerated blood clearance (ABC) phenomenon). We proposed that anti-PEG IgM, induced by the PEGylated liposomes, is responsible for the phenomenon, based on the observation that IgM thus produced selectively binds to the surface of PEGylated liposomes, subsequently leading to substantial complement activation. Interestingly, we found that under certain circumstances administration of conventional liposomes without PEG-coating also caused a strong ABC response upon injection of a second dose of PEGylated liposomes, but not of conventional liposomes. This suggests that also conventional liposomes not modified with PEG can promote an IgM response against PEG. We report here that, irrespective of the presence or absence PEG-coating, a single first dose of liposomes is capable of inducing a strong anti-PEG IgM response and, under certain circumstances, also weak responses against other lipid components. A good correspondence was observed between the amount of IgM associating with both PEGylated and conventional liposomes, concomitant complement activation triggered by those liposomes and the magnitude of the ABC phenomenon against those liposomes. Taken together, our results demonstrate that the ABC phenomenon is fully attributable to production of anti-PEG IgM by the first dose of liposomes and the subsequent complement activation upon a second dose of PEGylated but not conventional liposomes. Although the responsible immunogenic epitopes of the liposomes remain to be determined, the immunogenicity of 'empty' liposomes presents a serious concern in the development of liposomal formulations and their use in the clinic. Furthermore, our findings as described here raise important concerns with regard to the safety and efficiency of liposomes currently under development for clinical use.
(キーワード): Animals / Immunoglobulin M / Injections, Intravenous / Liposomes / Male / Metabolic Clearance Rate / Polyethylene Glycols / Rats / Rats, Wistar
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2007.02.010
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 17399838; ● Search Scopus @ Elsevier (PMID): 17399838; ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2007.02.010

(DOI: 10.1016/j.jconrel.2007.02.010, PubMed: 17399838) Yoshimasa Isakari, Yasuo Harada, Dai Ishikawa, Kuniko Matsumura-Takeda, Shinji Sogo, Tatsuhiro Ishida, Takao Taki and Hiroshi Kiwada :
Efficient gene expression in Megakaryocytic cell line using Nucleofection.,
International Journal of Pharmaceutics, Vol.338, No.1-2, 157-164, 2007.

(要約): To clarify the mechanism of platelet production from megakaryocytes, expression of target proteins by gene transfection was examined using various gene delivery techniques. Transfection into hematopoietic cells, including megakaryocytes, by conventional gene delivery techniques such as electroporation and lipofection are known to be difficult. In this study, in addition to electroporation and lipofection, we tested other gene-transfer methods (nucleofection, transfection using inactivated virus envelope, and transferrin-linked cationic polymer) with the green fluorescent protein (GFP) gene into the human megakaryocytic cell line MEG-01. We found that nucleofection, which uses a combination of special electrical parameters and specific solutions, was the best, judging from the expression ratio of GFP-positive cells (approximately 70% of cells) and low toxicity. The efficiency of GFP expression was not related to the amount of pDNA delivered into the MEG-01 cells. To verify the utility of nucleofection, the thrombopoietin (TPO) receptor c-mpl was transfected into MEG-01 cells. Transfected cells showed a higher responsiveness to TPO than mock-transfected MEG-01 cells. We propose that nucleofection is a useful method for transfecting target genes to megakaryocytic cells when addressing the mechanism of platelet production.
(キーワード): Cell Line / Electroporation / Genetic Vectors / Humans / Liposomes / Megakaryocytes / Receptors, Thrombopoietin / Sendai virus / Transfection
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2007.01.042
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 17331684; ● Search Scopus @ Elsevier (PMID): 17331684; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ijpharm.2007.01.042

(DOI: 10.1016/j.ijpharm.2007.01.042, PubMed: 17331684) Tomotaka Kobayashi, Tatsuhiro Ishida, Yurie Okada, Saori Ise, Hideyoshi Harashima and Hiroshi Kiwada :
Effect of Transferrin receptor-targeted liposomal doxorubicin in P-glycoprotein-mediated drug resistant tumor cells.,
International Journal of Pharmaceutics, Vol.329, No.1-2, 94-102, 2007.

(要約): The over-expression of P-glycoprotein (P-gp) has been associated with the development of multidrug resistance (MDR) in cancer cells. In this study, we examined whether transferrin receptor (Tf-R) targeted liposomes can efficiently deliver encapsulated doxorubicin (DXR) into MDR cells (SBC-3/ADM) via Tf-R-mediated endocytosis thus overcoming MDR by by-passing P-gp-mediated drug efflux. We prepared four types of liposome, i.e. untargeted and Tf-R-targeted, made of either egg-PC/cholesterol or hydrogenated egg PC/cholesterol. Only with the targeted EPC-liposome we achieved significant delivery of encapsulated DXR and increased cytotoxicity of encapsulated DXR on the MDR cells (3.5-fold higher than free DXR). Confocal microscopy and an intracellular drug-accumulation assay indicated that the targeted liposomes efficiently delivered DXR into cells where it readily accumulated in the nucleus, in both drug-sensitive and MDR cells. These findings suggest that the targeted liposomes are rapidly internalized via Tf-R-mediated endocytosis followed by release of their contents into the cytoplasm. The rapid internalization and content release, most likely facilitated by the higher fluidity of the EPC-based liposomes, may explain why only targeted EPC-liposomes were able to prevent drug efflux by P-gp and to consequently circumvent MDR. Our results indicate that in order to achieve MDR circumvention by means of liposomal encapsulation of DXR the liposomes not only need to be targeted, but also to have the proper physicochemical properties for adequate release of the drug. Furthermore, these in vitro results suggest that Tf-R targeted EPC-liposomes are a potentially useful drug delivery system to circumvent P-gp-mediated MDR of tumors.
(キーワード): Antibiotics, Antineoplastic / Cell Line, Tumor / Doxorubicin / Drug Delivery Systems / Drug Resistance, Neoplasm / Humans / Liposomes / Neoplasms / P-Glycoprotein / Receptors, Transferrin
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2006.08.039
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 16997518; ● Search Scopus @ Elsevier (PMID): 16997518; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ijpharm.2006.08.039

(DOI: 10.1016/j.ijpharm.2006.08.039, PubMed: 16997518) Tatsuhiro Ishida, Kazutaka Atobe, Xinyu Wang and Hiroshi Kiwada :
Accelerated blood clearance of PEGylated liposomes upon repeated injections: Effect of doxorubicin-encapsulation and high-dose first injection.,
Journal of Controlled Release, Vol.115, No.3, 251-258, 2006.

(要約): The "accelerated blood clearance (ABC) phenomenon", causing PEGylated liposomes to be cleared very rapidly from the circulation upon repeated injection, has been reported to occur in rodents and rhesus monkeys. This rapid clearance was reported to be caused by the binding of PEG-specific IgM, which was generated by the first dose of injected liposomes, to the second dose of liposomes and the subsequent activation of complement, serving in turn as an opsonin. Although there are several PEGylated liposomal formulations, such as Doxil/Caelyx loaded with doxorubicin (DXR), in clinical use, the rapid clearance phenomenon has never been reported for such formulations. In the present article, we report that a first injection of PEGylated liposomes containing encapsulated DXR failed to induce the ABC phenomenon. Likewise, no rapid clearance of the test dose was observed when the first dose of "empty" PEGylated liposomes (without DXR) exceeded 5 micromol phospholipids/kg. By contrast, "empty" PEGylated liposomes at a low dose (1 micromol phospholipids/kg) induced the phenomenon as before. Western blot analysis revealed abundant binding of IgM to PEGylated liposomes when these were incubated in serum from rats that had received "empty" PEGylated liposomes. Substantially less binding of IgM was found when the liposomes were incubated in serum from rats treated with DXR-loaded PEGylated liposomes. For both the empty and the DXR-containing liposomes the amounts of IgM binding to the liposomes decreased with an increasing dose of injected liposomes. Serum obtained from rats following injection of empty PEGylated liposomes caused complement activation by addition of PEGylated liposomes in an inversely dose-dependent manner: the lower the dose, the higher the complement activation. By contrast, no complement activation was detected with serum from rats that had been treated with DXR-loaded PEGylated liposomes. These findings suggest that encapsulation of DXR as well as a relatively high lipid dose abrogate the immune response against PEGylated liposomes which is observed with the same liposomes but without DXR and at low doses. Our observations may thus have important implications for the development, evaluation and therapeutic use of liposomal cytotoxic drug formulations requiring multiple injection schemes.
(キーワード): Animals / Antibiotics, Antineoplastic / Antigen-Antibody Reactions / Chemistry, Pharmaceutical / Cholesterol / Complement Activation / Dose-Response Relationship, Immunologic / Doxorubicin / Drug Compounding / Immunoglobulin M / Injections, Intravenous / Liposomes / Male / Metabolic Clearance Rate / Phosphatidylethanolamines / Polyethylene Glycols / Radiopharmaceuticals / Rats / Rats, Wistar / Spleen / Tissue Distribution / Tritium
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2006.08.017
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 17045355; ● Search Scopus @ Elsevier (PMID): 17045355; ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2006.08.017

(DOI: 10.1016/j.jconrel.2006.08.017, PubMed: 17045355) Tatsuhiro Ishida, Masako Ichihara, Xinyu Wang and Hiroshi Kiwada :
Spleen plays an important role in the induction of accelerated blood clearance of PEGylated liposomes.,
Journal of Controlled Release, Vol.115, No.3, 243-250, 2006.

(要約): It is well known that steric stabilization of the surface of liposomes by a polyethyleneglycol (PEG) conjugated lipid results in reduced recognition of the liposomes by the cells of the mononuclear phagocyte system and consequently extended circulation times of the liposomes (t1/2 approximately 20 h in rat). Recently, we reported on the "accelerated blood clearance (ABC) phenomenon", causing PEGylated liposomes to be cleared very rapidly from the circulation upon repeated injection. We also reported that abundant binding of IgM, secreted into the blood stream after the first dose and, to PEGylated liposomes, plays an essential role in the induction of the ABC phenomenon. Spleen is well known to play a central role in the immune reaction and to produce IgM following a bacterial infection. The aim of the present study was to determine whether spleen contributes to the induction of the ABC phenomenon and to unravel its role in the phenomenon. In rats that were splenectomized (surgical removal of spleen) prior to the first injection of liposomes (0.001 micromol phospholipids/kg), the ABC phenomenon was totally abolished. In these rats serum IgM concentrations as well as the amounts of IgM bound to PEGylated liposomes were substantially reduced. Splenectomy attenuated the ABC phenomenon when performed until 3 days post-first injection. Removal of the spleen 4 days post-first injection left the ABC phenomenon unchanged. This finding indicates that the immune reaction in the spleen against the PEGylated liposomes occurs during at least 2-3 days following the first administration and then IgM reactive to PEGylated liposomes is produced. The present study proves that the spleen plays a critical role in the induction phase of the ABC phenomenon. For effective clinical application, many liposomal drug formulations will require multiple injections. The ABC phenomenon described in this and several preceding papers therefore has important implications for the development and evaluation of therapeutically useful liposomal formulations requiring multiple-dose administration.
(キーワード): Animals / Antigen-Antibody Reactions / Cholesterol / Complement Activation / Immunoglobulin G / Immunoglobulin M / Liposomes / Liver / Male / Metabolic Clearance Rate / Phosphatidylethanolamines / Polyethylene Glycols / Radiopharmaceuticals / Rats / Rats, Wistar / Spleen / Splenectomy / Tissue Distribution / Tritium
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2006.08.001
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 17011060; ● Search Scopus @ Elsevier (PMID): 17011060; ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2006.08.001

(DOI: 10.1016/j.jconrel.2006.08.001, PubMed: 17011060) Mario Jose Barichello, M. Handa, M. Kisyuku, Taiki Shibata, Tatsuhiro Ishida and Hiroshi Kiwada :
Inducing effect of liposomalization on the transdermal delivery of hydrocortisone: creation of a drug supersaturated state.,
Journal of Controlled Release, Vol.115, No.1, 94-102, 2006.

(要約): In order to investigate the effect of liposomal drugs on skin delivery, it was postulated that the process of liposomalization might lead the drug to an overpredicted solubility state which has far-reaching implications for drug skin permeation and accumulation. In this regard, conventional (CL) and flexible liposomes (FL) were prepared by the lipid film hydration method and the particles were downsized by sonication using hydrocortisone (HC) as a poorly water soluble model drug. The solutions derived from the whole CL and FL suspensions eluted on a Sephadex G-50 column (SG-50) demonstrated that most part of HC not only resides solely in the water phase but also it might exist in an improved solubility state. The results of the in vitro study using rat abdominal skin and occlusive application indicated that HC penetrated and accumulated much better solely than when associated with CL or FL. In regard to the penetration of the non-entrapped HC associated to liposomes bilayer fragments, a very small amount of phospholipids in the non-liposomal part eluted on SG-50 was found that could not justify by itself the penetration of HC associated to liposome bilayer fragments. It was proposed that all the steps of the liposomes preparation process might contribute for the increased HC solubility state, but definitively the presence of phospholipids played a crucial role on improving the HC solubility in the absence of sodium cholate. In comparison with commercially available ointments, the non-entrapped HC solution derived from the whole CL suspension eluted on SG-50 showed a higher concentration of HC accumulated and more uniformly distributed as well in the epidermis and dermis compartments. In addition, the thermodynamic activity of the non-entrapped HC solutions maintaining a driving force of the drug across the skin barrier pointed out that the level of HC solubility achieved during liposome preparation has far-reaching implication for drug skin permeation and accumulation in the experimental conditions used. The findings also indicated that the non-entrapped drug solutions obtained on the process of liposomalization could be useful on transdermal drug delivery systems, particularly for improving the permeation and accumulation capacity of poorly soluble drugs.
(キーワード): Administration, Cutaneous / Animals / Anti-Inflammatory Agents / Drug Carriers / Hydrocortisone / Liposomes / Male / Microscopy, Electron, Scanning / Ointments / Particle Size / Phospholipids / Rats / Rats, Wistar / Skin / Skin Absorption / Suspensions
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2006.07.008
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 16919352; ● Search Scopus @ Elsevier (PMID): 16919352; ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2006.07.008

(DOI: 10.1016/j.jconrel.2006.07.008, PubMed: 16919352) Foi Dang, Wenhao Li, LiGo Zhang, M Japasini, Tatsuhiro Ishida, Hiroshi Kiwada, N. Kaji, M. Tokeshi and Yoshinobu Baba :
Electrophoretic behavior of plasmid DNA in the presence of various intercalating dyes.,
Journal of Chromatography. A, Vol.1118, No.2, 218-225, 2006.

(要約): In the present study, the electrophoretic behavior of linear, supercoiled and nicked circular plasmid DNA in the presence of various intercalating dyes was characterized using pGL3 plasmid DNA as a model. The enzymatic digestion of pGL3 plasmid DNA with HindIIIwas monitored by capillary electrophoresis coupled with laser-induced fluorescence detection (CE-LIF). Nicked circular plasmid DNA was found to be relatively sensitive to enzymes, and was almost digested into the linear conformer after 10-min incubation, indicating that nicked circular plasmid DNA has little chance of targeting and entering the cell nucleus. Partly digested plasmid DNA containing only linear and supercoiled conformers can be used as a standard to confirm the migration order of plasmid DNA. In methylcellulose (MC) solution with YO-PRO-1 or YOYO-1, linear plasmid DNA eluted first, followed by supercoiled and nicked plasmid DNA, and nicked plasmid DNA eluted as a broad peak. With SYBR Green 1, nicked plasmid DNA eluted first as three sharp peaks, followed by linear and supercoiled plasmid DNA. The nuclear plasmid DNA from two transfected cell lines was successfully analyzed using the present procedure. Similar results were obtained with an analysis time of seconds using microchip electrophoresis with laser-induced fluorescence detection (mu-CE-LIF). To our knowledge, these results represent the first reported analysis of nuclear plasmid DNA from transfection cells by CE-LIF or mu-CE-LIF without pre-preparation, suggesting that the present procedure is a promising alternative method for evaluating transfection efficiency of DNA delivery systems.
(キーワード): 3T3 Cells / Animals / Cell Nucleus / Coloring Agents / DNA / Electrophoresis, Microchip / Humans / Intercalating Agents / Mice / Plasmids / Spectrometry, Fluorescence
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.chroma.2006.03.120
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 16643931; ● Search Scopus @ Elsevier (PMID): 16643931; ● Search Scopus @ Elsevier (DOI): 10.1016/j.chroma.2006.03.120

(DOI: 10.1016/j.chroma.2006.03.120, PubMed: 16643931) Tatsuhiro Ishida, Masako Ichihara, Xinyu Wang, Kenji Yamamoto, Jyunji Kimura, Eiji Majima and Hiroshi Kiwada :
Injection of PEGylated liposomes in rats elicits PEG-specific IgM, which is responsible for rapid elimination of a second dose of PEGylated liposomes.,
Journal of Controlled Release, Vol.112, No.1, 15-25, 2006.

(要約): Steric stabilization of the surface of liposomes by a PEG conjugated lipid results in reduced recognition of the liposomes by the cells of the mononuclear phagocyte system and consequently extended their circulation times (t(1/2) approximately 20h in rat). Recently, we reported on the "accelerated blood clearance phenomenon", causing "invisible" PEGylated liposomes to be cleared very rapidly from the circulation upon repeated injection. In addition, we reported that certain serum factor(s) secreted into the blood after the first dose of PEGylated liposomes play an essential role in the phenomenon. The aim of the present study was to identify the major serum protein(s) responsible for the phenomenon and to unravel their mode of action. The amount of protein binding to PEGylated liposomes during incubation with serum hardly correlated with the extent of the phenomenon. PEGylated liposomes incubated with serum obtained from rats pre-injected 5 days before with the same liposomes showed a much more complex pattern of bound proteins than when incubated with naïve serum, as revealed by 2D-PAGE and SDS-PAGE. Subsequent analysis with LC-MS/MS and Western blot showed that the major pre-treated serum protein binding to PEGylated liposomes was IgM. Semi-quantitative analysis showed that larger amount of IgM bound to PEGylated liposomes compared to conventional liposomes. It was further demonstrated that PEGylated liposomes could activate the complement system due to IgM binding when incubated in serum from rats pre-injected with PEGylated liposomes, while conventional liposomes were not. These findings suggest that the selective binding of IgM to the second injected PEGylated liposomes and the subsequent complement activation by IgM resulted in the accelerated clearance and enhanced hepatic uptake of the second injected PEGylated liposomes. Based on the results described here, we are drawing attention to the potential occurrence of unexpected immune reactions upon intravenous administration of PEGylated liposomes or other particles and, by extension, PEGylated proteins and DNAs.
(キーワード): Animals / Complement Activation / Immunoglobulin M / Injections, Intravenous / Kupffer Cells / Liposomes / Liver / Male / Polyethylene Glycols / Protein Binding / Rats / Rats, Wistar / Spleen
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2006.01.005
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 16515818; ● Search Scopus @ Elsevier (PMID): 16515818; ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2006.01.005

(DOI: 10.1016/j.jconrel.2006.01.005, PubMed: 16515818) Tatsuhiro Ishida, Wenhao Liu, Zhung Li and Hiroshi Kiwada :
Stimulatory effect of polyethylene glycol (PEG) on gene expression in mouse liver following hydrodynamics-based transfection.,
The Journal of Gene Medicine, Vol.8, No.3, 324-334, 2006.

(要約): Rapid intravenous injection of a large volume of plasmid DNA (pDNA), i.e. a transfection procedure based on hydrodynamics, is known to be an efficient and liver-specific method of in vivo gene delivery. However, the gene expression is transient. We investigated the effect of addition of polyethylene glycol (PEG) to a solution of naked pDNA (luciferase) on the expression of the gene in mouse liver following transfection by the hydrodynamics-based technique. In addition, the mechanism leading to the enhancement of the gene expression was studied. The addition of 1% (w/v) PEG2000 to the pDNA solution enhanced the resulting gene expression in the liver. Increasing the PEG2000 concentration to more than 1 and up to 10% (w/v) rather diminished the gene expression level. By contrast, increasing the molecular weight of PEG to over 2000 up to 10 000 did not affect the level of gene expression. Histopathological and serum-chemistry examinations indicated that hydrostatic or osmotic pressure increased tissue and hepatocellular damage in a PEG-concentration-dependent manner, and resulted in a decrease in gene expression. Quantitative evaluation showed that the enhanced gene expression resulted from stabilization of the pDNA introduced into the hepatocytes and an enhancement of the transport of intact pDNA to the nucleus. For most gene therapy applications and gene function studies, sustained expression of the introduced gene(s) is necessary. This simple method to achieve enhanced gene expression in liver may have a great potential for a wide variety of laboratory studies in molecular and cellular biology as well as possibly for future clinical applications in humans.
(キーワード): Animals / Cell Membrane / DNA (DNA) / Drug Carriers / Gene Expression Profiling / 遺伝子治療 (gene therapy) / Gene Transfer Techniques / Hepatocytes / Injections, Intravenous / Liver / Luciferases / Male / Mice / Osmosis / Permeability / Plasmids / Polyethylene Glycols / Transfection
(出版サイトへのリンク): ● Publication site (DOI): 10.1002/jgm.850
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 16288498; ● Search Scopus @ Elsevier (PMID): 16288498; ● Search Scopus @ Elsevier (DOI): 10.1002/jgm.850

(DOI: 10.1002/jgm.850, PubMed: 16288498) Tatsuhiro Ishida, Yurie Okada, Tomotaka Kobayashi and Hiroshi Kiwada :
Development of pH-sensitive liposomes that efficiently retain encapsulated doxorubicin (DXR) in blood.,
International Journal of Pharmaceutics, Vol.309, No.1-2, 94-100, 2006.

(要約): We have reported that targeted, pH-sensitive sterically stabilized liposomes are able to increase the cytotoxicity of DXR in vitro against B lymphoma cells, but the rate of release of DXR in plasma was too rapid to permit the results to be extended to in vivo applications. The purpose of the study reported here is two-fold. First, to understand the mechanism of the rapid release of DXR from pH-sensitive sterically stabilized liposomes (PSL) in human plasma. Second, to reformulate the above liposomes to improve their drug retention, while retaining their pH sensitivity. The stability of the PSL formulations in human plasma was evaluated by comparing the rate of release of encapsulated DXR with that of HPTS, a water-soluble fluorescent marker. Since DXR, but not HPTS, a water soluble-less membrane permeable fluorescence marker, was rapidly released from liposomes in the presence of plasma, the rapid release of DXR is likely caused by the diffusion of DXR molecules through the lipid bilayer, not by the disruption of the membrane. In order to develop more stable PSL formulations, various molar ratios of the membrane rigidifying lipid, hydrogenated soy HSPC and/or CHOL, were added to the lipid composition and the rate of release of encapsulated solutes and pH-sensitivity were evaluated. The compositions that showed the best drug retention and pH-sensitivity were a mixture of DOPE/HSPC/CHEMS/CHOL/mPEG(2000)-DSPE at a molar ratio of 4:2:2:2:0.3 and DOPE/HSPC/CHEMS/CHOL at a molar ratio of 4:2:2:2. Our formulations, if targeted to internalizing antigens on cancer cells, may increase intracellular drug release rates within acidic compartment, resulting in a further increase in the therapeutic efficacy of targeted anticancer drug-containing liposomes.
(キーワード): Animals / Antibiotics, Antineoplastic / コレステロール (cholesterol) / 拡散 (diffusion) / Doxorubicin / Hydrogen-Ion Concentration / Lipids / リポソーム (liposomes) / Male / Mice / 分子量 (molecular weight) / Phosphatidylcholines / Phosphatidylethanolamines / プラズマ (plasma) / Polyethylene Glycols / 溶解度 (solubility) / Technology, Pharmaceutical
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2005.11.010
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 16364578; ● Summary page in Scopus @ Elsevier: 2-s2.0-31144443980

(DOI: 10.1016/j.ijpharm.2005.11.010, PubMed: 16364578, Elsevier: Scopus) Lap Thi Nguyen, Tatsuhiro Ishida and Hiroshi Kiwada :
Gene Expression in Primary Cultured Mouse Hepatocytes with a Cationic Liposomal Vector, TFL-3: Comparison with Rat Hepatocytes,
Biological & Pharmaceutical Bulletin, Vol.28, No.8, 1472-1475, 2005.

(要約): We recently reported that a cationic liposomal vector, TFL-3, could be used to achieve significant gene expression in primary cultured rat hepatocytes (Nguyen et al., Biol. Pharm. Bull., 26, 880-885 (2003)). A combination of hepatocyte transplantation and hepatocyte-targeted gene transfer represents a potentially important strategy for expanding treatment options for liver disease. A widely applied approach to support cross-species is necessary before human applications can be realized. Therefore, in this study, we examined the utility of TFL-3 in another species of rodent hepatocytes, namely mouse hepatocytes. Gene expression in mouse hepatocytes by TFL-3 was successful and the level was higher than those in rat hepatocytes that we recently reported on. Interestingly, it appears that both the degree and rate of gene expression were dependent on the incubation time prior to lipofection as well as on the density of cells per dish, but these parameters were independent of the amount of pDNA associated with the cells. These significantly suggest that the culture time prior to and following lipofection, which are related to the biological condition of the cells, may be one of major factors that affect gene expression in hepatocytes and non- or less dividing cells.
(キーワード): gene delivery / cationic liposome / hepatocyte / non-dividing cell / plasmid quantification
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.28.1472
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 16079495; ● Search Scopus @ Elsevier (PMID): 16079495; ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.28.1472

(DOI: 10.1248/bpb.28.1472, PubMed: 16079495) Tatsuhiro Ishida, Masae Harada, Wang Xinyu, Masako Ichihara, Kenji Irimura and Hiroshi Kiwada :
Accelerated blood clearance of PEGylated liposomes following preceding liposome injection: Effects of lipid dose and PEG surface-density and chain length of the first-dose liposomes,
Journal of Controlled Release, Vol.105, No.3, 305-317, 2005.

(要約): We recently reported that a second dose of polyethylene glycol (PEG) (M.W. 2000)-modified liposomes (mPEG2000-liposomes) is rapidly cleared from the blood and accumulates in the liver when injected twice in the same rat or mouse at several-day intervals (referred to as the "accelerated blood clearance (ABC) phenomenon"). In the present study we observed that a high dose (5 micromol/kg) of conventional liposomes (CL: without a PEG-coating) can induce the same phenomenon, while a low lipid dose (0.001 micromol/kg) did not. The induction of the phenomenon by mPEG2000-liposomes decreased with increasing first dose (0.001-5 micromol/kg). We observed a strong inverse relationship between the dose of initially injected PEG2000-liposomes and the extent to which the ABC phenomenon was induced: the higher the dose the smaller the phenomenon. Increasing the PEG density at the liposome surface beyond 5 mol% attenuated rather than induced the induction of the phenomenon, but elongation of the PEG chain length up to M.W. 5000, had no effect. In a series of hematological, serum-biochemical and histopathological safety evaluations we observed neither acute toxicity nor any signs of hepatic damage during the induction of the ABC phenomenon. Morphological examination of the liver by transmission electron microscopy (TEM) showed extensive accumulation of the second dose of mPEG2000-liposomes in the Kupffer cells, even already after 15 min, suggesting that the PEG liposomes had somehow lost the protective effect of the surface-grafted PEG against rapid clearance. The observations reported in this paper may have a considerable impact on the design and engineering of PEGylated liposomal formulations for use in multiple drug therapy.
(キーワード): ATP-Binding Cassette Transporters / Animals / Biological Availability / Blood Cell Count / Excipients / Injections, Intravenous / Liposomes / Liver / Male / Microscopy, Electron, Transmission / Polyethylene Glycols / Radiopharmaceuticals / Rats / Rats, Wistar / Structure-Activity Relationship / Surface Properties / Tissue Distribution
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2005.04.003
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 15908032; ● Search Scopus @ Elsevier (PMID): 15908032; ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2005.04.003

(DOI: 10.1016/j.jconrel.2005.04.003, PubMed: 15908032) Wang Xinyu, Tatsuhiro Ishida, Masako Ichihara and Hiroshi Kiwada :
Influence of the physicochemical properties of liposomes on the accelerated blood clearance phenomenon in rat,
Journal of Controlled Release, Vol.104, No.1, 91-102, 2005.

(要約): We have recently reported that PEGylated liposomes (PL) are cleared rapidly from the blood circulation when they are administered twice in the same rat at certain intervals, even if the liposomes are sterically stabilized by a surface modification with PEG (referred to as the accelerated blood clearance (ABC) phenomenon, J. Control. Release, 88, 35-42 (2003)). Now we report on the influence of physicochemical properties (PEG-modification, size and surface charge) of either the first or the second dose of liposomes on the ABC phenomenon. When, for the first dose, conventional liposomes (CL; without a PEG coating) of 110-nm diameter were injected, only a very slight ABC phenomenon was observed, irrespective of the liposomal surface charge: both clearance rate and hepatic accumulation of the second injected PL were only slightly enhanced compared to those of a single dose of PL. Interestingly, when for the first injection small-size liposomes (60 nm) were used, either charged or PEG-modified, but not neutral, the ABC phenomenon was clearly manifest. Apparently, the induction of the ABC phenomenon is not only determined by the PEG coating but also by the size and surface charge of the first dose of liposomes. Also when for the second dose small-size PEGylated liposomes were used, the ABC phenomenon was observed after induction by a first injection of PL, whereas plasma kinetics and organ uptake of a second dose of negatively charged CL (NCL, 110 nm) or small-sized NCL (SNCL, 60 nm) were not altered. Apparently, the PEG coating on the second dose is essential for the liposomes to be susceptible to the ABC phenomenon. The results reported here suggest that the physicochemical properties of both the first and second dose of liposomes are important either for the induction of the phenomenon or for its expression. Our observations may have a considerable impact on the clinical application and engineering of liposomal formulations for use in multiple drug therapy.
(キーワード): Polyethylene glycol (PEG) / Accelerated blood clearance (ABC) phenomenons / Liposomes
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2005.01.008
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 15866337; ● Search Scopus @ Elsevier (PMID): 15866337; ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2005.01.008

(DOI: 10.1016/j.jconrel.2005.01.008, PubMed: 15866337) Koichiro Tsuchiya, Yasuhisa Kanematsu, Masanori Yoshizumi, Hideki Ohnishi, Kazuyoshi Kirima, Yuki Izawa, Michiyo Shikishima, Tatsuhiro Ishida, Shuji Kondo, Shoji Kagami, Yoshiharu Takiguchi and Toshiaki Tamaki :
Nitrite is an alternative source of NO in vivo,
American Journal of Physiology, Heart and Circulatory Physiology, Vol.288, No.5, H2163-H2170, 2005.

(要約): In this study, we investigated whether orally administered nitrite is changed to NO and whether nitrite attenuates hypertension in a dose-dependent manner. We utilized a stable isotope of [15N]nitrite (15NO2-) as a source of nitrite to distinguish between endogenous nitrite and that exogenously administered and measured hemoglobin (Hb)-NO as an index of circulating NO in whole blood using electron paramagnetic resonance (EPR) spectroscopy. When 1 mg/kg Na15NO2 was orally administered to rats, an apparent EPR signal derived from Hb15NO (A(Z) = 23.4 gauss) appeared in the blood. The peak blood HbNO concentration occurred at the first measurement after intake (5 min) for treatment with 1 and 3 mg/kg (HbNO: 4.93 +/- 0.52 and 10.58 +/- 0.40 microM, respectively) and at 15 min with 10 mg/kg (HbNO: 38.27 +/- 9.23 microM). In addition, coadministration of nitrite (100 mg/l drinking water) with N(omega)-nitro-L-arginine methyl ester (L-NAME; 1 g/l) for 3 wk significantly attenuated the L-NAME-induced hypertension (149 +/- 10 mmHg) compared with L-NAME alone (170 +/- 13 mmHg). Furthermore, this phenomenon was associated with an increase in circulating HbNO. Our findings clearly indicate that orally ingested nitrite can be an alternative to L-arginine as a source of NO in vivo and may explain, at least in part, the mechanism of the nitrite/nitrate-rich Dietary Approaches to Stop Hypertension diet-induced hypotensive effects.
(キーワード): 一酸化窒素 (nitric oxide) / hypertension / 電子スピン共鳴 (electron paramagnetic resonance)
(出版サイトへのリンク): ● Publication site (DOI): 10.1152/ajpheart.00525.2004
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 15626692; ● Search Scopus @ Elsevier (PMID): 15626692; ● Search Scopus @ Elsevier (DOI): 10.1152/ajpheart.00525.2004

(DOI: 10.1152/ajpheart.00525.2004, PubMed: 15626692) Wenhao Li, Tatsuhiro Ishida, Yurie Okada, Naoto Oku and Hiroshi Kiwada :
Increased Gene Expression by Cationic Liposomes (TFL-3) in Lung Metastases Following Intravenous Injection,
Biological & Pharmaceutical Bulletin, Vol.28, No.4, 701-706, 2005.

(要約): We recently showed that size, not surface charge, is a major determinant of the in vitro lipofection efficiency of pDNA/TFL-3 complex (lipoplex), even in the presence of serum. In this study, the effect of lipoplex size as a result of interaction with serum proteins on in vitro lipofection and the relationship of this with in vivo lipofection was examined in a murine lung metastasis model. As previously described, the pDNA to lipid ratio (P/L ratio) affected both the size and zeta potential of the lipoplex. In vitro studies also indicated that transgene expression in B16BL6 cells was largely dependent on the size of the lipoplex, both in the absence or presence (50% (v/v)) of serum. An in vivo lipofection experiment showed that predominant gene expression in lungs occurred only in tumor-bearing mice, not in normal mice. Based on the in vitro study, this tumor-related gene expression was not related to lipoplex size in the presence of serum (50% (v/v)), suggesting that the size alteration, as the result of interactions with serum proteins in the blood stream may not play an important role in the case of systemic injections. In addition, the efficient gene expression in tumor-bearing lung was not related to the progression of lung metastases. The area-specific gene expression in tumor-bearing lungs, which was largely dependent on the P/L ratio of the lipoplexes, was observed by fluorescent microscopy. Although the underlying mechanism for the area-specific transgene expression is not clear, it may be related to the interaction of lipoplexes with tumor cells, vascular endothelial cells under angiogenesis and normal cells in the lungs. The possibility that TFL-3 is a useful utility to the targeted delivery of pDNA to lungs and tumor-related lipofection is demonstrated. This result suggests that area-specific gene expression in lung metastases may be achieved by controlling the physicochemical properties of the lipoplex, i.e. the P/L ratio.
(キーワード): Animals / DNA / Gene Expression / Gene Therapy / Liposomes / Lung Neoplasms / Melanoma / Mice / Transfection
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.28.701
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 15802813; ● Search Scopus @ Elsevier (PMID): 15802813; ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.28.701

(DOI: 10.1248/bpb.28.701, PubMed: 15802813) Wenhao Li, Tatsuhiro Ishida, Rieko Tachibana, Mohamad Radwan Almofti, Xinyu Wang and Hiroshi Kiwada :
Cell type-specific gene expression, mediated by TFL-3, a cationic liposomal vector, is controlled by a post-transcription process of delivered plasmid DNA,
International Journal of Pharmaceutics, Vol.276, No.1-2, 67-74, 2004.

(要約): The issue of whether the TFL-3, a recently developed cationic liposome, achieves efficient gene expression in different mammalian cell lines (NIH/3T3, LLC, A431 and HeLa cells) was examined. The issue of whether gene expression is related to the amount of plasmid DNA (pDNA) delivered in cells or nuclei following transfection was also examined. The cells were transfected for 1h with pDNA/TFL-3 lipoplexes, and the transfection efficiency was determined by means of a luciferase activity assay. The amount of intracellular and intranuclear pDNA following the transfection was also quantitatively determined. Successful transgene expressions in all cell lines we tested were observed under our experimental conditions, suggesting that the TFL-3 represents a suitable nonviral vector system for the successful gene expression in mammalian cells in vitro. The degree and rate of gene expression were dependent on the type of cells used as well as the incubation time after transfection, but these parameters were independent of the amount of gene delivered to cells and nuclei. These results suggest that TFL-3 mediated gene expression is largely controlled by the process of post-transcription of the delivered pDNA, and not by the process of cellular entry of pDNA and cytoplasmic trafficking of pDNA into nuclei, which is dependent on the cell type. Therefore, the results obtained here clearly suggest that the cell type-specific improvement in transcription efficiency of pDNA and translation of the derived mRNA, together with an improved delivery system to enhance the nuclear delivery of pDNA, is necessary to achieve efficient transgene expression in mammalian cells.
(キーワード): Gene delivery / Cationic liposome / Lipoplex / DNA / Transfection
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2004.02.011
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 15113615; ● Search Scopus @ Elsevier (PMID): 15113615; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ijpharm.2004.02.011

(DOI: 10.1016/j.ijpharm.2004.02.011, PubMed: 15113615) Tatsuhiro Ishida, Takako Ichikawa, Masako Ichihara, Yasuyuki Sadzuka and Hiroshi Kiwada :
Effect of the physicochemical properties of initially injected liposomes on the clearance of subsequently injected PEGylated liposomes in mice.,
Journal of Controlled Release, Vol.95, No.3, 403-412, 2004.

(要約): Using mice as a model, we recently reported that the long-circulating properties of polyethylene glycol (PEG) (M.W. 2000)-modified liposomes (mPEG(2000)-liposomes) disappeared when they were intravenously injected at certain intervals [referred to as the "accelerated blood clearance (ABC) phenomenon"]. Herein, we report on a study of issue of whether physicochemical properties of a prior dose of liposomes such as degree of PEGylation, PEG chain length, lipid dose, surface charge, size, play a role in inducing this phenomenon. The injection of conventional liposomes (without a PEG-coating) significantly induced the phenomenon. The PEGylation of conventional liposomes attenuated the induction of the phenomenon somewhat with increasing molar content of PEG derivative and PEG chain length. These findings clearly suggest that the PEGylation of liposomes are not the major cause of the ABC phenomenon but, rather, played a role in preventing it. In addition, increasing the lipid dose in a prior dose of mPEG(2000)-liposomes (0-25 micromol/kg) increased the induction of the phenomenon in a sigmoid manner. The surface charge and size of the liposomes were not critical for the induction of the phenomenon, although generally these serve as determinants in the biodistribution of liposomes. The results reported here clearly indicate that the physicochemical properties of a prior dose of liposomes strongly affect the pharmacokinetic behavior of a subsequent injection of mPEG(2000)-liposomes: The extent of PEGylation and the lipid dose had an effect, but the surface charge and size did not. The results reported herein have a considerable impact on the design and engineering of liposomal formulations for use in multiple drug therapy as well as in therapy that involves the use of liposomal drugs.
(キーワード): Animals / 物理化学 (physical chemistry) / Drug Administration Schedule / Injections, Intravenous / 日本 (Japan) / リポソーム (liposomes) / Liver / Male / Metabolic Clearance Rate / Mice / Mice, Inbred Strains / Polyethylene Glycols / Radiopharmaceuticals / Time Factors
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2003.12.011
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 15023452; ● Search Scopus @ Elsevier (PMID): 15023452; ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2003.12.011

(DOI: 10.1016/j.jconrel.2003.12.011, PubMed: 15023452) Lap Thi Nguyen, Tatsuhiro Ishida, Sachiko Ukitsu, Wen Hao Li, Rieko Tachibana and Hiroshi Kiwada :
Culture Time-Dependent Gene Expression in Isolated Primary Cultured Rat Hepatocytes by Transfection with the Cationic Liposomal Vector TFL-3,
Biological & Pharmaceutical Bulletin, Vol.26, No.6, 880-885, 2003.

(要約): The development of a carrier system that enables the transfer of a functional exogenous gene to non- or less frequently dividing mammalian cells is essential for increasing the available options for the treatment of various diseases. The issue of whether TFL-3, a recently developed cationic liposome, can be successfully used to achieve gene expression in primary cultured rat hepatocytes was examined. The hepatocytes were transfected for 4 h with plasmid DNA (pDNA) in TFL-3 at various time points after 4-h preculture. The transfection efficiency was determined at various times posttransfection with pDNA coding for chloramphenicol acetyltransferase (CAT), luciferase, or beta-galactosidase. The amount of intranuclear pDNA present, as a consequence of the lipofection, was also quantitatively determined. Successful lipofections were observed for all pDNA tested, and the efficiencies were superior to that of commercially available LIPOFECTAMINE under our experimental conditions. The degree and rate of gene expression were dependent on incubation time prior to lipofection as well as on the density of the cells per dish, but this relationship did not hold for the amount of gene delivered to the nuclei. These results indicate that TFL-3 could be a useful vector for achieving sufficient gene expression in rat hepatocytes and suggest that the culture time prior to and following lipofection, which is related to the biological condition of the cells, may be one major factor affecting efficient gene expression in nondividing cells.
(キーワード): gene delivery / cationic liposome / hepatocyte / nondividing cell / plasmid quantification
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.26.880
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 12808305; ● CiNii @ 国立情報学研究所 (CRID): 1390282679603298048; ● Search Scopus @ Elsevier (PMID): 12808305; ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.26.880

(DOI: 10.1248/bpb.26.880, PubMed: 12808305, CiNii: 1390282679603298048) Tatsuhiro Ishida, Kaori Masuda, Takako Ichikawa, Masako Ichihara, Kenji Irimura and Hiroshi Kiwada :
Accelerated clearance of a second injection of PEGylated liposomes in mice.,
International Journal of Pharmaceutics, Vol.255, No.1-2, 167-174, 2003.

(キーワード): PEGylated liposomes / repeated injection / accelerated clearance / laboratory examination / polyethylene glycol (PEG) / PHASE-II / BLOOD CLEARANCE / OVARIAN-CANCER / IN-VITRO / DOXORUBICIN / BIODISTRIBUTION / CIRCULATION / TOXICITY / PHARMACOKINETICS
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/S0378-5173(03)00085-1
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 12672612; ● Search Scopus @ Elsevier (PMID): 12672612; ● Search Scopus @ Elsevier (DOI): 10.1016/S0378-5173(03)00085-1

(DOI: 10.1016/S0378-5173(03)00085-1, PubMed: 12672612) Tatsuhiro Ishida, Ryuhei Maeda, Masako Ichihara, Kenji Irimura and Hiroshi Kiwada :
Accelerated clearance of PEGylated liposomes in rats after repeated injections.,
Journal of Controlled Release, Vol.88, No.1, 35-42, 2003.

