新穎聚離子錯合型微胞運用於抗菌藥物輸送之研發

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研究生：	王韋婷 Wang, Wei-Ting
論文名稱：	新穎聚離子錯合型微胞運用於抗菌藥物輸送之研發 Development of Novel Polyion Complex Micelles for Antifungal Drug Delivery
指導教授：	薛敬和 Hsiue, Ging-Ho
口試委員:
學位類別：	碩士 Master
系所名稱：	工學院 - 化學工程學系 Department of Chemical Engineering
論文出版年：	2007
畢業學年度：	95
語文別：	中文
論文頁數：	99
中文關鍵詞：	兩性黴素B 、聚□唑啉、聚天冬胺酸、聚離子錯合型微胞、藥物控制釋放、體外抗黴菌效率
外文關鍵詞：	Amphotericin B, poly(2-ethyl-2-oxazoline), poly(aspartic acid), Polyion complex micelle, Drug controlled release, Antifungal activity
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本研究之目的是利用聚□唑啉-聚天冬胺酸兩團聯共聚物(Poly(2-ethyl-2-oxazoline)-block-Poly(aspartic acid)，PEOz-b-PAsp)以靜電作用力包覆正電藥物兩性黴素B (amphotericin B)，形成具有核殼結構 (core-shell structure)新穎性聚離子錯合型微胞 (polyion complex micelles，PIC micelles)做為藥物輸送載體。內核的聚胺基酸高分子Poly(aspartic acid) (PAsp)，為親水性高分子，側端具有羧基，在水溶液酸鹼值高於pKa (pH>5.2)環境下會解離，能以離子鍵攜帶大量陽離子藥物，亦提供疏水性物理作用力，增加藥物包覆效率。使用薄膜水合法製備出的AmB/PEOz-b-PAsp之聚離子錯合型微胞其平均粒徑在150 nm以下，且包覆率均達40 %以上。在藥物釋放部分，AmB/PEOz-b-PAsp之聚離子錯合型微胞在40小時可將60 % AmB釋放。在抗菌實驗中，AmB/PEOz-b-PAsp之聚離子錯合型微胞其最低抑制濃度 (MIC) 為20μg/mL。在三天後仍然有效抑制菌的生長，抗菌時效比Fungizone®更佳。成功將AmB/PEOz-b-PAsp PIC微胞運用於藥物傳遞，AmB/PEOz-b-PAsp PIC微胞有效率將AmB包覆和釋放，對於抑制真菌有長效作用，並且對於正常細胞沒有產生明顯毒性。綜合以上實驗結果得知，本研究中成功利用兩團聯共聚物建立出新穎性聚離子錯合型微胞，其具有奈米尺寸、低毒性，高藥物釋放效率等優點，對於藥物傳輸系統上具有相當應用之潛力。
關鍵字: 兩性黴素B (amphotericin B)、聚□唑啉、聚天冬胺酸、聚離子錯合型微胞、藥物控制釋放、體外抗黴菌效率

A novel poly(2-ethyl-2-oxazoline)-block-poly(aspartic acid) (PEOz-b-PAsp) was synthesized and investigated as a potential carrier for the amphotericin B (AmB) delivery in forming polyion complex (PIC) micelles. Nano-scale AmB/PEOz-b-PAsp PIC micelles were prepared by thin film method. The nano-scale PIC micelles with core-shell structure were formed with a hydrophilic outer shell and dissociation of the carboxylic group from PAsp to become a hydrophobic inner core for drug delivery application. The resulting nano-scale PIC micelles with AmB and PEOz-b-PAsp showed an average diameter about 108 nm. The drug content of the PIC micelles can be as high as 47 % in phosphate buffer solution with pH 7.4. The release of AmB from nano-scale PIC micelles was 60 % at 40 h in phosphate buffer solution with pH 7.4. The minimal inhibitory concentration (MIC) of PIC micelles was 20μg/mL, and antifungal activity of PIC micelles was better than Fungizone® during 72 hrs. In conclusion, AmB/PEOz-b-PAsp PIC micelles were developed and optimized for drug delivery to allow efficient antifungal activity with low cytotoxicity. Engineering of biodegradable polymers to form non-covalent drug-polymer interactions of PIC micelles constitutes a useful approach for the future design of drug carriers.
Keywords: Amphotericin B, Diblock copolymer, Polyion complex micelle, Drug controlled release, Antifungal activity.

