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dc.contributor.authorZhao, Wei-Yuen_US
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dc.description.abstract本研究是藉由團聯共聚物cholesterol-p (HEMA-co-lysine) ( PI )與磷脂質(DPPC)自我組裝成脂雙層結構,內外為親水性,夾層為疏水性的微脂粒複合體(SPLexes)。再與另一團聯共聚物 Foliate-PEG-P ( HEMA-co- histidine-MAAc ) ( PII )電性交聯至其表面 ,形成能夠包覆siRNA且具酸鹼應答、生物相容性的微脂粒複合體。外殼PII 之PEG鏈段可提供載體穩定循環之特性,且交聯層MAAc分子與histidine於酸性環境下,質子化呈正電排斥離開載體表面,提供酸鹼應答而釋放siRNA。 本實驗使用不同重量比之二團聯共聚物(PI 及PII)與磷脂質(DPPC)對於微脂粒複合體粒徑與界面電位之影響。實驗結果顯示能製備出粒徑70~80 nm且粒徑均一、表面電中性之微脂粒複合體。利用上述最佳條件包覆siRNA-VEGF轉染至癌細胞中,材料毒性分析結果顯示,此微脂粒複合體為低毒性,在達到基因抑制的條件下,為有效及安全的siRNA傳輸載體。而經由胞外藥物釋放模擬實驗證實,微脂粒複合體於中性環境(pH=7.4)下,可以穩定包覆siRNA;而於酸性環境下,MAAc分子被質子化而不帶電,使PII高分子脫離微脂粒複合體表面後,微脂粒複合體因含有胺基且帶正電,與溶酶體融合而釋放內核之siRNA。轉染至HeLa細胞48 hr結果顯示,可有效抑制74.5 ± 4.5 %的VEGF蛋白表達,同時能夠誘導細胞凋亡。 此外,光動力治療是使用光敏劑結合特定波長光激發後而達到治療目的,可以重覆使用並能夠選擇性地使腫瘤細胞壞死,而不傷害周圍正常組織。而光化學內化是藥物控制釋放的技術,藉光敏劑的光化學作用,使細胞內的胞器膜破裂而釋放溶酶體內物質進入細胞質。本研究以光敏劑20FTPP的光內化作用,結合上述微脂粒複合體的基因治療來增加siRNA傳輸與基因抑制效果。結果顯示20FTPP-micelle的光內化作用具有低細胞毒性,並觀察細胞質內酸化現象。共軛交顯微鏡影像中,觀察到自由基的產生且含有20FTPP經光內化作用而造成膜破裂會的溶酶體與含有siRNA的溶酶體溶合,釋放siRNA進入細胞質。利用此光內化作用機制,微脂粒複合體轉染至HeLa細胞48 hr結果顯示,可抑制90% VEGF蛋白表現。zh_TW
dc.description.abstract英文摘要 In this research, the block copolymer cholerterol-p(HEMA-co-lysine) and phospholipid (DPPC) were synthesized and self-assembled into the liposome-like structure , and formed the SPLexes ( Small Particular Lipoplexs ). The block copolymer , foliate-PEG-P(HEMA-co-histidine -MMAc) , crosslink to the surface of the lipoplex by electric interaction. The PEG segments exist in the outer shell of lipoplex and provide the characterstic that could be stable in blood stream . MAAc and hisdidine moiety are responded and protonated by acidified environment and trigger the siRNA release. The particle sizes and polydispersity were discussed to evaluate the affection of the weight ratio of block copolymers PI, PII and DPPC. From the result , the uniform and optimal particle size of lipoplex was around 70~80 nm . Based the optimal conditions , siRNA-VEGF was encapsulated with SPLexes efficiently and could be the potential candidate for siRNA delivery. For the result of MTS analysis , SPLexes showed a low cytotoxicity. For siRNA release, siRNA/SPLexes was stabilized at pH=7.4 and siRNA released under acidic condition . Due to MMAc molecules of PII protonated to become neutral , they caused the PII disassociated from the SPLexes surface. For anticancer