(要約): Polyethylene glycol-modified liposomes (PEGylated liposomes) represent promising carrier systems for therapeutic agents. Herein, we report on a study of the effect of repeated injection of PEGylated liposomes on their pharmacokinetics in rats. The first dose resulted in a reduction in the circulation time and an increase in hepatic accumulation of the second dose in a time-interval of injection-dependent manner. No significant increases in the number of Kupffer cells were detectable, although the liver most likely played an important role in the accelerated clearance. Interestingly, the acceleration in clearance became less pronounced, when the third dose was injected at 4, 7 or 14 days after the second injection (the second dose was given 5 weeks after the first injection). An accelerated clearance was evoked in normal rats by the transfusion of serum from rats that had received PEGylated liposomes 5 days earlier, indicating that humoral serum factor(s) are also involved in causing the accelerated clearance. A complement consumption assay indicated that the complement system is not the factor. In summary, multiple injections of PEGylated liposomes clearly altered their pharmacokinetic behavior in rats. It is likely that cellular immunity (Kupffer cells) and humoral immunity are required to cause the phenomenon. The results reported here have a considerable impact in and important implications on the clinical application, design and engineering of PEGylated liposomes for use in repeated intravenous administration.
(キーワード): Animals / Cell Count / Injections, Intravenous / Kupffer Cells / Liposomes / Liver / Male / Phosphatidylcholines / Polyethylene Glycols / Rats / Rats, Wistar / Spleen / Tissue Distribution
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/S0168-3659(02)00462-5
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 12586501; ● Search Scopus @ Elsevier (PMID): 12586501; ● Search Scopus @ Elsevier (DOI): 10.1016/S0168-3659(02)00462-5

(DOI: 10.1016/S0168-3659(02)00462-5, PubMed: 12586501) Sayaka Yamamoto, Tatsuhiro Ishida, Akiko Inoue, Junko Mikami, Masahiro Muraguchi, Yasukazu Ohmoto and Hiroshi Kiwada :
HEPC-based liposomes trigger cytokine release from peripheral blood cells: effects of liposomal size, dose and lipid composition,
International Journal of Pharmaceutics, Vol.236, No.1-2, 125-133, 2002.

(キーワード): Liposome / Cytokine / Human peripheral blood cell / Whole-blood induction / Immune system
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/S0378-5173(02)00026-1
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11891076; ● Search Scopus @ Elsevier (PMID): 11891076; ● Search Scopus @ Elsevier (DOI): 10.1016/S0378-5173(02)00026-1

(DOI: 10.1016/S0378-5173(02)00026-1, PubMed: 11891076) Rieko Tachibana, Hideyoshi Harashima, Tatsuhiro Ishida, Yasuo Shinohara, Mari Hino, Hiroshi Terada, Yoshinobu Baba and Hiroshi Kiwada :
Effect of Cationic Liposomes in an in Vitro Transcription and Translation System,
Biological & Pharmaceutical Bulletin, Vol.25, No.4, 529-531, 2002.

(要約): The effects of cationic liposomes complexed with plasmid DNA on the process of transcription was examined using a recently developed rapid cell free translation system. The findings indicate that the liposome itself inhibited the process when the ratio of DNA/liposome typically used in transfection studies was used.
(キーワード): cationic liposome / 転写 (transcription) / rapid translation system (RTS500) / gene delivery
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.25.529
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11995939; ● Search Scopus @ Elsevier (PMID): 11995939; ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.25.529

(DOI: 10.1248/bpb.25.529, PubMed: 11995939) João N. Moreira, Tatsuhiro Ishida, Rogério Gaspar and Theresa M. Allen :
Use of the post-insertion technique to insert peptide ligands into pre-formed Stealth liposomes with retention of binding activity and cytotoxicity,
Pharmaceutical Research, Vol.19, No.3, 265-269, 2002.

(要約): Simple methods for the large-scale manufacture of ligand-targeted liposomes will be needed if clinical trials are to proceed. We tested a recently developed technology for inserting peptide ligands into preformed Stealth liposomes. Antagonist G-targeted liposomes (PLG) were prepared and loaded with doxorubicin and their cellular association and cytotoxicity were evaluated using the human small cell lung cancer H69 cell line. The hexapeptide antagonist G was covalently coupled via a thioether bond to the terminus of polyethylene glycol (PEG) in micelles formed from maleimide-derivatized poly(ethylene glycol) (Mr 2000) distearoylphosphatidylethanolamine followed by transfer into preformed liposomes during a one-step incubation. For cellular association, we used radiolabeled liposomes. Cytotoxicity was evaluated using the MTT in vitro proliferation assay. The postinsertion approach to the formation of peptide-targeted liposomes led to the production of PLG bearing a maximum of approximately 0.3 microg antagonist G/micromol phospholipid. These liposomes had increased cellular association to H69 cells relative to nontargeted liposomes and, when loaded with doxorubicin, they resulted in similar levels of cytotoxicity to those obtained by conventional coupling techniques. The postinsertion technique is a simple, effective means for the production of biologically active peptide-targeted liposomes.
(キーワード): Binding Sites / Cell Line / Humans / Ligands / リポソーム (liposomes) / Peptides / Technology, Pharmaceutical
(出版サイトへのリンク): ● Publication site (DOI): 10.1023/A:1014434732752
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11934232; ● Search Scopus @ Elsevier (PMID): 11934232; ● Search Scopus @ Elsevier (DOI): 10.1023/A:1014434732752

(DOI: 10.1023/A:1014434732752, PubMed: 11934232) Tatsuhiro Ishida, Yoshihiro Takanashi, Hisako Doi, Isao Yamamoto and Hiroshi Kiwada :
Encapsulation of an antivasospastic drug, fasudil, into liposomes, and in vitro stabiliy of the fasudil-loaded liposomes gradient.,
International Journal of Pharmaceutics, Vol.232, No.1-2, 59-67, 2002.

(要約): The objectives of this work were to develop a liposomal fasudil, an antivasospastic drug, as a possible means to deliver the encapsulated drug to the brain, and to characterize the stability of the liposomal formulation in vitro. Transmembrane electrochemical gradients of H+ or ammonium sulfate were created, and their effect on the uptake of fasudil into preformed hydrogenated soy phosphatidylcholine/cholesterol (HSPC/CHOL) liposomes were examined. Fasudil was successfully loaded into preformed liposomes in response to sulfate ion (SO4(2-)) and, in part, by H+. Encapsulation levels approaching 100% could be achieved up to a drug to lipid ratio of 0.364 (mol/mol). A stability study of the fasudil-loaded liposomes was performed by storage at 4 degrees C in 4-(2-hydroxyethyl)-1-piperazineethanesulphonic acid (HEPES)-buffer (pH 7.4) and by incubation in human cerebrospinal fluid (CSF) at 37 degrees C. The formulations were stable with respect to drug retention as well as size alteration, for the period studied. A leakage study clearly showed the sustained release properties of the fasudil-loaded liposomes in human CSF. We recently reported that the intrathecal administration of liposomal fasudil significantly decreased ischemia, with no obvious adverse effect in a rat model [Neurol. Med. Chir. 41 (2001) 109]. Taken together, efficient encapsulation of fasudil into preformed liposomes, their long-term stability at 4 degrees C and the sustained release characteristics in CSF indicate that fasudil-loaded liposomes could be potential candidates for further clinical evaluation.
(キーワード): 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Chemistry, Pharmaceutical / Drug Stability / Humans / リポソーム (liposomes) / Vasodilator Agents
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/S0378-5173(01)00896-1
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11790490; ● CiNii @ 国立情報学研究所 (CRID): 1570291226801262464; ● Search Scopus @ Elsevier (PMID): 11790490; ● Search Scopus @ Elsevier (DOI): 10.1016/S0378-5173(01)00896-1

(DOI: 10.1016/S0378-5173(01)00896-1, PubMed: 11790490, CiNii: 1570291226801262464) 高梨吉裕, 石田竜弘, 目黒俊成, J Zhang, 山本勇夫 :
くも膜下出血後の脳血管簾縮に対する髄液内投与可能な徐放性塩酸ファスジル(エリル)の開発,
脳卒中の外科, Vol.30, 133-136, 2002年. Tatsuhiro Ishida, M.J. Kirchmeier, E.H. Moase, S. Zalipsky and T.M. Allen :
Targeted delivery and triggered release of liposomal doxorubicin (DXR) enhances cytotoxicity against human B-cell lymphoma cells.,
Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol.1515, No.2, 144-158, 2001.

(要約): Dioleoylphosphatidylethanolamine (DOPE)-containing liposomes that demonstrated pH-dependent release of their contents were stabilized in the bilayer form through the addition of a cleavable lipid derivative of polyethylene glycol (PEG) in which the PEG was attached to a lipid anchor via a disulfide linkage (mPEG-S-S-DSPE). Liposomes stabilized with either a non-cleavable PEG (mPEG-DSPE) or mPEG-S-S-DSPE retained an encapsulated dye at pH 5.5, but treatment at pH 5.5 of liposomes stabilized with mPEG-S-S-DSPE with either dithiothreitol or cell-free extracts caused contents release due to cleavage of the PEG chains and concomitant destabilization of the DOPE liposomes. While formulations loaded with doxorubicin (DXR) were stable in culture media, DXR was rapidly released in human plasma. pH-Sensitive liposomes, targeted to the CD19 epitope on B-lymphoma cells, showed enhanced DXR delivery into the nuclei of the target cells and increased cytotoxicity compared to non-pH-sensitive liposomes. Pharmacokinetic studies suggested that mPEG-S-S-DSPE was rapidly cleaved in circulation. In a murine model of B-cell lymphoma, the therapeutic efficacy of an anti-CD19-targeted pH-sensitive formulation was superior to that of a stable long-circulating formulation of targeted liposomes despite the more rapid drug release and clearance of the pH-sensitive formulation. These results suggest that targeted pH-sensitive formulations of drugs may be able to increase the therapeutic efficacy of entrapped drugs.
(キーワード): Animals / Antigens, CD19 / Cell Nucleus / Chemistry, Pharmaceutical / Doxorubicin / Drug Carriers / Drug Delivery Systems / Humans / Hydrogen-Ion Concentration / Liposomes / Lymphoma / Mice / Mice, Inbred BALB C / Mice, SCID / Neoplasm Transplantation / Polyethylene Glycols / Tumor Cells, Cultured
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/S0005-2736(01)00409-6
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11718670; ● Search Scopus @ Elsevier (PMID): 11718670; ● Search Scopus @ Elsevier (DOI): 10.1016/S0005-2736(01)00409-6

(DOI: 10.1016/S0005-2736(01)00409-6, PubMed: 11718670) Yoshihiro Takanashi, Tatsuhiro Ishida, Toshinari Meguro, Marc J. Kirchmeier, Theresa M. Allen and John H. Zhang :
Intrathecal application with liposome-entrapped Fasudil for cerebral vasospasm following subarachnoid hemorrhage in rats,
Journal of Clinical Neuroscience, Vol.8, No.6, 557-561, 2001.

(出版サイトへのリンク): ● Publication site (DOI): 10.1054/jocn.2001.0998
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1054/jocn.2001.0998

(DOI: 10.1054/jocn.2001.0998) Tatsuhiro Ishida, Kazumi Yasukawa, Hiroko Kojima, Hideyoshi Harashima and Hiroshi Kiwada :
Effect of cholesterol content in activation of the classical versus the alternative pathway of rat complement system induced by hydrogenated egg phosphatidylcholine-based liposomes,
International Journal of Pharmaceutics, Vol.224, No.1-2, 69-79, 2001.

(要約): Liposomes composed of hydrogenated egg phosphatidylcholine (HEPC) and cholesterol (CHOL) were found to activate the rat complement (C) system in a CHOL content-dependent manner. Liposomes containing 22 or 33 mol% CHOL activated the C system in a Ca(2+)-dependent manner, suggesting that C activation occurred via the classical pathway. Liposomes containing 44 mol% CHOL activated the C system in a Ca(2+) independent manner, suggesting that C activation occurred via the alternative pathway. The CHOL content appeared to dictate the pathway by which the C system was activated. This C activation was inhibited by removal of serum component(s), which adsorb to the liposomes. Activation of the alternative pathway, induced by the liposomes, was reduced by the depletion of IgG and IgM, whereas the classical pathway activation was reduced by the depletion of IgG, but not IgM. In addition, the removal of adsorbed serum component(s) by treatment with 44 mol% CHOL-containing liposomes decreased serum IgG and IgM levels that adsorb to the same liposomes, whereas the removal of adsorbed serum component(s) by treatment with 22 mol% CHOL-containing liposomes only slightly decreased serum IgG levels, which adsorbs to the same liposomes. Collectively, both IgG and IgM, which are specifically adsorbed to the liposomes in a CHOL-content dependent manner, were responsible for C activation via the alternative pathway induced by the 44 mol% CHOL containing liposomes. IgG alone would be partially responsible for C activation via the classical pathway induced by 22 or 33 mol% CHOL-containing liposomes. The discovery of this unique C-activating property of liposomes will be of value in attempts to decipher the underlying mechanism of C activation by providing a useful model membrane system.
(キーワード): Liposomes / Drug delivery system / Complement activation / Antibodies
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/S0378-5173(01)00737-2
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11472816; ● Search Scopus @ Elsevier (PMID): 11472816; ● Search Scopus @ Elsevier (DOI): 10.1016/S0378-5173(01)00737-2

(DOI: 10.1016/S0378-5173(01)00737-2, PubMed: 11472816) Tran Minh Huong, Tatsuhiro Ishida, Hideyoshi Harashima and Hiroshi Kiwada :
Species Difference in Correlation between in Vivo/ in Vitro LiposomeComplement Interactions,
Biological & Pharmaceutical Bulletin, Vol.24, No.4, 439-441, 2001.

(要約): The objective of this study was to investigate the correlation between in vitro and in vivo liposome-complement interactions. Third component of the complement (C3) fragments associated with hydrogenated egg phosphatidylcholine (HEPC)-based liposomes in vivo and complement-dependent destabilization in vitro were determined as an indication of liposome-complement interaction in vivo and in vitro, respectively. C3 fragments on the liposomes were detected in both rats and guinea pigs. Pretreatment with K76COOH (K76), a complement inactivating agent, reduced the binding of C3 fragments. These findings indicated that the liposomes remarkably activated the complement system in both animals in vivo. Interestingly, significant complement-dependent liposome destabilization was observed in rat serum, but not in guinea pig serum, indicating that the liposomes activated the complement system in rats, but not in guinea pigs in vitro. Taken together, it is apparent that in vitro complement activation by the liposomes is not in agreement with in vivo complement activation in ginea pigs. This discrepancy in the liposome-complement interaction would suggest the need for further investigation to utilize the information obtained from the liposome-complement interaction to predict in vivo behavior of the liposomes.
(キーワード): liposome / complement system / liposome destabilization / rat / guinea pig
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.24.439
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11305612; ● Search Scopus @ Elsevier (PMID): 11305612; ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.24.439

(DOI: 10.1248/bpb.24.439, PubMed: 11305612) Yoshihiro Takanashi, Tatsuhiro Ishida, Toshinari Meguro, Hiroshi Kiwada, John H Zhang and Isao Yamamoto :
Efficacy of Intrathecal Liposomal Fasudil for Experimental Cerebral Vasospasm after Subarachnoid Hemorrhage,
Neurosurgery, Vol.48, No.4, 894-901, 2001.

(要約): To investigate the safety and efficacy of liposomal fasudil in a sustained-release form for the prevention of cerebral vasospasm after subarachnoid hemorrhage (SAH). Eighteen rats were divided into three groups, each of which received 2.5 mg/kg of liposomal fasudil, 5 mg/kg of liposomal fasudil, or drug-free liposomes after SAH. Next, experimental SAH was induced in 15 dogs by injection of autologous arterial blood into the cisterna magna twice after baseline vertebral angiography. In six dogs, 0.94 mg/kg of liposomal fasudil was injected into the cisterna magna (treatment group). In four dogs, drug-free liposomes were similarly injected (placebo group), and the remaining five dogs were not treated with liposomal injection after SAH (control group). Angiography was repeated on Day 7, and cerebrospinal fluid was collected before the dogs were killed. A high dose of liposomal fasudil caused no significant changes in mean arterial blood pressure and did not induce seizures during the observation period. Gross and microscopic examination of the brains revealed no abnormalities, but severe vasospasm was noted in the rat basilar artery, mainly in the group treated with drug-free liposomes. Likewise, in the canine placebo and control groups, significant vasospasm occurred in the basilar artery on Day 7. In the treatment group, vasospasm in the basilar artery was significantly ameliorated (P < 0.01). In vivo, 90% of fasudil was released from liposomes in the cerebrospinal fluid. A single injection of intrathecal liposomal fasudil is safe and effective for the prevention of vasospasm in experimental SAH.
(キーワード): 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Animals / Basilar Artery / Dogs / Dose-Response Relationship, Drug / リポソーム (liposomes) / Rats / Subarachnoid Hemorrhage / Treatment Outcome / Vasodilation / Vasodilator Agents / Vasospasm, Intracranial
(出版サイトへのリンク): ● Publication site (DOI): 10.1097/00006123-200104000-00041
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11322450; ● Search Scopus @ Elsevier (PMID): 11322450; ● Search Scopus @ Elsevier (DOI): 10.1097/00006123-200104000-00041

(DOI: 10.1097/00006123-200104000-00041, PubMed: 11322450) Tran Minh Huong, Tatsuhiro Ishida, Hideyoshi Harashima and Hiroshi Kiwada :
The complement system enhances the clearance of phosphatidylserine (PS)-liposomes in rat and guinea pig,
International Journal of Pharmaceutics, Vol.215, No.1-2, 197-205, 2001.

(要約): In this study, we investigated the contribution of the complement system to the biodistribution of phosphatidylserine (PS)-containing liposomes in rat and guinea pig. It appeared that the inclusion of PS in the liposome formulation accelerates the rate of liposome uptake by liver, resulting in rapid elimination of the liposomes from blood circulation. Pretreatment with K76COOH (K76), an anti-complement agent, decreased the rapid uptake of PS-containing liposomes by guinea pig liver, resulting in increasing blood concentration of the liposomes. Significant complement-dependent liposome destabilization was observed in vitro in both animals, whereas the complement-dependent destabilization in vivo was likely only a part of the process of the clearance of the PS-containing liposomes. This discrepancy suggests that the rate of complement-dependent liposome uptake by liver is much faster than the rate of complement-dependent liposome destabilization in vivo. Pretreatment of K76 dramatically inhibited the binding of C3 fragments, one of dominant opsonins, to PS-containing liposomes in guinea pig under both in vivo and in vitro conditions. This finding suggests that the C3 fragments in the system are responsible for the clearance of the PS-containing liposomes in guinea pig. In rat, in contrast to guinea pig, in vivo binding of C3 fragments was not inhibited by K76-pretreatment, while in vitro binding was inhibited. This discrepancy may be due to different experimental conditions between in vitro and in vivo assay. Nevertheless, based on the observations in this study, the complement components are most likely involved in the clearance of the PS-containing liposomes in rat. Taken together, the activity of PS in enhancing the liposome clearance appears to be mediated by the complement components, presumably C3 fragments, in both guinea pig and rat. This is a first report showing the mechanism on the hepatic uptake of the PS-containing liposomes in guinea pig.
(キーワード): Liposomes / Biodistribution / Complement system / Rat / Guinea pig
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/S0378-5173(00)00691-8
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11250105; ● Summary page in Scopus @ Elsevier: 2-s2.0-0035857696

(DOI: 10.1016/S0378-5173(00)00691-8, PubMed: 11250105, Elsevier: Scopus) Yoshihiro Takanashi, Tatsuhiro Ishida, Marc J. Kirchmeier, Ashfaq Shuaib and Theresa M. Alien :
Neuroprotection by intrathecal application of liposome-entrapped Fasudil in a rat model of ischemia,
Neurologia Medico-Chirurgica, Vol.41, No.3, 107-114, 2001.

(要約): Pharmacological treatment for cerebral ischemia cannot attain sufficiently high concentrations of the drugs in the cerebrospinal fluid (CSF) without precipitating systemic side effects. The objective of this study is the development of a liposomal drug delivery system that maintains effective concentrations of protein kinase inhibitors fasudil in the CSF, resulting in neuroprotection against cerebral ischemia. Focal cerebral ischemia in rats was induced by middle cerebral artery occlusion using an intraluminal suture technique. Treated rats received 0.25 mg liposome-entrapped fasudil via the cisterna magna 2 hours after ischemic insult. Control rats received drug-free liposomes. Neurological condition and the infarct size were assessed at 24 and 72 hours after ischemia. The concentration of liposome-entrapped fasudil in the CSF was measured before sacrifice. Treated animals showed significantly improved neurological outcomes after the 24-hour observation period compared to the control group (p < 0.001). Treatment with 0.25 mg liposomal fasudil resulted in a reduction in the infarct area (24 hours: 29.0 +/- 4.4%, 72 hours: 28.1 +/- 3.9% of total brain slices) compared to controls (49.6 +/- 4.6%, p < 0.001), but there was no statistical difference between 24 and 72 hours. At 24 hours post-administration, CSF concentrations of liposome-entrapped fasudil were 45.4 +/- 31.5 micrograms/ml (20% of the injected dose). A single intrathecal injection of liposomal fasudil can maintain a therapeutic drug concentration in the CSF over a period of time, significantly decreasing infarct size in a rat model of acute ischemia.
(キーワード): 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Animals / Brain Damage, Chronic / Brain Ischemia / Cerebral Infarction / Cisterna Magna / Drug Carriers / Drug Evaluation, Preclinical / Infarction, Middle Cerebral Artery / Injections, Spinal / Liposomes / Male / Neuroprotective Agents / Rats / Rats, Sprague-Dawley
(出版サイトへのリンク): ● Publication site (DOI): 10.2176/nmc.41.107
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11372552; ● Search Scopus @ Elsevier (PMID): 11372552; ● Search Scopus @ Elsevier (DOI): 10.2176/nmc.41.107

(DOI: 10.2176/nmc.41.107, PubMed: 11372552) Marc J. Kirchmeier, Tatsuhiro Ishida, Julie Chevrette and Theresa M. Allen :
Correlations between the rate of intracellular release of endocytosed liposomal doxorubicin and cytotoxicity as determined by a new assay,
Journal of Liposome Research, Vol.11, No.1, 15-29, 2001.

(要約): Previously, we showed that liposomes with surface-attached anti-CD19 were internalized into human B lymphoma cells through receptor-mediated endocytosis, resulting in improved anti-tumor efficacy 1-2 . In order to further increase the efficacy of antineoplastic drug-containing liposomes, we have taken advantage of this internalization process by producing triggered release liposomes that rapidly release drug from the enzyme-rich, acidic environment of lysosomes. To analyze the effectiveness of these triggered-release formulations, we developed a nuclear accumulation assay for doxorubicin (DXR) that allows us to determine the rate of cytoplasmic drug delivery subsequent to drug release from the endosomal/lysosomal compartments by examining the rate of accumulation of drug in cellular nuclei. We demonstrate the usefulness of this assay by comparing the kinetics of cytoplasmic drug delivery for DXR-containing, pH-sensitive, triggered release liposomes versus DXR-containing, non-sensitive, liposomal formulations. We see a significant correlation between the rate of nuclear accumulation of DXR and its in vitrocytotoxicity. This indicates that pH-sensitive formulations traffic drug to the cytoplasm and the nucleus significantly more rapidly than do non-sensitive formulations. We conclude that the development of triggered release liposomes is a promising strategy for further improving the therapeutic efficacy of liposomal antineoplastic drugs targeted selectively to cancer cells by surface-attached ligands that bind to internalizing epitopes.
(出版サイトへのリンク): ● Publication site (DOI): 10.1081/LPR-100103167
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19530916; ● Summary page in Scopus @ Elsevier: 2-s2.0-0035031851

(DOI: 10.1081/LPR-100103167, PubMed: 19530916, Elsevier: Scopus) H E Moase, W Qi, Tatsuhiro Ishida, Z Gabos, M B Longenecker, L G Zimmermann, L Ding, M Krantz and M T Allen :
Anti-MUC-1 immunoliposomal doxorubicin in the treatment of murine models of metastatic breast cancer,
Biochimica et Biophysica Acta (BBA) - Biomembranes, Vol.1510, No.1-2, 43-55, 2001.

(要約): The fate of breast cancer patients is dependent upon elimination or control of metastases. We studied the effect of antibody-targeted liposomes containing entrapped doxorubicin (DXR) on development of tumours in two models of breast cancer, pseudometastatic and metastatic, in mice. The former used the mouse mammary carcinoma cell line GZHI, which expresses the human MUC-1 gene (L. Ding, E.N. Lalani, M. Reddish, R. Koganty, T. Wong, J. Samuel, M.B. Yacyshyn, A. Meikle, P.Y.S. Fung, J. Taylor-Papadimitriou, B.M. Longenecker, Cancer Immunol. Immunother. 36 (1993) 9--17). GZHI cells seed into the lungs of Balb/c mice following intravenous injection. The latter used the 4T1-MUC1 cell line, a MUC-1 transfectant of the mouse mammary carcinoma cell line 4T1, which metastasizes from a primary mammary fatpad (mfp) implant to the lungs (C.J. Aslakson, F.R. Miller, Cancer Res. 52 (1992) 1399--1405). B27.29, a monoclonal antibody against the MUC-1 antigen, was used to target sterically stabilized immunoliposomes (SIL[B27.29]) to tumour cells. In vitro, SIL[B27.29] showed high specific binding to both GZHI and 4T1-MUC1 cells. The IC(50) of DXR-loaded SIL[B27.29] was similar to that of free drug for GZHI cells. In the pseudometastatic model, mice treated with a single injection of 6 mg DXR/kg in DXR-SIL[B27.29] at 24 h after cell implantation had longer survival times than those injected with non-targeted liposomal drug. In the metastatic model, severe combined immune deficiency mice given weekly injectionsx3 of 2.5 mg DXR/kg encapsulated in either targeted or non-targeted liposomes were almost equally effective in slowing growth of the primary tumour and reducing development of lung tumours. Surgical removal of the primary tumour from mfp, followed by various chemotherapy regimens, was attempted, but removal of the primary tumour was generally incomplete; tumour regrowth occurred and metastases developed in the lungs in all treatment groups. DXR-SL reduced the occurrence of regrowth of the primary tumour, whereas neither targeted liposomal drug or free drug prevented regrowth. We conclude that monoclonal antibody-targeted liposomal DXR is effective in treating early lesions in both the pseudometastatic and metastatic models, but limitations to the access of the targeted liposomes to tumour cells in the primary tumour compromised their therapeutic efficacy in treating the more advanced lesions.
(キーワード): Liposome / 乳癌 (breast cancer) / Drug targeting / Metastasis / MUC-1 / Stealth liposome / Doxorubicin
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/S0005-2736(00)00334-5
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11342146; ● Search Scopus @ Elsevier (PMID): 11342146; ● Search Scopus @ Elsevier (DOI): 10.1016/S0005-2736(00)00334-5

(DOI: 10.1016/S0005-2736(00)00334-5, PubMed: 11342146) Tatsuhiro Ishida, Hiroko Kojima, Hideyoshi Harashima and Hiroshi Kiwada :
Biodistribution of liposomes and C3 fragments associated with liposomes:evaluation of their relationship,
International Journal of Pharmaceutics, Vol.205, No.1-2, 183-193, 2000.

(要約): The biodistribution of liposomes with two different kind phospholipids (hydrogenated egg phosphatidylcholine and egg phosphatidylcholine) plus cholesterol (CHOL) were investigated after intravenous administration to rats. Elimination of liposomes from blood circulation was affected by the lipid composition. It appeared that the inclusion of CHOL in liposomes accelerates the rate of liposome uptake by liver, resulting in rapid elimination of liposomes. The amount of C3 fragments bound to liposomes was quantitatively determined to assess the contribution of the complement system to liposome accumulation into organs and liposome destabilization in vivo and in vitro. The amount of bound C3 fragments was directly proportional to CHOL content, and the amount was also proportional to the CLh, CLs as well as CLrel. This relationship suggests that the complement system is responsible for the elimination of liposomes from blood circulation, presumably as a consequence of opsonization by C3 fragments and assembly of membrane attack complex (MAC) onto liposomes. In addition, substitution of cholesteryl methyl ether into the liposome formulation for CHOL significantly diminished not only the binding of C3 fragments but also the CLh, CLs and CLrel, resulting in increased mean resident time (MRT) of the liposomes. This result suggests that the hydroxyl-group on CHOL is a binding site for C3 fragments on the liposomes and that CHOL in a liposome formulation promotes the accumulation of liposomes into the liver and spleen, probably due to their uptake by phagocytic cells, and impairs the stability of the liposomes in blood circulation, via a mechanism involving the complement system.
(キーワード): Liposomes / Complement / C3 / Cholesterol / Drug delivery system (DDS)
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/S0378-5173(00)00511-1
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 11000555; ● Search Scopus @ Elsevier (PMID): 11000555; ● Search Scopus @ Elsevier (DOI): 10.1016/S0378-5173(00)00511-1

(DOI: 10.1016/S0378-5173(00)00511-1, PubMed: 11000555) Tatsuhiro Ishida, Dbbie L. Iden and Theresa M. Allen :
A combinatorial approach to producing sterically stabilized(Stealth)immunoliposomal drugs,
FEBS Letters, Vol.460, No.1, 129-133, 1999.

(キーワード): Long circulating liposome / Targeted drug delivery / Polyethylene glycol micelle / Liposomal doxorubicin / Immunoliposome / Antibody transfer
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/S0014-5793(99)01320-4
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1016/S0014-5793(99)01320-4

(DOI: 10.1016/S0014-5793(99)01320-4) Tatsuhiro Ishida, Shinya Iida, Kouichi Funato and Hiroshi Kiwada :
A novel plasma factor initiating complement activation on cetylmannoside-modified liposomes in human plasma,
International Journal of Pharmaceutics, Vol.164, No.1-2, 91-102, 1998.

(キーワード): Liposome / Cetylmannoside / Classical complement pathway / Plasma protein / Complement activating factor (CAF)
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/S0378-5173(97)00403-1
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1016/S0378-5173(97)00403-1

(DOI: 10.1016/S0378-5173(97)00403-1) Shicheng Liu, Tatsuhiro Ishida and Hiroshi Kiwada :
Characterization of Bovine Serum Factor Triggering the Lysis of Liposomes via Complement Activation,
Biological & Pharmaceutical Bulletin, Vol.21, No.4, 390-397, 1998.

(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.21.390
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.21.390

(DOI: 10.1248/bpb.21.390) 小島弘子, 石田竜弘, 原島秀吉, 際田弘志 :
リポソーム膜中のコレステロール含量が及ぼす補体第3成分(C3)の結合と体内動態への影響,
Drug Delivery System, Vol.13, 55-61, 1998年. Tatsuhiro Ishida, Kouichi Funato, Shigeo Kojima, Ritsuko Yoda and Hiroshi Kiwada :
Enhancing effect of cholesterol on the elimination of liposomes from circulation is mediated by complement activation,
International Journal of Pharmaceutics, Vol.156, No.1, 27-37, 1997.

(キーワード): Drug delivery system / Liposome / Cholesterol / Complement activating factor / Complement
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/S0378-5173(97)00174-9
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1016/S0378-5173(97)00174-9

(DOI: 10.1016/S0378-5173(97)00174-9) S Liu, Tatsuhiro Ishida and Hiroshi Kiwada :
Effect of Serum Components from Different Species on Destabilizing Hydrogenated Phosphatidylcholine-Based Liposomes,
Biological & Pharmaceutical Bulletin, Vol.20, No.8, 874-880, 1997.

(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.20.874
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.20.874

(DOI: 10.1248/bpb.20.874) 石田竜弘, 篠原美加, 際田弘志 :
セチルマンノシド修飾リポソームへのC3フラグメントの結合における粒子径の影響,
Drug Delivery System, Vol.12, No.3, 155-160, 1997年.

(出版サイトへのリンク): ● Publication site (DOI): 10.2745/dds.12.155
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.2745/dds.12.155

(DOI: 10.2745/dds.12.155) H Harashima, T M Huong, Tatsuhiro Ishida, Y Manabe, H Matsuo and Hiroshi Kiwada :
Synergistic Effect Between Size and Cholesterol Content in the Enhanced Hepatic Uptake Clearance of Liposomes Through Complement Activation in Rats,
Pharmaceutical Research, Vol.13, No.11, 1704-1709, 1996.

(出版サイトへのリンク): ● Publication site (DOI): 10.1023/A:1016401025747
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1023/A:1016401025747

(DOI: 10.1023/A:1016401025747) AJ Ferdous, Tatsuhiro Ishida, M Shinohara, H Harashima and Hiroshi Kiwada :
Size-dependent release of carboxyfluorescein from cetylmannoside-modifide liposomes in human plasma,
Biopharmaceutics & Drug Disposition, Vol.17, No.2, 145-154, 1996.

(出版サイトへのリンク): ● Publication site (DOI): 10.1002/(SICI)1099-081X(199603)17:2<145::AID-BDD942>3.0.CO;2-Y
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1002/(SICI)1099-081X(199603)17:2<145::AID-BDD942>3.0.CO;2-Y

(DOI: 10.1002/(SICI)1099-081X(199603)17:2<145::AID-BDD942>3.0.CO;2-Y) 石田竜弘, 篠原美加, 岩田房子, 大本安一, 際田弘志 :
抗ヒトC3モノクローナル抗体を用いたリポソーム表面上のC3フラグメント定量,
Drug Delivery System, Vol.9, 25-30, 1994年.

(出版サイトへのリンク): ● Publication site (DOI): 10.2745/dds.9.25
(文献検索サイトへのリンク): ● Summary page in Scopus @ Elsevier: 2-s2.0-0343672284

(DOI: 10.2745/dds.9.25, Elsevier: Scopus)

MISC

Hideyoshi Harashima and Tatsuhiro Ishida :
Editorial: Advanced Liposome Research,
Advanced Drug Delivery Reviews, Vol.154-155, 1, 2020.

(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.addr.2020.10.013
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1016/j.addr.2020.10.013

(DOI: 10.1016/j.addr.2020.10.013)

総説・解説

A Sherif Gaballa, Taro Shimizu, Hidenori ANDO, Haruka Takata, Sherif Abdallah Emam Emam, Eslam Mostafa Ramadan Abdelhameed, W Youssef Naguib, M Fatma Mady, A Khaled Khaled and Tatsuhiro Ishida :
Treatment-induced and pre-existing anti-PEG antibodies: Prevalence, clinical implications, and future perspectives,
Journal of Pharmaceutical Sciences, Vol.113, No.3, 555-578, Mar. 2024.

(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.xphs.2023.11.001
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1016/j.xphs.2023.11.001

(DOI: 10.1016/j.xphs.2023.11.001) 池田真由美, 福田達也, 岩尾康範, 小田切優樹, 丸山徹, 石田竜弘, 異島優 :
血清アルブミンに存在する超硫黄の解析と創薬応用,
薬学雑誌, Vol.144, No.1, 51-56, 2024年1月.

(出版サイトへのリンク): ● Publication site (DOI): 10.1248/yakushi.23-00162-3
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1248/yakushi.23-00162-3

(DOI: 10.1248/yakushi.23-00162-3) 清水太郎, 濱本英利, 石田竜弘 :
イオン液体を利用した外用剤・経皮吸収製剤の開発と疾患治療への応用,
Drug Delivery System, Vol.38, No.3, 230-238, 2023年7月.

(出版サイトへのリンク): ● Publication site (DOI): 10.2745/dds.38.230
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.2745/dds.38.230

(DOI: 10.2745/dds.38.230) Ibrahim Mohamed, Eslam Mostafa Ramadan Abdelhameed, Nehal Ali Emam Elsadek Emam Elhewan, Sherif Abdallah Emam Emam, Taro Shimizu, Hidenori ANDO, Yu Ishima, Elgarhy Helmy Omar, Sarhan A Hatem, Hussein K Amal and Tatsuhiro Ishida :
Polyethylene glycol (PEG): The nature, immunogenicity, and role in the hypersensitivity of PEGylated products,
Journal of Controlled Release, Vol.351, 215-230, Nov. 2022.

(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2022.09.031
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2022.09.031

(DOI: 10.1016/j.jconrel.2022.09.031) Nana Matsuo, Hidenori ANDO, Yusuke Doi, Taro Shimizu, Yu Ishima and Tatsuhiro Ishida :
The challenge to deliver oxaliplatin (l-OHP) to solid tumors: development of liposomal l-OHP formulations,
Chemical & Pharmaceutical Bulletin, Vol.70, No.5, 351-358, May 2022.

(出版サイトへのリンク): ● Publication site (DOI): 10.1248/cpb.c22-00099
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1248/cpb.c22-00099

(DOI: 10.1248/cpb.c22-00099) Yu Ishima, Toru Maruyama, Masaki Otagiri, G Victor T Chuang and Tatsuhiro Ishida :
The new delivery strategy of albumin carrier utilizing the interaction with albumin receptors,
Chemical & Pharmaceutical Bulletin, Vol.70, No.5, 330-333, May 2022.

(出版サイトへのリンク): ● Publication site (DOI): 10.1248/cpb.c21-01024
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1248/cpb.c21-01024

(DOI: 10.1248/cpb.c21-01024) Giuseppe Curigliano, 松村保広, 石田竜弘 :
最新の免疫腫瘍微小環境の理解とADC，DDSの革新的イノベーション,
がん分子標的治療, Vol.19, No.2, 47-55, 2022年1月. Hidenori ANDO and Tatsuhiro Ishida :
An RNAi therapeutic, DFP-10825, for intraperitoneal and intrapleural malignant cancers,
Advanced Drug Delivery Reviews, Vol.154-155, 27-36, Aug. 2020.

(要約): RNA interference (RNAi), a potent post-transcriptional gene-silencing action, has received considerable attentions as a novel therapeutic tool to treat intractable cancers. In recent days, we have developed a novel RNAi-based therapeutic formulation, DFP-10825, for the treatment of intractable advanced cancers developed in coelomic cavities. DFP-10825 was composed of chemically synthesized short hairpin RNA (shRNA) against thymidylate synthase (TS), a key enzyme for cancer proliferation, and cationic liposomes, and achieved high therapeutic effect on the mouse models of peritoneally disseminated gastric and ovarian cancers and malignant pleural mesothelioma without severe side effects by intracoelomic direct treatment. We further designed a freeze-dried DFP-10825 formulation for mass industrial production. DFP-10825 is undergoing in pre-clinical phase and goes to clinical trials. This review introduces a DFP-10825 formulation, a potent novel RNAi-based therapeutic maximizing the benefit of RNAi molecule (shRNA).
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.addr.2020.08.002
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32781056; ● Search Scopus @ Elsevier (PMID): 32781056; ● Search Scopus @ Elsevier (DOI): 10.1016/j.addr.2020.08.002

(DOI: 10.1016/j.addr.2020.08.002, PubMed: 32781056) G Kozma, Taro Shimizu, Tatsuhiro Ishida and J Szebeni :
Anti-PEG antibodies: Properties, formation and role in adverse immune reactions to PEGylated nano-biopharmaceuticals,
Advanced Drug Delivery Reviews, Vol.154-155, 163-175, Aug. 2020.

(徳島大学機関リポジトリ): ● Metadata: 116267
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.addr.2020.07.024
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1016/j.addr.2020.07.024

(徳島大学機関リポジトリ: 116267, DOI: 10.1016/j.addr.2020.07.024) Yu Ishima, Toru Maruyama, Masaki Otagiri and Tatsuhiro Ishida :
Drug Delivery System for Refractory Cancer Therapy via an Endogenous Albumin Transport System,
Chemical & Pharmaceutical Bulletin, Vol.68, No.7, 583-588, Jul. 2020.

(出版サイトへのリンク): ● Publication site (DOI): 10.1248/cpb.c20-00026
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1248/cpb.c20-00026

(DOI: 10.1248/cpb.c20-00026) Tatsuhiro Ishida, Shigeru Kawakami and Ken-ichi Hosoya :
Foreward in Recent advances in research on particulate formulations such as lipoproteins, liposomes, extracellular vesicles, and iPS-derived cells,
Biological & Pharmaceutical Bulletin, Vol.43, No.4, 575, Apr. 2020.

(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b20-ctf4304
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.b20-ctf4304

(DOI: 10.1248/bpb.b20-ctf4304) 清水太郎, 異島優, 石田竜弘 :
タンパクのPEG修飾によるPEG免疫応答の誘導,
薬学雑誌, Vol.140, No.2, 163-169, 2020年2月.

(出版サイトへのリンク): ● Publication site (DOI): 10.1248/yakushi.19-00187-5
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1248/yakushi.19-00187-5

(DOI: 10.1248/yakushi.19-00187-5) 安藤英紀, 石田竜弘 :
臨床応用可能な体腔内投与型RNAi 製剤(DFP-10825)の開発と難治性がんに対する治療,
Medchem News, Vol.30, No.1, 19-24, 2020年2月.

(出版サイトへのリンク): ● Publication site (DOI): 10.14894/medchem.30.1_19
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.14894/medchem.30.1_19

(DOI: 10.14894/medchem.30.1_19) 安藤英紀, 清水太郎, 石田竜弘 :
リポソームDDS 製剤開発における免疫系の制御と動態解析の重要性,
オレオサイエンス, Vol.20, No.2, 71-76, 2020年2月.

(出版サイトへのリンク): ● Publication site (DOI): 10.5650/oleoscience.20.71
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1390283659849385728; ● Search Scopus @ Elsevier (DOI): 10.5650/oleoscience.20.71

(DOI: 10.5650/oleoscience.20.71, CiNii: 1390283659849385728) 安藤英紀, 田島健次, 松島得雄, 石田竜弘 :
ナノフィブリル化バクテリアセルロース(Fibnano)を用いた腹腔内投与型がん治療製剤への応用,
Cellulose Communications, Vol.26, No.4, 173-177, 2019年12月. 田島健次, 小瀬亮太, 松島得雄, 石田竜弘, 安藤英紀 :
フルーツ由来新奇酢酸菌によるナノセルロースの合成とその応用,
日本醸造協会誌, Vol.114, No.9, 540-549, 2019年9月.

(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1050287462784741632

(CiNii: 1050287462784741632) M Mohamed, Lila Selim Ahmed Ali Abu Amr, Taro Shimizu, E Alaaeldin, A Hussein, H Sarhan, J Szebeni and Tatsuhiro Ishida :
PEGylated liposomes: immunological responses,
Science and Technology of Advanced Materials, Vol.20, No.1, 710-724, Jun. 2019.

