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09월 04일 13시 이후 : 초록수정 불가능, 일정확인 및 검색만 가능
Oligopeptide/drug-derived cationic nanoparticles for in vivo delivery of siRNAs
2009년 8월 14일 09시 11분 13초
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금 09시 : 40분
Nanomaterials and Nucleic Acids for Molecular Therapy
School of Pharmacy, Seoul National University, Seoul, South Korea, Korea
Recently, small interfering RNAs (siRNAs) have been emerging as a potential anticancer therapeutics (1) with several candidates in preclinical trials. The limited delivery of naked siRNAs to cancer cells and the polygenic nature of cancer, however, hampered the development of siRNA monotherapy as potent anticancer strategy. Substantial progress has been made in siRNA delivery technologies using cationic lipid or polymer-based systems (2-4). Moreover, the combination therapy of siRNAs and anticancer drugs has been attempted to enhance the therapeutic outcome (5). In this study, we tested the use of oligopeptide or cationic anticancer drug-derived nanoparticles as a delivery system of siRNAs. Cationic nanoparticles composed of oligopeptide or anticancer drug-derived cationic lipids could form electrostatic complexes with negatively charged siRNAs. When compared with Lipofectamine 2000 (L2K), the cationic nanoparticles provided increased cellular delivery of siRNAs in various cell lines such as KB, A549, HeLa, and Hep3B tumor cells. Unlike L2K showing confluency-dependent transfection efficiency, the cationic nanoparticles exhibited the confluency-independent delivery of siRNA with high efficiency. More than 95% of the cells were positive for siRNA following its delivery with the cationic nanoparticles at 90% of cell confluency. A survivin-specific siRNA delivered using the cationic nanoparticles effectively reduced the mRNA expression of the target genes in the cell lines tested. siMcl complexed to the cationic nanoparticles provided significantly higher anticancer activity than did the cationic nanoparticle alone or luciferase-specific siRNA complexed to the cationic nanoparticles. In vivo study revealed the enhanced antitumor effects by delivery of siRNA using the cationic anticancer drug-derived nanoparticles. Compared to the untreated control group, the cationic nanoparticle-treated group exhibited signficantly reduced tumor growth. The highest tumor growth inhibition in nude mice was observed in the group treated with siMcl delivered with the cationic nanoparticles. These results suggest the potential of dual function cationic nanoparticles which can deliver therapeutic siRNAs while exerting anticancer activity per se. The combined treatment of anticancer siRNAs with anticancer cationic nanoparticles may potentiate the efficacy of cancer therapy.
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