目    錄
摘    要………………………………………………………I
Abstract………………………………………………………II
目    錄………………………………………………………III
圖 目 錄………………………………………………………VII
表 目 錄………………………………………………………XI



第一章 研究背景與動機....................................1
第二章 相關理論與文獻....................................4
2-1. 生物可分解高分子....................................4
2-2聚醯胺 (polyamide)與聚胺基酸(polyamino acid)..........6
2-2-1聚胺基酸............................................7
2-2-2聚醯胺..............................................7
2-3 聚□唑啉 (poly(2-oxazoline)).........................9
2-3-1起始劑 (initiators).................................11
2-3-2反應機構............................................12
2-3-4性質與應用..........................................14
2-4 聚天冬胺酸 (polyaspartic acid).......................15
2-4-1起始劑 (initiators).................................17
2-4-2反應機構............................................18
2-4-5性質與應用..........................................19
2-5 藥物介紹 (amphotericin B，AmB).......................21
2-5 高分子微胞在藥物制放上的應用.........................26
2-5-1高分子微胞的化學結構................................26
2-5-2藥物包覆的方式......................................27
2-6 聚離子錯合型微胞 (polyion complex micelles)..........31
第三章 實驗方法..........................................34
3-1 實驗藥品.............................................34
3-2 實驗儀器與裝置.......................................36
3-3 名詞對照.............................................37
3-4 兩團聯共聚物poly(2-ethyl-2-oxazoline)-b-poly(aspartic acid) (PEOz-b-PAsp)之合成................................38
3-4-1 N-carboxy-β-benzyl-L-aspartate anhydride (Asp(OBzl)-NCA)之合成.......................................................38
3-5巨起始劑 (macroinitiator) PEOz-NH2之合成與鑑定........39
3-6 兩團聯共聚物poly(2-ethyl-2-oxazoline)-b-poly(β-benzyl- L-aspartate) (PEOz-b-PBAsp) 之合成.......................40
3-7兩團聯共聚物poly(2-ethyl-2-oxazoline)-b-poly(aspartic acid) (PEOz-b-PAsp)之合成................................41
3-8 鑑定與分析...........................................42
3-8-1分子量及分子量分佈..................................42
3-8-2 1H-NMR與FT-IR光譜分析..............................42
3-8-3 末端一級胺比例分析(TNBS method)....................42
3-9 兩團聯共聚物之酸鹼滴定分析...........................43
3-10 兩團聯共聚物之光學穿透度測試........................43
3-11 製備AmB/PEOz-b-PAsp 聚離子錯合型微胞 (polyion complex micelles，PIC micelles)..................................44
3-11-1 AmB/PEOz-b-PAsp PIC micelles之粒徑分析............44
3-11-2 AmB/PEOz-b-PAsp PIC micelles之藥物包覆量分析......44
3-11-3 AmB/PEOz-b-PAsp PIC micelles之表面結構分析........45
3-12 聚離子錯合型微胞之體外藥物釋放模擬..................46
3-13 聚離子錯合型高分子微胞之穩定性測試..................47
3-14 聚離子錯合型高分子微胞之細胞毒性....................48
3-15 聚離子錯合型微胞之體外抗菌實驗 (In vitro antifungal)..............................................49
第四章 結果與討論........................................50
4-1 Asp(OBzl)-NCA之合成與鑑定............................50
4-2巨起始劑 (macroinitiator) PEOz-NH2之合成與鑑定........54
4-3兩團聯共聚物PEOz-b-PBAsp 之合成與鑑定.................57
4-4兩團聯共聚物PEOz-b-PAsp之合成與鑑定...................61
4-5 兩團聯共聚物PEOz-b-PAsp之緩衝性質分析................64
4-6 兩團聯共聚物PEOz-b-PAsp之光學穿透度分析..............66
4-7 兩團聯共聚物PEOz-b-PAsp之細胞毒性....................69
4-8聚離子錯合型高分子微胞 (AmB/PEOz-b-PAsp PIC micelles) 之性質分析.................................................71
4-8-1 AmB及聚離子錯合物微胞全波長掃瞄之吸收光譜..........73
4-8-2 粒徑分析...........................................75
4-8-3 聚離子錯合型微胞之藥物包覆量分析...................78
4-8-4聚離子錯合型微胞之表面型態分析......................80
4-9聚離子錯合型微胞之體外藥物釋放模擬....................82
4-9聚離子錯合型微胞之穩定性測試..........................84
4-10聚離子錯合型微胞之細胞毒性...........................85
4-12聚離子錯合型微胞之體外抗菌試驗.......................87
第五章 結論..............................................91
第六章 參考文獻..........................................93