(要約): A commonly held view is that nanocarriers conjugated to polyethylene glycol (PEG) are non-immunogenic. However, many studies have reported that unexpected immune responses have occurred against PEG-conjugated nanocarriers. One unanticipated response is the rapid clearance of PEGylated nanocarriers upon repeat administration, called the accelerated blood clearance (ABC) phenomenon. ABC involves the production of antibodies toward nanocarrier components, including PEG, which reduces the safety and effectiveness of encapsulated therapeutic agents. Another immune response is the hypersensitivity or infusion reaction referred to as complement (C) activation-related pseudoallergy (CARPA). Such immunogenicity and adverse reactivities of PEGylated nanocarriers may be of potential concern for the clinical use of PEGylated therapeutics. Accordingly, screening of the immunogenicity and CARPA reactogenicity of nanocarrier-based therapeutics should be a prerequisite before they can proceed into clinical studies. This review presents PEGylated liposomes, immunogenicity of PEG, the ABC phenomenon, C activation and lipid-induced CARPA from a toxicological point of view, and also addresses the factors that influence these adverse interactions with the immune system.
(徳島大学機関リポジトリ): ● Metadata: 115719
(出版サイトへのリンク): ● Publication site (DOI): 10.1080/14686996.2019.1627174
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31275462; ● Summary page in Scopus @ Elsevier: 2-s2.0-85068089055

(徳島大学機関リポジトリ: 115719, DOI: 10.1080/14686996.2019.1627174, PubMed: 31275462, Elsevier: Scopus) 石田竜弘 :
生体内動態の理解を基盤としたリポソームDDSの開発∼臨床応用を目指して∼ 第11回日本DDS学会水島賞によせて,
Drug Delivery System, Vol.33, No.4, 318-328, 2018年9月.

(出版サイトへのリンク): ● Publication site (DOI): 10.2745/dds.33.318
(文献検索サイトへのリンク): ● Summary page in Scopus @ Elsevier: 2-s2.0-85059276671

(DOI: 10.2745/dds.33.318, Elsevier: Scopus) 異島優, 丸山徹, 石田竜弘, 小田切優樹 :
内因性アルブミン輸送システムを利用した腫瘍選択的NO供与によるEPR効果の制御,
Drug Delivery System, Vol.33, No.2, 130-138, 2018年3月.

(要約): EPR効果は，高分子抗がん療法の開発の基礎となり得るが，低い血管透過性を有するがん領域では，このEPR効果のみでは十分な送達性が得られない．したがって，一酸化窒素(NO)のような血管調節分子で内因性EPR効果を増強することは極めて有望な戦略である．筆者らは，ヒト血清アルブミン二量体のS―ニトロソ化体(SNO―HSA Dimer)がEPR効果の増強剤であることを検討してきた．ここでは，すでに承認されたPEG化リポソーム・ドキソルビシン(Doxil®)およびアルブミン結合型パクリタキセル・ナノ粒子(Abraxane®)の2種類の高分子抗がん剤を用い，血管透過性が高いC26や血管透過性が低いB16担がんモデル，臨床病態に近いとされているSUIT2ヒト膵臓がん同所性モデルにて得られた結果を中心に報告する．
(キーワード): EPR effect / Nitric oxide / Human serum albumin / Endogenous Albumin Transport / Antitumor activity
(出版サイトへのリンク): ● Publication site (DOI): 10.2745/dds.33.130
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1390282763015033344; ● Search Scopus @ Elsevier (DOI): 10.2745/dds.33.130

(DOI: 10.2745/dds.33.130, CiNii: 1390282763015033344) 清水太郎, 異島優, 石田竜弘 :
Accelerated blood clearance (ABC) 現象における動物種差,
Drug Delivery System, Vol.32, No.5, 396-401, 2017年11月.

(出版サイトへのリンク): ● Publication site (DOI): 10.2745/dds.32.396
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1390001204641700864; ● Search Scopus @ Elsevier (DOI): 10.2745/dds.32.396

(DOI: 10.2745/dds.32.396, CiNii: 1390001204641700864) Lila Selim Ahmed Ali Abu Amr and Tatsuhiro Ishida :
Metronomic chemotherapy and nanocarrier platforms,
Cancer Letters, Vol.400, 232-242, Aug. 2017.

(要約): The therapeutic concept of administering chemotherapeutic agents continuously at lower doses, relative to the maximum tolerated dose (MTD) without drug-free breaks over extended periods -known as "metronomic chemotherapy"- is a promising approach for anti-angiogenic cancer therapy. In comparison with MTD chemotherapy regimens, metronomic chemotherapy has demonstrated reduced toxicity. However, as a monotherapy, metronomic chemotherapy has failed to provide convincing results in clinical trials. Therapeutic approaches including combining the anti-angiogenic "metronomic" therapy with conventional radio-/chemo-therapy and/or targeted delivery of chemotherapeutic agents to tumor tissues via their encapsulation with nanocarrier-based platforms have proven to potentiate the overall therapeutic outcomes. In this review, therefore, we focused on the mutual contribution made by nanoscale drug delivery platforms to the therapeutic efficacy of metronomic-based chemotherapy. In addition, the influence that the dosing schedule has on the overall therapeutic efficacy of metronomic chemotherapy is discussed.
(キーワード): Administration, Metronomic / Angiogenesis Inhibitors / Animals / Antineoplastic Combined Chemotherapy Protocols / Dose-Response Relationship, Drug / Drug Carriers / Drug Compounding / Humans / Maximum Tolerated Dose / Nanomedicine / Nanoparticles / Neoplasms
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.canlet.2016.11.007
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 27838415; ● Summary page in Scopus @ Elsevier: 2-s2.0-85006801883

(DOI: 10.1016/j.canlet.2016.11.007, PubMed: 27838415, Elsevier: Scopus) 清水太郎, 異島優, 石田竜弘 :
ナノ粒子に対する補体活性化の功罪,
Drug Delivery System, Vol.32, No.3, 199-207, 2017年8月.

(出版サイトへのリンク): ● Publication site (DOI): 10.2745/dds.32.199
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1390282679617948032; ● Search Scopus @ Elsevier (DOI): 10.2745/dds.32.199

(DOI: 10.2745/dds.32.199, CiNii: 1390282679617948032) Lila Selim Ahmed Ali Abu Amr, Hiroshi Kiwada and Tatsuhiro Ishida :
Liposomal delivery systems: design optimization and current applications,
Biological & Pharmaceutical Bulletin, Vol.40, No.1, 1-10, Jan. 2017.

(要約): The liposome, a closed phospholipid bilayered vesicular system, has received considerable attention as a pharmaceutical carrier of great potential over the past 30 years. The ability of liposomes to encapsulate both hydrophilic and hydrophobic drugs, coupled with their biocompatibility and biodegradability, make liposomes attractive vehicles in the field of drug delivery. In addition, great technical advances such as remote drug loading, triggered release liposomes, ligand-targeted liposomes, liposomes containing combinations of drugs, and so on, have led to the widespread use of liposomes in diverse areas as delivery vehicles for anti-cancer, bio-active molecules, diagnostics, and therapeutic agents. In this review, we summarize design optimization of liposomal systems and invaluable applications of liposomes as effective delivery systems.
(キーワード): Animals / Drug Delivery Systems / Humans / Liposomes
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b16-00624
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28049940; ● Search Scopus @ Elsevier (PMID): 28049940; ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.b16-00624

(DOI: 10.1248/bpb.b16-00624, PubMed: 28049940) 清水太郎, 石田竜弘 :
Poly(ethylene glycol)に対する抗体の特性，評価，抑制,
Drug Delivery System, Vol.31, No.4, 300-307, 2016年6月.

(要約): PEG(poly(ethylene glycol))修飾は，バイオ医薬品の生体内安定性を向上させる最も標準的な方法である．しかし，PEG修飾体投与後にPEGに特異的な抗体(抗PEG抗体)が誘導され，繰り返し投与時のPEG修飾体の血中滞留性を著しく低下させることが明らかになっている．これまでに，実験動物だけでなく，ヒトにおいても抗PEG抗体の誘導が確認されている．また，さまざまなPEG修飾体投与によって，さまざまな特性を持った抗PEG抗体が誘導されることも明らかになっている．PEG修飾技術による治療効果の向上を損なわないためにも，抗PEG免疫応答の正しい理解と抑制法の開発は非常に重要である．本稿では，抗PEG抗体の特性・評価・抑制法について概説する．
(キーワード): PEGylated drug / Anti-PEG antibody / Accelerated blood clearance
(出版サイトへのリンク): ● Publication site (DOI): 10.2745/dds.31.300
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1390001204640457984; ● Search Scopus @ Elsevier (DOI): 10.2745/dds.31.300

(DOI: 10.2745/dds.31.300, CiNii: 1390001204640457984) 石田竜弘 :
PEGに対する免疫反応∼PEG修飾製剤の安全性に関する研究∼,
製剤機械技術学会誌, Vol.24, No.5, 78-83, 2015年12月. Masami Ukawa, Hidenori ANDO, Taro Shimizu and Tatsuhiro Ishida :
Pharmaceutics of Nanoparticles,
Nanomaterials in Pharmacology, 219-238, Nov. 2015.

(出版サイトへのリンク): ● Publication site (DOI): 10.1007/978-1-4939-3121-7_11
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1007/978-1-4939-3121-7_11

(DOI: 10.1007/978-1-4939-3121-7_11) Lila Selim Ahmed Ali Abu Amr, Tatsuhiro Ishida and Hiroshi Kiwada :
Selective delivery of oxaliplatin to tumor tissue by nanocarrier system enhances overall therapeutic efficacy of the encapsulated oxaliplatin,
Biological & Pharmaceutical Bulletin, Vol.37, No.2, 206-211, Feb. 2014.

(要約): Oxaliplatin (trans-l-diaminocyclohexane oxalatoplatinum; l-OHP), a third-generation platinum antitumor drug, is currently approved in combination with 5-flurouracil (5-FU)/leucovorin (FOLFOX) for standard first- and second-line treatment of metastatic or advanced-stage colorectal cancer. Despite l-OHP's better tolerability in comparison with other platinum compounds such as cisplatin and carboplatin, its clinical efficiency is limited by the dose-limiting side effects including cumulative neurotoxicity and acute dysesthesias. In addition, like other platinum chemotherapeutic agents, l-OHP therapy is limited by reduced accumulation levels in tumor tissues, nonselective accumulation in healthy organs and/or tissues, inactivation by conjugation with glutathione, and the development of drug resistance. Accordingly, successful outcome of cancer treatment using l-OHP requires selective delivery of a relatively high concentration of the drug to tumor tissues. In this review we focus on utilization of different drug-delivery vehicles such as liposomes, polymeric nanocarriers, and carbon nanotubes in enhancing selective delivery of l-OHP to tumor tissues and consequently improving overall efficacy of l-OHP-containing drug-delivery systems.
(キーワード): Animals / Antineoplastic Agents / Colorectal Neoplasms / Drug Carriers / Humans / Nanoparticles / Organoplatinum Compounds
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b13-00540
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 24492717; ● CiNii @ 国立情報学研究所 (CRID): 1390282679609960064; ● Summary page in Scopus @ Elsevier: 2-s2.0-84893510536

(DOI: 10.1248/bpb.b13-00540, PubMed: 24492717, CiNii: 1390282679609960064, Elsevier: Scopus) Lila Selim Ahmed Ali Abu Amr, Tatsuhiro Ishida and Hiroshi Kiwada :
The accelerated blood clearance (ABC) phenomenon: Clinical challenge and approaches to manage,
Journal of Controlled Release, Vol.172, No.1, 38-47, Aug. 2013.

(要約): Despite the clinical introduction of an increasing number of polyethylene glycol (PEG)-conjugated substances, PEG has been named as the cause of an unexpected immunogenic response known as the "accelerated blood clearance (ABC) phenomenon." This phenomenon has been extensively observed during the repeated administration of PEG-conjugated substances and PEGylated nanocarriers including PEGylated liposomes, PEGylated nanoparticles, PEGylated micelles, etc., resulting in the increased clearance and reduced efficacy of PEG-conjugated substances/PEGylated nanocarriers. In this review, therefore, we focused on the possible mechanisms underlying the induction of such a phenomenon and emphasized the factors affecting its magnitude. In addition, the clinical implications of the ABC phenomenon on the therapeutic efficacy of PEG-conjugated substances/PEGylated nanocarriers, along with the new approaches that can be applied to manage and/or abrogate the induction of the ABC phenomenon, are also discussed.
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.jconrel.2013.07.026
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 23933235; ● Search Scopus @ Elsevier (PMID): 23933235; ● Search Scopus @ Elsevier (DOI): 10.1016/j.jconrel.2013.07.026

(DOI: 10.1016/j.jconrel.2013.07.026, PubMed: 23933235) Tatsuhiro Ishida and Hiroshi Kiwada :
Anti-polyethyleneglycol (PEG) antibody response to PEGylated substances.,
Biological & Pharmaceutical Bulletin, Vol.36, No.6, 889-891, Jun. 2013.

(要約): In contrast to the general assumption that polyethyleneglycol (PEG)-conjugated substances lack immunogenicity and antigenic, it has been reported that they can elicit antibodies against PEG (mainly anti-PEG immunoglobulin M (IgM)). In patients, the presence of anti-PEG antibodies may limit therapeutic efficacy of PEGylated substances as a consequence of inducing rapid clearance of and neutralizing biological activity of the substances. Here, we introduce specific examples of PEGylated substances including several PEGylated proteins and PEGylated particles (PEGylated nanocarriers) which induce anti-PEG antibody responses. Finally, we emphasize that the immunogenicity of PEGylated substances should be tested in the development stage and that the titer of anti-PEG antibodies in patients should be pre-screened and monitored prior to and throughout a course of treatment with a PEGylated substance.
(キーワード): Animals / Drug Carriers / Humans / Immunoglobulin M / Nanoparticles / Pharmaceutical Preparations / Polyethylene Glycols / Proteins
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b13-00107
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 23727911; ● Search Scopus @ Elsevier (PMID): 23727911; ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.b13-00107

(DOI: 10.1248/bpb.b13-00107, PubMed: 23727911) 石田竜弘, 際田弘志 :
PEG修飾製剤による抗PEG抗体分泌誘導,
ファルマシア:最前線, Vol.49, No.6, 503-507, 2013年6月. Tatsuhiro Ishida and Hiroshi Kiwada :
Alteration of tumor microenvironment for improved delivery and intratumor distribution of nanocarriers.,
Biological & Pharmaceutical Bulletin, Vol.36, No.5, 692-697, May 2013.

(要約): Nanocarrier-based cancer chemotherapeutics are thought to increase therapeutic efficiency and reduce the side effects of associated chemotherapeutic agents by altering the agents' pharmacokinetics and tissue distribution following intravenous administration. In spite of these favorable properties, nanocarrier-based cancer chemotherapeutics are not always effective because of their heterogeneous intratumoral localization. Homogeneous distribution of nanocarriers in a tumor would improve the efficacy of nanocarrier-based cancer chemotherapeutics. In this article, we describe and discuss some trials that attempt to manipulate the barriers in the tumor microenvironment that hinder extravasation through the tumor vasculature and penetration of nanocarriers in solid tumors. Alterations of the tumor microenvironment that relate directly to the intratumoral distribution of nanocarriers may be potential strategies to improve the delivery of nanocarrier-based cancer chemotherapeutics.
(キーワード): Animals / Antineoplastic Agents / Drug Carriers / Humans / Nanoparticles / Neoplasms / Tumor Microenvironment
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.b13-00121
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 23649327; ● Search Scopus @ Elsevier (PMID): 23649327; ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.b13-00121

(DOI: 10.1248/bpb.b13-00121, PubMed: 23649327) 石田竜弘 :
リポソームDDSの開発研究∼トランスレーショナルリサーチの実現を目指して∼,
薬剤学, Vol.71, 315-320, 2011年11月.

(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1390845713054819072

(CiNii: 1390845713054819072) 石田竜弘, 際田弘志 :
PEG修飾リポソーム製剤繰り返し投与による血中滞留性低下,
C&I Commun., Vol.36, 19-21, 2011年.

(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1520290884281863808

(CiNii: 1520290884281863808) 石田竜弘 :
生体内動態検討を基盤としたリポソームDDSの開発∼第2回日本DDS学会奨励賞(臨床)受賞によせて∼,
Drug Delivery System, Vol.25, No.5, 511-516, 2010年10月.

(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1520290883385786880

(CiNii: 1520290883385786880) Lila Selim Ahmed Ali Abu Amr, Tatsuhiro Ishida and Hiroshi Kiwada :
Targeting anticancer drugs to tumor vasculature using cationic liposomes.,
Pharmaceutical Research, Vol.27, No.7, 1171-1183, Mar. 2010.

(要約): Liposomal drug delivery systems improve the therapeutic index of chemotherapeutic agents, and the use of cationic liposomes to deliver anticancer drugs to solid tumors has recently been recognized as a promising therapeutic strategy to improve the effectiveness of conventional chemotherapeutics. This review summarizes the selective targeting of cationic liposomes to tumor vasculature, the merits of incorporating the polymer polyethylene-glycol (PEG), and the impact of the molar percent of the cationic lipid included in cationic liposomes on liposomal targeting efficacy. In addition, the discussion herein includes the therapeutic benefit of a dual targeting approach, using PEG-coated cationic liposomes in vascular targeting (of tumor endothelial cells), and tumor targeting (of tumor cells) of anticancer drugs. Cationic liposomes have shown considerable promise in preclinical xenograft models and are poised for clinical development.
(キーワード): Antineoplastic Agents / Cations / Drug Delivery Systems / Humans / Liposomes / Neoplasms / Neovascularization, Pathologic
(出版サイトへのリンク): ● Publication site (DOI): 10.1007/s11095-010-0110-1
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 20333455; ● Search Scopus @ Elsevier (PMID): 20333455; ● Search Scopus @ Elsevier (DOI): 10.1007/s11095-010-0110-1

(DOI: 10.1007/s11095-010-0110-1, PubMed: 20333455) 小出裕之, 浅井知浩, 畑中剣太朗, 清水広介, 横山昌幸, 石田竜弘, 際田弘志, 奥直人 :
PEG化キャリア頻回投与によるaccelerated blood clearance現象の機構解明,
薬学雑誌, Vol.129, No.12, 1445-1451, 2009年12月.

(要約): Liposomes modified with polyethylene glycol (PEG) can stably exist in the bloodstream because the PEG on the liposomes attracts a water shell to the liposomal surface. Since these liposomes are long circulating nanocarriers, they are used as drug and gene delivery tools. Repeat injection of PEGylated liposomes, however, is known to induce the accelerated blood clearance (ABC) phenomenon. In the ABC phenomenon, PEGylated liposomes that are injected subsequent to the first injection are cleared rapidly from the bloodstream and accumulate in the liver, resulting in loss of their long-circulating characteristics. The induction of ABC phenomenon is related to the production of anti-PEG IgM from splenic B cells. To elucidate the mechanism of the phenomenon, we firstly examined the relationship between the induction of ABC phenomenon and the concentration of PEGylated liposomes, and observed that the high dose of those did not induce the phenomenon. Next, we investigated whether polymeric micelles trigger ABC phenomenon or not. Finally, the size-dependency of ABC phenomenon was investigated by use of variously sized PEGylated liposomes and polymeric micelles having PEG chains. Our data suggest that the initiation of ABC phenomenon would be size-dependent, and particles smaller than 30 nm did not induce ABC phenomenon. We anticipate that the elucidation of the ABC phenomenon will be helpful for the development of DDS formulations.
(キーワード): polyethylene glycol / liposome / accelerated blood clearance / polymeric micelle / nanocarrier
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/yakushi.129.1445
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1390001206128807680; ● Search Scopus @ Elsevier (DOI): 10.1248/yakushi.129.1445

(DOI: 10.1248/yakushi.129.1445, CiNii: 1390001206128807680) Lila Selim Ahmed Ali Abu Amr, Tatsuhiro Ishida and Hiroshi Kiwada :
Recent advances in tumor vasculature targeting using liposomal drug delivery systems.,
Expert Opinion on Drug Delivery, Vol.6, No.12, 1297-1309, Dec. 2009.

(要約): Tumor vessels possess unique physiological features that might be exploited for improved drug delivery. The targeting of liposomal anticancer drugs to tumor vasculature is increasingly recognized as an effective strategy to obtain superior therapeutic efficacy with limited host toxicity compared with conventional treatments. This review introduces recent advances in the field of liposomal targeting of tumor vasculature, along with new approaches that can be used in the design and optimization of liposomal delivery systems. In addition, cationic liposome is focused on as a promising carrier for achieving efficient vascular targeting. The clinical implications are discussed of several approaches using a single liposomal anticancer drug formulation: dual targeting, vascular targeting (targeting tumor endothelial cells) and tumor targeting (targeting tumor cells).
(キーワード): Angiogenesis Inhibitors / Animals / Antineoplastic Agents / Cations / Drug Delivery Systems / Drug Design / Humans / Liposomes / Neoplasms / Neovascularization, Pathologic
(出版サイトへのリンク): ● Publication site (DOI): 10.1517/17425240903289928
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 19780711; ● Search Scopus @ Elsevier (PMID): 19780711; ● Search Scopus @ Elsevier (DOI): 10.1517/17425240903289928

(DOI: 10.1517/17425240903289928, PubMed: 19780711) 石田竜弘, 田上辰秋, 際田弘志 :
siRNA を利用したArgonaute2 遺伝子knockdown によるがん治療法の開発,
和光純薬時報, Vol.77, No.2, 8-11, 2009年4月. Tatsuhiro Ishida and Hiroshi Kiwada :
Accelerated blood clearance (ABC) phenomenon upon repeated injection of PEGylated liposomes.,
International Journal of Pharmaceutics, Vol.354, No.1-2, 56-62, Apr. 2008.

(要約): We and a Dutch group reported that "empty" PEGylated liposomes (approximately 100 nm) lose their long-circulating characteristic when they are administrated twice in the same animal with certain intervals (referred to as the accelerated blood clearance (ABC) phenomenon). Very recently, we showed that anti-PEG IgM, induced by the first dose of "empty" PEGylated liposomes, is responsible for inducing the phenomenon, based on the observation that IgM thus produced selectively binds to the surface of subsequently injected PEGylated liposomes, leading to substantial complement activation. It is generally believed that nanocarriers coated with a polymer, such as PEG, have no or lower immunogenicity. However, the results indicated evidence that unexpected immune responses occur even to such polymer-coated liposomes. Such immunogenicity of "empty" liposomes presents a serious concern in the development of liposomal formulations and their use in the clinic. In addition, through series of our studies, it was demonstrated that the magnitude of the ABC phenomenon depends on the physicochemical property of injected liposomes as a first dose, time interval between injection, lipid dose and drug-encapsulation.
(キーワード): Animals / Complement Activation / Drug Administration Schedule / Drug Carriers / Immunoglobulin M / Injections, Intravenous / Liposomes / Polyethylene Glycols
(出版サイトへのリンク): ● Publication site (DOI): 10.1016/j.ijpharm.2007.11.005
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 18083313; ● Search Scopus @ Elsevier (PMID): 18083313; ● Search Scopus @ Elsevier (DOI): 10.1016/j.ijpharm.2007.11.005

(DOI: 10.1016/j.ijpharm.2007.11.005, PubMed: 18083313) 石田竜弘, 際田弘志 :
ポリエチレングリコール修飾リポソーム投与時に生ずるaccelerated blood clearance (ABC)現象,
薬学雑誌, Vol.128, No.2, 233-243, 2008年2月.

(要約): PEGylated liposomes (approximately 100nm in diameter) lose their long-circulating characteristic upon repeated injection at certain intervals in the same animal (referred to as the "accelerated blood clearance (ABC) phenomenon"), as described by our group and by researchers in the Netherlands. Recently, it was demonstrated by our group that anti-PEG IgM, induced by the first dose of PEGylated liposomes, is responsible for the ABC phenomenon. The IgM produced in this manner then selectively bound to the surface of subsequently injected PEGylated liposomes, leading to substantial complement activation. It is generally believed that nanocarriers coated with a polymer, such as PEG, have no immunogenicity. However, unexpected immune responses occurred even in response to polymer-coated liposomes. This immunogenicity to PEGylated liposomes presents a serious concern in the development and clinical use of liposomal formulations. In this review, we demonstrate our recent observations regarding with the ABC phenomenon against liposomes.
(キーワード): PEGylated liposomes / anti-PEG IgM / polyethylene glycol / PEG / accelerated blood clearance (ABC) phenomenon / repeated injection / complement activation
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/yakushi.128.233
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1390001206127402624; ● Search Scopus @ Elsevier (DOI): 10.1248/yakushi.128.233

(DOI: 10.1248/yakushi.128.233, CiNii: 1390001206127402624) 石田竜弘 :
腫瘍血管の構造変化がナノ粒子抗がん剤の効果を変化させる,
ファルマシア, Vol.44, No.2, 168-169, 2008年2月. 石田竜弘, 際田弘志 :
ポリマー修飾ナノ微粒子投与による免疫活性化に関する研究,
表面, Vol.45, No.10, 357-371, 2007年10月. 石田竜弘 :
デリバリーによる新たな創薬,
薬事日報, Vol.10368, 8, 2007年4月. 石田竜弘, 際田弘志 :
リポソームと細胞の相互作用(DDSへの応用),
膜, Vol.32, No.1, 18-24, 2007年1月.

(出版サイトへのリンク): ● Publication site (DOI): 10.5360/membrane.32.18
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.5360/membrane.32.18

(DOI: 10.5360/membrane.32.18) Tatsuhiro Ishida, Yoshihiro Takanashi and Hiroshi Kiwada :
Safe and efficient drug delivery system with liposomes for intrathecal application of an antivasospastic drug, fasudil.,
Biological & Pharmaceutical Bulletin, Vol.29, No.3, 397-402, Mar. 2006.

(要約): Pharmacological treatment for cerebral ischemia and cerebral vasospasm following subarachnoid hemorrhage (SAH) cannot attain sufficiently high concentrations of the drugs in the cerebrospinal fluid (CSF) without precipitating systemic side effects. We recently developed a liposomal drug delivery system for intrathecal application that can maintain effective concentrations of cerebral vasodilator, fasudil, in the CSF. A single intrathecal injection of liposomal fasudil could maintain a therapeutic drug concentration in the CSF over a period time due to their sustained-release property, significantly decreasing infarct size in a rat model of acute ischemia and reducing vasoconstriction of the rat and dog basilar artery in a model of SAH. In this review, we are introducing our new less-invasive intrathecal drug delivery system that provides an alternative and safe method to deliver therapeutic agents.
(キーワード): 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Animals / Brain Ischemia / Chemistry, Pharmaceutical / Cholesterol / Chromatography, High Pressure Liquid / Drug Carriers / Drug Delivery Systems / Half-Life / Humans / Injections, Spinal / Liposomes / Neuroprotective Agents / Solubility / Vasodilator Agents
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/bpb.29.397
(文献検索サイトへのリンク): ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 16508135; ● Search Scopus @ Elsevier (PMID): 16508135; ● Search Scopus @ Elsevier (DOI): 10.1248/bpb.29.397

(DOI: 10.1248/bpb.29.397, PubMed: 16508135) 石田竜弘, 際田弘志 :
がん治療を目指した機能性リポソームの開発研究,
化学工業, Vol.57, 39-43, 2006年. 石田竜弘 :
リポソームDDSの開発研究,
薬剤学, Vol.65, 28-33, 2005年. 石田竜弘, 際田弘志 :
ポリエチレングリコール表面修飾リポソームの繰り返し投与時に発現するaccelerated blood clearance(ABC)現象,
Drug Delivery System, Vol.19, No.6, 495-510, 2004年11月.

(要約): We and a Dutch group have recently reported the accelerated blood clearance (ABC) phenomenon upon repeated injection of PEGylated liposomes, that is the enhanced accumulation of PEGylated liposomes in liver and consequently rapidly cleared the liposomes from blood circulation. The phenomenon is a general characteristic of liposomes and the induction of the phenomenon depends on the physicochemical property and dose of liposomes and animal species. In addition, our study indicated that the IgM secreted in response to first dose is involved in the occurrence of the phenomenon. In this article, our and a Dutch group's recent results related to the ABC phenomenon were described.
(キーワード): liposome / PEGylated liposome / polyethyleneglycol(PEG) / repeated injection / accelerated blood clearance(ABC)phenomenon
(出版サイトへのリンク): ● Publication site (DOI): 10.2745/dds.19.495
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1390001204640586880; ● Search Scopus @ Elsevier (DOI): 10.2745/dds.19.495

(DOI: 10.2745/dds.19.495, CiNii: 1390001204640586880) 石田竜弘 :
脳脊髄腔投与可能なDDSの開発とその脳保護効果の検討,
薬学雑誌, Vol.124, No.8, 541-547, 2004年8月.

(要約): To date, the pharmacologic approach to cerebral vasospasm and ischemia has been hampered in part by an inability to attain sufficiently high concentrations of drugs in the cerebrospinal fluid (CSF). To overcome this limitation of current drug therapy, we have developed a sustained-release preparation of the protein kinase inhibitor fasudil. Experimental cerebral vasospasm in rats and dogs was induced by double injection of autologous arterial blood into the cisterna magna. Focal cerebral ischemia in rats was induced by middle cerebral artery occlusion using an intraluminal suture technique. A single intrathecal injection of liposomal fasudil can maintain a therapeutic the drug concentration in the CSF due to the sustained-release property of liposomes, significantly decreasing intarct size of acute ischemia and decreasing vasoconstriction of the basilar artery in cerebral vasospasm. This novel approach for the treatment of cerebral vasospasm and ischemia may have significant potential for use in the clinical setting.
(キーワード): cerebral vasospasm / cerebral ischemia / subarachnoid hemorrhage / liposomal drug delivery system / fasudil
(出版サイトへのリンク): ● Publication site (DOI): 10.1248/yakushi.124.541
(文献検索サイトへのリンク): ● CiNii @ 国立情報学研究所 (CRID): 1390282681105634816; ● Search Scopus @ Elsevier (DOI): 10.1248/yakushi.124.541

(DOI: 10.1248/yakushi.124.541, CiNii: 1390282681105634816) 石田竜弘, 高梨吉裕, 際田弘志 :
脳脊髄腔内直接投与可能なDDSの開発とその脳保護効果,
月刊薬事, Vol.46, No.7, 1333-1338, 2004年6月. 石田竜弘, 際田弘志 :
DDS研究の現状,
科学フォーラム, 22-28, 2003年12月. 石田竜弘 :
機能性リポソームの開発とその癌治療への応用,
月刊薬事, Vol.45, No.7, 1125-1132, 2003年5月. 石田竜弘 :
癌とDDS,
癌と人, Vol.30, 28-29, 2003年3月. Tatsuhiro Ishida, H Harashima and Hiroshi Kiwada :
Liposome clearance.,
Bioscience Reports, Vol.22, No.2, 197-224, Apr. 2002.

(出版サイトへのリンク): ● Publication site (DOI): 10.1023/a:1020134521778
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1023/a:1020134521778

(DOI: 10.1023/a:1020134521778) 石田竜弘 :
リポソームへの機能性の付加による細胞内薬物送達システムの開発,
Drug Delivery System, Vol.17, 136-137, 2002年. Hideyoshi Harashima, Tatsuhiro Ishida, Hiroyuki Kamiya and Hiroshi Kiwada :
Pharmacokinetics of Targeting with Liposomes,
Critcal Reviews in Therapeutic Drug Carrier Systems, Vol.19, No.3, 235-275, 2002.

(出版サイトへのリンク): ● Publication site (DOI): 10.1615/CritRevTherDrugCarrierSyst.v19.i3.20
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.1615/CritRevTherDrugCarrierSyst.v19.i3.20

(DOI: 10.1615/CritRevTherDrugCarrierSyst.v19.i3.20) Tatsuhiro Ishida, H Harashima and Hiroshi Kiwada :
Interactions of Liposomes with Cells In Vitro and In Vivo:Opsonins and Receptors,
Current drug metabolism, Vol.2, No.4, 397-409, Dec. 2001.

(出版サイトへのリンク): ● Publication site (DOI): 10.2174/1389200013338306
(文献検索サイトへのリンク): ● Search Scopus @ Elsevier (DOI): 10.2174/1389200013338306

(DOI: 10.2174/1389200013338306) 石田竜弘 :
MDRモジュレーターとリポソーム化抗癌剤による多剤耐性癌克服の試み,
Xenobio.Metabol.And.Dispos., Vol.15, No.5, 486-488, 2000年10月. 石田竜弘, 際田弘志 :
リポソーム,
色材, Vol.72, 184-191, 1999年.

