多功能性樹枝型高分子基因傳送系統之設計與開發

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標題:	多功能性樹枝型高分子基因傳送系統之設計與開發 The Design and Development of Multifunctional Dendrimer-Based Gene Delivery Systems
作者:	郭榮華
貢獻者:	藥物科技研究所
關鍵字:	非病毒性載體陽離子性高分子基因樹枝型高分子胜? 巨噬細胞 Non-viral vector Cationic polymer Gene Dendrimer Peptide Macrophages
日期:	2009
上傳時間:	2010-03-26 16:45:38 (UTC+8)
出版者:	台南縣：嘉南藥理科技大學藥物科技研究所
摘要:	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。其中人體安全性與目前使用之過度帶正電高分子載體息息相關，而過度帶正電性亦可能降低其在血液中之安定性及與血液中之成分互相作用，進而活化免疫系統。另外，目前非病毒性載體之提高轉染效率集中於調整複合體大小，表面電荷及改變組成，然而對於如何一系列地克服細胞外及細胞內輸送障礙，仍然無法充分提供合理解釋。本計畫的主要目的即為以合理性設計理念開發多功能性樹枝型高分子基因傳送系統，以克服非病毒性基因傳送系統之缺失，達成兼具安全性及效率性之高分子基因傳送系統。本計畫擬將先以多功能性帶負電之蛋白質（白蛋白）及多醣類分子（玻尿酸，果膠）來披覆陽離子性樹枝型高分子ploypropylenimine (PPI) dendrimers/DNA 複合體，以期提高複合體在體外血液中之安定性，降低複合體對細胞之毒性及提高對目標細胞受體之結合力。我們又擬將陽離子性樹枝型高分子表面之胺基與病毒胜肽(Tat 胜肽及SV40 large T-antigen-derived 胜肽)共價結合，克服非病毒性載體之重大核膜輸送障礙，改善細胞內交通途徑，並提高其基因轉染效率。我們將結合上述二種多功能性組合，篩選出多功能性樹枝型高分子基因傳送系統配方之最佳化以期能發揮加成性之效果。最後將測試多功能性樹枝型高分子基因傳送系統對免疫系統與血液之生物相容性，以模擬在體內給藥條件下是否能降低質體DNA 對巨噬細胞之發炎反應刺激以進一步應用於人體之基因療法。 A successful polymeric gene delivery system must fulfill both safety and efficacy. The excess cationic charges of polymeric gene delivery systems are closely related to its safety in vivo. The blood stability of cationic polymeric gene delivery systems can be reduced by the interactions between excess cationic charges and blood components, leading to activate immune responses. Moreover, current strategies in enhancing transfection efficiency of non-viral vectors are focused only on adjusting the size, surface charge, vector composition of complexes. Systemically sufficient explanations on how to overcome a variety of extra- and intra- cellular delivery barriers of non-viral vectors are still far away from success. Therefore, the aim of this proposal is to develop multifunctional dendrimer-based gene delivery systems with enhancing both safety and efficacy by the concept of “rational design”for overcoming the drawbacks of non-viral gene delivery systems. Firstly, we will use the coating made by functional negative bio-molecules (albumin, hyaluronic acid, and pectin) to shield ploypropylenimine (PPI) dendrimers/DNA complexes for increasing its extra-cellular stability, reducing cytotoxicity of resulted complexes, and enhancing binding ability to targeted cell receptor. After then, PPI dendrimers will covalently conjugate to virus peptides (Tat peptide and SV40 large T-antigen-derived peptide) by reacting amine groups in its surface for overcoming the major nuclear barrier of non-viral vectors, improving intracellular trafficking pathways, and enhancing transfection efficiencies. By combining coating shielding and peptide conjugation to PPI dendrimers/DNA complexes, we will optimize and screen the formulations of multifunctional dendrimer-based gene delivery systems for synergetic effects. Finally, we will evaluate the biocompatibility of multifunctional dendrimer-based gene delivery systems in immune systems and human blood under administration conditions to simulate whether or not the inflammation activations induced by plasmid DNA can be reduced.
關聯:	計畫編號：NSC98-2221-E041-002
显示于类别:	[藥學系(所)] 科技部計畫

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