酸鹼響應的雙性嵌段共聚物之高分子液胞應用於親疏水性雙藥物載體

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研究生：	林耿緯 Lin, Keng-Wei.
論文名稱：	酸鹼響應的雙性嵌段共聚物之高分子液胞應用於親疏水性雙藥物載體 pH-Sensitive Polymersomes Formed from AB2-Type Amphiphilic Block Copolymers for Both Hydrophilic and Hydrophobic Drug Release
指導教授：	彭之皓 Peng, Chi-How
口試委員:	陳俊太 Chen, Jiun-Tai 王潔 Wang, Jane
學位類別：	碩士 Master
系所名稱：	理學院 - 化學系 Department of Chemistry
論文出版年：	2019
畢業學年度：	108
語文別：	中文
論文頁數：	104
中文關鍵詞：	高分子液胞、酸鹼響應、阿黴素、羅丹明B
外文關鍵詞：	polymersome, pH-response, doxorubicin, rhodamine B
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以化療藥物進行癌症治療時，常因為藥物缺乏專一性而導致嚴重副作用，且常誘發癌症細胞之多重抗藥性(multi drug resistance)，導致治療效果不彰。奈米載體 (nanocarriers) 攜帶化療藥物，在分子上做修飾，設計出有刺激響應行為的載體，再提升專一性，並又使用雞尾酒療法，同時攜帶二種以上之藥物，有希望能解決癌細胞之多重抗藥性問題。本研究設計支鏈型雙嵌段共聚物 PEG113-b-(PDPA32)2 做為奈米藥物載體的材料，藉由兩性高分子之兩端親疏水性差異，自組裝形成一種類似於脂質體，外殼層為疏水區域、核心層為親水區域結構之高分子液胞 (polymersome)，可同時包覆親/疏水藥物。除此之外，經過分子設計，擁有酸鹼響應性質，使其在癌細胞偏酸之環境釋放藥物。本研究攜帶疏水藥物阿黴素 (doxorubicin, Dox) 以及親水染料羅丹明 B (Rhodamine B) 來測試高分子液胞的酸鹼刺激響應 (pH-response) 行為。

To prevent the drug resistance of cancer cells and enhance the drug release efficiency, we designed block copolymers of PEG113-b-(PDPA32)2 with pH-sensitive hydrophobicity segment poly(2-(diisopropylamino) ethyl methacrylate) (PDPA) as polymersome type of nanocarriers, which could collapse and drug release in the tumor tissue because of the low pH. Polymersome, a class of artificail vesicles containing hydrophilic zone and hydrophobic zone in their core and shell, repectively, is usually self-assembled from amphiphilic diblock copolymer. It exhibits good mechanical stability, which could bring both hydrophilic and hydrophobic drugs for cocktail therapy. In this study, we characterize the pH-response of nanocarriers with hydrophilic dye of Rhodamine B and hydrophobic drug of Doxorubicin.

