In Vitro Efficacy of a Sterically Stabilized Immunoliposomes Targeted to Membrane Type 1 Matrix Metalloproteinase (MT1-MMP)(Biopharmacy)
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概要
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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.
- 社団法人日本薬学会の論文
- 2007-05-01
著者
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HARASHIMA Hideyoshi
Graduate School of Pharmaceutical Sciences, Hokkaido University
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Ishida Tatsuhiro
Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Inst
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Kiwada Hiroshi
Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Inst
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Kiwada Hiroshi
徳島大学 ヘルスバイオサイエンス研究部薬物動態制御学
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Kiwada Hiroshi
Department Of Pharmacokinetics And Biopharmaceutics Subdivision Of Biopharmaceutical Sciences Instit
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Kiwada Hiroshi
Faculty Of Pharmaceutifal Sciences The University Of Tokushima
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原島 秀吉
北大院・薬学研究科
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ASAI Tomohiro
Department of Cardiovascular Surgery, Okayama University Graduate School of Medicine, Dentistry, and
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OKU Naoto
Department of Radiobiochemistry, School of Pharmaceutical Sciences, University of Shizuoka
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Oku Naoto
タイ
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Kamada Haruhiko
医薬基盤研究所 創薬プロテオミクスプロジェクト
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Kiwada Hiroshi
Department Of Pharmacokinetics And Biopharmaceutics Faculty Of Pharmaceutical Sciences The Universit
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Kamiya Hiroyuki
Lab. For Molecular Design Of Pharmaceutics Fac. Of Pharmaceutical Sciences Hokkaido Univ.
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KOBAYASHI Hideo
Drug Metabolism & Physicochemistry Research Laboratory, Tokyo R&D Center, Daiichi Pharmaceutical Co.
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HASHIMOTO Kouichi
Drug Metabolism & Physicochemistry Research Laboratory, Tokyo R&D Center, Daiichi Pharmaceutical Co.
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KIKUCHI Hiroshi
Drug Metabolism & Physicochemistry Research Laboratory, Tokyo R&D Center, Daiichi Pharmaceutical Co.
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ATOBE Kazutaka
Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Inst
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ISHIDA Emi
Drug Metabolism and Physicochemistry Research Laboratory, R&D Division, Daiichi Pharmaceutical Co.,
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YASUDA Jyunko
Daiichi Fine Chemical Co.. Ltd.
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AOKI Takanori
Daiichi Fine Chemical Co.. Ltd.
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OBATA Ken-ichi
Daiichi Fine Chemical Co.. Ltd.
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AKITA Hidetaka
Graduate School of Pharmaceutical Sciences, Hokkaido University
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Oku Naoto
Department Of Medical Biochemistry And Coe Program In The 21st Century University Of Shizuoka School
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Asai Tomohiro
Department Of Cardiovascular Surgery Okayama University Graduate School Of Medicine Dentistry And Ph
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Asai Tomohiro
Department Of Medical Biochemistry And Coe Program In The 21st Century University Of Shizuoka School
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Kamada Hitoshi
Institute For Life Support Technology Yamagata Promotional Organization For Industrial Technology
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Akita Hidetaka
Lab. For Molecular Design Of Pharmaceutics Fac. Of Pharmaceutical Sciences Hokkaido Univ.
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Shim Chang
Faculty Of Pharmaceutical Sciences University Of Tokyo : (present Address) College Of Pharmacy Seoul
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Harashima Hideyoshi
Department Of Pharmacokinetics And Pharmaceutics Graduate School Of Pharmaceutical Sciences The Univ
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Murata-kamiya Naoko
Inst. Indust. Ecolog. Sci. Univ. Occup. Environ. Hith.
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Akita Hidetaka
Graduate School Of Pharmaceutical Sciences Hokkaido University
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Atobe Kazutaka
Department Of Pharmacokinetics And Biopharmaceutics Subdivision Of Biopharmaceutical Sciences Instit
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Ishida Emi
Drug Metabolism And Physicochemistry Research Laboratory R&d Division Daiichi Pharmaceutical Co.
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Ishida Tatsuhiro
Dep. Of Pharmacokinetics And Biopharmaceutics Subdivision Of Biopharmaceutical Sciences Inst. Of Hea
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Ishida Tatsuhiro
Department Of Pharmacokinetics And Biopharmaceutics Subdivision Of Biopharmaceutical Science Institu
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Ishida Tatsuhiro
Department Of Pharmacokinetics And Biopharmaceutics Institute Of Health Biosciences The University O
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Harashima Hideyoshi
Graduate School Of Pharmaceutical Sciences Hokkaido University:crest Japan Science And Technology Corporation (jst)
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OKU Naoto
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Setsunan University
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