講演・発表

Yoshino Kawaguchi, Taro Shimizu, Hiroki Tanaka, Toshiro Hirai, Tatsuhiro Ishida, Hidetaka Akita and Yasuo Yoshioka :
Modification of PEG-lipids and phospholipids in mRNA-lipid nanoparticle vaccines reduce adverse reactions with sustained efficacy,
2024 ISV Annual Congress, Seoul, Oct. 2024. Shoichiro Fukuda, Haruka Takata, Takashi Nakae, Noboru Tatsumi, Hidetoshi Hamamoto, Hidenori ANDO and Tatsuhiro Ishida :
Enhanced effect of ionic liquid on intestinal absorption of macromolecules (< 10 kDa),
39th JSSX and 26th North American ISSX Meeting, Hawaii, Sep. 2024. Mako Fukumoto, Hidenori ANDO, Reon Kuramoto, Haruka Takata and Tatsuhiro Ishida :
A unique immunization method to induce antibodies: intravenous administration of PEGylated exosomes with splenic uptake,
CRS 2024 Annual Meeting & Exposition, Bologna, Jul. 2024. Haruka Yamamoto, Hidenori ANDO, Haruka Takata, Yasukazu Omoto and Tatsuhiro Ishida :
Development of a novel human TNF-alpha vaccine formulation: Immunization with inactivated human TNF-alpha variant to induce anti-TNF-alpha antibodies,
CRS 2024 Annual Meeting & Exposition, Bologna, Jul. 2024. Shoichiro Fukuda, Hidenori ANDO, Chihiro Kato, Haruka Takata, Takashi Nakae, Noboru Tatsumi, Hidetoshi Hamamoto and Tatsuhiro Ishida :
Ionic liquids improve intestinal absorption of macromolecules of lower molecular weights,
CRS 2024 Annual Meeting & Exposition, Bologna, Jul. 2024. Matsuo Cristina Amorim Nana, Hidenori ANDO, Haruka Takata and Tatsuhiro Ishida :
Protein-bound cisplatin may increase therapeutic index for cisplatin by reducing its adverse effects,
CRS 2024 Annual Meeting & Exposition, Bologna, Jul. 2024. Hidenori ANDO, Haruka Takata, Taro Shimizu and Tatsuhiro Ishida :
A unique spleen-targeted antigen delivery system to obtain antigen-specific antibodies,
CRS 2024 Annual Meeting & Exposition, Bologna, Jul. 2024. Haruka Takata, Shunji Abe, Hidenori ANDO and Tatsuhiro Ishida :
Effect of anti-PEG IgM on the intramuscular vaccination and pharmacokinetics of mRNA/LNP,
CRS 2024 Annual Meeting & Exposition, Bologna, Jul. 2024. Tatsuhiro Ishida :
Immunological responses against PEGylated materials: the induction of anti-PEG antibodies by cosmetics and mRNA LNP,
Liposome Research Days 2024, Glasgow, Jun. 2024. Hitoshi Matsumoto, Haruka Takata, Hidenori ANDO and Tatsuhiro Ishida :
In vivo tumor targeting by NH2-terminated PEG-modified liposomes,
Liposome Research Days 2024, Glasgow, Jun. 2024. Shunji Abe, Haruka Takata, Taro Shimizu, Hidenori ANDO and Tatsuhiro Ishida :
Effect of anti-PEG IgM on vaccine efficacy and phrmacokinetics of intramuscuraly administrated PEGylated lipid nanoparticles,
Liposome Research Days 2024, Glasgow, Jun. 2024. Rina Yamade, Haruka Takata, Hidenori ANDO and Tatsuhiro Ishida :
Induction of anti-PEG antibodies by PEGylated liposomes following oral administration,
Liposome Research Days 2024, Glasgow, Jun. 2024. Haruka Takata, Hidenori ANDO and Tatsuhiro Ishida :
Effect of administration route on the anti-PEG IgM induction by PEGylated liposomes,
Liposome Research Days 2024, Glasgow, Jun. 2024. Haruka Takata, Shunji Abe, Taro Shimizu, Hidenori ANDO and Tatsuhiro Ishida :
Impact of pre-existing anti-PEG IgM on the mRNA/LNP i.m. vaccination,
16th International Symposium on Nanomedicine, Osaka, Nov. 2023. Taro Shimizu, Yoshino Kawaguchi and Tatsuhiro Ishida :
Role of B cells in antitumor immune responses induced by antigen-loaded hydroxyl PEG-modified liposomes,
16th International Symposium on Nanomedicine, Osaka, Nov. 2023. Hitoshi Matsumoto, Haruka Takata, Ayano Sawa-Aihara, Taro Shimizu, Hidenori ANDO and Tatsuhiro Ishida :
Investigation of therapeutic efficacy of proteasome inhibitor-encapsulated PEG-modified liposomes for UUO-induced renal fibrosis,
16th International Symposium on Nanomedicine, Osaka, Nov. 2023. Shoichiro Fukuda, Hidenori ANDO, Chihiro Kato, Haruka Takata, T Nakae, N Tatsumi, H Hamamoto and Tatsuhiro Ishida :
The molecular weight limitation on increased intestinal absorption by ionic liquids,
16th International Symposium on Nanomedicine, Osaka, Nov. 2023. E Kaneko, H Tsujisaki, M Fujiwara, Hidenori ANDO, Tatsuhiro Ishida, H Tani and K Tajima :
Suppression of mechanical stress in suspension culture of mammalian cells by nanofibrillated bacterial cellulose,
The 5th International Cellulose Conference (ICC2022+1), Hiroshima, Sep. 2023. Tatsuhiro Ishida :
Immunological responses against PEGylated materials: the induction of anti-PEG antibodies,
1st BI Nanocarrier Symposium 2023 Nanocarrier Technology in Drug Discovery, Development and Clinic, Kobe, Feb. 2023. Haruka Yamamoto, Hidenori ANDO, Omoto Yasukazu, Taro Shimizu, Yu Ishima and Tatsuhiro Ishida :
Induction of neutralizing antibodies by immunization with inactivated human TNF-alpha in mice,
15th International Symposium on Nanomedicine, Tokushima, Dec. 2022. Shunto Yamamoto, Hidenori ANDO, Taro Shimizu, Yu Ishima and Tatsuhiro Ishida :
Development of a novel technique for antibody induction against membrane proteins by spleen immunization with membrane protein-loaded PEG-modified liposomes,
15th International Symposium on Nanomedicine, Tokushima, Dec. 2022. Takaaki Matsuzaki, Taro Shimizu, Hidenori ANDO, Yu Ishima, K Yamanaka, H Hamamoto and Tatsuhiro Ishida :
An ionic liquids-based topical antitumor vaccine: a mechanism for induction of antitumor immunity via topical application of cancer-antigen peptides,
15th International Symposium on Nanomedicine, Tokushima, Dec. 2022. Aiko Hashimoto, Yu Ishima, Hidenori ANDO, Taro Shimizu and Tatsuhiro Ishida :
Differential organ-specific distribution of human serum albumin denatured by various modifications,
15th International Symposium on Nanomedicine, Tokushima, Dec. 2022. Riku Uehara, Hidenori ANDO, Taro Shimizu, Yu Ishima and Tatsuhiro Ishida :
Neutralization of acidic tumor microenvironment by dosing of sodium potassium citrate (K/Na citrate) enhances antitumor effects of Abraxane®,
15th International Symposium on Nanomedicine, Tokushima, Dec. 2022. Shoichiro Fukuda, Hidenori ANDO, Atsuya Maruyama, Takashi Nakae, Noboru Tatsumi, Hidetoshi Hamamoto, Taro Shimizu, Yu Ishima and Tatsuhiro Ishida :
The mechanism investigation of intestinal absorption enhancement of drugs using ionic liquids,
15th International Symposium on Nanomedicine, Tokushima, Dec. 2022. Eslam Mostafa Ramadan Abdelhameed, Hidenori ANDO, Haruka Yamamoto, Mako Fukumoto, Taro Shimizu, Yu Ishima and Tatsuhiro Ishida :
Preparation, optimization, and evaluation of anionic DPPG-based LNPs for delivery of peptide antigens,
15th International Symposium on Nanomedicine, Tokushima, Dec. 2022. Nana Matsuo, Hidenori ANDO, Taro Shimizu, Yu Ishima and Tatsuhiro Ishida :
Oral sodium bicarbonate enhances accumulation and antitumor effects of PEGylated liposomal doxorubicin (Doxil®),
15th International Symposium on Nanomedicine, Tokushima, Dec. 2022. Yoshino Kawaguchi, Taro Shimizu, Hidenori ANDO, Yu Ishima and Tatsuhiro Ishida :
Transfusion of mouse B cells, embedded antigens with hydroxyl PEG-modified liposomes in vitro, induces cellular immune responses in mice,
15th International Symposium on Nanomedicine, Tokushima, Dec. 2022. A S Gaballa, Taro Shimizu, Hidenori ANDO, Yu Ishima, Sherif Abdallah Emam Emam, M Ibrahim, M F Mady, W Y Naguib, A K Khaled and Tatsuhiro Ishida :
Accelerated blood clearance of PEGylated liposomal antitumor agents after topical application of PEG derivatives containing cosmetics in a mouse model,
15th International Symposium on Nanomedicine, Tokushima, Dec. 2022. Hidenori ANDO, K Tajima, T Matsushima, T Kusano and Tatsuhiro Ishida :
Functions of exosomes secreted from nano-fibrillated bacterial cellulose-based 3D spheroids derived from cancer cells or mesenchymal stem cells,
15th International Symposium on Nanomedicine, Tokushima, Dec. 2022. Taro Shimizu, H Hamamoto and Tatsuhiro Ishida :
Application of ionic liquids for transcutaneous delivery of hydrophilic macromolecules,
15th International Symposium on Nanomedicine, Tokushima, Dec. 2022. Takeru Hirai, Nanami Tasaka, Hidenori ANDO, Taro Shimizu, Tatsuhiro Ishida and Yu Ishima :
Biological roles of supersulfide in human hair,
Redox Week in Sendai 2022, Sendai, Oct. 2022. Yamade Rina, Taro Shimizu, Hirakawa Naoki, Hidenori ANDO, Yu Ishima and Tatsuhiro Ishida :
Human serum albumin (HSA)-based nanocarriers efficiently deliver antigens to the spleen and induce antigen-specific humoral immunity,
14th International Symposium on Nanomedicine, Nov. 2021. Haruka Takata, Taro Shimizu, Ueda Hiro, Hidenori ANDO, Yu Ishima and Tatsuhiro Ishida :
The induction level of anti-PEG IgM by PEGylated liposomes depends on the route of administration and the presence of nucleic acids,
14th International Symposium on Nanomedicine, Nov. 2021. Hidenori ANDO, Tajima Kenji, Matsushima Tokuo, Kusano Takatomo and Tatsuhiro Ishida :
Evaluation of exosomes derived from spheroids prepared by 3D cell culture system using nano-fibrillated bacterial cellulose,
14th International Symposium on Nanomedicine, Nov. 2021. Taro Shimizu, Haruka Takata, Milad Reda Qelliny and Tatsuhiro Ishida :
Evaluation of immunogenicity and adverse effects of nucleic acid-loaded nanoparticles,
14th International Symposium on Nanomedicine, Online, Nov. 2021. Tatsuhiro Ishida and Taro Shimizu :
A novel antigen delivery system: Antigen-selective delivery to splenic marginal zone B cells via repeated injections of PEGylated liposomes,
13th Anniversary International Symposium on Nanomedicine, Kobe, Dec. 2019. Taro Shimizu and Tatsuhiro Ishida :
Liposomal anticancer drugs enhanced antitumor effect of cancer immunotherapy by modulating immune systrem,
13th Anniversary International Symposium on Nanomedicine, Kobe, Dec. 2019. Mayumi Ikeda, Yu Ishima, T Maruyama, T Akaike, M Otagiri and Tatsuhiro Ishida :
A novel S-sulfhydrated human serum albumin suppresses reactive oxygen species induced by kidney injuries,
17th International Symposium on Blood Substitutes & Oxygen Therapeutics, Nara, Nov. 2019. Taro Shimizu, Kohga Miyahara, G Kozma, Hidenori ANDO, Yu Ishima, J Szebeni and Tatsuhiro Ishida :
Pre-treatment with Doxebo suppresses anti-PEG IgM immune responses through PEG-specific immune tolerance,
17th International Symposium on Blood Substitutes & Oxygen Therapeutics, Nara, Nov. 2019. Tatsuhiro Ishida :
Immunological response to PEGylated liposomes: production of anti-PEG antibodies and their affection on PK of second dose,
17th International Symposium on Blood Substitutes & Oxygen Therapeutics, Nara, Nov. 2019. Tatsuhiro Ishida and Taro Shimizu :
A novel antigen delivery system: Antigen-selective delivery to splenic marginal zone B cells via repeated injections of PEGylated liposomes,
Liposome Research Days 2019, Sapporo, Sep. 2019. Nehal Ali Emam Elsadek Emam Elhewan, Taro Shimizu and Tatsuhiro Ishida :
PEG-G-CSF immunogenicity in mice: Anti-PEG IgM induction,
Liposome Research Days 2019, Sapporo, Sep. 2019. Sherif Abdallah Emam Emam, Hidenori ANDO, Taro Shimizu and Tatsuhiro Ishida :
The impact of cell-type tropism on the intratumor accumulation of exosomes derived from cancer cells,
Liposome Research Days 2019, Sapporo, Sep. 2019. M Mohamed, Taro Shimizu and Tatsuhiro Ishida :
Macrophages contribute to anti-PEG IgM production and the subsequent accelerated blood clearance of PEGylated liposomes,
Liposome Research Days 2019, Sapporo, Sep. 2019. Taro Shimizu, Shunsuke Takese, Yu Ishima and Tatsuhiro Ishida :
Combination of cancer vaccines with liposomal oxaliplatin increased anti-cancer therapeutic efficacy by stimulating antitumor immunity,
Liposome Research Days 2019, Sapporo, Sep. 2019. Maho Tagami, Hidenori ANDO, Ai Ikeda, K Eshima, C.L Huang, H Wada and Tatsuhiro Ishida :
Enhanced therapeutic efficacy of liposomal weak-base anticancer drugs by daily oral administration of sodium bicarbonate,
Liposome Research Days 2019, Sapporo, Sep. 2019. Haruka Takata, Taro Shimizu and Tatsuhiro Ishida :
Gene therapy with lipoplexes may worsen inflammation via formation of immune complexes with pre-existing anti-DNA antibodies in SLE-prone mice,
Liposome Research Days 2019, Sapporo, Sep. 2019. Yuna Shimazaki, Hidenori ANDO, Taro Shimizu, Yu Ishima and Tatsuhiro Ishida :
Immunization method to obtain antigen-specific antibodies by antigen delivery to splenic marginal zone B cells using PEGylated liposomes,
Liposome Research Days 2019, Sapporo, Sep. 2019. Mayumi Ikeda, Yu Ishima, H Watanabe, T Maruyama, M Otagiri and Tatsuhiro Ishida :
Functional Elucidation of Polysulfides In Serum Albumin and Development of Biomimetic Donor of Polysulfides,
2019 CRS Annual Meeting & Exposition, Valencia, Jul. 2019. Tatsuhiro Ishida and Taro Shimizu :
Immunological responses against PEGylated liposomes: the application of ABC phenomenon into cancer vaccine,
12th International Symposium on Nanomedicine, Ube, Dec. 2018. Kohki Tachibana, Tamotsu Tanaka, Kentaro Kogure, Tatsuhiro Ishida and Keiichiro Okuhira :
Sphingosine-1-phosphate (S1P) affects the secretion of high density lipoprotein (HDL)-constituent protein,
12th International Symposium on Nanomedicine, Ube, Dec. 2018. Mayumi Ikeda, Taro Shimizu, Yu Ishima and Tatsuhiro Ishida :
A Novel S-Sulfhydrated Serum Albumin Preparation Suppresses Melanin Synthesis,
AAPS PharmSci 360, Washington, D.C., Nov. 2018. Tatsuhiro Ishida :
Immunological responses against PEGylated liposomes: Application for cancer vaccine,
13th France-Japan Drug Delivery Systems Symposium, Shima, Oct. 2018. Tatsuhiro Ishida :
Anti-polyethylene-glycol Antibody Response to PEGylated Nanoparticles,
CLINAM summit 2018, Basel, Sep. 2018. Emam Emam Abdallah Sherif, Hidenori ANDO, Lila Selim Ahmed Ali Abu Amr, Yu Ishima, A M Mahdy, S F Ghazy and Tatsuhiro Ishida :
The effect of liposome co-incubation with cancer cells on the secretion, uptake propensity and expression of certain surface proteins of cancer cell-derived exosomes (extracellular vesicles),
2018 CRS Annual Meeting & Exposition, New York, Jul. 2018. Nanami Tasaka, Mayumi Ikeda, Taro Shimizu, Yu Ishima and Tatsuhiro Ishida :
Reactive Sulfur Species in Human Hair Keratin Respond To Oxidative Stress,
5th World Congress on Hydrogen Sulfide in Biology&Medicine, Toronto, Jun. 2018. Shota Fujimoto, Naoki Muguruma, Michiyasu Nakao, Yoshihiko Miyamoto, Tatsuhiro Ishida, Shigeki Sano and Tetsuji Takayama :
Near-Infrared Molecular Imaging of Gastrointestinal Stromal Tumors using a Novel Fluorescent Probe Indocyanine Green (ICG)-Labeled Dasatinib.,
Digetive Disease Week2018, Washington, D.C., Jun. 2018. Mayumi Ikeda, Nanami Tasaka, Taro Shimizu, Yu Ishima and Tatsuhiro Ishida :
A Novel S-Sulfhydrated Human Serum Albumin Preparation Suppresses Melanin Synhtesis,
5th World Congress on Hydrogen Sulfide in Biology&Medicine, Toronto, Jun. 2018. Tatsuhiro Ishida :
Immunological responses to PEGylated materials ABC phenomenon and application to vaccine,
International Seminar Programme Drug Innovation (University of Utrecht), Utrecht, Jan. 2018. Tatsuhiro Ishida :
Immunological responses against PEGylated materials: the accelerated blood clearance (ABC) issue,
International Symposium on Nanomedicine 2017, Sendai, Dec. 2017. Takuma Maitani, Masami Ukawa, S Ishii, G Nohara, H Abutani, N Anderson and Tatsuhiro Ishida :
Investigation on antitumor effect and systemic toxicity by repeated injection of thermosensitive liposome encapsulating doxorubicin (ThermoDox®),
ILS Liposome Advances and Liposome Research Days Combined Conference, Athens, Sep. 2017. Tatsuhiro Ishida :
Immunological response to PEGylated nanoparticles: Anti-PEG antibody issues,
ILS Liposome Advances and Liposome Research Days Combined Conference, Athens, Sep. 2017. Tatsuhiro Ishida, Hidenori ANDO, M Fukushima, C.L Huang and H Wada :
An industrial method of manufacturing a novel RNAi anticancer drug, DFP-10825, for the treatment of peritoneal disseminated gastric cancer,
AACR Annual Meeting 2017, Washington, D.C., Apr. 2017. C Jin, K Eshima, M Fukushima, Tatsuhiro Ishida, C.L. Huang and H Wada :
DFP-10825 ip delivery provides a new effective treatment option to peritoneal disseminated cancers,
AACR Annual Meeting 2017, Washington, D.C., Apr. 2017. Masami Ukawa, Yuki Kanazawa and Tatsuhiro Ishida :
Doxorubicin enhanced nuclear entry of liposomal DNA via induction of the nuclear swelling,
International Symposium on Drug Delivery and Pharmaceutical Sciences: Beyond the History, Kyoto, Mar. 2017. Tatsuhiro Ishida :
Developent of RNAi-based anticancer drug: What is problem for clinical application and how establish a useful RNAi drug,
2016 International Conference of the Korea Society of Pharmaceutical Sciences and Technology, Seoul, Dec. 2016. Tatsuhiro Ishida :
Development of a RNAi-based anticancer drug.,
12th France-Japan Drug Delivery Systems Symposium, Paris, Oct. 2016. Tatsuhiro Ishida :
Anti-PEG immunity against PEGylated materials.,
An international workshop for Immune Effects of Nanomedicines: Clinical and Experimental Evidence, Prediction and Prevention., Budapest, Jun. 2016. Takuma Takayama, Taro Shimizu, Masami Ukawa and Tatsuhiro Ishida :
Liposomal doxorubicin (DXR) exerts antitumor effect via securing antitumor immunity against DXR in tumor microenvironment,
Liposome Advances 2015, London, Dec. 2015. Nozomi Kinjoh, Hidenori ANDO, Noriko Saito-Tarashima, Noriaki Minakawa and Tatsuhiro Ishida :
Targeted gene silencing by introduction of intelligent RNA expression device (iRed),
Liposome Advances 2015, London, Dec. 2015. Yuka Kitayama, Ryo Abe, Taro Shimizu and Tatsuhiro Ishida :
Anti-PEG IgM production induced by siRNA-containing PEGylated liposome,
Liposome Advances 2015, London, Dec. 2015. Mizuki Awata, Risako Fujita, Yu Mima, Munehira Kawanishi, Taro Shimizu and Tatsuhiro Ishida :
Altering PEGylated liposomes modification from DSPE-PEG-OCH3 to DSPE-PEG-OH suppresses secretion of anti-PEG IgM and proliferation of PEG-specific B cell,
Liposome Advances 2015, London, Dec. 2015. Noriko Saito-Tarashima, Kinjo Nozomi, Kojima Takamitsu, Hidenori ANDO, Tatsuhiro Ishida and Noriaki Minakawa :
Gene silencing via RNA interference (RNAi) machinery using 4'-thioDNA as an artificial template,
The 42nd International Symposium on Nucleic Acids Chemistry, Himeji, Sep. 2015. Tatsuhiro Ishida :
The role of B cells and anti-PEG IgM in the ABC phenomenon against PEGylated liposome,
LNP interactions with the immune system; Mechanistic Insights, Cambridge, Mar. 2015. Tatsuhiro Ishida :
Anti-PEG immunity against PEGylated materials,
11th DDS Symposium France-Japan, Awaji, Oct. 2014. Taro Shimizu, Yuki Watanabe, Yu Mima, Tatsuhiro Ishida and Hiroshi Kiwada :
Antigen delivery with PEGylated liposome and presentation via MZ-B cells enhanced induction of antigen-specific cytotoxic T lymphocyte,
Liposome Research Days 2014, Copenhagen, Aug. 2014. Munehira Kawanishi, Yosuke Hashimoto, Taro Shimizu, I Sagawa, Tatsuhiro Ishida and Hiroshi Kiwada :
Comprehensive analysis of proteins bound on PEGylated liposome relating to the accelerated blood clearance (ABC) phenomenon by shotgun analysis,
Liposome Research Days 2014, Copenhagen, Aug. 2014. Sakiko Kobayashi, Lila Selim Ahmed Ali Abu Amr and Tatsuhiro Ishida :
Influence of retention time of liposome in thoracic cavity and release rate of Pemetrexed encapsulated in it for malignant pleural methothelioma therapy,
Liposome Research Days 2014, Copenhagen, Aug. 2014. Yukako Fujiwara, Hiroyuki Nakamura, Tatsuhiro Ishida and Hiroshi Kiwada :
Increased PEG-coated liposomal l-OHP accumulation in the liver relates antitumor effect against M5076 ovarian sarcoma liver metastasis,
Liposome Research Days 2014, Copenhagen, Aug. 2014. Yu Mima, Taro Shimizu, Hiroshi Kiwada and Tatsuhiro Ishida :
Inclusion of ganglioside into PEGylated liposome suppresses the anti-PEG immunity against PEGylated liposome,
Liposome Research Days 2014, Copenhagen, Aug. 2014. Chihiro Katoh, Lila Selim Ahmed Ali Abu Amr and Tatsuhiro Ishida :
The effect of intrapleural environment and physicochemical properties of liposome/lipoplex on its retention time after intrapleural injection,
Liposome Research Days 2014, Copenhagen, Aug. 2014. Tatsuhiro Ishida :
Immunological Response to PEGylated Nanocarriers: Anti-PEG immunity,
Liposome Research Days 2014, Copenhagen, Aug. 2014. Kohsuke Takahashi, Miho Nishio and Tatsuhiro Ishida :
Long interval between Doxil® treatments causes Doxil® resistance in Colon26-bearing mouse,
Liposome Research Days 2014, Copenhagen, Aug. 2014. Yusuke Doi, Tatsuhiro Ishida and Hiroshi Kiwada :
Characterization of optimally designed liposomal formulation of Oxaliplatin,
The 41st Annual Meeting & Exposition of the Controlled Release Society, Chicago, Jul. 2014. Tatsuhiro Ishida :
Improvement of tumor-targeting therapy with nanocarrier system by changing the tumor microenvironment,
Shnchrotron Radiation in Nano-medicine and Advanced Health Care (SRNAHC), Kobe, Jan. 2014. Noriko Saito-Tarashima, Kojima Takamitsu, Hashimoto Yosuke, Kazuhiro Furukawa, Naoshi Yamazaki, Hiroshi Kiwada, Tatsuhiro Ishida, Noriaki Minakawa and Yoshiharu Takiguchi :
A novel approach of gene suppression using an intelligent shRNA expressing device (iRed),
9th Annual Meeting of the Oligonucleotide Therapeutics Society, Naples(Italy), Oct. 2013. Taro Shimizu, Tatsuhiro Ishida and Hiroshi Kiwada :
Potentiation of specific antibody response against antigen encapsulated in PEGylated liposomes via active transport of the liposomes from marginal zone into follicle,
5th Asian Arden Conference, Nagoya, Aug. 2013. Taro Shimizu, Tatsuhiro Ishida and Hiroshi Kiwada :
Transport of PEGylated liposomes to follicle induced by pre-stimulation of empty liposomes: Potentiating specific antibody responses against antigen encapsulated in the liposomes,
40th Annual Meeting & Exposition of the Controlled Release Society, Hawaii, Jul. 2013. Yosuke Hashimoto, Taro Shimizu, Tatsuhiro Ishida and Hiroshi Kiwada :
Serum anti-PEG IgM concentration is a determinant factor on hepatic accumulation of PEGylated liposome in the accelerated blood clearance phenomenon,
40th Annual Meeting & Exposition of the Controlled Release Society, Hawaii, Jul. 2013. Yu Mima, Yosuke Hashimoto, Taro Shimizu, Tatsuhiro Ishida and Hiroshi Kiwada :
Accelerated blood clearance phenomenon upon PEGylated protein,
40th Annual Meeting & Exposition of the Controlled Release Society, Hawaii, Jul. 2013. Miho Nishio, Hiroyuki Nakamura, Tatsuhiro Ishida and Hiroshi Kiwada :
PEGylated liposomes injected sequentially distribute in different region of solid tumor,
40th Annual Meeting & Exposition of the Controlled Release Society, Hawaii, Jul. 2013. Risako Fujita, Yosuke Hashimoto, Taro Shimizu, Tatsuhiro Ishida and Hiroshi Kiwada :
Effect of terminal group of PEG on induction of ABC phenomenon to PEGylated liposome,
40th Annual Meeting & Exposition of the Controlled Release Society, Hawaii, Jul. 2013. Tatsuhiro Ishida :
Immunological response to PEGylated nanocarriers: anti-PEG immunity,
2013 Cancer Nanotechnology Gordon Research Conference, Mount Snow Resort, West Dover, VT, USA, Jul. 2013. Tatsuhiro Ishida and Lila Selim Ahmed Ali Abu Amr :
Huang C., Wada, H., Fukushima, M., Kiwada. H., An entirely novel nanoparticle carrying a bioactive shRNA molecule (DFP-10825) could be clinically effective against the high risk patients with mesothelioma relapsed or refractory after treatment with pemetrexed based chemotherapy.,
24th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Dublin, Nov. 2012. Tatsuhiro Ishida and Hiroshi Kiwada :
Improvement of tumor-targeting therapy with nanocarrier system by changing the tumor microenvironment.,
10th DDS Symposium France-Japan, France, Oct. 2012. Tatsuhiro Ishida and Hiroshi Kiwada :
Improved intratumoral delivery of PEG-coated siRNA-lipoplexes by combination with metronomic S-1 dosing in a murine solid tumor model.,
Oligonucleotide Delivery: Biology, Engineering and Development, Austria, Oct. 2012. Taro Shimizu, Tatsuhiro Ishida and Hiroshi Kiwada :
Activation of splenic marginal zone B cell by PEGylated liposome with lower dose: triggering transport of antigen-containing second dose PEGylated liposome from marginal zone to follicle,
39th Annual Meeting & Exposition of the Controlled Release Society, Québec City, Jul. 2012. Hiroyuki Nakamura, Yusuke Doi, Tatsuhiro Ishida and Hiroshi Kiwada :
Sequential dose of l-OHP containing PEGylated liposome improve the intratumor delivery and efficacy of PEGylated liposomal anticancer agents.,
39th Annual Meeting & Exposition of the Controlled Release Society, Québec City, Jul. 2012. Yosuke Hashimoto, Tatsuhiro Ishida and Hiroshi Kiwada :
Anti-PEG IgM response against PEG-coated liposome is further increased by immune stimulation of siRNA via TLR7,,
39th Annual Meeting & Exposition of the Controlled Release Society, Québec City, Jul. 2012. Taro Shimizu, Tatsuhiro Ishida and Hiroshi Kiwada :
Contribution of spleen marginal zone B cells on anti-PEG IgM responses against PEGylated liposomes and transport of PEGylated liposomes.,
International Liposome Society 2011 meeting, University of London,, London, Dec. 2011. Naoto Moriyoshi, Mariko Matsunaga, Kazuya Nakamura, Tatsuhiro Ishida and Hiroshi Kiwada :
Development of new cancer treatment strategy that combines PEG-coated siRNA-lipoplex with metronomic S-1 dosing.,
International Liposome Society 2011 meeting, University of London,, London, Dec. 2011. Tatsuhiro Ishida and Hiroshi Kiwada :
Biological responses against lipid membrane containing PEG.,
3rd International Symposium on Surface and Interface of Biomaterials (SIB2011), Sapporo, Jul. 2011. Tatsuhiro Ishida and Hiroshi Kiwada :
Improvement of tumor-targeting therapy with nanocarrier system by changing the tumor microenviroment,
2011 RCAA International Symposium Endogenous Ligands Modulating Anticancer Agents, Seoul, Feb. 2011. Yuki Hashiguchi, Taro Shimizu, Masako Ichihara, Tatsuhiro Ishida and Hiroshi Kiwada :
PEG on nanocarriers induces anti PEG IgM production as a result of activation of immune system.,
Nano in Cancer: Linking Chemistry, Biology and Clinical Applications in vivo, Miami, Jan. 2011. Tatsuhiro Ishida, Kazuya Nakamura, Yusuke Doi, Naoto Moriyoshi and Hiroshi Kiwada :
A novel double modulation strategy in cancer treatment with chemotherapeutic agent and siRNA: S-1 improves siRNA accumulation and then Bcl-2 knockdown by the siRNA increases chemosensitivity of 5-FU.,
Nano in Cancer: Linking Chemistry, Biology and Clinical Applications in vivo, Miami, Jan. 2011. Yuki Hashiguchi, Taro Shimizu, Tatsuhiro Ishida and Hiroshi Kiwada :
Sequential treatment, pre-dose with empty PEGylated liposome (SL) and second dose antigen-encapsulating SL, promotes activation in a primary immune response.,
International Liposome Research Days & Lipids, Liposomes & Membrane Biophysics, Vancouver, Aug. 2010. Haruna Matsumoto, Yusuke Doi, Tatsuhiro Ishida and Hiroshi Kiwada :
Tumor localization and therapeutic effect of PEG-coated liposomal anticancer agent: Tumor type-dependency.,
International Liposome Research Days & Lipids, Liposomes & Membrane Biophysics, Vancouver, Aug. 2010. Tomoko Okada, Yusuke Doi, Lila Selim Ahmed Ali Abu Amr, Tatsuhiro Ishida and Hiroshi Kiwada :
Metronomic oral S-1, a fluoropyrimidine anticancer agent, dosing affects tumor accumulation of PEG-coated liposome.,
International Liposome Research Days & Lipids, Liposomes & Membrane Biophysics, Vancouver, Aug. 2010. Mariko Matsunaga, Kazuya Nakamura, Yusuke Doi, Naoto Moriyoshi, Tatsuhiro Ishida and Hiroshi Kiwada :
DEVELOPMENT OF NEW CANCER TREATMENT STRATEGY THAT COMBINES siRNA-LIPOPLEX WITH ORAL TEGAFUR ANTICANCER DRUG S-1.,
International Liposome Research Days & Lipids, Liposomes & Membrane Biophysics, Vancouver, Aug. 2010. Takahiro Iwaki, Tatsuaki Tagami, Kazuya Nakamura, Tatsuhiro Ishida and Hiroshi Kiwada :
THE EFFECT OF PEGYLATION OF siRNA-LIPOPLEX ON INTRACELLULAR UPTAKE QUANTITY OF SIRNA AND INTRACELLULAR BEHAVIOR OF siRNA.,