摘要 ...................................................................................................................................... I
Abstract .............................................................................................................................. II
謝誌 ................................................................................................................................... III
目錄 ................................................................................................................................... IV
圖目錄 ............................................................................................................................ VIII
表目錄 ................................................................................................................................. X
式目錄 ............................................................................................................................... XI
附錄 .................................................................................................................................. XII
第一章 文獻回顧 ........................................................................................................ 13
1-1 癌症治療 ................................................................................................................ 13
1-1-1 癌症種類 ............................................................................................................ 13
1-1-2 癌症之治療方式 ................................................................................................ 13
1-1-3 標靶藥物治療 .................................................................................................... 15
1-2 治療癌症之奈米級藥物載體原理........................................................................ 17
1-2-1 增強通透與滯留效應 (Enhanced Permeability and Retention Effect, EPR) .. 17
1-2-2 腫瘤微環境 (Tumor Microenvironment) ......................................................... 18
1-2-3 核內體逃脫 (Endosomal Escape) ..................................................................... 19
1-3 高分子微胞/液包特性 .......................................................................................... 21
1-3-1 刺激響應型高分子液胞奈米載體 (Stimuli-Responsive Polymersomeric Nanocarrier) ................................................................................................................... 21
1-3-2 高分子微胞酸鹼響應機構 ................................................................................ 23
1-4 自由基聚合............................................................................................................ 25
V
1-4-1 活性自由基聚合(Control/Living radical polymerization, LRP) ...................... 25
1-4-2 原子轉移自由基聚合反應 (Atom Transfer Radical Polymerization, ATRP) 28
1-4-3 鈷金屬錯合物調控活性自由基聚合(Cobalt-mediated radical polymerization, CMRP) ........................................................................................................................... 29
1-4-4 聚合反應誘發之自組裝行為 (Polymerization- induced silf-assembly, PISA) 32
1-5 研究動機 ................................................................................................................ 32
第二章 實驗方法與步驟............................................................................................ 34
2-1 水相鈷金屬錯合物調控活性自由基聚合反應 ................................................... 34 2-1-1 N-乙烯基吡咯烷酮 (NVP) 之活性自由基聚合 ............................................. 34
2-1-2 兩性嵌段共聚物(amphiphilic) 之乳液聚合反應 ............................................ 34
2-1-3 PVP-b-PVAc兩性嵌段共聚物(amphiphilic) 行成之微胞粒徑分析 ............. 34
2-2 在光引發劑系統下進行鈷金屬錯合物調控活性自由基聚合反應 ................... 35
2-3 AB2-type支鏈型雙嵌段共聚物之合成與鑑定 ................................................... 35
2-3-1 2,2’-bis(methyl-α-bromoisobutyrate) propionic acid之合成 ............................ 35
2-3-2 AB2-type巨引發劑PEG-BBPA之合成 .......................................................... 36
2-3-3 Poly(ethylene glycol)113-b-poly(2-diisopropylamino32)2 (PEG113-b- (PDPA32)2)之支鏈型雙嵌段共聚物合成 ..................................................................... 37
2-4 PEG113-b-PDPA63共聚物之合成與鑑定 ............................................................. 38
2-4-1 PEG113-Br 巨引發劑之合成 ............................................................................. 38
2-4-2 Poly(ethylene glycol)113-b-poly(2-Diisopropylamino)63(PEG113-b-PDPA63)之共聚物合成 ........................................................................................................................ 39
2-5 高分子之材料特性與刺激響應分析 ................................................................... 39
2-5-1 臨界微胞濃度 (Critical Micelle Concentration, CMC) 之測定47 ................. 39
2-5-2 酸鹼性質滴定48 ................................................................................................ 40
2-5-3 高分子對酸鹼值之靈敏度測定49 .................................................................... 40
2-6 高分子奈米液胞製備與響應分析........................................................................ 40
2-6-1 高分子奈米液胞製程 ........................................................................................ 40
2-6-2 高分子奈米液胞粒徑分析 ................................................................................ 42
VI
2-6-3 高分子奈米液胞酸鹼響應分析 ........................................................................ 42
2-7 以PEG113-b-(PDPA32)2支鏈型雙嵌段共聚物包覆及釋放阿黴素 .................... 43
2-7-1 製備包覆阿黴素之高分子奈米液胞與分析 .................................................... 43
2-7-2 製作阿黴素濃度對螢光放射強度之減量線 .................................................... 44
2-7-3 包覆阿黴素之高分子奈米液胞在酸鹼響應下之釋放 .................................... 45
2-8 以PEG-b-(PDPA32)2 支鏈型雙嵌段共聚物包覆及釋放羅丹明B ................... 46
2-8-1 製備包覆羅丹明B之高分子奈米液胞與分析 ............................................... 46
2-8-2 製作羅丹明B濃度對螢光放射強度之減量線 ............................................... 48
2-8-3 包覆羅丹明B之高分子奈米液胞在酸鹼響應下之釋放 ............................... 48
2-9 以PEG-b-(PDPA32)2 支鏈型雙嵌段共聚物包覆及釋放阿黴素與羅丹明B ... 48
2-9-1 製備包覆阿黴素與羅丹明B之高分子奈米液胞與分析 ............................... 48
2-9-2 包覆阿黴素與羅丹明B之高分子奈米液胞在酸鹼響應下之釋放 ............... 49
第三章 以水溶性CoII(Salen-NEt2)錯合物 活性自由基聚合 .............................. 51
3-1 實驗設計 ................................................................................................................ 51 3-2 CoII(Salen-NEt2)-NVP巨起始劑與氧氣反應之探討 ........................................ 52
3-3 PVP-b-PVAc 之聚合反應誘發之自組裝行為 ................................................... 54 3-4 N-乙烯基吡咯烷酮之光引發水相活性自由基聚合 ........................................... 60 3-5 N,N-二甲基丙烯酰胺之光引發水相活性自由基聚合 ....................................... 61
3-6 結論 ........................................................................................................................ 63
第四章 高分子液胞奈米載體包覆親疏水性藥物 ................................................... 65
4-1 實驗設計 ................................................................................................................ 65
4-2 PEG113-b-(PDPA32)2支鏈型雙嵌段共聚物與PEG-b-PDPA63直鏈型雙嵌段共聚物之酸鹼響應性比較.................................................................................................... 66
4-2-1 使用苾 (pyrene) 及動態光散射儀 (dynamic laser scattering, DLS) 不同方式下探討酸鹼響應 ........................................................................................................ 66
4-2-2 使用鹽類下加強離子強度對酸鹼響應的影響 ................................................ 70
VII
4-3 PEG113-b-(PDPA32)2奈米液胞之粒徑與酸鹼響應分析 ..................................... 73
4-3-1 PEG113-b-(PDPA32)2液胞性質 .......................................................................... 73
4-3-2 酸鹼值對PEG113-b-(PDPA32)2液胞粒徑之影響 ............................................. 75
4-4 以PEG113-b-(PDPA32)2奈米液胞攜帶阿黴素 .................................................... 76
4-4-1 包覆阿黴素之PEG113-b-(PDPA32)2液胞 ......................................................... 76
4-4-2 包覆阿黴素之奈米液胞於不同酸鹼值下釋放藥物之效率 ............................ 78
4-5 以PEG113-b-(PDPA32)2奈米液胞攜帶羅丹明B ................................................ 79
4-5-1 包覆羅丹明B之PEG113-b-(PDPA32)2液胞 .................................................... 79
4-5-2 包覆羅丹明B之奈米液胞於不同酸鹼值下釋放藥物之效率 ....................... 81
4-5-3 以雙重乳化法製備高分子液胞53 .................................................................... 82
4-5-4 利用雙重乳化法包覆羅丹明B進行包覆效率探討之PEG113-b-(PDPA32)2液胞 83
4-6 以PEG113-b-(PDPA32)2奈米液胞攜帶阿黴素及羅丹明B ................................ 84
4-6-1 同時包覆阿黴素及羅丹明B之PEG113-b-(PDPA32)2液胞 ............................ 84
4-6-2 包覆阿黴素及羅丹明B之奈米液胞於不同酸鹼值下釋放藥物之效率 ....... 85
4-7 結論 ........................................................................................................................ 86
第五章 藥品與儀器.................................................................................................... 88
第六章 參考文獻 ........................................................................................................ 92
附錄 .................................................................................................................................... 97
                                

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