activity , siRNA/SPLexes inhibited the VEGF protein expression to 74.5 ± 4.5 % and induced the apoptosis efficiently. Photochemical internalization ( PCI ) is a technology based on photochemical reactions inducing rupture of endocytic vesicles and releasing siRNA into the cytoplasm.The main point of this research is contributed to the effort to develop lipoplexes based siRNA delivery systems via photochemical reactions . The results show that the 20FTPP-micelles bear were low photocytotoxicity . The observation indicates the production of reactive oxygen species in cytoplasm. The results of CLSM images show that endocytic vesicles ( containing 20FTPP -micelles and siRNA/SPLexes respectively) are fused, and siRNA are released from endo/lysosome. Finally , through the mechanism , the siRNA/SPLexes inhibited the VEGF protein expression to 90%.en_US
dc.description.tableofcontents目錄 謝誌 i 中文摘要 ii 英文摘要 iii 目錄 v 表目錄 viii 圖目錄 viii 一、研究動機 1 二、文獻回顧 3 2-1 奈米粒子於癌症治療 3 2-1-1 奈米藥物治療 3 2-1-2 奈米藥物傳輸 3 2-1-3 藥物載體之吞噬機制 6 2-2 功能型高分子性質及其應用 7 2-2-1 生物相容性材料 7 2-2-2 酸鹼應答型高分子 8 2-2-3 溫度應答型高分子 9 2-3 高分子載體種類 9 2-3-1 高分子與高分子系統 9 2-3-2 高分子與微脂粒系統 10 2-4 siRNA與基因載體 11 2-4-1 siRNA 11 2-4-2 VEGF 12 2-4-3 基因載體 13 2-4-4 siRNA載體種類 14 2-5 光內化作用 18 2-5-1 光動力療法 18 2-5-2 光內化作用 19 三、實驗方法 23 3-1 實驗藥品 23 3-2 儀器與裝置 24 3-3 SPLexes之製備與最佳化設計 24 3-4 微脂粒複合體之鑑定 28 3-5 微脂粒複合粒子包覆siRNA之最佳化條件 28 3-6 巨噬細胞之吞噬行為 28 3-7 SPLexes於生物體內之穩定度 29 3-8 SPLexes之酸鹼應答分析 29 3-9 SPLexes之細胞存活率與材料毒性分析 29 3-10 siRNA/SPLexes對細胞基因抑制的表現 30 3-11 siRNA/SPLexes於細胞內累積量與誘導細胞凋亡 31 3-12 20FTPP-micelle製備 32 3-13 20FTPP-micelle之細胞存活率與光內化作用毒性分析 32 3-14 自由基生成與siRNA/SPLexes於細胞內之分布 33 3-15 觀察20FTPP-micelle經光內化作用於細胞內之酸鹼值變化 33 3-16 轉染siRNA/SPLexes並結合光內化作用於細胞內之基因抑制 34 四、實驗結果與討論 35 4-1 SPLexes界面電位 35 4-2 實驗設計SPLexes最適化條件組成 36 4-3 巨噬細胞之吞噬行為 37 4-4 SPLexes模擬生物體內之穩定度 38 4-5 SPLexes包覆siRNA之最佳化條件 40 4-6 SPLexes之酸鹼應答分析 41 4-7 siRNA/SPLexes對細胞毒殺性測試 44 4-8 siRNA/SPLexes對細胞基因抑制的表現 46 4-9 siRNA/SPLexes於細胞內之累積量 46 4-10 siRNA/SPLexes誘導細胞凋亡 47 4-11 20FTPP-micelle劑量與光照時間 49 4-12 自由基生成與siRNA/SPLexes於細胞內之分布 52 4-13 20FTPP-micelle經光內化作用於細胞內之酸鹼值變化 53 4-14 轉染siRNA/SPLexes並結合光內化作用於細胞內之基因抑制 55 五、結論 56 六、文獻回顧 58zh_TW
dc.titleLipoplex Crosslinking with Multifunctional Polymer and Enhancing by Photochemical Internalization for siRNA Deliveryen_US
dc.typeThesis and Dissertationzh_TW
item.openairetypeThesis and Dissertation-
item.fulltextno fulltext-
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