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研究生： 王朝暉
Chau-Hui Wang
論文名稱： 新型聚□唑啉/聚乳酸團聯共聚物在藥物及基因傳輸上的應用
New Drug/Gene Delivery Systems based on PEOz and PLLA Block Copolymers
指導教授： 薛敬和
Ging-Ho Hsiue
口試委員:
學位類別： 博士
Doctor
系所名稱： 工學院 - 化學工程學系
Department of Chemical Engineering
論文出版年： 2004
畢業學年度： 93
語文別： 中文
論文頁數： 218
中文關鍵詞： 聚□唑啉 、聚乳酸 、團聯共聚物 、微胞 、基因治療
外文關鍵詞： Polyoxazoline, Polylactide, Block copolymer, Micelle, Gene therapy
相關次數： 點閱：4  下載：0 
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    • 本研究設計一環境應答高分子微胞作為智慧型抗癌藥物載體，利用血液與細胞內酸鹼值的改變控制藥物的釋放，避免藥物產生的副作用。聚□唑啉/聚乳酸ABA三團聯共聚物 (PLLA-PEOz-PLLA) 包含A鏈段的疏水性聚乳酸PLLA與B鏈段親水性聚□唑啉PEOz，為同時具有生分解性與酸鹼敏感性之高分子。人體內某些特定地方酸鹼值與正常值不同，如癌細胞周圍與細胞內酸性胞器等。理論上以靜脈注射投藥時，高分子奈米微胞會因為腫瘤或發炎組織附近血管通透性增加而累積，接著經由胞飲作用進入細胞內，核內體之酸鹼值由於氫離子的進入緩慢下降至pH 4~5，藉由此酸鹼值的降低可以改變微胞結構並釋放藥物。粒徑與界面電位分析結果說明PLLA-PEOz-PLLA微胞在中性水相環境下形成核殼結構，提供攜帶疏水性藥物的空間。當酸鹼值下降，PEOz之間會產生分子內與分子間氫鍵而聚集收縮，微胞結構遭到破壞。體外藥物釋放模擬顯示微胞在中性生理環境下非常安定，19天之內藥物並無明顯釋放；反之在酸性條件下則大量釋放藥物。由細胞毒殺實驗結果可知增加微胞濃度至1000 μg/mL時其生長抑制效果接近直接使用抗癌藥物doxorubicin。共軛焦顯微鏡影像證明微胞結構在細胞酸性胞器內被破壞，藥物成功地在細胞質內被釋放。由於胞飲作用比擴散作用緩慢，因此藥物微胞的生長抑制效果比直接使用doxorubicin慢。

    在基因治療方面，本研究設計兩性團聯共聚物folate-polyethylenimine-block-poly(L-lactide) (FEA) 作為非病毒基因載體。利用縮合反應將PLLA與葉酸鍵結上polyethylenimine (PEI) 以加強細胞吞噬性與癌細胞之標的性。PLLA為生分解性與疏水性高分子，與PEI連接形成團聯共聚物後有改質的效果，可以包覆DNA並提高高分子疏水性，增加細胞對聚複合體的吞噬效果；惡性腫瘤因為快速分裂的特性所以對葉酸的需求極大，癌細胞表面葉酸受體的數量較正常細胞多，因此將葉酸鍵結在高分子上，希望藉由受體媒介胞飲作用進入細胞，達到對癌症細胞標的治療的效果。PEOz水解後以酸鹼滴定分析證明PEI與FEA的酸鹼緩衝能力大幅提昇，具有突破核內體的能力。高分子與報導基因蟲螢光酶編碼質體 (luciferase encoding plasmid) pUHC-13-3形成的聚複合體基因表現效果可藉由測量冷光強度分析。原子力顯微鏡影像顯示B-PEI聚複合體為扁圓形而FEA為球型。細胞毒性分析結果顯示FEA成功地降低PEI對細胞的毒性，與B-PEI及L-PEI相較之下FEA細胞存活率大幅提昇。整體來說FEA有效地降低高分子對細胞的毒性但是也降低了基因轉殖的效率，因此以適當修飾過的FEA攜帶基因，增加劑量補足甚至超越與B-PEI基因轉染效率之間的差距。

    Polymeric micelles based on poly(L-lactide)-poly(2-ethyl-2- oxazoline)-poly(L-lactide) (PLLA-PEOz-PLLA) ABA triblock copolymers were designed as intracellular drug carriers. The PLLA-PEOz-PLLA micelles adopt a “flower-like” arrangement with A-blocks at the core and a B-block on the shell under neutral condition. The deformation of the core-shell structure is then promoted by the aggregation of PEOzs due to the formation of inter- and intra-hydrogen bonding between protonated nitrogen and carbonyl groups. The doxorubicin (DOX)-loaded micelles were stable at pH 7.4 aqueous solution over 19 days. In contrast, about 60 wt.% of DOX was released from micelles at pH 5.0 within the first 3 h. The growth inhibition effect of micelles approached that of free DOX at a concentration of 1000 μg/mL after 24 h of coincubation with HeLa cells. The result of CLSM observation indicated that the release of drug was successfully triggered in the acidic organelles due to the deformation of the micelle structure. The combined mechanisms of pH-triggered release and biodegradability emerge as having great potential to overcome the disadvantages of conventional dosage forms.