International Liposome Research Days & Lipids, Liposomes & Membrane Biophysics, Vancouver, Aug. 2010. Masako Ichihara, Ami Imoto, Yuki Hashiguchi, Yumi Uehara, Tatsuhiro Ishida and Hiroshi Kiwada :
Spleen cells secret anti-PEG IgM following intravenous injection of PEGylated liposome.,
International Liposome Research Days & Lipids, Liposomes & Membrane Biophysics, Vancouver, Aug. 2010. Tatsuhiro Ishida and Hiroshi Kiwada :
Immunostimulatory properties of liposomes containing PEG.,
International Liposome Research Days & Lipids, Liposomes & Membrane Biophysics, Vancouver, Aug. 2010. Yusuke Doi, Tomoko Okada, Haruna Matsumoto, Tatsuhiro Ishida and Hiroshi Kiwada :
Alteration of tumor microenvironment by metronomic S-1 dosing results in augmentation of EPR effect against PEG-coated liposomes.,
4th International Liposome Society Conference. Liposome advances: Progress in Drug and Vaccine Delivery, London, Dec. 2009. Tatsuhiro Ishida, Kazuya Nakamura, Mariko Matsunaga, Yusuke Doi and Hiroshi Kiwada :
A novel double modulation strategy in cancer treatment with chemotherapeutic agent and siRNA: siRNA-induced Bcl-2 knockdown increases chemosensitivity against 5-FU and S-1 improves siRNA accumulation in human colorectal tumor xenograft model.,
4th International Liposome Society Conference. Liposome advances: Progress in Drug and Vaccine Delivery, London, Dec. 2009. H Koide, T Asai, M Yokoyama, Tatsuhiro Ishida, Hiroshi Kiwada and N Oku :
Elucidation of ABC phenomenon caused by repeat injection of PEGylated nanocarrier.,
4th International Liposome Society Conference. Liposome advances: Progress in Drug and Vaccine Delivery, London, Dec. 2009. Tatsuhiro Ishida and Hiroshi Kiwada :
Improvement of tumor-targeting therapy with nanocarriers by changing the tumor microenvironment.,
2009 International Symposium of the Intelligent Drug Delivery System, Seoul, Apr. 2009. Tatsuhiro Ishida, Lila Selim Ahmed Ali Abu Amr, Takuya Suzuki, Yusuke Doi and Hiroshi Kiwada :
Oxaliplatin encapsulated in PEG-coated cationic liposome induces significant tumor growth suppression via dual-targeting approach in murine solid tumor model.,
AACR 100th Annual Meeting 2009, USA, Apr. 2009. Yusuke Doi, Yurie Hira, Tatsuhiro Ishida and Hiroshi Kiwada :
Synergistic antitumor activity of metronomic S-1 dosing in combination with oxaliplatin (1-OHP) containing PEGylated liposome in a murine solid tumor model.,
AACR 100th Annual Meeting 2009, USA, Apr. 2009. Tatsuhiro Ishida :
Improvement of tumor targeting therapy with nanocarriers by changing the tumor microenvironment.,
International exchange program between University of Tokushima and Seoul National University, Seoul, Mar. 2009. Tatsuhiro Ishida and Hiroshi Kiwada :
Improvement of tumor targeting therapy with nanocarriers by changing the tumor microenvironment.,
6th international workshop on Drug Delivery Systems for Nanomedicine, Prague (the Czech Republic), Oct. 2008. Tatsuaki Tagami, Kazuya Nakamura, Taro Shimizu, Tatsuhiro Ishida and Hiroshi Kiwada :
Effect of siRNA on anti-PEG IgM production in the accelerated blood clearance (ABC) phenomenon when formulated with PEGylated cationic liposome.,
11th Liposome Research Days conference, Yokohama, Jul. 2008. Takuya Suzuki, Kazuya Nakamura, Tatsuaki Tagami, Jose Mario Barichello, T Asai, Tatsuhiro Ishida, N Oku and Hiroshi Kiwada :
Anticancer activity of Argonaute2 (Ago2) gene silencing induced by siRNA in mouse tumor xenograft model.,
11th Liposome Research Days conference, Yokohama, Jul. 2008. Taro Shimizu, Tatsuhiro Ishida and Hiroshi Kiwada :
Interaction of PEGylated liposomes with splenic marginal zone B cells may trigger production of anti-PEG IgM in the ABC phenomenon.,
11th Liposome Research Days conference, Yokohama, Jul. 2008. Shinji Kizuki, Jose Mario Barichello, Tatsuaki Tagami, H Kikuchi, Tatsuhiro Ishida and Hiroshi Kiwada :
The impact of novel siRNA-lipoplex preparation method on cellular uptake pathway and gene knockdown efficiency.,
11th Liposome Research Days conference, Yokohama, Jul. 2008. Yusuke Doi, Yurie Hira, Tatsuhiro Ishida and Hiroshi Kiwada :
Metronomic dosing of oral anticancer agent affects microenvironment in solid tumor, resulting in enhanced intratumor accumulation and distribution of nanocarrior.,
11th Liposome Research Days conference, Yokohama, Jul. 2008. Lila Selim Ahmed Ali Abu Amr, Takuya Suzuki, Yusuke Doi, Tatsuhiro Ishida and Hiroshi Kiwada :
Oxaliplatin (l-OHP) targeting to angiogenic vessels by PEGylated cationic liposomes suppresses the angiogenesis in a dorsal air sac mouse model.,
11th Liposome Research Days conference, Yokohama, Jul. 2008. Jose Mario Barichello, Shinji Kizuki, Tatsuaki Tagami, T Asai, Tatsuhiro Ishida, K Hiroshi, N Oku and Hiroshi Kiwada :
Application of vortex-mixing during lipoplex formation affects siRNA-liposome association, siRNA internalization in cells and the RNAi effect.,
11th Liposome Research Days conference, Yokohama, Jul. 2008. M Matsushita, (名) Asai, Y Suzuki, Tatsuhiro Ishida, N Maeda, T Dewa, Hiroshi Kiwada, (名) Nango and N Oku :
Antiangiogenic effect by Argonaute2 knockdown used polycation liposome.,
11th Liposome Research Days conference, Yokohama, Jul. 2008. Tatsuhiro Ishida and Hiroshi Kiwada :
Improvement of tumor targeting therapy with nanocarriers by changing the tumor microenvironment.,
11th Liposome Research Days conference, Yokohama, Jul. 2008. Taro Shimizu, Tatsuhiro Ishida and Hiroshi Kiwada :
Accelerated blood clearance (ABC) phenomenon on PEGylated nanocarrier: Unexpected immune-reaction against PEGylated liposome.,
International Symposium on ``Nanotoxicology Assessment and Biomedical, Environmental Application of Fine Particles and Nanotubes'' (ISNT2008), Sapporo, Jun. 2008. Tatsuhiro Ishida and Hiroshi Kiwada :
Unexpected immunological response against sterically stabilized, PEGylated, liposome after intravenous injection.,
International Symposium on ``Nanotoxicology Assessment and Biomedical, Environmental Application of Fine Particles and Nanotubes'' (ISNT2008), Sapporo, Jun. 2008. Taisuke Matsuo, Naoshi Yamazaki, Tatsuhiro Ishida, Hiroshi Kiwada, Yasuo Shinohara and Masatoshi Kataoka :
Design, preparation and directional insertion of peptides into lipid bilayer membrane and heir application for the preparation of liposome of which surface could be coated by externally added antibody,
International symposium on system cell engineering by multi-scale manipulation, Nagoya, Nov. 2007. H Miyauchi, K Ichikawa, T Urakami, S Yonezawa, K Shimizu, Tatsuhiro Ishida, Hiroshi Kiwada, T Asai and N Oku :
Antigen-conjugated liposomes enhanced hyposensitization immune therapy with extra-low doses.,
34th Annual Meeting & Exposition of the Controlled Release Society, USA, Jul. 2007. T Asai, Y Suzuki, S Matsushita, J Yokota, Tatsuhiro Ishida, Hiroshi Kiwada and N Oku :
Development of antineovascular RNAi cancer therapy targeting to Argonaute 2.,
American Society of Gene Therapy's 10th annual Meeting, Seattle USA, May 2007. Barichello M. Jose, Tatsuhiro Ishida, Soares A. L. Luiz, Shinji Kizuki, Tatsuaki Tagami, Kiyomi Hirose, Hideo Kobayashi, Kouichi Hashimoto, Hiroshi Kikuchi and Hiroshi Kiwada :
Agitation during siRNA-cationic liposomes (CL) complex formation is a key step to improve in vitro RNA interference by lipofection.,
American Society of Gene Therapy's 10th annual Meeting, Seattle USA, May 2007. Tatsuhiro Ishida, Tatsuaki Tagami, Barichello M. Jose, Kiyomi Hirose, Naoshi Yamazaki, Tomohiro Asai, Naoto Oku and Hiroshi Kiwada :
Argonaute2 (Ago2) gene silencing by liposomal transfection with siRNA for Ago2 induces apoptosis on HT1080 cells and HUVECs.,
American Society of Gene Therapy's 10th annual Meeting, Seattle USA, May 2007. Taisuke Matsuo, Naoshi Yamazaki, Tatsuhiro Ishida, Hiroshi Kiwada, Yasuo Shinohara and Masatoshi Kataoka :
Mutant coat proteins of Pf3 bacteriophage as models of membrane proteins and their interactions with lipid bilayer membrane,
Pre-Satellite Meeting of the 3rd Pharmaceutical Sciences World Congress (PSWC 2007) for and by Ph.D. students and postdoctoral fellows, Amsterdam, Apr. 2007. Taisuke Matsuo, Naoshi Yamazaki, Tatsuhiro Ishida, Hiroshi Kiwada, Yasuo Shinohara and Masatoshi Kataoka :
Mutant coat proteins of Pf3 bacteriophage as models of membrane proteins and their interactions with lipid bilayer membrane,
International symposium on system cell engineering by multi-scale manipulation, Nagoya, Nov. 2006. Tatsuhiro Ishida and Hiroshi Kiwada :
Immunological responses to liposome carriers,
The 1st FIP-APSTJ Joint Work Shop on Gene Delivery, Sapporo, Jul. 2006. Tatsuhiro Ishida, Kazutaka Atobe, Wang Xinyu and Hiroshi Kiwada :
The influence of administration of PEGylated liposomal doxorubicin as a first dose on induction of accelerated blood clearance (ABC) phenomenon.,
8th US-Japan symposium on drug delivery systems, Hawaii, Dec. 2005. Tatsuhiro Ishida, Masako Ichihara, Masae Harada, Shuntarou Kashima, Wang Xinyu and Hiroshi Kiwada :
IgM secreted in response to the first injection of PEGylated liposomes involves in induction of the ABC phenomenon.,
31st Annual Meeting and Exposition of the Controlled Release Society., Hawaii, Jun. 2004. Hiroshi Kiwada and Tatsuhiro Ishida :
Immunological responses to nano-drug carriers.,
The 2nd Japan-Korea Joint Symposium on Drug Delivery and Therapy, Kyoto, May 2004. Tatsuhiro Ishida, Masako Ichihara, Shuntarou Kashima, Wang Xinyu and Hiroshi Kiwada :
IgM secreted in response to injection of PEGylated liposomes causes accelerated blood clearance of a subsequent dose.,
9th Liposome Research Days Conference, Hsinchu, Taiwan, May 2004. Tatsuhiro Ishida :
Nano drug carrier0biological milieu interactions: Immunological reaponses to PEGylated liposomes.,
International Symposium on Single-Molecule Bioanalysis and Nano-biodevice (SMBN) 2004, Kagawa, Mar. 2004. Tatsuhiro Ishida, J M Kirchmeier, S Zalipsky and M T Allen :
Targeted delivery and subsequent programmed release of liposomal doxorubicin with Stealth pH-sensitive liposomes.,
7th Liposome Research Days Conference, California, USA, Apr. 2000. 川口桂乃, 清水太郎, 田中浩揮, 平井敏郎, 石田竜弘, 秋田英万, 吉岡靖雄 :
PEG脂質及びヘルパー脂質の至適化によるmRNAワクチンの副反応の低減,
第28回日本ワクチン学会・第65回日本臨床ウイルス学会合同学術集会, 2024年10月. Matsuo Cristina Amorim Nana, Hidenori ANDO, Haruka Takata and Tatsuhiro Ishida :
Protein-bound cisplatin can induce therapeutic action for cisplatin with lessening its adverse events,
APSTJ Global Education Seminar 2024, Oct. 2024. 松尾アモリムクリスティーナ菜々, 安藤英紀, 髙田春風, 石田竜弘 :
HPLC/ICP-MS測定系を用いたシスプラチンのタンパク結合解析とタンパク結合形シスプラチンが副作用および抗腫瘍効果に与える影響の評価,
第45回生体膜と薬物の相互作用シンポジウム, 2024年10月. 森川芽衣, 福田翔一郎, 安藤英紀, 髙田春風, 中江崇, 辰巳昇, 濱本英利, 石田竜弘 :
イオン液体を用いた中分子化合物の経皮吸収促進技術の開発:吸収における分子量閾値の探索,
第45回生体膜と薬物の相互作用シンポジウム, 2024年10月. 成岡光夏, 安藤英紀, 髙田春風, 清水太郎, 石田竜弘 :
幼若マウスへ投与されたPEG修飾リポソームに対する免疫応答の評価:投与経路による抗PEG抗体誘導性の違い,
第45回生体膜と薬物の相互作用シンポジウム, 2024年10月. 金侑里, 髙田春風, 清水太郎, 安藤英紀, 石田竜弘 :
PEG誘導体含有化粧水の連日皮膚塗布で確認された抗PEG IgM誘導に対する脾臓およびT細胞の関与,
第45回生体膜と薬物の相互作用シンポジウム, 2024年10月. 菅菜奈子, 安藤英紀, 松尾アモリムクリスティーナ菜々, 角南尚哉, 土井祐輔, 髙田春風, 石田竜弘 :
オキサリプラチン封入リポソームとリツキサン®の併用投与におけるヒトリンパ腫移植マウスに対する抗腫瘍効果とマクロファージの貪食活性に関する検討,
第45回生体膜と薬物の相互作用シンポジウム, 2024年10月. 川上萌, 髙田春風, 安藤英紀, 石田竜弘 :
骨髄腫同所移植モデルマウスの作製およびCOOH末端PEG修飾リポソームの集積性の検討,
第45回生体膜と薬物の相互作用シンポジウム, 2024年10月. 松本仁志, 髙田春風, 安藤英紀, 石田竜弘 :
アミン末端PEG修飾リポソームを用いた酸性環境標的化DDSの開発,
第45回生体膜と薬物の相互作用シンポジウム, 2024年10月. 福本真子, 安藤英紀, 松島得雄, 草野貴友, 髙田春風, 石田竜弘 :
3D培養細胞由来エクソソームの特性及び構成タンパクの評価,
第45回生体膜と薬物の相互作用シンポジウム, 2024年10月. 工藤聡太郎, 安藤英紀, 川口桂乃, 清水太郎, 髙田春風, 石田竜弘 :
異なるPEG末端を持つmRNA搭載PEG修飾脂質ナノ粒子の脾臓免疫細胞への移行性とタンパク質発現評価,
第45回生体膜と薬物の相互作用シンポジウム, 2024年10月. 山本遥香, 安藤英紀, 髙田春風, 大本安一, 石田竜弘 :
生体内で抗PD-1抗体を誘導するPD-1ペプチドワクチンの開発の基礎的検討:免疫後の抗体誘導評価と抗腫瘍効果,
第45回生体膜と薬物の相互作用シンポジウム, 2024年10月. 水町健太, 清水太郎, 川口桂乃, 髙田春風, 安藤英紀, 石田竜弘 :
脾臓辺縁帯B細胞標的化リポソームをSLEモデルマウス・MRL/lprマウスに投与した際の標的化能力低下の原因究明,
第45回生体膜と薬物の相互作用シンポジウム, 2024年10月. 阿部舜史, 髙田春風, 清水太郎, 安藤英紀, 石田竜弘 :
mRNA搭載脂質ナノ粒子に修飾されたPEGに対する免疫応答に脾臓および胸腺が与える影響,
第45回生体膜と薬物の相互作用シンポジウム, 2024年10月. 福田翔一郎, 髙田春風, 中江崇, 辰巳昇, 濱本英利, 安藤英紀, 石田竜弘 :
イオン液体による中分子化合物の経口吸収促進機構の解明;消化管密着結合及び消化管吸収部位への影響,
第45回生体膜と薬物の相互作用シンポジウム, 2024年10月. Hitoshi Matsumoto, Haruka Takata, Hidenori ANDO and Tatsuhiro Ishida :
Acidic environment targeting by NH2-terminated PEG-modified liposomes,
2024 Tokushima Bioscience Retreat, Sep. 2024. Shoichiro Fukuda, Haruka Takata, Takashi Nakae, Noboru Tatsumi, Hidetoshi Hamamoto, Hidenori ANDO and Tatsuhiro Ishida :
Ionic liquids improve intestine absorption of macromolecules,
2024 Tokushima Bioscience Retreat, Sep. 2024. Matsuo Cristina Amorim Nana, Hidenori ANDO, Haruka Takata and Tatsuhiro Ishida :
Protein-bound form of cisplatin may potentiate therapeutic outcome of cisplatin treatment via minimizing its adverse effects,
2024 Tokushima Bioscience Retreat, Sep. 2024. 菅菜奈子, 安藤英紀, 松尾アモリムクリスティーナ菜々, 角南尚哉, 土井祐輔, 髙田春風, 石田竜弘 :
ヒトリンパ腫移植マウスにおけるオキサリプラチン封入PEG修飾リポソームとリツキサン併用時における抗腫瘍効果の検討:マクロファージの寄与,
第32回DDSカンファランス, 2024年9月. 成岡光夏, 安藤英紀, 髙田春風, 清水太郎, 石田竜弘 :
幼若マウスに腹腔内投与されたPEG修飾リポソームの抗PEG抗体誘導性と脾臓集積性の評価,
第32回DDSカンファランス, 2024年9月. 工藤聡太郎, 安藤英紀, 川口桂乃, 清水太郎, 髙田春風, 石田竜弘 :
脾臓送達技術を用いて投与したmRNA搭載PEG修飾脂質ナノ粒子の脾臓免疫細胞への移行性とタンパク質発現評価,
第29回創剤フォーラム若手研究会, 2024年9月. 阿部舜史, 髙田春風, 清水太郎, 安藤英紀, 石田竜弘 :
PEG修飾脂質ナノ粒子の筋肉内投与による抗PEG抗体誘導への脾臓及びT細胞の寄与,
日本核酸医薬学会第9回年会, 2024年7月. 石田竜弘, 阿部舜史, 髙田春風 :
抗PEG IgMが及ぼす筋肉内投与型mRNA/LNPワクチンへの影響,
日本核酸医薬学会第9回年会, 2024年7月. 石田竜弘, 清水太郎, 福田翔一郎, 髙田春風, 安藤英紀 :
イオン液体を用いた中分子化合物の吸収促進技術の開発,
第40回日本DDS学会学術集会, 2024年7月. Hidenori ANDO, Haruka Takata, Taro Shimizu and Tatsuhiro Ishida :
Induction of antigen-specific antibodies by a unique antigen delivery system targeting to spleen,
第40回日本DDS学会学術集会, Jul. 2024. Shunji Abe, Haruka Takata, Taro Shimizu, Hidenori ANDO and Tatsuhiro Ishida :
Impact of ant-PEG IgM on in vivo performance of PEGylated mRNA/LNP via intramuscularly injection,
第40回日本DDS学会学術集会, Jul. 2024. Haruka Takata, Shunji Abe, Hidenori ANDO and Tatsuhiro Ishida :
Effect of administration route on the anti-PEG IgM induction by PEGylated nanoparticles,
第40回日本DDS学会学術集会, Jul. 2024. 水町健太, 川口桂乃, 髙田春風, 清水太郎, 安藤英紀, 石田竜弘 :
全身性エリテマトーデス(SLE)治療を目指した脾臓辺縁帯B細胞標的化リポソーム開発におけるMRL/lprマウスモデル使用時の課題,
第40回日本DDS学会学術集会, 2024年7月. 松本仁志, 髙田春風, 清水太郎, 安藤英紀, 石田竜弘 :
PEG修飾リポソームを用いた新たな腫瘍ターゲティング戦略,
第40回日本DDS学会学術集会, 2024年7月. 金侑里, 髙田春風, 清水太郎, 安藤英紀, 石田竜弘 :
PEG誘導体含有化粧水の連日皮膚塗布で確認された抗PEG IgM誘導に対する脾臓およびT細胞の関与,
第40回日本DDS学会学術集会, 2024年7月. 酒井宏水, 久禮智子, 山田恭史, 伊藤格, 清水太郎, 石田竜弘, 東寛 :
人工赤血球(ヘモグロビンベシクル)を齧歯類に投与した後のアナフィラキシー反応の有無の検証,
第40回日本DDS学会学術集会, 2024年7月. 松尾アモリムクリスティーナ菜々, 安藤英紀, 田島健次, 髙田春風, 松島得雄, 草野貴友, 石田竜弘 :
細菌由来ナノセルロースの経口摂取による腸内細菌叢調節が食事性肥満モデルマウスの体重増加に与える影響の評価,
第78回日本栄養・食糧学会大会, 2024年5月. 松尾アモリムクリスティーナ菜々, 安藤英紀, 髙田春風, 石田竜弘 :
白金製剤シスプラチンのタンパク結合形が副作用と抗腫瘍効果に与える影響の評価,
日本薬剤学会第39年会, 2024年5月. 福田翔一郎, 加藤千尋, 髙田春風, 中江崇, 辰巳昇, 濱本英利, 安藤英紀, 石田竜弘 :
イオン液体による中分子化合物の経口吸収促進機構の解明に関する検討;消化管上皮タイトジャンクションと化合物の消化管内滞留性への影響,
日本薬剤学会第39年会, 2024年5月. 菅菜奈子, 安藤英紀, 松尾アモリムクリスティーナ菜々, 角南尚哉, 土井祐輔, 髙田春風, 安倍正博, 石田竜弘 :
ヒト悪性リンパ腫細胞の異種移植モデルに対するオキサリプラチン封入リポソームの単独あるいは抗体医薬との併用における抗腫瘍効果の検討,
日本薬剤学会第39年会, 2024年5月. 金侑里, 髙田春風, 清水太郎, 安藤英紀, 石田竜弘 :
化粧水塗布による抗PEG IgM誘導メカニズムに関する検討:脾臓およびT細胞の関与,
日本薬剤学会第39年会, 2024年5月. 成岡光夏, 安藤英紀, 髙田春風, 清水太郎, 石田竜弘 :
幼若マウスに対するPEG修飾リポソームの投与による抗PEG抗体誘導の評価,
日本薬剤学会第39年会, 2024年5月. 原悠斗, 安藤英紀, 山本遥香, 髙田春風, 大本安一, 石田竜弘 :
キャリアフリーでhTNFαペプチドを免疫して誘導した抗hTNFα抗体の評価と動物種間(マウス・ウサギ)での抗体誘導の比較,
日本薬剤学会第39年会, 2024年5月. 髙田春風, 阿部舜史, 清水太郎, 安藤英紀, 石田竜弘 :
ポリエチレングリコール(PEG)に対する抗体が及ぼすCOVID-19 mRNAワクチン筋肉内投与後のタンパク質翻訳への影響,
日本薬学会第144年会, 2024年3月. 川口桂乃, 清水太郎, 髙田春風, 安藤英紀, 石田竜弘 :
B細胞は補体結合リポソームを他の抗原提示細胞へ受け渡す,
日本薬学会第144年会, 2024年3月. 清水太郎, 石田竜弘 :
ナノ粒子に対する免疫応答を逆手にとった脾臓標的化法の開発,
日本薬学会第144年会, 2024年3月. 福本真子, 安藤英紀, 松島得雄, 草野貴友, 髙田春風, 石田竜弘 :
細菌由来ナノセルロースを3D培養基材として用いて調製したエクソソームの有用性検討;エクソソームの分泌特性とタンパク発現の評価,
日本薬学会第144年会, 2024年3月. 山本遥香, 安藤英紀, 髙田春風, 大本安一, 石田竜弘 :
生体内で抗PD-1抗体を誘導するPD-1ペプチドワクチン開発の基礎的検討:免疫後の抗血清を用いた結合性評価,
日本薬学会第144年会, 2024年3月. 出合祐梨, 清水太郎, 安藤英紀, 石田竜弘 :
脾臓辺縁帯B細胞を標的としたがんペプチドワクチンと化学療法剤の併用による抗腫瘍効果誘導に関する検討,
日本薬学会第144年会, 2024年3月. 松尾アモリムクリスティーナ菜々, 安藤英紀, 髙田春風, 石田竜弘 :
CDDPのタンパク結合率制御による副作用軽減と治療効果増強に関する研究:遊離型またはタンパク結合型CDDPが腎臓に与える副作用の評価,
日本薬学会第144年会, 2024年3月. 山出莉奈, 髙田春風, 安藤英紀, 石田竜弘 :
抗PEG抗体誘導にPEG修飾リポソームの投与経路が及ぼす影響,
日本薬学会第144年会, 2024年3月. 石田竜弘 :
ポリエチレングリコール(PEG)に対する免疫反応∼PEG抗体の誘導とその影響∼,
日本化学会第104春季年会, 2024年3月. 山本遥香, 安藤英紀, 髙田春風, 大本安一, 石田竜弘 :
新規hTNFαワクチン製剤の開発を目指した不活化hTNFα誘導体のマウスへの免疫と抗体誘導評価,
第2回日本抗体学会学術大会, 2023年12月. 福本真子, 安藤英紀, 倉本伶音, 髙田春風, 石田竜弘 :
エクソソームの脾臓免疫による抗体誘導評価:ホスト細胞膜表面に対する結合性評価,
第2回日本抗体学会学術大会, 2023年12月. 石田竜弘 :
イオン液体を用いた中分子化合物の吸収促進技術の開発,
第10回DDS製剤臨床応用FG合宿討論会, 2023年11月. 髙田春風, 阿部舜史, 安藤英紀, 石田竜弘 :
mRNA/LNPによるタンパク翻訳へ抗PEG IgMが及ぼす影響,
第10回DDS製剤臨床応用FG合宿討論会, 2023年11月. 高田正希, 安藤英紀, 田島健次, 松島得雄, 草野貴友, 浅田元子, 中村嘉利, 石田竜弘 :
物性の異なるナノセルロースを用いて調製したパクリタキセル包埋CNFの調製∼腹膜播種モデルマウスでの抗腫瘍効果の検討∼,
第62回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2023年10月. 橋本愛子, 異島優, 安藤英紀, 石田竜弘 :
アルブミンを基盤とした臓器特異的移行性を有するDDSキャリアの作製,
第62回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2023年10月. 出合祐梨, 清水太郎, 安藤英紀, 石田竜弘 :
脾臓辺縁帯B細胞を標的としたがんペプチドワクチンによる抗腫瘍効果誘導に関する検討,
第62回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2023年10月. 川口桂乃, 清水太郎, 髙田春風, 安藤英紀, 石田竜弘 :
補体結合リポソームによる抗原搭載法を利用した新規B細胞ワクチンの開発,
第27回日本ワクチン学会・第64回日本臨床ウイルス学会合同学術集会, 2023年10月. 福田翔一郎, 安藤英紀, 加藤千尋, 髙田春風, 中江崇, 辰巳昇, 濱本英利, 石田竜弘 :
イオン液体を新規吸収促進剤として用いた中分子化合物の経口吸収改善効果に関する検討,
第44回生体膜と薬物の相互作用シンポジウム, 2023年10月. 山本舜人, 安藤英紀, 清水太郎, 髙田春風, 石田竜弘 :
膜タンパク質搭載PEG修飾リポソームの脾臓辺縁帯領域から濾胞領域への送達による膜タンパク質に対する抗体誘導,
第44回生体膜と薬物の相互作用シンポジウム, 2023年10月. 石田竜弘 :
イオン液体を用いた中分子化合物の吸収促進技術の開発,
徳島大学・九州大学BINDS合同シンポジウム, 2023年10月. Fukuda Shoichiro, Hidenori ANDO, Chihiro Kato, Haruka Takata, Takashi Nakae, Noboru Tatsumi, Hidetoshi Hamamoto and Tatsuhiro Ishida :
The molecular weight limitation on increased intestinal absorption by ionic liquids,
日本薬物動態学会第38回年会, Sep. 2023. 金子瑛一郎, 辻崎晴人, 藤原政司, 安藤英紀, 石田竜弘, 谷博文, 田島健次 :
ナノフィブリル化バクテリアセルロースを用いた浮遊細胞培養における機械的ストレスの低減,
セルロース学会第30回年次大会, 2023年9月. 松尾アモリムクリスティーナ菜々, 安藤英紀, 田島健次, 松島得雄, 草野貴友, 石田竜弘 :
細菌由来ナノセルロースを用いたHepG2肝がんスフェロイドの作製検討と薬物代謝活性評価,
セルロース学会第30回年次大会, 2023年9月. 金子瑛一郎, 辻崎晴人, 藤原政司, 安藤英紀, 石田竜弘, 谷博文, 田島健次 :
ナノフィブリル化バクテリアセルロースを用いたCHO細胞の浮遊培養における細胞死の抑制と抗体生産性への影響,
第75回日本生物工学会大会, 2023年9月. 阿部舜史, 髙田春風, 清水太郎, 安藤英紀, 石田竜弘 :
筋注後筋組織から血中に漏出した脂質ナノ粒子(LNP)の体内動態に抗PEG IgMが与える影響,
遺伝子・デリバリー研究会第21回夏期セミナー, 2023年8月. Najmina Mazaya, 大石春陽, 石橋賢太, 小林慎吾, 柴田真由香, 岸村顕広, 清水太郎, 石田竜弘, 森健, 田中賢, 片山佳樹 :
ポリカルボキシベタインの構造とこれを修飾したリポソームの血中滞留性・抗原性に及ぼす効果,
第39回日本DDS学会学術集会, 2023年7月. 森健, 劉一イ, 石橋賢太, 片山佳樹, 清水太郎, 石田竜弘, 森尚寛, 黒木喜美子, 北尾彰朗 :
柔軟で特徴のないPEGを捕捉するための抗PEG抗体の認識戦略,
第39回日本DDS学会学術集会, 2023年7月. 石田竜弘, Sherif Armia, 清水太郎, 安藤英紀, 異島優 :
化粧水の塗布による抗PEG IgMの誘導が抗がん剤封入PEG修飾リポソームの抗腫瘍効果に与える影響,
第39回日本DDS学会学術集会, 2023年7月. 田中晴樹, 安藤英紀, 山本舜人, 清水太郎, 異島優, 石田竜弘 :
がん細胞由来膜タンパク質を搭載したPEG修飾リポソームを脾臓に送達する技術を利用したがんワクチンの開発:細胞性免疫誘導の評価,
第39回日本DDS学会学術集会, 2023年7月. 工藤聡太郎, 安藤英紀, 川口桂乃, 清水太郎, 異島優, 石田竜弘 :
末端構造の異なるPEG修飾リポソームの単独あるいは繰り返し投与における脾臓免疫細胞への移行性評価,
第39回日本DDS学会学術集会, 2023年7月. 福本真子, 安藤英紀, Sherif Emam Abdallah Emam, 松尾アモリムクリスティーナ菜々, 松島得雄, 草野貴友, 清水太郎, 異島優, 石田竜弘 :
NFBCを新規培養基材として用いた3D培養の有用性に関する研究:得られたエクソソームの細胞増殖と細胞内取り込みに与える影響の評価,
第39回日本DDS学会学術集会, 2023年7月. 山本舜人, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
がん細胞由来膜タンパク質を搭載したPEG修飾リポソームを脾臓に送達する技術を利用したがんワクチンの開発:腫瘍増殖抑制効果の評価,
第39回日本DDS学会学術集会, 2023年7月. 山出莉奈, 髙田春風, 清水太郎, 安藤英紀, 石田竜弘 :
PEG修飾リポソームの経口投与による抗PEG抗体誘導メカニズムに関する基礎的検討,
第39回日本DDS学会学術集会, 2023年7月. 上原陸, 安藤英紀, 清水太郎, 異島優, 江島清, 石田竜弘 :
アルカリ化剤の経口投与による腫瘍酸性環境改善とアブラキサン®の併用による抗腫瘍効果増強,
第39回日本DDS学会学術集会, 2023年7月. 福田翔一郎, 安藤英紀, 中江崇, 辰巳昇, 濱本英利, 清水太郎, 異島優, 石田竜弘 :
イオン液体による難吸収性中分子化合物の腸管吸収促進効果の検討,
第39回日本DDS学会学術集会, 2023年7月. 岡田直人, 清水太郎, 安藤英紀, 石田竜弘, 石澤啓介, 北原隆志 :
血液腫瘍患者における抗PEG抗体価の定量評価によるPEG修飾G-CSF関連有害事象の予測,
医療薬学フォーラム2023 / 第31回クリニカルファーマシーシンポジウム, 2023年7月. 髙田春風, 清水太郎, 阿部舜史, 安藤英紀, 石田竜弘 :
デキサメタゾンの事前投与によるmRNA封入PEG修飾脂質ナノ粒子投与時の抗PEG抗体誘導抑制に関する検討,
日本薬剤学会第38年会, 2023年5月. Mohamed Ibrahim, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
化粧水塗布時の含有PEGの皮膚透過と抗PEG IgM誘導に関する検討,
日本薬剤学会第38年会, 2023年5月. 山本舜人, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
膜タンパク質搭載PEG修飾リポソームの脾臓送達による各種がん細胞上の膜タンパク質に対する抗体誘導,
日本薬剤学会第38年会, 2023年5月. 山本遥香, 安藤英紀, 大本安一, 清水太郎, 異島優, 石田竜弘 :
抗ヒトTNFα抗体の生体内誘導を実現するTNFα由来ペプチドの免疫と抗体誘導評価,
日本薬剤学会第38年会, 2023年5月. 福本真子, 安藤英紀, Sherif Emam Abdallah Emam, 松尾アモリムクリスティーナ菜々, 松島得雄, 草野貴友, 清水太郎, 異島優, 石田竜弘 :
NFBCを新規培養基材として用いた3D培養の有用性に関する研究:培養時のエクソソーム分泌性と得られたエクソソームの細胞増殖等に与える影響の評価,
日本薬剤学会第38年会, 2023年5月. 松尾アモリムクリスティーナ菜々, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
HPLCとICP-MSを組み合わせたオキサリプラチン遊離型とタンパク結合型の分離評価法の確立,
日本薬剤学会第38年会, 2023年5月. 福田翔一郎, 安藤英紀, 丸山敦也, 中江崇, 辰巳昇, 濱本英利, 清水太郎, 異島優, 石田竜弘 :
イオン液体を基剤とした難吸収性中分子化合物の腸管吸収改善の検討,
日本薬剤学会第38年会, 2023年5月. 川口桂乃, 安藤英紀, 松尾アモリムクリスティーナ菜々, 田島健次, 長澤一樹, 松島得雄, 草野貴友, 石田竜弘 :
ナノフィブリル化バクテリアセルロースの経口摂取がもたらす腸内細菌叢の多様性変動と食事性肥満の改善,
第77回日本栄養・食糧学会大会, 2023年5月. 石田竜弘 :
ナノキャリア表面のPEGに対する免疫反応:抗PEG抗体の誘導,
ナノ学会第21回大会, 2023年5月. 平井傑琉, 長船裕輝, 清水太郎, 安藤英紀, 石田竜弘, 異島優 :
免疫グロブリン中に含まれる超硫黄分子の検出とその機能解明,
日本薬学会第143年会, 2023年3月. 山出莉奈, 清水太郎, 平川尚樹, 安藤英紀, 異島優, 石田竜弘 :
モデル抗原搭載アルブミンナノ粒子とアジュバントの併用によるがん治療効果検討,
日本薬学会第143年会, 2023年3月. 松木佑樹, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
ドキソルビシン封入リポソーム搭載脾臓細胞による抗腫瘍効果の検討,
日本薬学会第143年会, 2023年3月. 川口桂乃, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
B細胞に搭載されたヒドロキシ末端PEG修飾リポソームは補体受容体を介して他の抗原提示細胞へと受け渡される,
日本薬学会第143年会, 2023年3月. 茂木啓佑, 森戸克弥, 髙山健太郎, 石田竜弘, 長澤一樹 :
PEG修飾リポソーム化オキサリプラチン投与マウスにおける不安様及びうつ様行動の誘発に関する研究,
日本薬学会第143年会, 2023年3月. 谷澤輝嗣, 稲垣舞, 小迫英尊, 安藤英紀, 石田竜弘, 立川正憲 :
抗ヒト脳微小血管内皮細胞抗体の標的受容体の探索,
日本薬学会第143年会, 2023年3月. 池田真由美, 福田達也, 岩尾康範, 小田切優樹, 丸山徹, 石田竜弘, 異島優 :
血清アルブミンに存在する超硫黄の解析と創薬応用,
日本薬学会第143年会, 2023年3月. 山本遥香, 安藤英紀, 大本安一, 清水太郎, 異島優, 石田竜弘 :
抗hTNFα抗体を生体内で誘導するhTNFαペプチド配列の探索と抗体誘導評価,
日本薬学会第143年会, 2023年3月. 角南尚哉, 安藤英紀, 土井祐輔, 清水太郎, 異島優, 安倍正博, 石田竜弘 :
悪性リンパ腫に対するオキサリプラチン封入PEG修飾リポソームと抗体医薬の併用による抗腫瘍効果の検討,
日本薬学会第143年会, 2023年3月. 異島優, 丸山徹, 小田切優樹, 石田竜弘 :
アルブミン受容体の特性を生かしたアクティブターゲティング型DDSキャリアの開発,
日本薬学会第143年会, 2023年3月. 異島優, 池田真由美, 岩尾康範, 丸山徹, 小田切優樹, 赤池孝章, 石田竜弘 :
内因性超硫黄化タンパク質の発見,
日本薬学会第143年会, 2023年3月. Rina Yamade, Taro Shimizu, Hidenori ANDO, Yu Ishima and Tatsuhiro Ishida :
Investigation of the usefulness of human serum albumin nanoparticles as antigen delivery carriers to the spleen,
日本薬剤学会第2回英語セミナー, Feb. 2023. 石田竜弘 :
リポソームDDS研究の新たな展開,
日本薬学会北海道支部特別講演会, 2023年1月. 山本遥香, 安藤英紀, 大本安一, 川口桂乃, 清水太郎, 異島優, 石田竜弘 :
不活化ヒト TNFα 誘導体のマウスへの免疫による中和抗体の誘導評価,
第1回日本抗体学会設立記念学術大会, 2022年11月. Taro Shimizu, 濱本英利 and Tatsuhiro Ishida :
Ionic liquid-based transcutaneous delivery of macromolecules,
日本薬物動態学会第37回年会, Nov. 2022. 松尾アモリムクリスティーナ菜々, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
白金製剤と血漿タンパク質との相互作用:時間依存性に関する検討,
日本薬物動態学会第37回年会, 2022年11月. 水町健太, 清水太郎, 上田大, 髙田春風, 安藤英紀, 異島優, 石田竜弘 :
全身性エリテマトーデスモデルマウス由来B細胞の取り込み能についての検討,
第61回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2022年11月. 山本遥香, 安藤英紀, 大本安一, 清水太郎, 異島優, 石田竜弘 :
Humira®(adalimumab)投与時の抗薬物抗体(ADA)誘導に関する検討:マウス型抗ヒトTNFαモノクローナル抗体をマウスに投与した際のADA誘導,
第61回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2022年11月. 髙田春風, 清水太郎, 阿部舜史, 安藤英紀, 異島優, 石田竜弘 :
デキサメタゾンが及ぼすPEG修飾ナノ粒子による抗PEG抗体誘導への影響,
第16回次世代を担う若手医療薬科学シンポジウム, 2022年10月. 山本舜人, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
膜タンパク質搭載PEG修飾リポソームの脾臓送達による抗膜タンパク質抗体誘導,
第43回生体膜と薬物の相互作用シンポジウム, 2022年10月. 髙田春風, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
PEG修飾リポソームの投与経路がおよぼす抗PEG抗体誘導への影響に関する検討,
第43回生体膜と薬物の相互作用シンポジウム, 2022年10月. 岡田直人, 中村信元, 清水太郎, 安藤英紀, 相澤風花, 新村貴博, 八木健太, 合田光寛, 石田竜弘, 石澤啓介 :
免疫不全リスクを有する患者における新型コロナワクチンによる抗体獲得能に関連する因子の検討,
第32回日本医療薬学学会, 2022年9月. 池田真由美, 異島優, 丸山徹, 小田切優樹, 石田竜弘 :
超硫黄分子のレドックス制御機構の解明と抗酸化剤への応用,
第30回DDSカンファランス, 2022年9月. 角南尚哉, 安藤英紀, 土井祐輔, 清水太郎, 異島優, 安倍正博, 石田竜弘 :
オキサリプラチン封入PEG修飾リポソームの悪性リンパ腫治療への展開,
第27回創剤フォーラム若手研究会, 2022年9月. 福田翔一郎, 安藤英紀, 丸山敦也, 中江崇, 辰巳昇, 濱本英利, 清水太郎, 異島優, 石田竜弘 :
イオン液体による薬物の腸管吸収促進メカニズムの検討,
第27回創剤フォーラム若手研究会, 2022年9月. 松尾アモリムクリスティーナ菜々, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
重曹の経口投与によるDoxil®の腫瘍集積性向上と抗腫瘍効果増強,
第27回創剤フォーラム若手研究会, 2022年9月. 清水太郎, 石田竜弘 :
核酸搭載PEG修飾脂質ナノ粒子に対する免疫応答評価とその制御,
日本薬剤学会第3回超分子薬剤学FGシンポジウム, 2022年9月. 中野琉人, 平川尚樹, 安藤英紀, 清水太郎, 石田竜弘, 異島優 :
難水溶性薬物に対する溶解補助及び動態改善を企図した新規アルブミンナノ粒子の有用性評価,
日本薬剤学会第3回超分子薬剤学FGシンポジウム, 2022年9月. 川口桂乃, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
B細胞に標的化されたヒドロキシ末端PEG修飾リポソームは補体受容体を介して他の免疫細胞へと受け渡される,
日本薬剤学会第3回超分子薬剤学FGシンポジウム, 2022年9月. 岡田直人, 中村信元, 清水太郎, 安藤英紀, 相澤風花, 新村貴博, 八木健太, 合田光寛, 石田竜弘, 石澤啓介 :
免疫不全リスクを有する患者における新型コロナワクチンによる抗体獲得能に影響を与える因子の検討,
第32回日本医療薬学会年会, 2022年9月. 立花洸季, 楠本嵩志, 前橋梨花, 樹山友絵, 永尾綾菜, 辻田麻紀, 異島優, 石田竜弘, 奥平桂一郎 :
ApoA-1 binding proteinの加齢に伴う血清中濃度の変化およびその抗炎症作用,
フォーラム2022:衛生薬学・環境トキシコロジー, 2022年8月. 平井傑琉, 清水太郎, 安藤英紀, 石田竜弘, 異島優 :
毛髪中に含まれる超硫黄分子の検出および機能解明,
フォーラム2022:衛生薬学・環境トキシコロジー, 2022年8月. 異島優, 池田真由美, 酒井真紀, 長船裕輝, 岩尾康範, 丸山徹, 小田切優樹, 石田竜弘 :
様々な生体液に含まれる超硫黄分子の生理的意義の解明,
フォーラム2022:衛生薬学・環境トキシコロジー, 2022年8月. 石橋賢汰, 岸村顕広, 清水太郎, 森健, 石田竜弘, 片山佳樹 :
イオン間距離の異なるベタインポリマー修飾リポソームに対する抗体産生,
遺伝子・デリバリー研究会第20回夏期セミナー, 2022年8月. 阿部舜史, 髙田春風, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
血中の抗PEG抗体が筋肉内投与後のmRNA搭載LNPのタンパク質発現に与える影響に関する検討,
遺伝子・デリバリー研究会第20回夏期セミナー, 2022年8月. 髙田春風, 清水太郎, 上田大, 安藤英紀, 異島優, 石田竜弘 :
siRNA搭載PEG修飾リポソームの投与経路がおよぼす抗PEG抗体誘導への影響に関する検討,
遺伝子・デリバリー研究会第20回夏期セミナー, 2022年8月. 阿部舜史, 髙田春風, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
mRNA搭載LNP構成成分のPEG脂質が示す免疫原性及びアナフィラキシー様反応への影響,
日本核酸医薬学会第7回年会, 2022年8月. 上田大, 清水太郎, 安藤英紀, 異島優, 山吉麻子, 石田竜弘 :
核酸搭載リポソームの物理化学的性質が抗核酸抗体の誘導に与える影響の検討,
日本核酸医薬学会第7回年会, 2022年8月. 川口桂乃, 安藤英紀, 田島健次, 長澤一樹, 清水太郎, 異島優, 石田竜弘 :
ナノフィブリル化バクテリアセルロースの経口摂取による腸内細菌叢の変動と肥満抑制効果の評価,
セルロース学会第29回年次大会, 2022年7月. 髙田春風, 安藤英紀, 田島健次, 清水太郎, 異島優, 松島得雄, 草野貴友, 石田竜弘 :
ナノフィブリル化バクテリアセルロースを懸濁剤として用いたシクロスポリンA製剤の調製と乾癬治療効果の評価,
セルロース学会第29回年次大会, 2022年7月. 平井傑琉, 田坂菜々美, 清水太郎, 安藤英紀, 石田竜弘, 異島優 :
毛髪中に含まれる超硫黄分子の検出および機能解明,
第49回日本毒性学会学術年会, 2022年7月. 十鳥有希菜, 平川尚樹, 木下遼, 清水太郎, 安藤英紀, 石田竜弘, 異島優 :
スルホサリチル酸を用いた新規アルブミンナノ粒子化法の開発と敗血症への応用,
第49回日本毒性学会学術年会, 2022年7月. 向井愛菜, 清水太郎, 安藤英紀, 石田竜弘, 異島優 :
致死性エンドトキシンショックに対するヒト血清アルブミンの治療効果の機序,
第49回日本毒性学会学術年会, 2022年7月. 橋本怜奈, 清水太郎, 安藤英紀, 石田竜弘, 異島優 :
皮膚角質層に含まれる超硫黄分子の検出,
第49回日本毒性学会学術年会, 2022年7月. 倉本伶音, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
緑色蛍光タンパク質(EGFP)をモデル抗原として封入したPEG修飾エクソソームの脾臓送達による抗原特異的抗体の誘導,
第38回日本DDS学会学術集会, 2022年6月. 角南尚哉, 安藤英紀, 清水太郎, 異島優, 安倍正博, 石田竜弘 :
オキサリプラチン封入PEG修飾リポソームの悪性リンパ腫に対する治療効果の検討,
第38回日本DDS学会学術集会, 2022年6月. 橋本愛子, 異島優, 安藤英紀, 清水太郎, 石田竜弘 :
アルブミンを基盤とした臓器特異的移行性を有するDDSキャリアの作製,
第38回日本DDS学会学術集会, 2022年6月. 山出莉奈, 清水太郎, 平川尚樹, 安藤英紀, 異島優, 石田竜弘 :
ヒト血清アルブミンナノ粒子(HSAnp)を利用したDDSの新規開発とがんワクチンへの展開,
第38回日本DDS学会学術集会, 2022年6月. 山本遥香, 安藤英紀, 大本安一, 清水太郎, 異島優, 石田竜弘 :
抗TNFαモノクローナル抗体(Humira)をマウスに投与した際の抗薬物抗体の誘導評価,
第38回日本DDS学会学術集会, 2022年6月. 山本舜人, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
抗原とオボアルブミンを共封入したPEG修飾リポソームの脾臓送達による抗原特異的抗体誘導の増強効果,
第38回日本DDS学会学術集会, 2022年6月. 髙田春風, Milad Qelliny, 清水太郎, 上田大, 安藤英紀, 異島優, 石田竜弘 :
ガングリオシドを用いた抗核酸抗体誘導抑制効果の検討,
日本薬剤学会第37年会, 2022年5月. 阿部舜史, 髙田春風, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
mRNA封入脂質ナノ粒子構成成分のPEGに対する抗PEG抗体の誘導及びアナフィラキシー様反応への影響,
日本薬剤学会第37年会, 2022年5月. 山本舜人, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
抗原封入PEG修飾リポソームを利用した抗体誘導におけるOVAのアジュバント効果の検証,
日本薬剤学会第37年会, 2022年5月. 山本舜人, 安藤英紀, 冨田康治, 前田典之, 清水太郎, 異島優, 石田竜弘 :
末端構造の異なるPEGで作製した抗原封入リポソームの静脈内投与による抗体誘導に関わる免疫細胞の評価,
日本薬学会第142年会, 2022年3月. 松﨑隆朗, 清水太郎, 安藤英紀, 異島優, 山中勝弘, 三輪泰司, 濱本英利, 石田竜弘 :
イオン液体を用いた経皮吸収ワクチンによる皮膚およびリンパ節における免疫細胞の活性化評価,
日本薬学会第142年会, 2022年3月. 川口桂乃, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
脾臓中B細胞は補体受容体介在性に捕捉した抗原キャリアを他の抗原提示細胞へ輸送する,
日本薬学会第142年会, 2022年3月. 清水太郎, 山口雪洲, 安藤英紀, 異島優, 石田竜弘 :
新型コロナウイルスに対する効率的な抗体誘導を目指した脾臓辺縁帯B細胞標的化ワクチン開発に関する検討,
日本薬学会第142年会, 2022年3月. 茂木啓佑, 森戸克弥, 髙山健太郎, 安川岳志, 森本博敏, 松浦留架, 魚住嘉伸, 石田竜弘, 長澤一樹 :
オキサリプラチンのPEGリポソーム化による腸内細菌叢の変化への影響,
日本薬学会第142年会, 2022年3月. 藤本将太, 六車直樹, 中尾允泰, 安藤英紀, 三宅孝典, 樫原孝典, 石田竜弘, 佐野茂樹, 高山哲治 :
消化管間質腫瘍(GIST)に対する新たな内視鏡診断法の確立に向けた蛍光分子イメージング技術の開発,
第18回日本消化管学会学術集会, 2022年2月. 山本舜人, 安藤英紀, 前田典之, 清水太郎, 異島優, 石田竜弘 :
抗原封入リポソームの脾臓免疫による抗体誘導に関するPEG末端構造の影響,
第60回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2021年11月. 高田正希, 安藤英紀, 赤木俊介, 田島健次, 松島得雄, 草野貴友, 清水太郎, 異島優, 石田竜弘 :
表面物性の異なるナノフィブリル化バクテリアセルロースを用いたパクリタキセル製剤の開発と腹膜播種治療評価,
第60回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2021年11月. 上原陸, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
重曹経口投与による腫瘍内微小環境中性化にともなう遺伝子発現解析,
第60回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2021年11月. 松尾菜々, 異島優, 安藤英紀, 清水太郎, 石田竜弘 :
Sulfane sulfur付加型HSAを用いた還元ストレス誘導を介するがん治療戦略,
第60回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2021年11月. 清水太郎, Qelliny Milad, 髙田春風, 上田大, 安藤英紀, 異島優, 石田竜弘 :
核酸搭載PEG修飾カチオン性リポソームによる抗PEG抗体および抗核酸抗体誘導に及ぼすガングリオシド修飾の影響,
第60回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2021年11月. 橋本愛子, 異島優, 安藤英紀, 清水太郎, 石田竜弘 :
アルブミンを基盤とした臓器特異的移行性を有するDDSキャリアの作製,
第15回次世代を担う若手のための医療薬科学シンポジウム, 2021年10月. 茂木啓佑, 平尾彩香, 阿部礼奈, 森戸克弥, 髙山健太郎, 土井祐輔, 安藤英紀, 石田竜弘, 長澤一樹 :
