新樹枝狀聚胺基甲酸酯與其衍生物之合成及做為質體DNA傳輸載體效率之研究

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標題:	新樹枝狀聚胺基甲酸酯與其衍生物之合成及做為質體DNA傳輸載體效率之研究 Syntheses of New Poly(Urethane-Amine) Dendrimers and Their Derivatives and Study on Plasmid Dna Delivery Efficiency
作者:	蕭明達
貢獻者:	生物科技系(所)
關鍵字:	cytotoxicity vaccine dendrimer poly(urethane-amine) transfection efficiency
日期:	2011
上傳時間:	2012-01-03 13:57:06 (UTC+8)
摘要:	基因治療是指將一段正常基因送進病人細胞中，使細胞能夠合成正常生理所需的蛋白質，進而治療疾病。基因透過傳遞系統有效率地傳送至細胞，需要一安全且轉染率高的基因載體。在陽離子型高分子的基因傳遞系統中，高分子與DNA 自組裝地形成一奈米尺度的複合體，並藉由細胞胞飲作用進入細胞質，且能夠保護DNA 免於受到核酸酵素分解。然而，陽離子型高分子/DNA 複合體經由胞飲作用進入細胞之後，主要仍留在內質體及溶小體中，限制了它們繼續在細胞質中運輸，因此，DNA 自內質體釋出將是基因傳輸系統中達成轉染效果的限制步驟。除此之外，PLL、 PDMAEMA、及PEI 都是非生物可分解的材料，且具有明顯得細胞毒性，為了改善上述高分子的缺點，本研究室將以下五項特性作為合成新的陽離子型高分子基因傳遞系統結構設計的準則：(1)聚集DNA 的能力(2)水溶蝕性(3)生物相容性(低細胞毒性)(4)pKa 值介於5.0-7.4(5)容易合成。以目前而言，質體DNA 被廣泛用於治療藥物及疫苗接種，然而，深入的研究發現，DNA 接種疫苗成功關鍵在於傳輸系統。高分子材料亦被常用於疫苗接種的傳遞系統，而此類的高分子乃以物理包陷的方式包覆 DNA 疫苗且成功地傳遞至細胞。本研究主要目的在設計具低細胞毒性、高基因傳輸能力之高分子傳遞系統，研究擬分三年完成，計畫主要工作如下：第一年新樹枝狀陽離子型聚胺基甲酸酯之合成及其質子海綿效應與DNA/高分子奈米複合體基因轉染效率關係之研究第二年合成具標靶功能之新型樹枝狀poly(urethane-amine)及轉染效率之研究第三年Poly(DL-lactide-co-glycolide)-Poly(urethane-amine)奈米微粒作為質體DNA 疫苗傳輸載體之研究 Gene therapy is defined as delivery of therapeutic gene expression into patient’s host cells to enable production of proteins to correct or moderate disease. To achieve gene delivery, safe vectors with selective and high transfection efficiency are required. The polycation/DNA complexes not only can protect the DNA from nuclease degradation, but also has a nanoscale size small enough to enter the cell via endocytosis. However, the delivery vehicle is localized in the endosomes and will ultimately be trafficked to the lysosome. Release of the delivery vehicle from these compartments into cytoplasm is believed to be the limiting step in transfection mediated by many cationic polymers. In addition, these polycations such PLL、PDMAEMA、and PEI are nonbiodegradable materials and associated with a considerable degree of cytotoxicity. In point of improving their drawback, we outlined five criteria to drive the rational synthesis to formulate new cationic polymer gene delivery systems. (1) DNA condensation capability(size of complex below 150 nm to allow efficient endocytosis) (2)hydrolytic degradation (3)biocompatibility(to minimize potential toxic effect) (4)pKa between lysosome pH(~5.0)and pH(~7.4)(to provide buffer capacity) (5) facile synthesis. The goal of this project is to design new biodegradable cationic polymers with low cytotoxicity and high transfection efficiency that can be used as vectors for gene delivery. Works of this project were carried out by the following three years. First year Synthesis of new cationic poly(urethane-amine) dendrimer and study on relation between proton sponge effect and transfection efficiency of DNA/polymer nano-complexes Second year Characterizations of folic acid-conjugate poly(urethane-amine) dendrimer and study on transfection efficiency for gene delivery. Third year Study on characterizations of Poly(DL-lactide-co-glycolide)-Poly(urethane-amine) microsphere (nanosphere) as a DNA vaccine carrier and their delivery efficiency.
關聯:	計畫編號：99-2221-E-041-003-MY3 計畫年度：100；起迄日期：2011-08-01~2012-07-31 核定金額：858,000元
顯示於類別:	[生物科技系(所)] 科技部計畫

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