    On the other hand, the ability of amphiphilic block copolymers that comprise polyethylenimine (PEI) and poly(L-lactide) (PLLA) to modulate the delivery of plasmid DNA was evaluated. Folate-polyethylenimine-block-poly(L-lactide) (FEA) was synthesized by linking folic acid and PLLA to PEI diamine. Water-soluble polycation PEI provides gene-loading capability. Additionally, PEI, which consists of second amine and tertiary amide functional groups, is considered to exhibit high transfection efficiency and endosomal disrupting capacity. Hydrophobic PLLA that is incorporated into the gene delivery vector is believed to enhance the cell interactions and tissue permeability of the delivery system. Polymeric carrier containing folic acid is expected to be able to identify tumor surface receptors and transfect cells by receptor-mediated endocytosis. The results of agarose retardation assay indicated that the FEA began to form polyplexes at a P/D ratio of over 10X, whereas branched polyethylenimine (B-PEI) formed polyplexes with DNA at a ratio of above 1X. The spherical particle morphology was supplemented with a particle size of approximately 100 nm at 10X P/D ratio. However, FEA exhibited lower cytotoxicity but also lower transfection efficiency than those of B-PEI and L-PEI, and the expression of luciferase increased as the free folic acid concentration declined.

    目錄 第一部份 酸鹼應答型高分子微胞做為細胞內藥物傳輸載體以及在癌症治療上的應用 1 第一章 研究背景與動機 2 第二章 相關理論與文獻 6 2-1 聚□唑啉 (poly(2-oxazoline)) 6 2-2 聚酯 (polyester) 與聚醯胺 (polyamide) 12 2-3 高分子微胞在藥物制放上的應用 15 第三章 實驗方法 24 3-1 實驗藥品 24 3-2 實驗儀器與裝置 25 3-3 合成PLLA-PEOz-PLLA ABA三團聯共聚物 26 3-4 鑑定與分析 27 3-5 臨界微胞濃度分析 28 3-6 酸鹼滴定分析 29 3-7 光學穿透度測試 29 3-8 製備PLLA-PEOz-PLLA高分子微胞 29 3-9 粒徑與界面電位分析 29 3-10 體外藥物釋放模擬 30 3-11 細胞存活率與細胞毒殺實驗 30 3-12 共軛焦顯微鏡觀測藥物分佈與微胞之內吞作用 32 第四章 結果與討論 33 4-1 合成PLLA-PEOz-PLLA三團聯共聚物 33 4-2 PLLA-PEOz-PLLA之熱性質 42 4-3 臨界微胞濃度 44 4-4 相轉移溫度 48 4-5 酸鹼應答與滴定 56 4-6 粒徑與界面電位分析 61 4-7 細胞存活率 67 4-8 體外藥物釋放模擬 70 4-9 細胞毒殺實驗 75 4-10 藥物擴散與藥物微胞內吞作用觀測 77 第五章 結論 88 第六章 參考文獻 91 第二部份 新型高分子-基因混成奈米載體在基因治療上的應用 96 第一章 研究背景與動機 97 第二章 相關理論與文獻 100 2-1 基因傳遞的過程 100 2-2 病毒基因載體 106 2-3 陽離子高分子基因載體 108 2-4 共聚合高分子基因載體 110 2-5 質體 112 第三章 實驗方法 113 3-1 實驗藥品 113 3-2 實驗儀器與裝置 114 3-3 合成folate-polyethylenimine-block-poly(L-lactide) 116 3-4 鑑定與分析 119 3-5 酸鹼滴定 119 3-6 菌株培養與DNA純化 120 3-7 製備聚複合體 120 3-8 電泳分析 121 3-9 粒徑分析與原子力顯微鏡型態分析 121 3-10 細胞培養與細胞存活率 122 3-11 蟲螢光酶基因轉染與蛋白質含量分析 122 第四章 結果與討論 124 4-1 合成folate-polyethylenimine-block-poly(L-lactide) 124 4-2 酸鹼滴定分析 135 4-3 質體DNA複製與萃取 135 4-4 聚複合體粒徑分析 137 4-5 膠體電泳分析 139 4-6 表面型態分析 143 4-7 基因轉染效果比較 147 4-8 細胞毒性分析 158 第五章 結論 162 第六章 參考文獻 164 第三部分 溫度/酸鹼敏感性聚乙基□唑啉與聚乳酸水膠之合成與性質探討 169 第一章 研究背景與動機 170 第二章 相關理論與文獻 171 2-1 智慧型水膠 172 2-2 生分解性水膠 175 第三章 實驗方法 180 3-1 實驗藥品 180 3-2 實驗儀器與裝置 181 3-3 PEOz/3PLA系列環境敏感型水膠 181 3-4 鑑定與分析 184 3-5 SEM表面型態分析 185 3-6 水膠平衡膨潤率測試 185 3-7 水膠應答可逆性測試 186 3-8 藥物穿透性測試 186 3-9 藥物釋放 187 第四章 結果與討論 188 4-1 PEOz/3PLA化學性交聯水膠 188 4-2 3PLA-TMA之合成 190 4-3 水膠的合成與性質 192 4-4 表面形態分析 197 4-5 平衡膨潤率 199 4-6 水膠對溫度應答之可逆性 201 4-7 酸鹼值敏感性 201 4-8 體外藥物釋放 204 4-9 藥物穿透性實驗 209 第五章 結論 213 第六章 參考文獻 214 著作目錄 216

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