細胞穿透性胜太---樹枝型高分子基因傳送系統之設計與開發

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Title:	細胞穿透性胜太---樹枝型高分子基因傳送系統之設計與開發 The Design and Development of Cell Penetrating Peptide---Dendrimer Gene Delivery System
Authors:	郭榮華詹明修
Contributors:	嘉南藥理科技大學藥物科技研究所
Date:	2012
Issue Date:	2014-10-20 21:50:26 (UTC+8)
Abstract:	一個成功之高分子基因傳送系統必須兼具安全性與效率性。帶正電性樹枝型高分子因為其分子量分布較小，奈米級球狀結構等特質而深具興趣發展成高分子基因傳送系統，然而其表面之一級胺基使得其具備細胞毒性及過度之人體免疫刺激反應，再者樹枝型高分子在細胞內之傳送仍受限於內含體之輸送障礙使得其轉染效率仍較病毒性載體為低。另一方面，近年來應用細胞穿透性胜肽在細胞內輸送已廣泛地獲得認同，雖然其對細胞之毒性亦相對於其他帶正電性高分子低，並且有些新發現的細胞穿透性胜肽能直接逃脫細胞內內含體之障礙，然而其在質體DNA 輸送應用仍有使用上之一些限制及缺失。故本計畫即是在樹枝型高分子之表面共價結合細胞穿透性胜肽，希望開發出新一代的非病毒性載體，以提高載體之基因轉染效率並改善其生物相容性。本計畫擬選擇新發現之Rath 胜肽進行研究，因其具有非傳統之細胞內傳送交通路徑，可以避免內含體之障礙而直接目標於細胞核之傳送。除了考慮細胞毒性，轉染效率外，本計畫也把未來人體試驗中不可或缺之生物相容性與安定性，載體與細胞之分子層次上交互作用考慮進來，以期未來應用於臨床。因此，本計畫將進行實證各種成為成功之樹枝型高分子基因傳送系統的因素。 A successful polymeric gene delivery system must fulfill both safety and efficacy. Cationic dendrimers have attractive characteristics such as low polydispersity and nano-sized spherical architecture, which make them particular interesting for the development of polymeric gene delivery systems. However, dendrimers with free primary amine groups at the surface are reported to show cytotoxicity, over-reacted immune responses, and relatively lower transfection efficiency to viral vectors by its limiting ability to overcome endosomal barriers. In another aspect, applications of cell penetrating peptides for intra-cellular delivery have widely gained acknowledgements. Although cell penetrating peptides have relatively lower cytotoxicity to other cationic polymers and some novel cell penetrating peptides have directly escaping abilities from endosomal entrapment, they exhibit some limitations and disadvantages for the applications of plasmid DNA delivery. Therefore, the aim of this proposal is to develop new generations of non-viral vectors with enhanced transfection efficiencies and improved biocompatibility by surface covalent conjugation of dendrimers with cell penetrating peptides. We will select the novel Rathpeptide as the cell penetrating peptide in this proposal, due to its non-endocytic mechanism of uptake. This is favorable as it avoids endosomal entrapment and directly targets nuclear transport. In addition to cytotoxicity and transfection efficiency examinations, we also investigate biocompatibility, stability, and molecular interactions between vectors and cells, which were crucial in future clinic trials. Thus, the attempts in this proposal will be made to prove all the characteristics needed to be the best candidate for dendrimer-based gene delivery systems.
Relation:	計畫編號：NSC99-2221-E041-002-MY3 計畫年度：101；起迄日期：2012-08-01~2013-7-31
Appears in Collections:	[Dept. of Pharmacy] MOST Project

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