Complex Formation with Plasmid DNA Increases the Cytotoxicity of Cationic Liposomes(Biopharmacy)
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概要
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Cationic liposomes (CL) are one of the most widely studied non-viral vectors for gene delivery. It is wellknown 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 ther-apeutics 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.
- 社団法人日本薬学会の論文
- 2007-04-01
著者
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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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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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ATOBE Kazutaka
Department of Pharmacokinetics and Biopharmaceutics, Subdivision of Biopharmaceutical Sciences, Inst
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Nguyen Lap
Department Of Pharmacokinetics And Biopharmaceutics Subdivision Of Biopharmaceutical Sciences Instit
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Barichello Jose
Department Of Pharmacokinetics And Biopharmaceutics Subdivision Of Biopharmaceutical Sciences Instit
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Kamada Hitoshi
Institute For Life Support Technology Yamagata Promotional Organization For Industrial Technology
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Atobe Kazutaka
Department Of Pharmacokinetics And Biopharmaceutics Subdivision Of Biopharmaceutical Sciences Instit
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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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