PEG修飾リポソーム製剤化oxaliplatin投与ラットにおいて甘味感受性の低下を誘発するその舌組織への蓄積に対する口腔冷却の影響,
第31回日本医療薬学会年会, 2021年10月. 安藤英紀, 赤木俊介, 田島健次, 清水太郎, 異島優, 松島得雄, 草野貴友, 石田竜弘 :
ナノフィブリル化バクテリアセルロース(NFBC)を利用した3次元細胞培養に関する基礎的検討,
セルロース学会第28回年次大会, 2021年9月. 赤木俊介, 安藤英紀, 田島健次, 松島得雄, 草野貴友, 清水太郎, 異島優, 石田竜弘 :
ナノフィブリル化バクテリアセルロース(NFBC)を用いた3次元培養によるヒト肝がんHepG2細胞の機能変動評価,
セルロース学会第28回年次大会, 2021年9月. 山出莉奈, 平川尚樹, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
高い抗体産生誘導能を有する抗原搭載アルブミンナノ粒子の開発,
日本薬剤学会第2回超分子薬剤学FGシンポジウム, 2021年9月. Yoshino Kawaguchi, Taro Shimizu, Hidenori ANDO, Yu Ishima and Tatsuhiro Ishida :
Enhancement of the anti-tumor effect of B cell-based vaccines via increasing the loading amount of antigens by utilizing novel antigen carrier system,
2021 Tokushima Bioscience Retreat, Sep. 2021. 松尾菜々, 異島優, 安藤英紀, 清水太郎, 石田竜弘 :
活性イオウ付加型ヒト血清アルブミンの腫瘍への送達は小疱形成を介した細胞死を誘導する,
第29回DDSカンファランス, 2021年9月. 石田竜弘 :
抗PEG抗体誘導の種差と薬物動態への影響,
第48回日本毒性学会学術年会, 2021年7月. 安藤英紀, 山口雪洲, 清水太郎, 異島優, 石田竜弘 :
新規脾臓免疫で誘導した抗体の多様性および結合性の評価,
第37回日本DDS学会学術集会, 2021年6月. 清水太郎, 島崎優奈, 安藤英紀, 異島優, 石田竜弘 :
脾臓辺縁帯B細胞を標的としたペプチド封入リポソームによる免疫誘導に関する検討,
第37回日本DDS学会学術集会, 2021年6月. 石橋賢汰, 清水太郎, 石田竜弘 :
イオン間距離の異なるベタインポリマー修飾リポソームに対する抗体産生,
第37回日本DDS学会学術集会, 2021年6月. 髙田春風, 清水太郎, 川口桂乃, 安藤英紀, 異島優, 石田竜弘 :
投与経路が及ぼすPEG修飾リポソーム投与時の抗PEG抗体誘導に与える影響に関する検討,
第37回日本DDS学会学術集会, 2021年6月. 坂元智香, 清水太郎, 安藤英紀, 異島優, 小林勝則, 石橋賢樹, 三輪泰司, 濱本英利, 石田竜弘 :
イオン液体を用いたIL-23 特異的siRNAの経皮送達はイミキモド誘発乾癬モデルマウスの皮膚症状を改善する,
日本核酸医薬学会第6回年会, 2021年6月. 髙田春風, Milad Reda Qelliny, 清水太郎, 上田大, 安藤英紀, 異島優, 石田竜弘 :
ガングリオシドによるDNA搭載PEG修飾カチオン性リポソーム投与時のPEG及びDNAに対する抗体の産生への影響の検討,
日本核酸医薬学会第6回年会サテライト若手シンポジウム, 2021年6月. 安藤英紀, 石田竜弘 :
実用性の高い腹腔内投与型核酸製剤の開発と腹膜播種治療評価,
日本核酸医薬学会第6回年会サテライト若手シンポジウム, 2021年6月. 石田竜弘 :
PEG修飾によるドラッグデリバリーシステム(DDS)の開発,
第43回日本血栓止血学会学術集会, 2021年5月. 安田健吾, 木下遼, 前田仁志, 皆吉勇紀, 櫻木美菜, 水田夕稀, 山崎啓之, 異島優, 石田竜弘, 渡邊博志, 丸山徹 :
マクロファージ及び線維芽細胞を標的可能なレドックス応答性ナノラジカルスカベンジャーの開発と肝疾患治療への応用,
日本薬剤学会第36年会, 2021年5月. 橋本愛子, 濱眞壱, 異島優, 安藤英紀, 清水太郎, 石田竜弘 :
様々なヒト血清アルブミン受容体を介した薬物キャリアの開発,
日本薬剤学会第36年会, 2021年5月. 向井愛菜, 異島優, 安藤英紀, 清水太郎, 石田竜弘 :
致死性エンドトキシンショックに対するヒト血清アルブミンの治療効果の機序解明,
日本薬剤学会第36年会, 2021年5月. 橋本怜奈, 異島優, 安藤英紀, 清水太郎, 石田竜弘 :
紫外線による皮膚角質中に含まれる活性イオウ分子種の変動,
日本薬剤学会第36年会, 2021年5月. 角南尚哉, 安藤英紀, 中江崇, 三輪泰司, 辰巳昇, 濱本英利, 清水太郎, 異島優, 石田竜弘 :
イオン液体を基剤としたLixisenatide製剤の開発と腸管吸収評価,
日本薬剤学会第36年会, 2021年5月. 丸山敦也, 安藤英紀, 中江崇, 三輪泰司, 濱本英利, 清水太郎, 異島優, 石田竜弘 :
イオン液体を用いた難経口吸収性化合物の腸管吸収促進効果の検討,
日本薬剤学会第36年会, 2021年5月. 上田大, 髙田春風, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
全身性エリテマトーデスモデルマウス由来マイクロパーティクルにおけるプロテオーム解析,
日本薬剤学会第36年会, 2021年5月. 川口桂乃, 粟田瑞月, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
細胞ワクチンへの応用を目指した補体受容体標的化キャリアを用いる新規B細胞抗原刺激法の確立,
日本薬剤学会第36年会, 2021年5月. 川口桂乃, 粟田瑞月, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
効果的な細胞免疫療法の開発に向けたB細胞への新規抗原刺激法の有用性評価,
日本薬剤学会第36年会, 2021年5月. Nehal Emam Elsadek Emam Ali Elhewan, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
Pegfilgrastim (PEG-G-CSF) induces anti-PEG IgM in a dose dependent manner and causes the accelerated blood clearance (ABC) phenomenon upon repeated administer,
日本薬剤学会第36年会, 2021年5月. 安藤英紀, 石田竜弘 :
臨床実用を志向した腹腔内投与型核酸製剤の開発,
日本薬剤学会第36年会, 2021年5月. 山本舜人, 山口雪洲, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
抗原封入リポソームの脾臓免疫による抗原特異的IgGの誘導とサブクラス多様性の評価,
日本薬剤学会第36年会, 2021年5月. 山出莉奈, 平川尚樹, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
効率的な体液性免疫誘導に向けたアルブミンナノキャリアの開発,
日本薬剤学会第36年会, 2021年5月. 松﨑隆朗, 清水太郎, 安藤英紀, 異島優, 三輪泰司, 濱本英利, 石田竜弘 :
経皮吸収型がんペプチドワクチンによるE.G7-OVA担がんマウスにおける腫瘍成長抑制効果,
日本薬剤学会第36年会, 2021年5月. 高田正希, 赤木俊介, 安藤英紀, 清水太郎, 異島優, 松島得雄, 草野貴友, 石田竜弘 :
菌由来セルロースナノファイバーを用いた細胞の三次元培養と機能性評価,
日本薬剤学会第36年会, 2021年5月. 上原陸, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
重曹経口投与による腫瘍酸性環境の中性化とDoxil®の抗腫瘍効果の増強,
日本薬剤学会第36年会, 2021年5月. 山口雪洲, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
新規脾臓免疫法による特異抗体の誘導とその多様性および結合親和性の評価,
日本薬剤学会第36年会, 2021年5月. 松木佑樹, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
マレイミド-チオール結合を介した抗がん剤封入リポソームの脾臓細胞への搭載とそのがん細胞障害性の評価,
日本薬剤学会第36年会, 2021年5月. 倉本伶音, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
エクソソームの脾臓免疫で得た抗血清(ポリクローナル抗体)の結合性評価,
日本薬剤学会第36年会, 2021年5月. 福田悠花, 中島祟樹, 異島優, 安藤英紀, 清水太郎, 長野一也, 柴田寛子, 石田竜弘 :
PEG修飾タンパクの凝集体形成が及ぼす抗PEG抗体産生・血中滞留性への影響,
日本薬剤学会第36年会, 2021年5月. 坂元智香, 清水太郎, 安藤英紀, 異島優, 小林勝則, 石橋賢樹, 三輪泰司, 濱本英利, 石田竜弘 :
経皮送達可能なsiRNA含有イオン液体製剤による新規乾癬治療,
日本薬剤学会第36年会, 2021年5月. 小川真依, 立花洸季, 石田竜弘, 奥平桂一郎 :
多発性硬化症治療薬FTY720によるABCトランスポーターA1発現に対する影響とそのメカニズム,
日本薬剤学会第36年会, 2021年5月. 有井紗由季, 上田将弘, 重永章, 大髙章, 猪熊翼, 山田健一, 石田竜弘, 奥平桂一郎 :
新規タンパク分解誘導剤によるチミジル酸合成酵素阻害メカニズムの解明,
日本薬剤学会第36年会, 2021年5月. 赤木俊介, 安藤英紀, 田島健次, 松島得雄, 草野貴友, 清水太郎, 異島優, 石田竜弘 :
物性の異なるナノフィブリル化バクテリアセルロースを用いた新規PTX製剤の開発と腹膜播種治療評価,
日本薬剤学会第36年会, 2021年5月. 立花洸季, 小川真依, 石田竜弘, 異島優, 奥平桂一郎 :
免疫抑制剤フィンゴリモドによるABCトランスポーターの増加を介した泡沫化マクロファージへの脂質蓄積への影響,
日本薬剤学会第36年会, 2021年5月. 髙田春風, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
核酸搭載PEG修飾リポソームが全身性エリテマトーデスの発症時期，増悪に与える影響,
日本薬剤学会第36年会, 2021年5月. 濵眞壱, 異島優, 安藤英紀, 清水太郎, 石田竜弘 :
アルブミン結合型パクリタキセル製剤AbraxaneⓇの変性アルブミン受容体を介した薬物輸送メカニズム,
日本薬剤学会第36年会, 2021年5月. Sherif Emam Abdallah Emam, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
Cell-type tropism promotes the intratumor accumulation of PEGylated cancer cell-derived exosomes,
日本薬剤学会第36年会, 2021年5月. 清水太郎, 三輪泰司, 濱本英利, 石田竜弘 :
イオン液体を用いた中分子経皮送達法の開発,
日本薬剤学会第36年会, 2021年5月. 茂木啓佑, 平尾彩香, 阿部礼奈, 森戸克弥, 髙山健太郎, 土井祐輔, 安藤英紀, 石田竜弘, 長澤一樹 :
Oxaliplatinのpolyethylene glycol(PEG)修飾リポソーム製剤化による甘味感受性への影響,
日本薬学会第141年会, 2021年3月. 中野琉人, 平川尚樹, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
難溶性薬物に対する溶解補助及び動態改善を企図した新規アルブミンナノ粒子の開発,
日本薬学会第141年会, 2021年3月. 倉本伶音, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
エクソソームの脾臓免疫により誘導した抗体のエクソソームタンパク質への結合評価,
日本薬学会第141年会, 2021年3月. 宮原康嘉, 清水太郎, 安藤英紀, 異島優, Szebeni Janos, 石田竜弘 :
高用量PEG修飾リポソーム投与時の抗PEG抗体誘導抑制機序に関する検討,
日本薬学会第141年会, 2021年3月. 川口桂乃, 島崎優奈, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
脾臓B細胞上の補体受容体を介した抗原送達法を利用する新規細胞免疫療法の開発,
日本薬学会第141年会, 2021年3月. 松尾菜々, 異島優, 池田真由美, 安藤英紀, 清水太郎, 石田竜弘 :
活性イオウ付加アルブミンの設計と還元ストレス誘導による抗腫瘍効果の評価,
日本薬学会第141年会, 2021年3月. 山口雪洲, 安藤英紀, 島崎優奈, 清水太郎, 異島優, 石田竜弘 :
抗原封入リポソームの脾臓免疫で誘導された抗体の多様性・親和性評価,
日本薬学会第141年会, 2021年3月. 山出莉奈, 平川尚樹, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
ヒト血清アルブミン(HSA)を利用した脾臓への抗原送達による体液性免疫の誘導,
日本薬学会第141年会, 2021年3月. 角南尚哉, 安藤英紀, 丸山敦也, 三輪泰司, 濱本英利, 清水太郎, 異島優, 石田竜弘 :
イオン液体を用いたGLP-1受容体作動薬の腸管吸収性検討,
日本薬学会第141年会, 2021年3月. 立花洸季, 小川真依, 石田竜弘, 異島優, 奥平桂一郎 :
免疫抑制剤フィンゴリモドがマクロファージへの脂質蓄積に与える影響,
日本薬学会第141年会, 2021年3月. 山口雪洲, 島崎優奈, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
脾臓標的化リポソーム技術を用いた短期間で抗体を誘導する抗体産生誘導技術の開発,
第59回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2020年12月. 向井愛菜, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
致死性エンドトキシンショックに対するヒト血清アルブミンの治療効果,
第59回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2020年12月. 松木佑樹, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
脾臓細胞搭載抗がん剤封⼊カチオン性リポソームによるがん細胞障害性のin vitro評価,
第59回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2020年12月. 橋本怜奈, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
皮膚角質中に含まれる活性イオウ分子種の検出,
第59回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2020年12月. 異島優, 池田真由美, 澤智裕, 赤池孝章, 石田竜弘 :
ヒト血清アルブミンにおけるパースルフィド化の生理的意義の解明とその臨床応用,
第73回日本酸化ストレス学会・第20回日本NO学会合同学術集会, 2020年10月. 異島優, 池田真由美, 田坂菜々美, 石田竜弘 :
酸化型ポリスルフィドタンパク質によるユニークな抗酸化作用機構,
第73回日本酸化ストレス学会・第20回日本NO学会合同学術集会, 2020年10月. 酒井真紀, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
ストレプトゾトシン誘発Ⅰ型糖尿病モデルマウスにおける血清活性イオウ分子の変動,
第93回日本生化学会大会, 2020年9月. 長船裕輝, 池田真由美, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
生体液中の活性イオウ分子種含有タンパク質の同定と生理学的意義の解明,
第93回日本生化学会大会, 2020年9月. 清水太郎, 吉岡千尋, 島崎優奈, 竹瀬俊輔, 石橋賢樹, 三輪泰司, 濱本英利, 石田竜弘 :
イオン液体を用いた経皮吸収型がんペプチドワクチン開発に関する検討,
第36回日本DDS学会学術集会, 2020年8月. 島居伶奈, 宮原涼, 龍神尭昌, 岸村顕広, 清水太郎, 石田竜弘, 森健, 片山佳樹 :
ポリカルボキシベタイン修飾リポソームはABC現象を誘導する,
第36回日本DDS学会学術集会, 2020年8月. 松木佑樹, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
抗がん剤搭載脾臓細胞によるがん細胞障害性評価に関する検討,
第36回日本DDS学会学術集会, 2020年8月. 坂元智香, 清水太郎, 安藤英紀, 異島優, 小林勝則, 石橋賢樹, 三輪泰司, 濱本英利, 石田竜弘 :
イオン液体を用いたsiRNAの経皮送達による新規乾癬治療法の開発,
第36回日本DDS学会学術集会, 2020年8月. 川口桂乃, 粟田瑞月, 島崎優奈, 吉岡千尋, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
ヒドロキシ末端PEG修飾リポソームによる抗原刺激を利用した新規B細胞ワクチンの開発,
第36回日本DDS学会学術集会, 2020年8月. 異島優, 池田真由美, 石田竜弘 :
ヒト生体液におけるポリスルフィドプールの発見とその生理学的意義,
第47回日本毒性学会学術年会, 2020年6月. 山口雪洲, 島崎優奈, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
脾臓辺縁帯B細胞への抗原送達による抗体産生誘導技術の開発,
日本薬剤学会第35年会, 2020年5月. 丸山敦也, 安藤英紀, 三輪泰司, 濱本英利, 清水太郎, 異島優, 石田竜弘 :
インドシアニングリーンを用いたイオン液体の腸管吸収促進効果の検討,
日本薬剤学会第35年会, 2020年5月. 福田悠花, 中島祟樹, 長野一也, 異島優, 石田竜弘 :
PEG修飾タンパクのPEG鎖長や修飾数が及ぼす抗PEG抗体産生と血中滞留性低下への影響,
日本薬剤学会第35年会, 2020年5月. 濵眞壱, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
アルブミン結合型パクリタキセル製剤であるAbraxane®の新たな腫瘍移行機序の発見,
日本薬剤学会第35年会, 2020年5月. 丸山敦也, 安藤英紀, 三輪泰司, 濱本英利, 清水太郎, 異島優, 石田竜弘 :
イオン液体によるインドシアニングリーンの経口吸収性改善の検討,
日本薬学会第140年会, 2020年3月. 川口桂乃, 粟田瑞月, 島崎優奈, 吉岡千尋, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
細胞ワクチン療法への利用に適したB細胞サブセットの同定に関する検討,
日本薬学会第140年会, 2020年3月. 金山忠史, 大川内健人, 清水太郎, 重永章, 大髙章, 石田竜弘, 奥平桂一郎 :
人工HDLの化学的性状と抗腫瘍効果への影響に関する検討,
日本薬学会第140年会, 2020年3月. 濵眞壱, 異島優, 安藤英紀, 清水太郎, 石田竜弘 :
アルブミン結合型パクリタキセル製剤であるAbraxane®の新たな腫瘍移行機序の発見,
日本薬学会第140年会, 2020年3月. 酒井真紀, 池田真由美, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
糖尿病患者血清におけるサルフェン硫黄の変動,
日本薬学会第140年会, 2020年3月. 長船裕輝, 池田真由美, 酒井真紀, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
ヒト唾液α-amylase活性に及ぼすサルフェン硫黄の影響,
日本薬学会第140年会, 2020年3月. 田坂菜々美, 池田真由美, 清水太郎, 安藤英紀, 奥平桂一郎, 異島優, 石田竜弘 :
毛髪キューティクルに存在するポリスルフィドの発見とイオウ供給による毛髪損傷抑制効果の検討,
日本薬学会第140年会, 2020年3月. 赤木俊介, 安藤英紀, 松島得雄, 草野貴友, 石田竜弘 :
新規セルロースナノファイバーゲルを用いた3次元培養法の開発,
第19回日本再生医療学会総会, 2020年3月. 石田竜弘 :
PEG修飾リポソームに対する免疫反応∼抗PEG抗体とABC現象の誘導,
高分子学会九州支部フォーラム, 2020年1月. Tatsuhiro Ishida :
Passive tumor targeting via EPR effect,
日本薬物動態学会第34回年会, Dec. 2019. 翁由紀子, 新島瞳, 川原勇太, 早瀬朋美, 清水太郎, 石田竜弘 :
PEG化第8因子製剤によるアナフィラキシーの経験,
第61回日本小児血液・がん学会学術集会, 2019年11月. 小川真依, 立花洸季, 石田竜弘, 奥平桂一郎 :
多発性硬化症治療薬FTY720のアポリポタンパク質発現に対する影響,
第58回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2019年11月. 内海彩花, 佐々木澄美, 楠本嵩志, 吉田徳幸, 石田竜弘, 井上貴雄, 奥平桂一郎 :
アンチセンスのキャリア非依存性取り込み機構に寄与する膜タンパク質の検討,
第58回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2019年11月. 有井紗由季, 上田将弘, 重永章, 大髙章, 石田竜弘, 奥平桂一郎 :
プロテインノックダウン法を用いたチミジル酸合成酵素分解誘導剤開発,
第58回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2019年11月. 福田悠花, 中島祟樹, 長野一也, 異島優, 石田竜弘 :
タンパク質へのPEG修飾数やPEG鎖長が及ぼす抗PEG抗体産生への影響,
第58回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2019年11月. 坂元智香, 清水太郎, 安藤英紀, 異島優, 小林勝則, 石橋賢樹, 三輪泰司, 濱本英利, 石田竜弘 :
siRNA含有イオン液体製剤の経皮送達による乾癬治療,
第58回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2019年11月. 上田大, 髙田春風, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
全身性エリテマトーデス病態時の脾臓免疫細胞によるマイクロパーティクルの取り込み変化の検討,
第58回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2019年11月. 赤木俊介, 安藤英紀, 田島健次, 松島得雄, 草野貴友, 石田竜弘 :
物理化学的性質の異なるナノフィブリル化バクテリアセルロース(NFBC)を用いたPTX製剤の開発とがん治療評価,
第58回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2019年11月. 異島優, 木下遼, 平川尚樹, 石田竜弘, 小田切優樹, 丸山徹 :
難治性膵臓がんにおけるアルブミンナノ粒子のサイズ最適化の検討,
第30回日本消化器癌発生学会総会, 2019年11月. 石田竜弘 :
リポソームを用いたDDSの開発研究,
日本油化学会第58回年会, 2019年9月. 楠本嵩志, 堂前純子, 田中直伸, 柏田良樹, 辻大輔, 伊藤孝司, 石田竜弘, 奥平桂一郎 :
天然物による膜トランスポーターABCA7の発現増強機構の解析,
第92回日本生化学会大会, 2019年9月. 佐々井雅樹, 清水太郎, 奥平桂一郎, 異島優, 石橋賢樹, 三輪泰司, 濱本英利, 石田竜弘 :
イオン液体を用いた新規インスリン含有経皮吸収製剤は糖尿病治療薬になりうる,
第28回DDSカンファランス, 2019年9月. 赤木俊介, 安藤英紀, 田島健次, 松島得雄, 草野貴友, 石田竜弘 :
両親媒性ナノフィブリル化バクテリアセルロース(Fibnano)の放出制御型がん治療製剤への応用,
セルロース学会第26回年次大会, 2019年7月. 一水翔太, 渡邊博志, 前田仁志, 清水太郎, 異島優, 石田竜弘, 二木史朗, 小田切優樹, 丸山徹 :
細胞膜透過型アルブミンの細胞内移行機序の解明∼マクロピノサイトーシス誘導とエンドソーム脱出経路∼,
第35回日本DDS学会学術集会, 2019年7月. 上田大, 髙田春風, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
マイクロパーティクルによる抗体産生誘導は全身性エリテマトーデスの症状進行に関与する,
第35回日本DDS学会学術集会, 2019年7月. 島崎優奈, 安藤英紀, 清水太郎, 異島優, 石田竜弘 :
脾臓への抗原デリバリー技術を利用した新規抗体産生技術の開発,
第35回日本DDS学会学術集会, 2019年7月. 異島優, 木下遼, 池田真由美, 丸山徹, 小田切優樹, 石田竜弘 :
抗体医薬を用いたがん治療に対するEPR増強剤SNO-HSA-dimerの効果,
第35回日本DDS学会学術集会, 2019年7月. 田坂菜々美, 池田真由美, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
毛髪ケラチン中に存在するポリスルフィドの酸化ストレス応答,
第72回日本酸化ストレス学会学術集会, 2019年6月. 井上改, 異島優, 池田真由美, 清水太郎, 安藤英紀, 石田竜弘 :
細胞培養系における血清アルブミン結合sulfane sulfurの役割,
第19回日本NO学会学術集会, 2019年6月. 池田真由美, 異島優, 酒井真紀, 清水太郎, 安藤英紀, 渡邊博志, 丸山徹, 小田切優樹, 石田竜弘 :
ヒト血清アルブミンに存在するポリスルフィドによるユニークな酸化ストレス応答,
第19回日本NO学会学術集会, 2019年6月. 藤本将太, 六車直樹, 中尾允泰, 安藤英紀, 宮本佳彦, 岡本耕一, 佐藤康史, 石田竜弘, 佐野茂樹, 高山哲治 :
新規蛍光プローブIndocyanine green (ICG) 標識Dasatinibを用いた消化管間質腫瘍 (GIST) の近赤外蛍光イメージング.,
第14回日本分子イメージング学会総会・学術集会, 2019年5月. 金山忠史, 大川内健人, 清水太郎, 重永章, 大髙章, 石田竜弘, 奥平桂一郎 :
腫瘍DDSキャリアとしての人工HDLの調製および動態の評価,
日本薬剤学会第34年会, 2019年5月. 赤木俊介, 安藤英紀, 田島健次, 松島得雄, 草野貴友, 石田竜弘 :
両親媒性ナノフィブリル化バクテリアセルロースを基剤とした放出制御型Paclitaxel製剤の開発,
日本薬剤学会第34年会, 2019年5月. 池田真由美, 異島優, 清水太郎, 安藤英紀, 奥平桂一郎, 渡邊博志, 丸山徹, 小田切優樹, 石田竜弘 :
血清アルブミンの酸化ストレス応答を模倣した新規抗酸化剤の設計,
日本薬剤学会第34年会, 2019年5月. 平川尚樹, 異島優, 木下遼, 清水太郎, 丸山徹, 奥平桂一郎, 石田竜弘 :
難治性膵臓がんへの高い移行性を有するアルブミンナノ粒子の開発,
日本薬剤学会第34年会, 2019年5月. 田神舞帆, 池田愛, 安藤英紀, 江島清, 和田洋巳, 石田竜弘 :
腫瘍内微小環境の改善によるDDS製剤の治療効果増強,
日本薬学会第139年会, 2019年3月. 異島優, 木下遼, 池田真由美, 丸山徹, 小田切優樹, 石田竜弘 :
一酸化窒素を利用した血管透過性制御とがん治療応用,
日本薬学会第139年会, 2019年3月. 橘茉里奈, 末永翔平, 楠本嵩志, 杉原涼, 髙田春風, 西辻和親, 辻田麻紀, 石田竜弘, 奥平桂一郎 :
炎症モデルマウスにおけるapoA-I結合タンパク質AIBPの抗炎症作用の検討,
日本薬学会第139年会, 2019年3月. 末永翔平, 金山忠史, 橘茉里奈, 楠本嵩志, 杉原涼, 西辻和親, 辻田麻紀, 石田竜弘, 奥平桂一郎 :
apoA-I結合タンパク質AIBPの抗炎症活性発現メカニズムの検討,
日本薬学会第139年会, 2019年3月. 楠本嵩志, 堂前純子, 田中直伸, 柏田良樹, 辻大輔, 伊藤孝司, 石田竜弘, 奥平桂一郎 :
膜タンパク質ABCA7を増加させる新規天然物,
日本薬学会第139年会, 2019年3月. 清水太郎, 異島優, 石田竜弘 :
タンパクのPEG修飾による抗PEG免疫応答の誘導,
日本薬学会第139年会, 2019年3月. 石田竜弘 :
PEG修飾製剤に対する免疫反応:ABC現象からがんワクチンに至るまで,
崇城大学 DDS 研究所・特別講演会, 2019年1月. 田神舞帆, 安藤英紀, Li Shyh-Dar, 石田竜弘 :
Continuous treatment with immune modulator can uniformize the effect of anti-tumor immunity,
第47回日本免疫学会学術集会, 2018年12月. 島崎優奈, 清水太郎, 安藤英紀, 石田竜弘 :
Expansion of the delivering technique of PEGylated liposomes to marginal zone B cells for immunization with peptide antigen,
第47回日本免疫学会学術集会, 2018年12月. 髙田春風, 清水太郎, 石田竜弘 :
Oligonucleotide therapeutics with pDNA/lipoplex would not cause systemic lupus erythematosus but exacerbate systemic lupus erythematosus via formation immune complexes (pDNA/lipoplex-anti DNA antibodies),
第47回日本免疫学会学術集会, 2018年12月. 石田竜弘 :
微粒子製剤に対する免疫反応:PEG修飾リポソームに対するABC現象とCARPA,
製剤種差検討会第7回事例報告会, 2018年11月. 末永翔平, 橘茉里奈, 杉原涼, 西辻和親, 辻田麻紀, 石田竜弘 :
アポA-I結合タンパク質(AIBP)の炎症抑制効果についての検討,
第57回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2018年11月. 平川尚樹, 異島優, 木下遼, 清水太郎, 丸山徹, 奥平桂一郎, 石田竜弘 :
共有結合型アルブミンナノ粒子を用いたセラノスティックナノDDS抗がん剤の開発,
第57回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2018年11月. 佐々井雅樹, 清水太郎, 異島優, 石橋賢樹, 三輪泰司, 濱本英利, 石田竜弘 :
イオン液体を用いた新規インスリン含有経皮吸収製剤の開発,
第57回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2018年11月. 宮原康嘉, 清水太郎, 異島優, Janos Szebeni, 石田竜弘 :
高投与量Doxebo前処置によるABC現象の抑制に関する検討,
第57回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2018年11月. 酒井真紀, 池田真由美, 今福匡司, 安藤英紀, 清水太郎, 異島優, 丸山徹, 石田竜弘 :
糖尿病患者における血清中サルフェン硫黄と抗酸化能の評価,
第57回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2018年11月. 川口桂乃, 渡辺優希, 清水太郎, 異島優, 石田竜弘 :
辺縁帯B細胞標的化抗原デリバリーシステムによる抗腫瘍免疫応答増強効果,
第57回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2018年11月. 金山忠史, 奥平桂一郎, 大川内健人, 清水太郎, 重永章, 大髙章, 石田竜弘 :
人工HDLの化学的性状と体内動態への影響に関する検討,
第57回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2018年11月. 長船裕輝, 池田真由美, 酒井真紀, 清水太郎, 安藤英紀, 異島優, 石田竜弘 :
生体液に含まれる活性イオウ分子種の検出,
第57回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2018年11月. 立花洸季, 田中保, 小暮健太朗, 石田竜弘, 奥平桂一郎 :
HDL構成タンパク質分泌に対するスフィンゴシン-1-リン酸及びフィンゴリモドの影響,
第57回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2018年11月. 中見祥一, 清水太郎, 異島優, 石田竜弘 :
Doxil前処置による養子免疫細胞のがん移行性向上に関する検討,
第57回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2018年11月. 池田愛, 安藤英紀, 江島清, 和田洋巳, 石田竜弘 :
腫瘍内微小環境の改善にともなうDoxilの抗腫瘍効果増強,
第57回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2018年11月. 藤本将太, 六車直樹, 岡本耕一, 佐藤康史, 宮本佳彦, 中尾允泰, 北村晋志, 宮本弘志, 佐野茂樹, 石田竜弘, 常山幸一, 高山哲治 :
Theranostics理論に基づく消化管間質腫瘍(GIST)の新規診断治療法の開発.,
第26回日本消化器関連学会週間(第96回日本消化器内視鏡学会総会), 2018年11月. 石田竜弘 :
PEG修飾製剤に対する抗PEG抗体の誘導とAccelerated blood clearance(ABC)現象,
第25回日本血液代替物学会年次大会, 2018年10月. 木庭遼, 西堀麻衣子, 永吉絹子, 貞苅良彦, 藤田逸人, 永井俊太郎, 大内田研宙, 大塚隆生, 植木隆, 石田竜弘, 中村雅史 :
放射光蛍光X線分析による白金錯体系薬剤の直腸癌組織内分布の可視化,
第56回日本癌治療学会学術集会, 2018年10月. 池田真由美, 異島優, 渡邊博志, 赤池孝章, 丸山徹, 小田切優樹, 石田竜弘 :
生体液中の活性イオウ分子種の検出と機能解明,
第40回生体膜と薬物の相互作用シンポジウム, 2018年10月. 立花洸季, 西辻和親, 田中保, 小暮健太朗, 石田竜弘, 奥平桂一郎 :
スフィンゴシン-1-リン酸(S1P)による高密度リポプロテイン(HDL)構成タンパク質分泌への影響,
第91回日本生化学会大会, 2018年9月. 立花洸季, 田中保, 小暮健太朗, 石田竜弘, 奥平桂一郎 :
HDL構成タンパク質分泌に対するスフィンゴシン-1-リン酸及びフィンゴリモドの影響,
第91回日本生化学会大会, 2018年9月. 横山桜子, 笹山瑞紀, 真田貴義, 高橋葉子, 異島優, 石田竜弘, 鈴木亮, 丸山一雄, 丸山徹, 根岸洋一 :
一酸化窒素ガスデリバリーのための超音波応答性ナノバブルの調製と虚血下肢における送達効果,
第62回日本薬学会関東支部大会, 2018年9月. 池田真由美, 異島優, 渡邊博志, 小田切優樹, 丸山徹, 石田竜弘 :
血清アルブミンに存在するサルフェン硫黄の酸化還元制御の解明と生体模倣的な硫黄送達システムの開発への応用,
第12回次世代を担う若手医療薬科学シンポジウム, 2018年9月. 安藤英紀, 望月啓志, 藤田研司, Kenji Tajima, Tokuo Matsushima, Takatomo Kusano, 石田竜弘 :
Advanced application of nano-fibrillated bacterial cellulose (Fibnano®) to anti-cancer therapy,
第67回高分子討論会, 2018年9月. 木下遼, 異島優, 渡邊博志, 清水太郎, 石田竜弘, 小田切優樹, 丸山徹 :
新規ナノEPR増強剤であるNO搭載型アルブミンダイマーと高分子抗がん剤の併用による次世代型難治性がん治療法の構築,
第1回超分子薬剤学FGシンポジウム, 2018年9月. 異島優, 木下遼, 池田真由美, 安藤英紀, 清水太郎, 小田切優樹, 丸山徹, 石田竜弘 :
ガス状リガンドと相互作用するヒト血清アルブミンの臨床応用,
第1回超分子薬剤学FGシンポジウム, 2018年9月. 山﨑仁王, 清水太郎, 異島優, 石田竜弘 :
ABC現象回避における末端マレイミドPEG-リン脂質の有用性に関する検討,
第27回DDSカンファランス, 2018年9月. 竹瀬俊輔, 清水太郎, 異島優, 石田竜弘 :
がん化学・免疫併用療法におけるオキサリプラチン封入リポソームの有用性に関する検討,
第27回DDSカンファランス, 2018年9月. 石田竜弘 :
臨床応用を目指した核酸医薬(DFP-10825)の開発,
日本核酸医薬学会第4回年会, 2018年7月. 安藤英紀, 望月啓志, 藤田研司, 田島健次, 松島得雄, 草野貴友, 石田竜弘 :
ナノフィブリル化バクテリアセルロース(Fibnano)を用いた新規パクリタキセル製剤の開発とがん治療への展開,
セルロース学会第25回年次大会, 2018年7月. 異島優, 石田竜弘, 金城雄樹, 丸山徹, 小田切優樹 :
多剤耐性菌および真菌に対するS‐ニトロソ化Alpha1―酸性糖蛋白質の効果,
医療薬学フォーラム 2018, 2018年6月. 平川尚樹, 木下遼, 異島優, 清水太郎, 丸山徹, 奥平桂一郎, 石田竜弘 :
共有結合型アルブミンナノ粒子をキャリアとしたナノDDS抗がん剤の開発及び有用性評価,
第34回日本DDS学会学術集会, 2018年6月. 川口桂乃, 島崎優奈, 渡辺優希, 清水太郎, 異島優, 石田竜弘 :
脾臓標的化ワクチンによる免疫誘導における辺縁帯B細胞の役割,
第34回日本DDS学会学術集会, 2018年6月. 宮下直樹, 奥平桂一郎, 石田竜弘 :
Xanthohumol を用いたDNAトランスフェクション効率の改善,
第34回日本DDS学会学術集会, 2018年6月. 石田竜弘, Szebeni Janos :
微粒子製剤に対する免疫反応:PEG修飾リポソームに対するABC現象とCARPAを例として,
第34回日本DDS学会学術集会, 2018年6月. 石田竜弘 :
生体内動態の理解を基盤としたリポソームDDSの開発:臨床応用を目指して,
第34回日本DDS学会学術集会, 2018年6月. 松岡里英, 安藤英紀, 石田竜弘 :
胃がん腹膜播種モデルにおいて腹腔内投与したカチオン性リポソームは腫瘍に選択的に集積する,
第34回日本DDS学会学術集会, 2018年6月. 池田愛, 木下遼, 安藤英紀, 江島清, 和田洋巳, 石田竜弘 :
がん細胞の代謝特異性を利用したドキソルビシンのがん細胞内送達法の開発,
第34回日本DDS学会学術集会, 2018年6月. 清水太郎, 吉岡千尋, 粟田瑞月, 川口桂乃, 異島優, 石田竜弘 :
ヒドロキシ末端PEG修飾リポソームを用いた新規脾臓標的化ワクチンの開発に関する検討,
第34回日本DDS学会学術集会, 2018年6月. 石田竜弘 :
リポソームによるDDS開発,
「中分子創薬シード展開クラスター」第1回勉強会, 2018年6月. 宮下直樹, 奥平桂一郎, 川原遥華, 津田雄介, 森本恭平, 辻耕平, 重永章, 大髙章, 石田竜弘 :
動脈硬化治療を指向した光制御型HDL構成ペプチドの開発,
日本薬剤学会第33年会, 2018年6月. 異島優, 渡辺佳織, 小田切優樹, 石田竜弘, 丸山徹 :
新規抗菌剤SNO-AGPの多剤耐性菌に対する克服効果,
日本薬剤学会第33年会, 2018年6月. 木下遼, 異島優, 渡邊博志, 清水太郎, 石田竜弘, 小田切優樹, 丸山徹 :
新規腫瘍DDSキャリアである共有結合型アルブミンナノ粒子の有用性評価,
日本薬剤学会第33年会, 2018年6月. 笹山瑞紀, 真田貴義, 高橋葉子, 異島優, 石田竜弘, 鈴木亮, 丸山一雄, 丸山徹, 根岸洋一 :
一酸化窒素ガスを内封した超音波応答性ナノバブルのin vivoでの機能性評価,
日本薬剤学会第33年会, 2018年5月. 関陽介, 植野美彦, 澤田麻衣子, 石田竜弘 :
分散評価システムの開発と導入ーー薬学部AO入試における書類審査での活用事例からーー,
平成30年度全国大学入学者選抜研究連絡協議会大会(第13回)研究会, 2018年5月. 長船裕輝, 池田真由美, 酒井真紀, 清水太郎, 異島優, 石田竜弘 :
生物由来健康食品に含まれる活性イオウ分子種の検出,
第71回日本酸化ストレス学会・第18回日本NO学会合同学術集会, 2018年5月. 池田真由美, 清水太郎, 丸山徹, 小田切優樹, 異島優, 石田竜弘 :
ポリスルフィド付加血清アルブミンによるメラニン産生の抑制,
第71回日本酸化ストレス学会・第18回日本NO学会合同学術集会, 2018年5月. 酒井真紀, 池田真由美, 今福匡司, 清水太郎, 丸山徹, 小田切優樹, 異島優, 石田竜弘 :
アルブミン製剤中のサルフェン硫黄含有量の差異と抗酸化能の評価,
第71回日本酸化ストレス学会・第18回日本NO学会合同学術集会, 2018年5月. 異島優, 木下遼, 池田真由美, 丸山徹, 小田切優樹, 石田竜弘 :
生理活性ガス運搬体としてのヒト血清アルブミン,
日本薬学会第138年会, 2018年3月. 田坂菜々美, 池田真由美, 清水太郎, 異島優, 石田竜弘 :
毛髪ケラチンに存在する活性イオウの発見と酸化ストレス応答,
日本薬学会第138年会, 2018年3月. 望月啓志, 安藤英紀, 藤田研司, 田島健次, 異島優, 石田竜弘 :
ナノファイバーバイオセルロースを用いた新規パクリタキセル製剤の開発,
日本薬学会第138年会, 2018年3月. 久保幸代, 清水太郎, 鵜川真実, 藤本麻葉, 松本陽子, 異島優, 石田竜弘 :
自然抗体としてのanti-PEG IgMがDoxilの血中濃度に与える影響,
日本薬学会第138年会, 2018年3月. 清水太郎, 久保幸代, 異島優, 石田竜弘 :
マクロファージによるPEG修飾体のin vitro取り込み量評価によるABC現象の発現予測に関する検討,
日本薬学会第138年会, 2018年3月. 橘茉里奈, 杉原涼, 藤見紀明, 西辻和親, 坂下直実, 辻田麻紀, 石田竜弘, 奥平桂一郎 :
ヒトアポA-I結合タンパク質AIBPの新規機能解明,
日本薬剤学会第32年会, 2018年3月. 楠本嵩志, 市野晨人, 西辻和親, 坂下直実, 堂前純子, 田中直伸, 柏田良樹, 石田竜弘, 奥平桂一郎 :
膜タンパク質ABCA7の発現を調節する化合物の探索,
日本薬学会第138年会, 2018年3月. 池田真由美, 異島優, 清水太郎, 居原秀, 赤池孝章, 丸山徹, 石田竜弘 :
ポリスルフィド運搬体としてのヒト血清アルブミン,
日本薬学会第138年会, 2018年3月. 石田竜弘 :
PEG修飾リポソームに対する免疫反応(ABC現象)の解明とワクチンへの応用,
日本薬学会北海道支部・特別講演会, 2018年1月. 竹瀬俊輔, 清水太郎, 石田竜弘 :
The combined effect of liposomal oxaliplatin with cancer vaccine on anticancer therapy,
第46回日本免疫学会学術集会, 2017年12月. 石田竜弘 :
難治性がん・希少がんを標的とした静注型がんワクチンの開発,
第5回TR推進合同フォーラム・ライフサイエンス技術交流会, 2017年11月. 松尾菜々, 池田真由美, 清水太郎, 異島優, 石田竜弘 :
新規抗がん剤としての活性イオウ付加アルブミンの設計,
第56回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2017年10月. 田坂菜々美, 池田真由美, 清水太郎, 異島優, 石田竜弘 :
毛髪中に存在する活性イオウの発見とその生理的意義,
第56回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2017年10月. 田神舞帆, 池田愛, 高山拓磨, 異島優, 清水太郎, 石田竜弘 :
抗PD-1抗体の併用はl-OHP liposomeによる抗腫瘍効果の個体差を減少させる,
第56回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2017年10月. 島崎優奈, 吉岡千尋, 粟田瑞月, 清水太郎, 石田竜弘 :
ペプチド抗原封入リポソーム投与による抗腫瘍免疫の誘導に関する検討,
第56回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2017年10月. 髙田春風, 久保幸代, 松岡里英, 清水太郎, 石田竜弘 :
pDNA搭載PEG修飾カチオニックリポソーム静脈内投与時の抗二本鎖DNA抗体分泌に関する検討,
第56回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2017年10月. 黄政龍, 大竹洋介, 住友亮太, 福井崇将, 石田竜弘 :
悪性胸膜中皮腫に対するTS shRNA-lipoplex(DFP10825)による核酸医療の開発,
第70回日本胸部外科学会定期学術集会, 2017年9月. 黄政龍, 大竹洋介, 住友亮太, 福井崇将, 石田竜弘 :
悪性胸膜中皮腫に対するTS shRNA-lipoplex(DFP10825)による核酸医療の開発(プレナリー),
第70回日本胸部外科学会定期学術集会, 2017年9月. 石田竜弘, 安藤英紀 :
新規RNAi薬剤体腔内投与による難治がん治療法の開発,
遺伝子・デリバリー研究会第17回夏期セミナー, 2017年9月. 松岡里英, 安藤英紀, 石田竜弘 :
腹腔内投与カチオン性リポソームの動態評価と胃がん腹膜播種治療における有用性に関する検討,
第26回DDSカンファランス, 2017年9月. 清水太郎, 久保幸代, 粟田瑞月, 北山由佳, 美馬優, 異島優, 石田竜弘 :
PEG特異的細胞測定法を用いた抗PEG免疫反応の評価,
第26回DDSカンファランス, 2017年9月. 石田竜弘 :
PEG修飾体に対するAccelerated blood clearance(ABC)現象,
第26回DDSカンファランス, 2017年9月. 清水太郎, 北山由佳, 異島優, 石田竜弘 :
siRNA搭載PEG修飾リポソームの静脈内投与後に腹腔から分泌されるanti-PEG IgM誘導機構の解明に関する検討,
第33回日本DDS学会学術集会, 2017年7月. 望月啓志, 安藤英紀, 藤田研司, 田島健次, 石田竜弘 :
胃がん腹膜播種治療におけるナノファイバーバイオセルロースの応用に関する検討,
第33回日本DDS学会学術集会, 2017年7月. 吉岡千尋, 粟田瑞月, 渡辺優希, 清水太郎, 石田竜弘 :
脾臓辺縁帯B細胞標的化能をもつポリマー修飾リポソームを用いた静注型ワクチン開発に関する検討,
第33回日本DDS学会学術集会, 2017年7月. 金沢有希, 鵜川真実, 石田竜弘 :
ドキソルビシン処置によるpDNAの発現の向上と核の形質変化に伴う核移行への影響,
第33回日本DDS学会学術集会, 2017年7月. 南川典昭, 田良島典子, 高橋知樹, 山本清義, 金城望, 安藤英紀, 石田竜弘, 小暮健太朗 :
化学修飾DNAを利用したRNA創薬,
第33回日本DDS学会学術集会, 2017年7月. 池田真由美, 異島優, 渡邊博志, 小田切優樹, 丸山徹, 石田竜弘 :
酸化ストレスに応答するポリスルフィド化血清タンパク質の同定,
第70回日本酸化ストレス学会学術集会, 2017年6月. 池田真由美, 異島優, 田坂菜々美, 清水太郎, 渡邊博志, 小田切優樹, 丸山徹, 石田竜弘 :
ヒト血清アルブミンに存在する活性イオウの検出とその機能解明,
第17回日本NO学会学術集会, 2017年5月. 清水太郎, 粟田瑞月, 吉岡千尋, 異島優, 石田竜弘 :
補体活性化能を持つポリマー修飾リポソームによる脾臓辺縁帯B細胞標的化に関する検討,
日本薬剤学会第32年会, 2017年5月. 田坂菜々美, 池田真由美, 清水太郎, 異島優, 石田竜弘 :
毛髪中における活性イオウの検出とその生物活性評価,
日本薬剤学会第32年会, 2017年5月. 川原遥華, 奥平桂一郎, 宮下直樹, 津田雄介, 森本恭平, 辻耕平, 重永章, 大髙章, 石田竜弘 :
光応答性アポリポタンパク質の開発,
日本薬剤学会第32年会, 2017年5月. 異島優, 池田真由美, 清水太郎, 渡邊博志, 小田切優樹, 丸山徹, 石田竜弘 :
活性酸素スカベンジャーとしての血清アルブミンパースルフィド,
日本薬剤学会第32年会, 2017年5月. 池田真由美, 異島優, 田坂菜々美, 清水太郎, 渡邊博志, 小田切優樹, 丸山徹, 石田竜弘 :
活性イオウトラフィックタンパク質としてのヒト血清アルブミンの役割,
日本薬剤学会第32年会, 2017年5月. Emam Emam Abdallah Sherif, 安藤英紀, 石田竜弘 :
A novel strategy to increase the yield of exosomes,
日本薬剤学会第32年会, 2017年5月. Elhewan Emam Elsadek Emam Ali Nehal, 清水太郎, 石田竜弘 :
Anti-PEG IgM-mediated accelerated blood clearance against PEG-G-CSF,
日本薬剤学会第32年会, 2017年5月. 藤本将太, 六車直樹, 宮本佳彦, 中尾允泰, 佐野茂樹, 安藤英紀, 石田竜弘, 高山哲治 :
KIT分子を標的としたGISTの分子イメージング,
第103回日本消化器病学会総会, 2017年4月. 望月啓志, 安藤英紀, 藤田研司, 田島健次, 石田竜弘 :
ナノファイバーバイオセルロースの腹腔内がん化学療法への応用に関する検討,
日本薬学会第137年会, 2017年3月. 米谷拓磨, 鵜川真実, 石井哲, 野原剛, 油谷輝, ANDERSON Nicholas, 石田竜弘 :
温度感受性リポソーム製剤(ThermoDox)の繰り返し投与による抗腫瘍効果の検討,
日本薬学会第137年会, 2017年3月. 石田竜弘, 福島正和, 江島清, 黄政龍, 和田洋巳 :
新規RNAi薬剤腹腔内投与による胃がん腹膜播種治療,
第89回日本胃癌学会総会, 2017年3月. 池田真由美, 異島優, 渡邊博志, 石田竜弘, 小田切優樹, 丸山徹 :
新規酸化ストレス早期発見に向けた血清パースルフィド定量の有用性評価,
第38回生体膜と薬物の相互作用シンポジウム, 2016年11月. 山﨑仁王, 異島優, 清水太郎, 石田竜弘 :
PEGリポソームへのアルブミン修飾は，抗PEG抗体の産生を抑制する,
第55回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2016年11月. 池田愛, 鵜川真実, 石田竜弘 :
l-OHP liposome とTAS-102併用による抗腫瘍効果の検討,
第55回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2016年11月. 松岡里英, 安藤英紀, 石田竜弘 :
胃がん腹膜播種治療における腹腔内投与カチオン性リポソームの有用性に関する検討,
第55回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2016年11月. 小林真也, 安藤英紀, Emam Emam Abdallah Sherif, 石田竜弘, 川添和義 :
Doxorubicin投与による血清中Exosome分泌変化に関する検討,
第55回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2016年11月. 中見祥一, 清水太郎, 中村教泰, 石田竜弘 :
PEG修飾有機シリカ粒子に対する免疫応答に関する検討,
第55回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2016年11月. 竹瀬俊輔, 高山拓磨, 西尾美穂, 清水太郎, 石田竜弘 :
抗がん剤封入リポソームとの併用によるがんワクチン効果の増強に関する検討,
第55回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2016年11月. 佐藤智恵美, 阿部真治, 岡田直人, 石田竜弘, 土屋浩一郎, 大髙章, 川添和義 :
地域薬局における災害対策の現状と課題,
第55回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2016年11月. 石田竜弘 :
DDSを基盤とするRNAi医薬の開発,
日本薬物動態学会第31回年会, 2016年10月. 松本陽子, 藤本麻葉, 清水太郎, 久保幸代, 曾根献文, 森繭代, 足立克之, 長阪一憲, 有本貴英, 織田克利, 川名敬, 石田竜弘, 藤井知行 :
ヒトにおける抗 PEG IgM 抗体の産生と PLD 投与への影響,
第75回日本癌学会学術総会, 2016年10月. 石田竜弘 :
Oxaliplatin (l-OHP)による末梢神経障害を緩和するDDS技術,
第26回日本医療薬学会年会, 2016年9月. 蔵田靖子, 清水太郎, 久保幸代, 石田竜弘, 田端雅弘, 二宮崇, 渡邊洋美, 中西将元, 槇本剛, 秦雄介, 狩野裕久, 西井和也, 木浦勝行, 北村佳久, 千堂年昭 :
血中抗PEG抗体がペグフィルグラスチムの有効性に与える影響に関する探索的検討,
第26回日本医療薬学会年会, 2016年9月. 山﨑仁王, 異島優, 清水太郎, 石田竜弘 :
PEGリポソーム頻回投与時の課題であるABC現象は，アルブミン修飾によって克服可能であるか?,
ナノライフサイエンス・オープンセミナー2016, 2016年9月. 松岡里英, 安藤英紀, 石田竜弘 :
新規胃がん腹膜播種治療開発のためのカチオン性リポソーム腹腔内投与の有用性探索,
ナノライフサイエンス・オープンセミナー2016, 2016年9月. 中見祥一, 清水太郎, 中村教泰, 石田竜弘 :
PEG修飾有機シリカ粒子に対するanti-PEG IgM応答に関する検討,
ナノライフサイエンス・オープンセミナー2016, 2016年9月. 柏木美咲, 西田健太朗, 柴俊輔, 室木究, 大石晃弘, 土井祐輔, 安藤英紀, 石田竜弘, 長澤一樹 :
オキサリプラチン封入PEG修飾リポソーム製剤投与ラットの後肢皮膚組織における白金蓄積及び手足症候群様症状の評価,
ナノライフサイエンス・オープンセミナー2016, 2016年9月. 竹瀬俊輔, 高山拓磨, 西尾美穂, 清水太郎, 石田竜弘 :
がんワクチンと抗がん剤封入リポソームの併用における投与計画の至適化に関する検討,
ナノライフサイエンス・オープンセミナー2016, 2016年9月. 池田愛, 鵜川真実, 石田竜弘 :
TAS-102とl-OHP liposomeの併用療法における投与計画の至適化に関する検討,
ナノライフサイエンス・オープンセミナー2016, 2016年9月. 清水太郎, 渡辺優希, 美馬優, 際田弘志, 石田竜弘 :
脾臓辺縁帯B細胞を標的としたリポソームワクチンの開発,
第25回DDSカンファランス, 2016年9月. 安藤英紀, 田中真生, 石田竜弘 :
大型放射光施設(SPring-8)における蛍光X線分析法を用いたオキサリプラチン腫瘍内分布の分析,
第25回DDSカンファランス, 2016年9月. 粟田瑞月, 吉岡千尋, 渡辺優希, 清水太郎, 石田竜弘 :
リポソーム修飾剤が脾臓辺縁帯B細胞結合能に与える影響,
第25回DDSカンファランス, 2016年9月. 川添和義, 阿部真治, 清水太郎, 石田竜弘, 大髙章 :
徳島大学発「インタラクティブYAKUGAKUJIN」の育成―新しい視点に立脚した教育の開発と実践―,
第1回日本薬学教育学大会, 2016年8月. 石田竜弘 :
Developent of RNAi-based anticancer drug: What is problem for clinical application and how establish a useful RNAi drug.,
第14回日本臨床腫瘍学会学術集会, 2016年7月. Tatsuhiro Ishida :
Developent of RNAi-based anticancer drug: What is problem for clinical application and how establish a useful RNAi drug,
第14回日本臨床腫瘍学会学術集会, Jul. 2016. 石田竜弘, 三輪泰司, 濱本英利 :
イオン液体の医用応用:Etoreat®の薬効評価,
第32回日本DDS学会学術集会, 2016年7月. 安藤英紀, Lila Selim Ahmed Ali Abu Amr, 加藤千尋, 福島正和, 黄政龍, 和田洋巳, 石田竜弘 :
核酸複合体(DFP-10825)の胸腔内直接投与を介した悪性胸膜中皮腫治療,
第32回日本DDS学会学術集会, 2016年7月. 清水太郎, 久保幸代, 藤本麻葉, 松本洋子, 川名敬, 石田竜弘 :
ヒトanti-PEG IgMがDoxilの体内動態に与える影響,
第32回日本DDS学会学術集会, 2016年7月. Emam Emam Abdallah Sherif, Hidenori ANDO, Lila Selim Ahmed Ali Abu Amr, M.A. Mahmoud, G.S. Fakhr-eldin and Tatsuhiro Ishida :
Interaction of cancer cells with liposomes; the extent of exsosome release,
第32回日本DDS学会学術集会, Jun. 2016. 粟田瑞月, 吉岡千尋, 渡辺優希, 清水太郎, 石田竜弘 :
脾臓辺縁帯B細胞標的化能をもつポリマー修飾リポソームの探索,
第32回日本DDS学会学術集会, 2016年6月. 北山由佳, 阿部遼, 清水太郎, 石田竜弘 :
siRNA搭載PEG修飾カチオニックリポソーム刺激によるPEG抗体産生に寄与する細胞群の検討,
第32回日本DDS学会学術集会, 2016年6月. 松岡里英, 安藤英紀, 前田典之, 石田竜弘 :
胃がん腹膜播種治療のためのDDSキャリア腹腔内投与後の動態検討,
第32回日本DDS学会学術集会, 2016年6月. 石田竜弘, 三輪泰司, 濱本英利 :
イオン液体の医用応用:Etoreat®の処方検討,
日本薬剤学会第31年会, 2016年5月. 清水太郎, 久保幸代, 石田竜弘 :
ヒトにおける抗PEG抗体保有率の調査,
日本薬剤学会第31年会, 2016年5月. 金城望, 安藤英紀, 田良島典子, 南川典昭, 石田竜弘 :
悪性胸膜中皮腫治療における新規shRNA発現化学修飾核酸の有用性の検討,
日本薬剤学会第31年会, 2016年5月. 安藤英紀, 小林早紀子, Lila Selim Ahmed Ali Abu Amr, 川添和義, 石田竜弘 :
ペメトレキセド封入カチオン性リポソームの胸腔内直接投与を介した悪性胸膜中皮腫治療,
日本薬剤学会第31年会, 2016年5月. 高山拓磨, 清水太郎, 鵜川真実, 石田竜弘 :
リポソーム化抗がん剤投与が引き起こす腫瘍免疫細胞の影響,
日本薬剤学会第31年会, 2016年5月. 金城望, 安藤英紀, 田良島典子, 南川典昭, 石田竜弘 :
Intelligent shRNA expression deviceのin vitro, in vivoにおける有用性評価,
日本薬学会第136年会, 2016年3月. 高山拓磨, 清水太郎, 鵜川真美, 石田竜弘 :
Doxil投与による腫瘍内免疫細胞の変動とこの変動による抗腫瘍効果への影響,
日本薬学会第136年会, 2016年3月. 本藤栄里, 美馬優, 清水太郎, 石田竜弘 :
ポリエチレングリコール修飾タンパク製剤Pegasysに対する抗PEG IgM応答,
日本薬学会第136年会, 2016年3月. 米谷拓磨, 鵜川真実, 石田竜弘 :
繰り返しhyperthermiaによる長期滞留性リポソームの腫瘍内集積性への影響,
ナノライフサイエンス・オープンセミナー2015, 2016年2月. 吉岡千尋, 粟田瑞月, 渡辺優希, 清水太郎, 石田竜弘 :
PEG修飾リポソームのPEG末端構造ががんワクチン効果に与える影響,
ナノライフサイエンス・オープンセミナー2015, 2016年2月. 望月啓志, 安藤英紀, 石田竜弘 :
Doxil®及びオキサリプラチン封入リポソームの腹腔内投与の有用性に関する検討,
ナノライフサイエンス・オープンセミナー2015, 2016年2月. 久保幸代, 本藤栄里, 阿部遼, 美馬優, 清水太郎, 石田竜弘 :
PEG化製剤に対するanti-PEG IgMの結合性と補体活性化能に関する検討,
ナノライフサイエンス・オープンセミナー2015, 2016年2月. 金沢有希, 高山拓磨, 鵜川真実, 石田竜弘 :
G2/M arrestを誘導するドキソルビシン処置による外来遺伝子発現向上の試み,
ナノライフサイエンス・オープンセミナー2015, 2016年2月. 藤川昂樹, 生駒照, 森戸克弥, 清蔭恵美, 徳田一徳, 清水太郎, 石田竜弘, 德村彰, 田中保 :
ヒト胃由来培養細胞におけるリゾホスファチジン酸誘導性小胞分泌現象の解析,
第88回日本生化学会大会, 2015年12月. 清水太郎, 渡辺優希, 美馬優, 際田弘志, 石田竜弘 :
脾臓辺縁帯B細胞を標的とした新規がんワクチンの開発,
第4回若手研究者シーズ発表会, 2015年11月. 石田竜弘, 河原昌美, 宮本祐司, 荻原琢男, 大槻純男, 宇都口直樹, 中田雄一郎, 岩本卓也 :
医療現場における抗がん薬製剤の現状と薬剤学的な課題-日本薬剤学会年会におけるラウンドテーブルセッションの実施を受けて-,
第25回日本医療薬学会, 2015年11月. 荻原琢男, 石田竜弘, 河原昌美, 宇都口直樹, 大槻純男, 宮本祐司, 中田雄一郎, 岩本卓也 :
医療現場における抗がん薬製剤の現状と薬剤学的な課題-日本薬剤学会とのジョイントシンポジウムでのアンケート結果の解析-,
第25回日本医療薬学会, 2015年11月. 金城望, 安藤英紀, 田良島典子, 南川典昭, 石田竜弘 :
Intelligent RNA expression devise(iRed)による標的遺伝子抑制に関する検討,
第37回生体膜と薬物の相互作用シンポジウム, 2015年11月. 本藤栄里, 美馬優, 清水太郎, 石田竜弘 :
PEG修飾タンパク製剤Pegasysに対する抗PEG免疫反応,
第37回生体膜と薬物の相互作用シンポジウム, 2015年11月. 田中真生, 高橋孝典, 寺田靖子, 八木直人, 石田竜弘 :
Oxaliplatin封入PEG修飾リポソームの繰り返し投与による腫瘍内微小環境の能動的制御,
第37回生体膜と薬物の相互作用シンポジウム, 2015年11月. 清水太郎, 高橋孝典, 石田竜弘 :
FTY720併用によるドキシルの細胞内取り込み向上に関する検討,
第37回生体膜と薬物の相互作用シンポジウム, 2015年11月. 望月啓志, 安藤英紀, 石田竜弘 :
抗がん剤徐放性製剤の腹腔内投与の有用性に関する検討,
第54回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2015年11月. 金沢有希, 高山拓磨, 鵜川真実, 石田竜弘 :
G2/M arrestを引き起こす抗がん剤であるドキソルビシン処置による外来遺伝子発現向上の試み,
第54回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2015年11月. 米谷拓磨, 鵜川真実, 石田竜弘 :
Hyperthermia時の腫瘍血管変化が与える長期滞留性リポソームの腫瘍内集積に関する検討,
第54回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2015年11月. 吉岡千尋, 粟田瑞月, 渡辺優希, 清水太郎, 石田竜弘 :
ヒドロキシ末端PEG修飾リポソームを用いた静注型ワクチン開発に関する基礎的検討,
第54回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2015年10月. 久保幸代, 本藤栄里, 阿部遼, 美馬優, 清水太郎, 石田竜弘 :
PEG化製剤に対するanti-PEG IgM結合特性に関する検討,
第54回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2015年10月. 渡辺優希, 清水太郎, 石田竜弘 :
PEG修飾リポソーム(PL)繰り返し投与時における脾臓内各種細胞による取り込みに関する検討,
第24回DDSカンファランス, 2015年9月. 本藤栄里, 美馬優, 清水太郎, 石田竜弘 :
ポリエチレングリコール修飾タンパク製剤Pegasys投与によるABC現象発現,
第24回DDSカンファランス, 2015年9月. 柏木美咲, 西田健太朗, 室木究, 柴俊輔, 池田理沙, 大石晃弘, 石田竜弘, 長澤一樹 :
PEGリポソーム製剤化オキサリプラチン投与ラットの後肢皮膚組織における手足症候群様症状の評価,
文部科学省私立大学戦略的研究基盤形成支援事業合同成果発表会, 2015年8月. 田中真生, 高橋孝典, 寺田靖子, 八木直人, 石田竜弘 :
Oxaliplatin封入PEG修飾リポソームの繰り返し投与による腫瘍内微小環境の能動的制御,
文部科学省私立大学戦略的研究基盤形成支援事業合同成果発表会, 2015年8月. 石田竜弘 :
PEG修飾製剤に対する免疫応答∼抗PEG-IgMの分泌誘導∼,
第5回薬剤学セミナー, 2015年7月. 渡邉奈美, 安藤英紀, 石田竜弘 :
胃がん腹膜播種モデルにおけるオキサリプラチン封入リポソーム静脈内投与による腫瘍増殖抑制効果,
第31回日本DDS学会学術集会, 2015年7月. 石田竜弘 :
大型放射光施設(SPring-8)における蛍光X線分析法を用いたオキサリプラチン封入PEG修飾リポソームの腫瘍内微小分布の検討,
第31回日本DDS学会学術集会, 2015年7月. 金城望, 安藤英紀, 田良島典子, 南川典昭, 石田竜弘 :
新規RNAi分子発現核酸デバイスのin vitro, in vivo有用性評価,
第31回日本DDS学会学術集会, 2015年7月. 田中保, 藤川昂樹, 森戸克弥, 清蔭恵美, 樋田一徳, 清水太郎, 石田竜弘, 德村彰 :
リゾホスファチジン酸が誘導する小胞分泌現象の解析,
第57回日本脂質生化学会, 2015年5月. 石田竜弘 :
日本医療薬学会とのジョイントシンポジウムでのアンケート結果報告,
日本薬剤学会第30年会, 2015年5月. 渡辺優希, 清水太郎, 石田竜弘 :
静脈内投与PEG修飾リポソームの濾胞への輸送に関与する脾臓細胞の検討,
日本薬剤学会第30年会, 2015年5月. 本藤栄里, 美馬優, 際田弘志, 石田竜弘 :
PEG修飾タンパク質Pegasys®投与によるABC現象誘導,
日本薬剤学会第30年会, 2015年5月. 田中真生, 蓮井太一, 高橋孝典, 寺田靖子, 八木直人, 石田竜弘 :
蛍光X線分析を用いたリポソーム化Oxaliplatinの腫瘍内分布の評価,
日本薬剤学会第30年会, 2015年5月. 高橋孝典, 石田竜弘 :
Doxil®を投与することによる抗がん剤耐性化についての検討,
日本薬剤学会第30年会, 2015年5月. 加藤千尋, Lila Selim Ahmed Ali Abu Amr, 安藤英紀, 石田竜弘 :
悪性胸膜中皮腫治療に向けたリポプレックスの胸腔内投与とその動態,
日本薬剤学会第30年会, 2015年5月. 阿部遼, 清水太郎, 石田竜弘 :
IV 投与PEGリポソームに対するanti-PEG IgM応答への腹腔内免疫細胞の関与,
日本薬剤学会第30年会, 2015年5月. 渡邉奈美, 安藤英紀, 石田竜弘 :
胃がん腹膜播種動物モデルにおけるオキサリプラチン封入リポソームの治療効果に関する検討,
日本膜学会第37年会, 2015年5月. 金城望, 安藤英紀, 田良島典子, 南川典昭, 石田竜弘 :
新規RNAi分子発現核酸デバイスを用いた標的遺伝子発現抑制効果,
日本膜学会第37年会, 2015年5月. 藤川昂樹, 森戸克弥, 生駒照, 清蔭恵美, 樋田一徳, 清水太郎, 石田竜弘, 德村彰, 田中保 :
ヒト胃由来培養細胞におけるリゾホスファチジン酸誘導性小胞分泌現象の解析,
日本膜学会第37年会, 2015年5月. 金城望, 安藤英紀, 田良島典子, 南川典昭, 石田竜弘 :
胸腔内がん治療を目指した新規核酸デバイスの有用性評価,
遺伝子・デリバリー研究会第15回シンポジウム, 2015年5月. 高橋孝典, 西尾美穂, 清水太郎, 石田竜弘 :
Doxil®投与によるがんのDoxil®耐性化,
日本薬学会第135年会, 2015年3月. 清水太郎, 西尾美穂, 橋本洋佑, 中瀬博, 際田弘志, 石田竜弘 :
オキサリプラチン封入リポソームの頻回投与が腫瘍免疫系に与える影響,
日本薬学会第135年会, 2015年3月. 本藤栄里, 美馬優, 橋本洋佑, 際田弘志, 石田竜弘 :
PEG修飾タンパク製剤Pegasysに対するABC現象誘導に関する検討,
日本薬学会第135年会, 2015年3月. 田良島典子, 小島孝光, 金城望, 古川和寛, 安藤英紀, 石田竜弘, 南川典昭 :
New strategy for suppression of gene expresstion using intelligent RNA expressing device (iRed),
日本化学会第95春季年会, 2015年3月. 石田竜弘 :
がん組織の3次元的空間制御に基づく核酸ドラッグデリバリーシステムの開発と課題,
第6回東北大学学際科学フロンティア研究所セミナー,第448回東北大学大学院薬学研究科セミナー, 2015年2月. 石田竜弘 :
腫瘍内微小環境の能動的制御に基づく新規DDSの開発,
仙台``プラズマフォーラム'', 2015年2月. 田良島典子, 小島孝光, 金城望, 古川和寛, 安藤英紀, 石田竜弘, 南川典昭 :
Intelligent RNA expressing device (iRed)を利用した核酸創薬の新手法,
第32回メディシナルケミストリーシンポジウム, 2014年11月. 清水太郎, 渡辺優希, 美馬優, 石田竜弘, 際田弘志 :
PEG修飾リポソームに対する免疫反応を利用した静脈内投与型がんワクチンの開発に関する研究,
第36回生体膜と薬物の相互作用シンポジウム, 2014年11月. 加藤千尋, Lila Selim Ahmed Ali Abu Amr, 安藤英紀, 石田竜弘, 際田弘志 :
悪性胸膜中皮腫治療のための核酸搭載カチオニックリポソームの胸腔内投与とその動態評価,
第36回生体膜と薬物の相互作用シンポジウム, 2014年11月. 美馬優, 清水太郎, 際田弘志, 石田竜弘 :
PEG修飾リポソーム膜へのガングリオシド添加による抗PEG免疫応答の抑制効果,
第36回生体膜と薬物の相互作用シンポジウム, 2014年11月. 渡邉奈美, 安藤英紀, 石田竜弘 :
胃がん腹膜播種に対するナノキャリアを用いた新規投与経路の検討,
第53回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2014年11月. 北山由佳, 美馬優, 川西宗平, 清水太郎, 石田竜弘 :
siRNA搭載PEG修飾カチオニックリポソーム静脈内投与時の抗体産生に寄与する細胞群に関する検討,
第53回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2014年11月. 金城望, 安藤英紀, 田良島典子, 南川典昭, 石田竜弘 :
Intelligent RNA expressing devise(iRed)の細胞内導入による標的遺伝子抑制,
第53回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2014年11月. 髙山拓磨, 清水太郎, 西尾美穂, 石田竜弘 :
Doxil®の抗腫瘍効果における免疫細胞の関与に関する検討,
第53回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2014年11月. 粟田瑞月, 美馬優, 川西宗平, 清水太郎, 石田竜弘 :
PEG修飾リポソームのPEG修飾剤末端構造の違いが免疫活性化に与える影響に関する検討,
第53回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2014年11月. 田良島典子, 齋藤陽太, 橋本洋佑, 古川和寛, 石田竜弘, 南川典昭 :
ハイブリッド型化学修飾核酸2´-O-MOE-4´-thioRNAの合成とアンチmiRNAとしてのin vitro/vivo機能評価,
アンチセンス・遺伝子・デリバリーシンポジウム2014, 2014年9月. 川西宗平, 橋本洋佑, 清水太郎, 際田弘志, 石田竜弘 :
Shotgun分析を用いたPEG修飾リポソーム結合タンパク質の網羅的解析,
第23回DDSカンファランス, 2014年9月. 阿部遼, 清水太郎, 石田竜弘, 際田弘志 :
PEG修飾リポソームの投与経路の違いがanti-PEG IgM分泌に及ぼす影響に関する検討(第2報),
第23回DDSカンファランス, 2014年9月. 渡邉奈美, 安藤英紀, 石田竜弘 :
腹水を伴う腹膜播種における新規静注型治療法の確立,
ナノライフサイエンス・オープンセミナー2014, 2014年8月. 髙山拓磨, 清水太郎, 西尾美穂, 石田竜弘 :
Doxil®投与による免疫細胞の変化に関する検討,
ナノライフサイエンス・オープンセミナー2014, 2014年8月. 金城望, 安藤英紀, 田良島典子, 南川典昭, 石田竜弘 :
Intelligent RNA expressing devise(iRed)のin vitroにおける標的遺伝子抑制に関する検討,
ナノライフサイエンス・オープンセミナー2014, 2014年8月. 粟田瑞月, 藤田理紗子, 美馬優, 川西宗平, 清水太郎, 石田竜弘 :
PEG修飾剤末端構造が免疫活性化に与える影響に関する検討,
ナノライフサイエンス・オープンセミナー2014, 2014年8月. 北山由佳, 美馬優, 川西宗平, 清水太郎, 石田竜弘 :
siRNA搭載PEG修飾リポプレックス静脈内投与による抗体産生への脾臓とその他の細胞群の関与に関する検討,
ナノライフサイエンス・オープンセミナー2014, 2014年8月. 加藤千尋, 石田竜弘, 際田弘志 :
In vivo imaging systemによる胸腔内投与リポプレックスの動態評価,
第30回日本DDS学会学術集会, 2014年7月. 清水太郎, 高橋孝典, 石田竜弘, 際田弘志 :
マウス肺癌細胞に対するFTY720とドキシルとの併用効果に関する検討,
第30回日本DDS学会学術集会, 2014年7月. 石田竜弘 :
腫瘍内微小環境の能動的制御に基づく新規DDSの開発,
第32回物性物理化学研究会, 2014年6月. 清水太郎, 渡辺優希, 美馬優, 石田竜弘, 際田弘志 :
脾臓辺縁帯B細胞による抗原封入PEG修飾リポソームの濾胞への輸送現象を利用した抗腫瘍免疫誘導効果,
日本薬剤学会第29年会, 2014年5月. 藤原由佳子, 中村浩之, 石田竜弘, 際田弘志 :
転移性肝臓がんの存在がオキサリプラチン封入PEG修飾リポソームの肝移行性へ与える影響,
日本薬学会第134年会, 2014年3月. 小林早紀子, Lila Selim Ahmed Ali Abu Amr, 石田竜弘, 際田弘志 :
リポソームからのPemetrexedの放出性が胸腔内移植腫瘍の増殖に与える影響,
日本薬学会第134年会, 2014年3月. 美馬優, 橋本洋佑, 清水太郎, 石田竜弘, 際田弘志 :
Ganglioside添加がPEG修飾リポソームに対する抗PEG IgM分泌に与える影響,
日本薬学会第134年会, 2014年3月. 清水太郎, 渡辺優希, 美馬優, 橋本洋佑, 石田竜弘, 際田弘志 :
PEG修飾リポソームを用いた脾臓濾胞への抗原送達が抗腫瘍免疫誘導に与える影響,
日本薬学会第134年会, 2014年3月. 石田竜弘 :
ナノテクノロジーを用いた薬物動態制御の可視化,
高分子学会九州支部・九州有機材料研究グループ研究会, 2014年3月. 橋本洋佑, 石田竜弘, 際田弘志 :
siRNA搭載PEG修飾リポプレックス投与時に誘導される抗PEG IgM分泌はB細胞に発現するTLR7の活性化により亢進される,
第23回アンチセンスシンポジウム, 2013年11月. 加藤千尋, Lila Selim Ahmed Ali Abu Amr, 石田竜弘, 際田弘志 :
脂質組成の異なるリポソーム胸腔内投与後の体内動態,
第23回アンチセンスシンポジウム, 2013年11月. 橋本洋佑, 石田竜弘, 際田弘志 :
siRNA搭載PEG修飾リポプレックス投与時に誘起される抗PEG IgM分泌亢進機構の解明,
第35回生体膜と薬物の相互作用シンポジウム, 2013年11月. 渡辺優希, 清水太郎, 石田竜弘, 際田弘志 :
PEG修飾リポソーム前刺激が二回目投与PEG修飾リポソームの脾臓内分布を変化させる,
第52回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2013年10月. 本藤栄里, 美馬優, 橋本洋佑, 石田竜弘, 際田弘志 :
PEGASYS投与により誘導されるanti-PEG IgMのPEG修飾タンパクに対する反応性,
第52回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2013年10月. 加藤千尋, Lila Selim Ahmed Ali Abu Amr, 石田竜弘, 際田弘志 :
In vivo imaging systemを用いたリポソーム胸腔内投与後の体内動態の評価,
第52回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2013年10月. 蓮井太一, 西尾美穂, 石田竜弘, 際田弘志 :
Oxaliplatin封入PEG修飾リポソーム製剤治療時の腫瘍内遺伝子発現変化の網羅的検討,
第52回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2013年10月. 石田竜弘 :
腫瘍内微小環境の能動的制御に基づくDDSの開発,
生体内の微小環境情報に基づいた物性制御による環境応答型インテリジェントナノDDSの創成キックオフシンポジウム, 2013年10月. 森博世, 木内奈央, 川合暢彦, 内田玲子, 川上恵実, 石田竜弘, 田中栄二 :
カチオン性リポソームを用いたRNA干渉法による骨格筋量制御効果の検討,
第72回日本矯正歯科学会大会プログラム・抄録集, 2013年10月. 石田竜弘 :
PEG修飾リポソームを用いたDDS開発の現状と課題,
ナノ製剤技術研究会, 2013年10月. 石田竜弘, 際田弘志 :
がん治療を指向したDDSの研究開発,
第23回日本医療薬学会年会, 2013年9月. 西尾美穂, 中村浩之, 石田竜弘, 際田弘志 :
腫瘍内血管系の動的変化がPEG修飾リポソームの腫瘍内分布に及ぼす影響,
第22回DDSカンファランス, 2013年9月. 藤田理紗子, 橋本洋佑, 清水太郎, 石田竜弘, 際田弘志 :
PEG修飾剤末端構造が与えるABC現象誘導への影響に関する検討,
第22回DDSカンファランス, 2013年9月. 美馬優, 橋本洋佑, 清水太郎, 石田竜弘, 際田弘志 :
高用量PEG修飾リポソームによる抗PEG IgMの分泌抑制に関する検討,
第22回DDSカンファランス, 2013年9月. 渡辺優希, 清水太郎, 石田竜弘, 際田弘志 :
PEG修飾リポソーム(SL)前刺激により変化する二回目PEG修飾リポソーム(SL)の脾臓内分布の検討,
ナノライフサイエンス・オープンセミナー2013, 2013年9月. 本藤栄里, 美馬優, 橋本洋佑, 石田竜弘, 際田弘志 :
PEG修飾タンパク投与時に分泌されるanti-PEG IgMによるABC現象の誘導,
ナノライフサイエンス・オープンセミナー2013, 2013年9月. 加藤千尋, Lila Selim Ahmed Ali Abu Amr, 石田竜弘, 際田弘志 :
脂質組成の違いが与える胸腔内投与後のリポソームの体内動態への影響,
ナノライフサイエンス・オープンセミナー2013, 2013年9月. 蓮井太一, 西尾美穂, 石田竜弘, 際田弘志 :
マイクロアレイ解析によるOxaliplatin封入PEG修飾リポソーム製剤治療後の腫瘍内遺伝子発現変化の検討,
ナノライフサイエンス・オープンセミナー2013, 2013年8月. 髙橋孝典, 中村浩之, 西尾美穂, 石田竜弘, 際田弘志 :
Oxaliplatin封入PEG修飾リポソーム頻回投与による抗腫瘍効果の検討,
ナノライフサイエンス・オープンセミナー2013, 2013年8月. 美馬優, 橋本洋佑, 清水太郎, 石田竜弘, 際田弘志 :
高用量PEG修飾リポソームを用いたABC現象の回避,
第29回日本DDS学会学術集会, 2013年7月. 加藤千尋, Lila Selim Ahmed Ali Abu Amr, 石田竜弘, 際田弘志 :
胸腔内投与後のリポソームの動態に関する研究,
第29回日本DDS学会学術集会, 2013年7月. 石田竜弘, 際田弘志 :
抗がん剤による腫瘍内微小環境変化を利用した新規DDSの開発,
第29回日本DDS学会学術集会, 2013年7月. 石田竜弘 :
研究における偶然性と必然性∼DDS研究を通して∼,
第1回次世代創薬研究者養成塾, 2013年6月. 橋本洋佑, 清水太郎, 石田竜弘, 際田弘志 :
siRNA搭載PEG修飾リポプレックス投与時に惹起される抗PEG IgM分泌応答機構の解明,
日本薬剤学会第28年会, 2013年5月. 清水太郎, 渡辺優希, 美馬優, 橋本洋佑, 石田竜弘, 際田弘志 :
脾臓辺縁体B細胞によるPEG修飾リポソームの濾胞への輸送現象を利用した特異的抗体誘導効果,
日本薬剤学会第28年会, 2013年5月. 清水太郎, 石田竜弘, 際田弘志 :
PEG修飾リポソームを用いた濾胞への抗原送達による抗体誘導効果,
第133年会日本薬学会, 2013年3月. 美馬優, 橋本洋佑, 清水太郎, 石田竜弘, 際田弘志 :
PEG修飾タンパクによるABC現象誘導に関する研究,
第133年会日本薬学会, 2013年3月. 石田竜弘 :
腫瘍内微小環境の能動的制御に基づく腫瘍選択的デリバリーシステムの開発,
日本薬学会第133年会, 2013年3月. 井本亜美, 清水太郎, 石田竜弘, 際田弘志 :
ABC現象を引き起こす抗PEG IgM分泌細胞の特定,
第133年会日本薬学会, 2013年3月. 藤田理紗子, 橋本洋佑, 清水太郎, 石田竜弘, 際田弘志 :
ABC現象誘導へのPEG修飾剤末端構造の影響に関する検討,
第133年会日本薬学会, 2013年3月. 盛山裕太, 美馬優, 清水太郎, 石田竜弘, 際田弘志 :
GangliosideのPEG修飾リポソーム膜への挿入がPEGに対する免疫応答に及ぼす影響,
第133年会日本薬学会, 2013年3月. 西尾美穂, 中村浩之, 石田竜弘, 際田弘志 :
PEG修飾リポソームの腫瘍内移行に血管系の経時的変化が与える影響,
第133年会日本薬学会, 2013年3月. 中村浩之, 土井祐輔, 石田竜弘, 際田弘志 :
S-1とoxaliplatin封入PEG修飾リポソーム併用療法における腫瘍内血管系の変化,
第133年会日本薬学会, 2013年3月. 長尾愛, 土井祐輔, 石田竜弘, 際田弘志 :
ABC現象がoxaliplatin封入PEG修飾リポソームとS-1併用療法に及ぼす影響に関する研究,
第133年会日本薬学会, 2013年3月. 新井真以, 橋本洋佑, 斎藤陽太, 古川和寛, 石田竜弘, 際田弘志, 南川典昭 :
新規ハイブリッド型修飾核酸の合成とアンチmiRNA活性の評価,
第133年会日本薬学会, 2013年3月. 吉良太孝, 山下ありさ, 山中直哉, 古川和寛, 山﨑哲男, 石田竜弘, 際田弘志, 南川典昭 :
ケミカルツールを用いたsiRNA-タンパク質間の相互作用様式解明,
第133年会日本薬学会, 2013年3月. 石田竜弘 :
腫瘍内微小環境の能動的制御による新規DDSの開発と治療への応用,
創剤フォーラム第18回若手研究会, 2012年11月. 清水太郎, 橋本洋佑, 石田竜弘, 際田弘志 :
PEG修飾リポソームの濾胞への輸送現象を利用した免疫誘導に関する検討,
創剤フォーラム第18回若手研究会, 2012年11月. 森吉直人, 石田竜弘, 際田弘志 :
Tegafur製剤S-1とTS標的shRNA含有lipoplexの併用療法による抗腫瘍効果の検討,
創剤フォーラム第18回若手研究会, 2012年11月. 北川瑞野, 石田竜弘, 際田弘志 :
細胞内導入後のsiRNA量の経時変化測定におけるreal time PCRの利用に関する検討,
創剤フォーラム第18回若手研究会, 2012年11月. 美馬優, 橋本洋佑, 清水太郎, 石田竜弘, 際田弘志 :
血中anti-PEG IgMがPEG修飾タンパクのクリアランスに与える影響,
創剤フォーラム第18回若手研究会, 2012年11月. 井本亜美, 清水太郎, 石田竜弘, 際田弘志 :
抗PEG-IgMを分泌する脾臓B細胞に関する検討,
創剤フォーラム第18回若手研究会, 2012年11月. Lila Selim Ahmed Ali Abu Amr, Tatsuhiro Ishida and Hiroshi Kiwada :
Gene knockdown of thymidylate synthase via RNA interference modulates the antitumor efficacy of pemetrexed in malignant mesothelioma xenograft model,
創剤フォーラム第18回若手研究会, Nov. 2012. E Alaaeldin, Lila Selim Ahmed Ali Abu Amr, Hiroyuki Nakamura, Tatsuhiro Ishida and Hiroshi Kiwada :
Effect of oxaliplatin on anti-PEG IgM and cytokine induced by IV injection of siRNA/PEG-cationic liposome complex.,
創剤フォーラム第18回若手研究会, Nov. 2012. 藤田理紗子, 清水太郎, 石田竜弘, 際田弘志 :
PEG修飾剤末端構造が与えるanti-PEG IgM分泌誘導への影響に関する検討,
創剤フォーラム第18回若手研究会, 2012年11月. 橋本洋佑, 藤田理紗子, 西尾美穂, 清水太郎, 石田竜弘, 際田弘志 :
血中anti-PEG IgM濃度とABC現象発現強度の定量的関係の評価,
創剤フォーラム第18回若手研究会, 2012年11月. 盛山裕太, 美馬優, 清水太郎, 石田竜弘, 際田弘志 :
GangliosideのPEG修飾リポソーム膜への挿入はABC現象を抑制する,
創剤フォーラム第18回若手研究会, 2012年11月. 長尾愛, 石田竜弘, 際田弘志 :
Oxaliplatin封入PEG修飾リポソームとS-1併用療法下におけるaccelerated blood clearance (ABC) 現象に関する検討,
創剤フォーラム第18回若手研究会, 2012年11月. 西尾美穂, 中村浩之, 石田竜弘, 際田弘志 :
血管系の変化がPEG修飾リポソームの腫瘍内移行に及ぼす影響,
創剤フォーラム第18回若手研究会, 2012年11月. 中村浩之, 土井祐輔, 石田竜弘, 際田弘志 :
S-1とoxaliplatin封入SL併用療法におけるSLの体内動態および腫瘍内環境の変化の評価,
創剤フォーラム第18回若手研究会, 2012年11月. 盛山裕太, 美馬優, 清水太郎, 石田竜弘, 際田弘志 :
ガングリオシドのPEG 修飾リポソーム膜への挿入はPEG に対する自然免疫活性化を抑制する,
第51回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2012年11月. 藤原由佳子, 石田竜弘, 際田弘志 :
オキサリプラチン封入ポリエチレングリコール修飾リポソームの転移性肝がんモデルマウスにおける抗腫瘍効果の検討,
第51回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2012年11月. 長尾愛, 石田竜弘, 際田弘志 :
腫瘍皮下移植モデルマウスにおけるS-1 とoxaliplatin 封入PEG 修飾リポソーム併用療法がABC 現象に与える影響の検討,
第51回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2012年11月. 美馬優, 橋本洋佑, 清水太郎, 石田竜弘, 際田弘志 :
血中anti-PEG IgM によるPEG 修飾タンパクのクリアランスに関する検討,
第51回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2012年11月. 川西宗平, 清水太郎, 橋本洋佑, 石田竜弘, 際田弘志 :
ショットガン分析によるPEG 修飾リポソームに結合するタンパクの解析,
第51回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2012年11月. 阿部遼, 清水太郎, 石田竜弘, 際田弘志 :
PEG修飾リポソームの投与経路の違いがanti-PEG IgM分泌に及ぼす影響に関する検討,
第51回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2012年11月. 吉良太孝, 山﨑尚志, 石田竜弘, 際田弘志, 南川典昭 :
ケミカルツールを利用したRNA干渉の発現機構解明,
アンチセンス,遺伝子,デリバリーシンポジウム2012, 2012年9月. 小島孝允, 橋本洋佑, 石田竜弘, 際田弘志, 南川典昭 :
4'-チオDNAを利用した新規RNAi法の開発,
バイオ関連化学シンポジウム, 2012年9月. 坪井香保里, 原田広毅, 横田康介, 松尾剛明, 西田健太朗, 石田竜弘, 長澤一樹 :
リポソーム製剤化oxaliplatinの末梢神経毒性の評価,
ナノライフサイエンス・オープンセミナー2012, 2012年8月. 阿部遼, 清水太郎, 美馬優, 石田竜弘, 際田弘志 :
PEG修飾リポソームの投与経路の違いが及ぼすanti-PEG IgM分泌への影響,
ナノライフサイエンス・オープンセミナー2012, 2012年8月. 川西宗平, 清水太郎, 橋本洋佑, 石田竜弘, 際田弘志 :
ショットガン分析を用いたPEG修飾リポソームに結合する血漿タンパクの解析,
ナノライフサイエンス・オープンセミナー2012, 2012年8月. 小林早紀子, 西尾美穂, 中村浩之, 石田竜弘, 際田弘志 :
Pemetrexed封入PEG修飾リポソームの調整と抗腫瘍効果の検討,
ナノライフサイエンス・オープンセミナー2012, 2012年8月. 藤原由佳子, 土井祐輔, 石田竜弘, 際田弘志 :
肝転移がんモデルマウスにおけるオキサリプラチン封入ポリエチレングリコール修飾リポソームの体内動態および抗腫瘍効果に関する検討,
ナノライフサイエンス・オープンセミナー2012, 2012年8月. 美馬優, 橋本洋佑, 清水太郎, 市原理子, 石田竜弘, 際田弘志 :
血中anti-PEGIgMがPEG修飾タンパクのクリアランスに与える影響に関する検討,
ナノライフサイエンス・オープンセミナー2012, 2012年8月. 美馬優, 橋本洋佑, 清水太郎, 市原理子, 石田竜弘, 際田弘志 :
遊離型PEG静脈内投与による抗PEGIgM応答に関する研究,
第28回日本DDS学会学術集会, 2012年7月. 長尾愛, 市原理子, 土井祐輔, 石田竜弘, 際田弘志 :
S-1とl-OHP封入PEG修飾リポソーム併用療法がaccelerated blood clearance(ABC)現象に与える影響の検討,
第28回日本DDS学会学術集会, 2012年7月. 鈴木卓也, 兵頭健治, 山本栄一, 市原理子, 石田竜弘, 際田弘志, 石原比呂之, 菊池寛 :
抗がん剤封入PEG修飾リポソームにおけるABC現象(第6報):イヌにおける薬物・脂質投与量とABC現象の関係,
第28回日本DDS学会学術集会, 2012年7月. 北川瑞野, 石田竜弘, 際田弘志 :
細胞内導入後のsiRNA量の経時的変化に関する検討,
第28回日本DDS学会学術集会, 2012年7月. 井本亜美, 市原理子, 清水太郎, 石田竜弘, 際田弘志 :
養子細胞移入法を用いた抗PEG-IgM分泌細胞に関する検討,
第28回日本DDS学会学術集会, 2012年7月. 清水太郎, 井本亜美, 市原理子, 石田竜弘, 際田弘志 :
脾臓辺縁帯B細胞によるPEG修飾リポソームの輸送機構に関する検討,
第28回日本DDS学会学術集会, 2012年7月. 市原理子, 清水太郎, 井本亜美, 石田竜弘, 際田弘志 :
PEG修飾リポソーム投与により誘導される抗PEG IgM分泌細胞は脾臓辺縁帯B細胞である,
第28回日本DDS学会学術集会, 2012年7月. 鈴木卓也, 兵頭健治, 山本栄一, 市原理子, 石田竜弘, 際田弘志, 石原比呂之, 菊池寛 :
抗がん剤封入PEG修飾リポソームにおけるABC現象(第5報):動物種差,
日本薬剤学会第27年会, 2012年5月. 市原理子, 清水太郎, 井本亜美, 石田竜弘, 際田弘志 :
脾臓辺縁帯B細胞がABC現象における抗PEG IgM分泌細胞である,
日本薬剤学会第27年会, 2012年5月. 橋本洋佑, 清水太郎, 石田竜弘, 際田弘志 :
PEG修飾リポソームの体内動態変動因子anti-PEG IgMの定量評価系の構築,
日本薬剤学会第27年会, 2012年5月. 清水太郎, 石田竜弘, 際田弘志 :
脾臓辺縁帯B細胞によるPEG修飾リポソーム輸送現象を利用した免疫誘導の試み,
日本薬剤学会第27年会, 2012年5月. 吉良太孝, 森吉直人, 石田竜弘, 際田弘志, 南川典昭 :
ケミカルツールを用いたRNA干渉発現の分子認識機構の解明,
日本薬学会第132年会, 2012年3月. 岡田知子, 土井祐輔, Lila Selim Ahmed Ali Abu Amr, 石田竜弘, 際田弘志 :
フッ化ピリミジン系経口抗癌剤S-1がPEG修飾カチオニックリポソームの腫瘍移行性に与える影響,
日本薬学会第132年会, 2012年3月. 中村浩之, 土井祐輔, 石田竜弘, 際田弘志 :
S-1とオキサリプラチン封入PEG修飾リポソームの併用療法におけるリポソームの体内動態の変化に関する検討,
日本薬学会第132年会, 2012年3月. 石田竜弘, 際田弘志 :
腫瘍内微小環境の能動的制御に基づくsiRNAデリバリー技術の開発とがん治療への展開,
日本薬学会第132年会, 2012年3月. 小島孝允, 森吉直人, 山﨑尚志, 石田竜弘, 際田弘志, 南川典昭 :
4'-チオDNAを利用した遺伝子発現抑制法の開発,
日本薬学会第132年会, 2012年3月. 清水太郎, 石田竜弘, 際田弘志 :
PEG修飾リポソームと脾臓辺縁帯B 細胞との相互作用に関する検討,
日本薬学会第132年会, 2012年3月. 鈴木卓也, 兵頭健治, 山本栄一, 市原理子, 石田竜弘, 際田弘志, 石原比呂之, 菊池寛 :
抗がん剤封入PEG修飾リポソームにおけるaccelerated blood clearance(ABC)現象:種差の検討,
膜シンポジウム2011, 2011年11月. 橋本洋佑, 市原理子, 石田竜弘, 際田弘志 :
ABC現象の主要因子であるanti-PEG IgMの定量評価系の確立,
第50回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2011年11月. 藤田理紗子, 市原理子, 石田竜弘, 際田弘志 :
Anti-PEG IgM分泌誘導においてPEG修飾剤末端構造が与える影響に関する検討,
第50回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2011年11月. 西尾美穂, 中村浩之, 松本春菜, 石田竜弘, 際田弘志 :
投与間隔がPEG修飾リポソームの腫瘍内分布に及ぼす影響∼がん種による違いに関する検討∼,
第50回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2011年11月. 吉良太孝, 井手志穂, 新井真衣, 森吉直人, 石田竜弘, 際田弘志, 松田彰, 南川典昭 :
RNA干渉機構解明のためのケミカルツールの合成とその応用,
日本薬学会中国四国支部学術大会, 2011年11月. 岡田知子, 土井祐輔, Lila Selim Ahmed Ali Abu Amr, 石田竜弘, 際田弘志 :
フッ化ピリミジン系経口抗癌剤がPEG修飾カチオニックリポソームの腫瘍移行性に与える影響,
第20回DDSカンファランス, 2011年9月. 松本春菜, 土井祐輔, 中村浩之, 西尾美穂, 石田竜弘, 原田雅史, 際田弘志 :
PEG修飾リポソームの腫瘍内分布領域可視化の試み,
第20回DDSカンファランス, 2011年9月. 森吉直人, 中村和也, 松永真理子, 石田竜弘, 際田弘志 :
Tegaful製剤S-1とsiRNA含有liposomeの併用による新規がん治療法の開発,
アンチセンス・遺伝子・デリバリーシンポジウム2011, 2011年9月. 橋本洋佑, 上原友美, 石田竜弘, 際田弘志 :
siRNAリポプレックス投与時のTLR刺激が及ぼすanti-PEGIgM分泌誘導への影響,
アンチセンス・遺伝子・デリバリーシンポジウム2011, 2011年9月. 石田竜弘 :
PEG修飾ナノキャリア投与時に惹起される免疫応答∼抗PEG-IgM分泌誘導とナノキャリアの体内動態への影響∼,
広島臓器移植セミナー, 2011年8月. 石田竜弘 :
腫瘍内微小環境変化を利用した核酸デリバリー戦略,
遺伝子・デリバリー研究会第11回夏期セミナー, 2011年8月. 鈴木卓也, 兵頭健治, 山本栄一, 市原理子, 石田竜弘, 際田弘志, 石原比呂之, 菊池寛 :
抗がん剤封入PEG 修飾リポソームにおけるABC 現象(第3報):イヌ，サルの検討,
第27回日本DDS学会学術集会, 2011年6月. 市原理子, 井本亜美, 橋口優紀, 藤田理紗子, 石田竜弘, 際田弘志 :
PEG修飾リポソーム投与マウス脾臓中の抗PEG IgM分泌担当細胞の探索,
第27回日本DDS学会学術集会, 2011年6月. 兵頭健治, 鈴木卓也, 山本栄一, 市原理子, 石田竜弘, 際田弘志, 石原比呂之, 菊池寛 :
抗がん剤封入PEG修飾リポソームにおけるABC現象(第4報):種差の検討,
第27回日本DDS学会学術集会, 2011年6月. 橋本洋佑, 森吉直人, 上原友美, 田上辰秋, 石田竜弘, 際田弘志 :
siRNA含有PEG修飾ナノキャリアによるanti-PEG IgM 誘導におけるトール様受容体(TLR)の関与,
第27回日本DDS学会学術集会, 2011年6月. 鈴木卓也, 兵頭健治, 山本栄一, 市原理子, 石田竜弘, 際田弘志, 石原比呂之, 菊池寛 :
抗がん剤封入PEG修飾リポソームにおけるABC現象(第2報):サルにおける検討,
日本薬剤学会第26年会, 2011年5月. 中村浩之, 土井祐輔, 市原理子, 石田竜弘, 際田弘志 :
S-1併用条件下でのPEG修飾リポソームの腫瘍内分布における投与間隔の影響,
日本薬学会第131年会, 2011年3月. 松永真理子, 中村和也, 森吉直人, 石田竜弘, 際田弘志 :
Tegafur製剤S-1とsiRNA含有リポソームの組み合わせによる新規がん治療戦略,
日本薬学会第131年会, 2011年3月. 岩木雄大, 田上辰秋, 中村和也, 石田竜弘, 際田弘志 :
リアルタイムRT-PCR及び共焦点顕微鏡を用いたsiRNAの細胞内動態評価,
日本薬学会第131年会, 2011年3月. 上原友美, 田上辰秋, 市原理子, 石田竜弘, 際田弘志 :
核酸含有PEG修飾ナノキャリアによるTLR刺激が及ぼすanti-PEGIgM分泌誘導への影響,
日本薬学会第131年会, 2011年3月. 石田竜弘 :
経口型抗がん剤のmetronomic dosing による腫瘍内微少環境変化を利用した革新的siRNAデリバリー技術の開発とがん治療への応用,
平成22年度厚生労働科学研究費研究成果等普及啓発事業医療機器開発推進研究低侵襲・非低侵襲医療機器(ナノテクノロジー)研究成果発表会, 2011年2月. 石田竜弘, 際田弘志 :
腫瘍内微小環境変化を利用したsiRNAデリバリーシステムの開発,
第32回生体膜と薬物の相互作用シンポジウム, 2010年11月. 中村浩之, 土井祐輔, 長尾愛, 松本春菜, 岡田知子, 市原理子, 石田竜弘, 際田弘志 :
PEG修飾リポソームの腫瘍内分布における投与間隔の影響,
第49回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2010年11月. 北川瑞野, 岩木雄大, 田上辰秋, 石田竜弘, 際田弘志 :
細胞内導入後のsiRNA量の経時的変化に関する検討,
第49回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2010年11月. 長尾愛, 市原理子, 土井祐輔, 石田竜弘, 際田弘志 :
抗PEG IgM抗体誘導におけるS-1とl-OHP封入PEG修飾リポソーム併用条件が与える影響の検討,
第49回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2010年11月. 井本亜美, 市原理子, 橋口優紀, 上原友美, 石田竜弘, 際田弘志 :
正常マウス脾臓細胞移入SCID マウスにおけるABC現象の再現,
第49回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2010年11月. 市原理子, 石田竜弘, 際田弘志 :
REG修飾ナノキャリア生体内投与後に生ずる免疫活性化(ABC現象)機構解明に関する検討,
第19回DDSカンファランス, 2010年9月. 石田竜弘, 田上辰秋, 上原友美, 森吉直人, 岩木雄大, 際田弘志 :
リポソームを用いた腫瘍へのsiRNAデリバリーシステムの開発,
遺伝子・デリバリー研究会第10回夏季セミナー, 2010年9月. 長尾愛, 市原理子, 土井祐輔, 石田竜弘, 際田弘志 :
S-1とl-OHP封入PEG修飾リポソームの併用条件下における抗PEGIgM抗体分泌の検討,
ナノライフサイエンス・オープンセミナー2010, 2010年8月. 北川瑞野, 岩木雄大, 田上辰秋, 石田竜弘, 際田弘志 :
トランスフェクション後の細胞内siRNA量の経時変化に関する検討,
ナノライフサイエンス・オープンセミナー2010, 2010年8月. 井本亜美, 市原理子, 橋口優紀, 上原友美, 石田竜弘, 際田弘志 :
正常マウス脾臓細胞移入SCIDマウスにおける抗PEG-IgM分泌に関する検討,
ナノライフサイエンス・オープンセミナー2010, 2010年8月. 岩木雄大, 中村和也, 田上辰秋, 石田竜弘, 際田弘志 :
siRNA-lipoplexへのPEG修飾がRNAi効果発現に与える影響,
ナノライフサイエンス・オープンセミナー2010, 2010年8月. 上原友美, 田上辰秋, 市原理子, 石田竜弘, 際田弘志 :
ナノ粒子ポリマー修飾剤の構造の違いが与える抗ポリマーIgMの分泌機構への影響に関する検討,
ナノライフサイエンス・オープンセミナー2010, 2010年8月. 市原理子, 石田竜弘, 際田弘志 :
RPG修飾リポソーム投与時に惹起されるABC現象に関する研究,
ナノライフサイエンス・オープンセミナー2010, 2010年8月. 石田竜弘 :
腫瘍へのsiRNAデリバリーシステムの開発∼効果と安全性の観点から∼,
第47回薬剤学懇談会研究討論会, 2010年6月. 市原理子, 井本亜美, 橋口優紀, 上原友美, 石田竜弘, 際田弘志 :
PEG修飾リポソーム投与により誘導される抗PEG IgM分泌における脾臓の役割に関する検討,
第26回日本DDS学会, 2010年6月. 橋口優紀, 清水太郎, 市原理子, 石田竜弘, 際田弘志 :
PEG修飾リポソームに対する抗PEG-IgM分泌における脾臓辺縁帯B細胞の関与について,
第26回日本DDS学会, 2010年6月. 森吉直人, 中村和也, 松永真理子, 石田竜弘, 際田弘志 :
テガフール製剤S-1とBcl-2標的siRNA封入liposomeの併用療法によるがん治療の有用性に関する検討,
第26回日本DDS学会, 2010年6月. 石田竜弘 :
生体内動態検討を基盤としたリポソームDDSの開発,
第26回日本DDS学会, 2010年6月. 松永真理子, 中村和也, 森吉直人, 石田竜弘, 際田弘志 :
腫瘍移行性向上を目指したsiRNA-lipoplexの改良と評価,
遺伝子・デリバリー研究会第10回シンポジウム, 2010年6月. 岩木雄大, 田上辰秋, 中村和也, 石田竜弘, 際田弘志 :
Lipoplexのエンドソーム/ライソソームからの脱出メカニズムに関する検討,
遺伝子・デリバリー研究会第10回シンポジウム, 2010年6月. 石田竜弘, 際田弘志 :
核酸デリバリーにおけるABC現象,
遺伝子・デリバリー研究会第10回シンポジウム, 2010年6月. 上原友美, 田上辰秋, 石田竜弘, 際田弘志 :
核酸デリバリーにおける修飾剤種が与えるポリマー特異性IgM分泌への影響,
遺伝子・デリバリー研究会第10回シンポジウム, 2010年6月. 市原理子, 井本亜美, 橋口優紀, 上原友美, 石田竜弘, 際田弘志 :
PEG修飾リポソーム投与マウス脾臓の抗PEG IgM分泌における役割,
日本薬剤学会第25年会, 2010年5月. Lila Selim Ahmed Ali Abu Amr, Yusuke Doi, Kazuya Nakamura, Tatsuhiro Ishida and Hiroshi Kiwada :
Sequential administration with oxaliplatin-containing PEG-coated cationic liposomes promotes a significant delivery of subsequent dose into murine solid tumor,
日本薬剤学会第25年会, May 2010. 土井祐輔, 松本春菜, 岡田知子, 石田竜弘, 際田弘志 :
ナノキャリアに対するEPR効果に寄与する腫瘍内微小環境変化に関する研究:S-1の低用量頻回投与(metronomic chemotherapy)から得られた知見,
日本薬学会第130年会, 2010年3月. 岩木雄大, 田上辰秋, 中村和也, 石田竜弘, 際田弘志 :
RNAi効果発現に対するLipoplexへのPEG修飾の影響に関する検討,
日本薬学会第130年会, 2010年3月. 橋口優紀, 清水太郎, 石田竜弘, 際田弘志 :
ABC現象における抗PEG-IgM分泌とMZ-B細胞の活性化について,
日本薬学会第130年会, 2010年3月. 上原友美, 田上辰秋, 石田竜弘, 際田弘志 :
ABC現象回避を目的としたlipoplexに対するpolymer修飾剤polyglycerolの有効性評価,
日本薬学会第130年会, 2010年3月. 中村和也, 松永真理子, 岩木雄大, 土井祐輔, 石田竜弘, 際田弘志 :
テガフール製剤S-1とBcl-2標的siRNA封入リポソームの併用によるdouble modulation therapyの有用性,
日本薬学会第130年会, 2010年3月. 松本春菜, 土井祐輔, 石田竜弘, 際田弘志 :
がん細胞種が及ぼす抗がん剤封入リポソームの腫瘍移行性とその治療効果への影響,
日本薬学会第130年会, 2010年3月. 岩木雄大, 城慎二, 中村和也, 田上辰秋, 石田竜弘, 際田弘志 :
LipoplexのPEG修飾による細胞内取り込み量の変化及びRNAi効果に与える影響に関する検討,
第48回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2009年11月. 松本春菜, 土井祐輔, 石田竜弘, 際田弘志 :
がん細胞種の違いが及ぼすPEG修飾リポソームの腫瘍移行及び分布への影響,
第48回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2009年11月. 岡田知子, 土井祐輔, Lila Selim Ahmed Ali Abu Amr, 石田竜弘, 際田弘志 :
フッ化ピリミジン系経口抗癌剤とOxaliplatin封入PEG修飾カチオニックリポソーム併用による抗腫瘍効果の検討,
第48回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2009年11月. 橋口優紀, 清水太郎, 石田竜弘, 際田弘志 :
ABC現象の要因とされる抗PEG-IgMの分泌と脾臓辺縁帯B細胞の活性化の関係について,
第48回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2009年11月. 上原友美, 田上辰秋, 石田竜弘, 際田弘志 :
ABC現象回避を目的としたポリグリセロール修飾リポプレックスの有効性評価,
第48回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2009年11月. 中村和也, 土井祐輔, 石田竜弘, 際田弘志 :
siRNAによるBcl-2遺伝子ノックダウンとS-1のメトロノミック療法の組み合わせによる相乗的な制がん効果,
第68回日本癌学会学術総会, 2009年10月. 土井祐輔, 石田竜弘, 際田弘志 :
S-1のmetronomic chemotherapyがもたらすナノキャリア腫瘍集積性向上に関わる腫瘍内微小環境変化,
第68回日本癌学会学術総会, 2009年10月. 石田竜弘 :
クスリはクスリ ∼クスリを正しく使っていただくために∼,
財団法人大正証券ヘルス財団健康の保持増進に関するセミナー, 2009年9月. 田上辰秋, 石田竜弘, 際田弘志 :
PEGを用いた核酸送達システムにおいて核酸がanti-PEG IgM分泌に与える影響,
第18回DDSカンファレンス, 2009年9月. 土井祐輔, 岡田知子, 松本春菜, 石田竜弘, 際田弘志 :
ナノキャリアに対するEPR効果に寄与する腫瘍内微小環境変化に関する検討:S-1の低用量頻回投与(metronomic chemotherapy)から得られた知見,
第18回DDSカンファレンス, 2009年9月. 中村和也, 松永真理子, 鈴木卓也, 田上辰秋, 石田竜弘, 際田弘志 :
Argonaute2標的siRNAの全身投与による制がん効果及び毒性の検討,
遺伝子・デリバリー研究会第9回シンポジウム, 2009年7月. 田上辰秋, 中村和也, 石田竜弘, 際田弘志 :
siRNA封入PEG修飾リポソーム投与時におけるsiRNA配列のanti-PEG IgM分泌に与える影響,
遺伝子・デリバリー研究会第9回シンポジウム, 2009年7月. 木元歩, 石原務, 古林千沙, 高崎奈央子, 水島徹, 檜垣恵, 水島裕, 石田竜弘, 際田弘志 :
ABC現象回避を目的としたステルス型ナノ粒子製剤の開発,
第25回日本DDS学会, 2009年7月. Lila Selim Ahmed Ali Abu Amr, 城慎二, 土井祐輔, 鈴木卓也, 石田竜弘, 際田弘志 :
Oxaliplatin encapsulated in PEG-coated cationic liposomes induces significant tumor growth suppression via dual-targeting approach in a murine solid tumor model,
第25回日本DDS学会, 2009年7月. 田上辰秋, 中村和也, 清水太郎, 山﨑尚志, 石田竜弘, 際田弘志 :
ポリエチレングリコール(PEG)を利用した核酸送達システムにおいてプラスミドDNA配列内のCpG除去が抗PEG抗体産生に与える影響,
第25回日本DDS学会, 2009年7月. 中村和也, 松永真理子, 鈴木卓也, 田上辰秋, 石田竜弘, 際田弘志 :
Argonaute2遺伝子を標的としたsiRNAによるがん治療法の有用性と安全性,
第25回日本DDS学会, 2009年7月. 松永真理子, 中村和也, 石田竜弘, 際田弘志 :
腫瘍移行性向上を目指したsiRNA-lipoplexの改良とその評価,
第25回日本DDS学会, 2009年7月. 橋口優紀, 清水太郎, 石田竜弘, 際田弘志 :
PEG修飾リポソームによる抗PEG-IgMの誘導と脾臓辺緑体B細胞の活性化の関係に関する検討,
第25回日本DDS学会, 2009年7月. 竹島秀美, 鈴木卓也, 土井祐輔, 石田竜弘, 際田弘志 :
In vivo imagingを利用したリポソームの腫瘍移行性の評価,
第25回日本DDS学会, 2009年7月. 石田竜弘, 際田弘志 :
核酸デリバリーにおける accelerated blood clearance (ABC)現象,
第25回日本DDS学会, 2009年7月. 石田竜弘, 浅井知浩, 奥直人, 際田弘志 :
Argonaute2標的siRNAリポプレックスを用いたがん治療戦略,
日本薬剤学会第24年会学術シンポジウム4 RNAi医薬の展望 –From Bench to Bedside -, 2009年5月. 石田竜弘 :
targeted delivery によるがん治療 ∼その現状と今後の課題について∼,
日本薬剤学会第24年会がん治療フォーカスグループシンポジウム, 2009年5月. 松永真理子, 中村和也, 鈴木卓也, 土井祐輔, 石田竜弘, 際田弘志 :
フッ化ピリミジン系経口抗がん剤併用によるsiRNA-lipoplexの腫瘍移行向上の試み,
日本薬剤学会第24年会, 2009年5月. Lila Selim Ahmed Ali Abu Amr, 鈴木卓也, 土井祐輔, 石田竜弘, 際田弘志 :
Oxaliplatin targeting to angiogenic vessels by PEG-coated cationic liposomes suppresses the angiogenesis in a dorsal air sac mouse model.,
日本薬剤学会第24年会, 2009年5月. 城慎二, 田上辰秋, 清水径, 石田竜弘, 際田弘志 :
siRNAリポプレックスのエンドソーム脱出ならびにキャリアからのsiRNA解離過程の評価,
日本薬学会第129年会, 2009年3月. 鈴木卓也, 中村和也, 松永真理子, 田上辰秋, 浅井知浩, 石田竜弘, 奥直人, 際田弘志 :
Argonaute2標的siRNAによる腫瘍新生血管傷害療法の試み,
日本薬学会第129年会, 2009年3月. 清水太郎, 賀登浩章, 石田竜弘, 際田弘志 :
PEG修飾リポソーム投与による脾臓辺縁帯B細胞の活性化,
日本薬学会第129年会, 2009年3月. 萩歩美, 土井祐輔, 平百合恵, 石田竜弘, 際田弘志 :
Oxaliplatin (1-OHP) 封入PEG修飾cationic liposomeによる抗腫瘍効果の検討,
日本薬学会第129年会, 2009年3月. 下田かおり, 跡部一孝, 浅井知浩, 石田竜弘, 菊池寛, 奥直人, 際田弘志 :
MT1-MMPを標的とした腫瘍細胞及び腫瘍新生血管ダブルターゲティングリポソームの開発に関する検討,
日本薬学会第129年会, 2009年3月. 土井祐輔, 平百合恵, 石田竜弘, 際田弘志 :
フッ化ピリミジン系経口抗癌剤S-1のmetronomic chemotherapyとoxaliplatin (1-OHP) 封入リポソーム併用療法の開発:本併用療法がもたらす 1-OHP腫瘍移行性向上に関する検討,
日本薬学会第129年会, 2009年3月. 田上辰秋, 中村和也, 清水太郎, 山﨑尚志, 石田竜弘, 際田弘志 :
CpG-free pDNAを使用したPEG修飾リポプレックス投与がABC現象に与える影響,
日本薬学会第129年会, 2009年3月. 小出裕之, 畑中剣太朗, 浅井知浩, 石田竜弘, 際田弘志, 横山昌幸, 奥直人 :
PEG修飾ナノキャリアー頻回投与によるABC現象の機構解明,
日本薬学会第129年会, 2009年3月. 中村和也, 田上辰秋, 石田竜弘, 際田弘志 :
Argonaute2標的siRNA細胞内導入による細胞増殖抑制効果∼細胞種による違い∼,
日本薬学会第129年会, 2009年3月. 石田竜弘 :
リポソームをプラットフォームにしたDDS開発研究,
第一回若手研究発表会徳島大学大学院ヘルスバイオサイエンス研究部, 2009年2月. 石田竜弘 :
ナノキャリアーを用いた抗がん剤デリバリーシステムの開発におけるin vivo イメージングの有用性,
第31回日本分子生物学会年会第81回日本生化学会大会合同大会BMB2008, 2008年12月. 清水径, 田上辰秋, 城慎二, 石田竜弘, 際田弘志 :
siRNAリポプレックスによる細胞内取り込み量及び遺伝子サイレンシング効果の経時的変化に関する検討,
第47回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2008年11月. 阿部正義, 清水太郎, 石田竜弘, 際田弘志 :
PEG化リポソーム投与による抗PEG-lgMの発想と精製法の研究,
第47回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2008年11月. 竹島秀美, 石田竜弘, 際田弘志 :
REG修飾リポソームの体内動態に及ぼす内封ドキソルビシンの影響,
第47回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2008年11月. 平百合恵, 土井祐輔, 石田竜弘, 際田弘志 :
フッ化ピリミジン系抗がん剤とOxaliplatin(l-OHP)封入リポソーム併用療法に関する研究:l-OHP放出性の違いが効果と毒性に及ぼす影響,
第47回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2008年11月. 松永真理子, 鈴木卓也, 中村和也, 土井祐輔, 石田竜弘, 際田弘志 :
フッ化ピリミジン系経口抗がん剤併用によるsiRNA-lipoplexの腫瘍移行向上の試み,
第47回日本薬学会・日本薬剤師会・日本病院薬剤師会中国四国支部学術大会, 2008年11月. 清水太郎, 石田竜弘, 際田弘志 :
ナノキャリアの生体反応性とバイオ応用に関する研究,
日本薬物動態学会第23回年会, 2008年11月. 土井祐輔, 平百合恵, 石田竜弘, 際田弘志 :
S-1 metronomic chemotherapy とオキサリプラチン封入ナノキャリア併用療法の開発:相乗的効果増強機構の解明に関する研究,
第46回日本癌治療学会総会, 2008年10月. 田上辰秋, 石田竜弘, 奥直人, 際田弘志 :
PEG修飾カチオニックリポソームを用いたArgonaute 2-siRNAによる抗腫瘍効果,
第67回日本癌学会学術総会, 2008年10月. 土井祐輔, 平百合恵, 石田竜弘, 際田弘志 :
S-1を用いたMetronomic chemotherapyによって生じる腫瘍内微小環境の変化がもたらすリポソームの腫瘍内移行性の向上,
第17回DDSカンファランス, 2008年9月. 中村和也, 鈴木卓也, 土井祐輔, 松永真理子, 田上辰秋, 浅井知浩, 石田竜弘, 奥直人, 際田弘志 :
Argonaute2標的siRNAとフッ化ピリミジン系経口抗がん剤の併用療法によるin vivo抗腫瘍効果の検討,
第17回DDSカンファランス, 2008年9月. 清水太郎, 石田竜弘, 際田弘志 :
投与量逆依存的なABC現象発現と脾臓B細胞活性化との相関に関する検討,
第17回DDSカンファランス, 2008年9月. 田上辰秋, 中村和也, 清水太郎, 石田竜弘, 際田弘志 :
PEG修飾siRNA-lipoplex投与時におけるanti-PEG IgM分泌に対するsiRNAの影響,
第30回生体膜と薬物の相互作用シンポジウム, 2008年8月. 石田竜弘 :
PEG修飾微粒子キャリアー投与時の免疫反応,
Frontier's Nanomedicine -Summer Workshop 2008-, 2008年8月. 小出裕之, 浅井知浩, 畑中剣太朗, 石田竜弘, 際田弘志, 横山昌幸, 奥直人 :
ナノキャリア頻回投与時におけるABC現象の機構解明,
第24回日本DDS学会, 2008年6月. 清水太郎, 名和田幸介, 吉岡靖雄, 石田竜弘, 中川晋作, 際田弘志 :
PEG修飾タンパクおよびPEG修飾アデノウイルス投与による抗PEG IgM誘導に関する検討,
第24回日本DDS学会, 2008年6月. 鈴木卓也, 中村和也, 田上辰秋, 廣瀬聖実, Barichello Mario Jose, 浅井知浩, 石田竜弘, 奥直人, 際田弘志 :
Argonaute2 (Ago2)標的siRNA-lipoplexを用いたin vivo抗腫瘍効果,
第24回日本DDS学会, 2008年6月. 中村和也, 鈴木卓也, 田上辰秋, Barichello Mario Jose, 石田竜弘, 際田弘志 :
siRNA―カチオニックリポソーム複合体の表面荷電が新生血管親和性に及ぼす影響,
第24回日本DDS学会, 2008年6月. 中村和也, 鈴木卓也, 田上辰秋, Barichello Mario Jose, 石田竜弘, 際田弘志 :
siRNA-カチオニックリポソーム複合体の新生血管親和性向上の要因の解明に関する研究,
日本薬剤学会第23年会, 2008年5月. 清水太郎, 名和田幸介, 成毛一恵, 石田竜弘, 際田弘志 :
ポリエチレングリコール修飾タンパク投与による抗PEG IgM誘導に関する研究,
日本薬剤学会第23年会, 2008年5月. 城慎二, Barichello Mario Jose, 田上辰秋, 菊池寛, 石田竜弘, 際田弘志 :
siRNAリポプレックスの新規調製法がもたらす細胞内取り込み機構の変化及びRNAi効果に与える影響に関する研究,
日本薬剤学会第23年会, 2008年5月. 土井祐輔, 平百合恵, 石田竜弘, 際田弘志 :
S-1を用いたlow dose chemotherapyによって生ずる腫瘍内微少環境の変化が与えるリポソームの腫瘍内動態変化に関する検討,
日本薬剤学会第23年会, 2008年5月. 萩歩美, 田上辰秋, 石田竜弘, 際田弘志 :
がん細胞およびがん新生血管に親和性を有するPEG修飾Cationic liposomeの開発に関する検討,
日本薬剤学会第23年会, 2008年5月. 下田かおり, 跡部一孝, 浅井知浩, 石田竜弘, 菊池寛, 奥直人, 際田弘志 :
抗がん剤リポソーム製剤化検討」資料収集および「腫瘍細胞および腫瘍新生血管を標的とした抗MT1-MMP抗体修飾リポソームの有用性に関する検討,
日本薬剤学会第23年会, 2008年5月. 鈴木卓也, 中村和也, 田上辰秋, 廣瀬聖実, M J Barichello, 浅井知浩, 石田竜弘, 菊池寛, 奥直人, 際田弘志 :
Argonaute2(Ago2)標的siRNA腫瘍内直接投与による抗がん効果の検討,
日本薬剤学会第23年会, 2008年5月. 田上辰秋, 中村和也, 清水太郎, 石田竜弘, 際田弘志 :
PEG修飾siRNAリポプレックス投与時におけるanti-PEG IgM分泌に関する検討,
日本薬剤学会第23年会, 2008年5月. 松尾泰佑, 山﨑尚志, 新山加菜美, 山本武範, 石田竜弘, 際田弘志, 片岡正俊, 篠原康雄 :
タグを付加したPf3 coat protein変異体の調製およびリポソームとの相互作用の解析,
2008年3月. 石田竜弘 :
リポソームを基盤としたDDSの開発研究∼効果増強と安全性の観点から∼,
第三回DDS熊本シンポジウム, 2008年2月. 石田竜弘 :
抗がん剤含有新生血管標的ナノキャリアの開発とその腫瘍休眠療法への展開,
とくしま健康・医療クラスター創成フォーラム2008, 2008年1月. 東満美, 日野出晴美, 柏田良樹, 吉田昌裕, 山﨑尚志, 土屋浩一郎, 山内あい子, 柴田洋文, 新垣尚捷, 滝口祥令, 荒木勉, 吉村好之, 姫田敏樹, 石田竜弘, 辻大輔, 木原勝 :
徳島大学薬学部OSCEトライアル実施体制の確立と検証,
第17回日本医療薬学会年会, 2007年9月. 石田竜弘 :
リポソームDDSによる体内動態制御に基づく創薬・育薬の試み,
Bio Japan2007, World Buisiness Forum, 2007年9月. 石田竜弘 :
PEG修飾リポソーム投与時に惹起される免疫反応に関する研究,
日本薬剤学会第22年会,奨励賞受賞講演, 2007年5月. 石田竜弘 :
ポリマー修飾ナノ微粒子の組織・細胞反応性とバイオ応用に関する研究,
花王芸術・科学財団第9回助成研究発表会, 2007年5月. 石田竜弘, 際田弘志 :
ポリエチレングリコール修飾リポソーム投与時に生ずるaccelerated blood clearance (ABC)現象,
日本薬学会第127年会,シンポジウムS6, 2007年3月.

研究会・報告書: 三好弘一, 前澤博, 足立昭夫, 佐瀬卓也, 入倉奈美子, 桑原義典, 立花さやか, 石田竜弘, 辻明彦, 英崇夫, 森賀俊広, 鬼島明洋, 誉田栄一, 岩本誠司, 佐藤一雄, 古谷俊介, 森田康彦 :
徳島大学アイソトープ総合センターニュース,
徳島大学アイソトープ総合センターニュース, Vol.6, 1-42, 2007年3月.

特許: 研究者総覧に該当データはありませんでした。
作品: 研究者総覧に該当データはありませんでした。
補助金・競争的資金: DDSを利用した分子イメージングにおけるノイズキャンセリング技術の基盤構築 (研究課題/領域番号: 24K03279 )
膜タンパクに対する抗体を誘導するエキソソームの脾臓免疫技術の基盤構築と応用研究 (研究課題/領域番号: 24K02194 )
免疫応答を抑制する生体適合性デンドリマーの作製と中間水コンセプトの検証 (研究課題/領域番号: 24K01558 )
イオン液体を用いた中分子医薬品の革新的・非侵襲的吸収促進技術の開発 (研究課題/領域番号: 23K17477 )
人工高分子PEGに対する生体防御反応の解明と統合的理解 (研究課題/領域番号: 23K28428 )
脳腫瘍移行性の高い免疫細胞の探索と免疫細胞への薬物搭載による脳腫瘍治療法の開発 (研究課題/領域番号: 22K19897 )
内因的アルブミン輸送システムの理解に基づく革新的アルブミンDDSキャリアの構築 (研究課題/領域番号: 21H02645 )
高活性抗体の誘導を実現する抗原発現エキソソームの脾臓免疫技術基盤の構築 (研究課題/領域番号: 21H02644 )
PEG修飾エクソソームを用いた脾臓辺縁体B細胞標的型コロナウイルスワクチンの開発 (研究課題/領域番号: 20F20411 )
イオン液体を利用した革新的腸管吸収デリバリー技術の開発 (研究課題/領域番号: 20K21898 )
動脈硬化治療法の確立に向けたHDLリモデリングの分子基盤の解明とその応用 (研究課題/領域番号: 20H04124 )
短時間高活性水熱前処理を用いた利益創出・エコ型バイオマス全成分有効利用法の開発 (研究課題/領域番号: 20H00644 )
PEG修飾タンパクによるアナフィラキシー誘導機構の解明とその制御に関する研究 (研究課題/領域番号: 19KK0279 )
超高アスペクト比ナノセルロースのネットワーク構造を活用した抗がん剤の効率的な送達 (研究課題/領域番号: 19H02549 )
イオン液体を利用した革新的経皮デリバリー技術の開発 (研究課題/領域番号: 18K19925 )
内因的アルブミンの膵臓がん取り込み機構に基づく新規多機能ナノ粒子の開発 (研究課題/領域番号: 18H02587 )
TI抗原としてのPEG化ナノキャリアを用いた静注型ネオワクチンアジュバントの開発 (研究課題/領域番号: 16K15108 )
核酸医薬デリバリーにおける自然免疫活性化機構の解明とその制御に関する研究（国際共同研究強化） (研究課題/領域番号: 15KK0310 )
iRed/iPedの完全化学合成を基軸とした実践的対がん創薬基盤研究 (研究課題/領域番号: 15H04656 )
核酸医薬デリバリーにおける自然免疫活性化機構の解明とその制御に関する研究 (研究課題/領域番号: 15H04639 )
血液型不適合生体肝移植時の抗体関連拒絶反応抑制を目指した薬物送達システムの開発 (研究課題/領域番号: 26670079 )
ｓｈＲＮＡ持続発現型人工ミニプラスミドによるＲＮＡｉ創薬の新展開 (研究課題/領域番号: 24390027 )
腫瘍内微小環境の能動的制御に基づく革新的ＤＤＳの開発とがん治療への展開 (研究課題/領域番号: 24390010 )
PEG修飾ナノキャリアによる静注型ネオワクチンアジュバントの開発 (研究課題/領域番号: 23659082 )
核酸医薬デリバリーにおける免疫活性化機構の解明とそのバイオ応用に関する研究 (研究課題/領域番号: 23390012 )
ナノキャリア腫瘍集積を支配するEPR効果の検証とその能動的制御による革新的DDS (研究課題/領域番号: 21689002 )
ナノキャリアの生体反応性とバイオ応用に関する研究 (研究課題/領域番号: 20390013 )
腫瘍内微小環境変化を利用した新規DDSの開発 (研究課題/領域番号: 20015033 )
Tumor dormant therapyへのリポソーム化抗がん剤の応用 (研究課題/領域番号: 19790128 )
がん新生血管を標的とした機能性リポソームによる革新的治療法の開発 (研究課題/領域番号: 18015036 )
試験管内タンパク質合成の分子基盤と細胞機能模倣に向けたその応用 (研究課題/領域番号: 17076011 )
ナノベクター標的化による新生血管選択的遺伝子発現法の開発とそのがん治療への応用 (研究課題/領域番号: 16790105 )
癌化学療法における多剤耐性の克服を目指した機能性リポソームの研究開発 (研究課題/領域番号: 14771310 )
研究者番号（50325271）による検索

その他: 研究者総覧に該当データはありませんでした。

研究者総覧で最新データを確認する

2024年12月4日更新

専門分野・研究分野: 生物薬剤学 (Biopharmaceutics)
所属学会・所属協会: 日本癌学会
日本薬学会
国際リポソーム研究会
日本薬物動態学会
日本DDS学会
日本薬剤学会
薬物の放出制御に関する国際会議
日本癌治療学会
遺伝子デリバリー研究会
日本膜学会
創剤フォーラム
American Society of Gene Therapy
American Association for Cancer Research
Controlled Rerease Society
日本胃癌学会
日本免疫学会
日本医療薬学会
日本核酸医薬学会
International Liposome Society
日本血液代替物学会
委員歴・役員歴: 研究者総覧に該当データはありませんでした。
受賞: 2003年11月, 奨励賞 (日本薬学会中国四国支部)
2004年9月, 第3回万有製薬薬剤学奨励賞 (万有生命科学振興国際交流財団)
2006年12月, 第5回上村修三郎「がん研究」奨励賞 (歯学部)
2007年5月, 日本薬剤学会奨励賞 (日本薬剤学会)
2007年5月, 第一回徳島大学若手研究者学長表彰 (徳島大学)
2010年6月, 日本DDS学会奨励賞 (日本DDS学会)
2017年2月, 康楽賞 (財団法人三木康楽会)
2018年6月, 日本DDS学会水島賞 (日本DDS学会)
2019年2月, 徳島大学大学院医歯薬学研究部長表彰 (大学院医歯薬学研究部)
2021年5月, 2020 Highly Cited Review Award for Biological and Pharmaceutical Bulletin (BPB) (日本薬学会)
2022年3月, 2021 Highly Cited Review Award for Biological and Pharmaceutical Bulletin (BPB) (日本薬学会)
2022年3月, The Most Published Author Award 20172021 in Biological and Pharmaceutical Bulletin (BPB) (日本薬学会)
2022年10月, 徳島県科学技術大賞科学技術振興部門 (徳島県)
2023年5月, 第17回(2023年度)タケル&アヤ・ヒグチ記念賞 (日本薬剤学会)
活動: 自己点検·評価委員会委員
LAN運営委員会(薬学)

リサーチマップで最新データを確認するＪグローバルで最新データを確認する

2024年12月1日更新

2024年11月30日更新

Ｊグローバル

Jグローバル最終確認日: 2024/11/30 01:15
氏名（漢字）: 石田竜弘
氏名（フリガナ）: イシダタツヒロ
氏名（英字）: Ishida Tatsuhiro
所属機関: 徳島大学教授

リサーチマップ

researchmap最終確認日: 2024/12/1 01:18
氏名（漢字）: 石田竜弘
氏名（フリガナ）: イシダタツヒロ
氏名（英字）: Ishida Tatsuhiro
プロフィール: リサーチマップAPIで取得できませんでした。
登録日時: 2011/8/31 00:00
更新日時: 2024/11/12 06:39
アバター画像URI: https://researchmap.jp/ishidaDDS/avatar.jpg
ハンドル: リサーチマップAPIで取得できませんでした。
eメール: リサーチマップAPIで取得できませんでした。
eメール（その他）: リサーチマップAPIで取得できませんでした。
携帯メール: リサーチマップAPIで取得できませんでした。
性別: リサーチマップAPIで取得できませんでした。
没年月日: リサーチマップAPIで取得できませんでした。
所属ID: 0344000000
所属: 徳島大学
部署: 大学院医歯薬学研究部薬物動態制御学分野
職名: 教授
学位: 薬学博士
学位授与機関: 徳島大学
URL: リサーチマップAPIで取得できませんでした。
科研費研究者番号: リサーチマップAPIで取得できませんでした。
Google Analytics ID: リサーチマップAPIで取得できませんでした。
ORCID ID: リサーチマップAPIで取得できませんでした。
その他の所属ID: リサーチマップAPIで取得できませんでした。
その他の所属名: リサーチマップAPIで取得できませんでした。
その他の所属部署: リサーチマップAPIで取得できませんでした。
その他の所属職名: リサーチマップAPIで取得できませんでした。
最近のエントリー: リサーチマップAPIで取得できませんでした。
Read会員ID: リサーチマップAPIで取得できませんでした。
経歴
受賞
Misc
論文
講演・口頭発表等
書籍等出版物
研究キーワード
研究分野
所属学協会
担当経験のある科目
その他: リサーチマップAPIで取得できませんでした。
Works: リサーチマップAPIで取得できませんでした。
特許
学歴
委員歴
社会貢献活動: リサーチマップAPIで取得できませんでした。

ＫＡＫＥＮで最新データを確認する

2024年11月30日更新

研究者番号: 50325271

所属（現在）: 2024/4/1 : 徳島大学, 大学院医歯薬学研究部(薬学域), 教授

所属（過去の研究課題 情報に基づく）*注記: 2018/4/1 – 2024/4/1 : 徳島大学, 大学院医歯薬学研究部(薬学域), 教授
2015/4/1 – 2017/4/1 : 徳島大学, 大学院医歯薬学研究部(薬学系), 教授
2015/4/1 : 徳島大学, 大学院医歯薬学研究部, 教授
2014/4/1 : 徳島大学, 大学院ヘルスバイオサイエンス研究部, 教授
2013/4/1 – 2014/4/1 : 徳島大学, ヘルスバイオサイエンス研究部, 教授
2013/4/1 : 徳島大学, ヘルスバイオサイエンス研究部, 教授(Professor)
2013/4/1 : 徳島大学, 大学院・へルスバイオサイエンス研究部, 教授
2011/4/1 – 2012/4/1 : 徳島大学, ヘルスバイオサイエンス研究部, 准教授
2007/4/1 – 2012/4/1 : 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 准教授
2006/4/1 – 2007/4/1 : 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 助教授
2005/4/1 – 2006/4/1 : 徳島大学, 大学院ヘルスバイオサイエンス研究部, 助教授
2004/4/1 : 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 助教授
2003/4/1 : 徳島大学, 薬学部, 助教授
2002/4/1 : 徳島大学, 薬学部, 講師

審査区分/研究分野

研究代表者

医学 / 薬学 / 医薬分子機能学
生物系 / 医歯薬学 / 薬学 / 医療系薬学
生物系 / 医歯薬学 / 薬学 / 物理系薬学
中区分90:人間医工学およびその関連分野
小区分90110:生体医工学関連
小区分90120:生体材料学関連

研究代表者以外

生物系 / 医歯薬学 / 薬学 / 物理系薬学
生物系 / 医歯薬学 / 薬学 / 創薬化学
理工系
生物系
小区分47060:医療薬学関連
小区分28030:ナノ材料科学関連
小区分59040:栄養学および健康科学関連
中区分64:環境保全対策およびその関連分野
中区分90:人間医工学およびその関連分野
小区分35020:高分子材料関連
小区分90120:生体材料学関連

キーワード

研究代表者

リポソーム / ドラッグデリバリーシステム / 癌化学療法 / 多剤耐性 / 遺伝子治療 / DDS / 遺伝子デリバリー / がん治療 / がん新生血管 / 癌 / 癌治療 / 癌新生血管 / 抗がん剤 / がん / モデル動物 / 体内動態制御 / ナノキャリア / 腫瘍 / EPR効果 / 腫瘍内微小環境 / メトロノミック・ケモセラピー / 抗がく剤 / 薬物動態 / 代謝学 / ワクチン / アジュバント / PEG / 抗原デリバリー / ポリエチレングリコール / 免疫反応 / ドラッグデリバリー / がん微小環境 / 血液型不適合肝移植 / 抗血液型抗体 / PEG修飾リポソーム / ＤＤＳ / 移植拒絶 / 免疫制御 / ＰＥＧ修飾リポソーム / TI抗原 / 核酸 / 免疫 / Anti-PEG IgM / 核酸デリバリー / 自然免疫活性化 / イオン液体 / 経皮吸収 / ペプチド / PEG修飾製剤 / 抗PEG抗体 / infusion reaction / CARPA / 経口投与 / 腸管吸収 / 中分子医薬品 / 吸収改善 / COVID-19 / コロナワクチン

研究代表者以外

膜タンパク質 / リポソーム / 試験管内タンパク質合成 / コートペプチド / 細胞機能模倣 / 再構成 / 高次構造 / フォールディング / 抗体 / プロテインA / 細胞機能の模倣 / マイクロチップ電気泳動 / ナノバイオデバイス / 合成ペプチド / マイクロファブリケーション / がん / 新生血管 / DDS / モデル動物 / 体内動態制御 / がん治療 / 抗がん剤 / 腫瘍内微小環境 / メトロノミック・ケモセラピー / ナノキャリア / 免疫系 / 抗PEG-IgM / B細胞 / ナノトキシコロジー / ポリエチレングリコール / 免疫反応 / ＤＤＳ / ＰＥＧ / ABC現象 / Anti-PEG IgM / 免疫活性化 / PEG / RNAi創薬 / 4'-チオDNA / PCR / 非天然塩基対 / クリックケミストリー / 免疫応答 / 核酸創薬 / DNAデバイス / 化学合成 / アルブミン / 膵臓がん / ドラッグデリバリーシステム / ナノ粒子 / ナノセルロース / ネットワーク構造 / 徐放 / 腹膜播種 / 薬剤送達 / 表面修飾 / シランカップリング / グラフト化 / 表面改質 / 開環重合 / 副作用低減 / 毒性低減 / 酸素移動容量係数 / 腹腔内滞留性向上 / ボトムアップ / バイオリファイナリー / セルロース合成菌 / 高密度リポ蛋白質 / 動脈硬化 / 高密度リポタンパク質 / アポリポタンパク質 / アポリポタンタンパク質 / バイオマス / 脾臓免疫 / 抗体誘導 / エキソソーム / 膜タンパク / ポリクローナル抗体 / 抗血清 / アルブミン受容体 / アクティブターゲティング / 脳腫瘍 / 免疫細胞 / 薬物送達 / 遊走 / デンドリマー / 生体適合性 / 水和 / エクソソーム / モノクローナル抗体 / ノイズキャンセリング / がんイメージング / 抗PEG抗体 / PET

研究課題研究成果共同研究者

「研究課題をさがす」で表示
テキスト（CSV）で出力

テキスト（CSV）で出力

2020年3月27日

次世代型「脳関門創薬」拠点形成：ヒト血液脳関門物流システム解明に基づく脳関門突破型抗体・核酸医薬の開発

立川正憲小迫英尊小暮健太朗石田竜弘山本圭田良島典子鬼塚正義福田達也中島公平藤原敏孝

2022年2月21日

B細胞を標的とした新規ワクチンの開発

清水太郎石田竜弘異島優安藤英紀

研究者を探す

石田 竜弘

Ｊグローバル

リサーチマップ

研究代表者

研究代表者以外

研究代表者

研究代表者以外

石田竜弘