圖目錄

圖2- 1. 生物可分解高分子分解途徑.........................6
圖2- 2. 三級醯胺之共振結構...............................9
圖2- 3. Oxazoline聚合反應之異構化........................10
圖2- 4. 聚合2-oxazoline之雙官能基起始劑..................11
圖2- 5. 反陰離子與成長物質的親核性比較...................13
圖2- 6. 2-oxazolines聚合之反應機構.......................13
圖2- 7. 常見生物可分解高分子.............................15
圖2- 8. 利用水解合成聚天冬胺酸...........................16
圖2- 9. 利用熱縮合法合成聚天冬胺酸.......................17
圖2- 10. Amine mechanism.................................18
圖2- 11. AM mechanism....................................18
圖2 12. 天冬胺酸結構.....................................19
圖2 13. Amphotericin B結構...............................22
圖2 14. 高分子微胞包覆藥物的方法 (a) 透析法(b) 乳化法....28
圖 2 15. 微胞所形成高分子藥物............................29
圖2-16. 化學鍵結包覆藥物之示意圖.........................30
圖2- 17. PEG-g-PAsp 形成PIC示意圖........................32
圖3- 1.  Asp(OBzl)-NCA合成示意圖.........................38
圖3- 2. 合成PEOz-NH2之示意圖.............................39
圖3- 3. 合成PEOz-b-PBAsp之示意圖.........................40
圖3- 4. 合成PEOz-b-PAsp之示意圖..........................41
圖3- 5. 以Glycine配置為標準品之一級胺濃度檢量線..........43
圖3- 6. Amphotericin B 在緩衝溶液(pH7.4)/ DMSO等比混合溶液之檢量線...................................................45
圖3-7. AmB 在pH 7.4 磷酸鹽緩衝溶液之檢量線...............46
圖4- 1. Asp(OBzl)-NCA及β-Benzyl L-aspartate之FT-IR光譜...52
圖4- 2. β-Benzyl L-aspartate之1H-NMR光譜.................53
圖4- 3. Asp(OBzl)-NCA之1H-NMR光譜........................53
圖4- 4. 單體2-ethyl-2-oxazoline之1H-NMR光譜..............55
圖4- 5. PEOz-NH2之1H-NMR光譜.............................56
圖4- 6. PEOz-NH2之FT-IR光譜    ..............................56
圖4- 7. PEOz-b-PBAsp之GPC鑑定分析........................58
圖4- 8. PEOz-b-PBAsp與PEOz-NH2之FT-IR光譜................60
圖4- 9. PEOz-b-PBAsp之1H-NMR光譜.........................60
圖4- 10. PEOz-b-PAsp之FT-IR光譜..........................63
圖4- 11. PEOz-b-PAsp之1H-NMR光譜.........................63
圖4- 12. PEOz-b-PAsp解離示意圖...........................64
圖4- 13. PEOz-b-PAsp之滴定曲線...........................65
圖4- 14. PEOz-b-PAsp於解離後產生之分子內與分子間氫鍵.....66
圖4- 15. PEOz-b-PAsp於解離後高分子鏈段形成聚集現象.......67
圖4- 16. PEOz-b-PAsp於不同pH值下光學穿透度之改變情形.....68
圖4- 17. PEOz-b-PAsp於不同pH值下之照片...................68
(a)A92B31；(b)A92B12.....................................68
圖4- 18. 兩團聯共聚物在各種濃度下與HT1080培養24小時之細胞存活率(n=4).............................................    70
圖4- 19. 兩團聯共聚物在各種濃度下與HT1080培養72小時之細胞存活率(n=4)................................................70
圖4- 20. 聚離子錯合型型微胞製備之示意圖..................72
圖4- 21. AmB及聚離子錯合型微胞之UV-Vis全波長掃瞄吸收光譜.74
圖4- 22.聚離子錯合型微胞形成之示意圖.....................75
圖4- 23. 不同AmB與Polymer莫耳比下之粒徑變化圖............77
圖4- 24. 聚離子錯合型微胞之藥物包覆率....................78
圖4- 25.聚離子錯合型微胞形成之示意圖.....................79
圖4- 26聚離子錯合型微胞之TEM影像.........................81
圖4- 27聚離子錯合型微胞之AFM影像.........................81
圖4- 28 聚離子錯合型微胞於pH7.4下體外藥物釋放行為........83
圖4- 29含有4 wt. %BSA之pH 7.4緩衝溶液下聚離子錯合型微胞之粒徑與時間關係圖(37℃).....................................84
圖4- 30 兩團聯共聚物、Fungizone®與聚離子錯合型微胞在各種濃度下與HT1080培養24小時之細胞存活率(n=4)..................86
圖4- 31 兩團聯共聚物、Fungizone®與聚離子錯合型微胞在各種濃度下與HT1080培養72小時之細胞存活率(n=4)..................86
圖4- 32 Fungizone®與聚離子錯合型微胞在不同濃度下與C. albicans培養24小時對其生長抑制效果(n=4)..................88
圖4- 33聚離子錯合型微胞在不同濃度下與C. albicans培養24小時對其生長抑制照片(n=4)......................................88
圖4- 34 Fungizone®在不同濃度下與C. albicans培養24小時對其生長抑制照片(n=4)..........................................89
圖4- 35 Fungizone®與聚離子錯合型微胞在不同濃度下與C. albicans培養72小時對其生長抑制效果（n=4).................89
圖4- 36聚離子錯合型微胞在不同濃度下與C. albicans培養72小時對其生長抑制照片(n=4)).....................................90
圖4- 37 Fungizone®在不同濃度下與C. albicans培養72小時對其生長抑制照片(n=4)..........................................90

表目錄
表2-1. 常見之生物可分解性高分子...........................5
表2-2. 聚合2-oxazoline常用之起始劑.......................12
表2-2. 各種鍵結型高分子微胞之比較........................33
表4- 1. Asp(OBzl)NCA之進料比與性質分析...................52
表4- 2. PEOz-NH2之進料比與性質分析.......................55
表4- 3. PEOz-b-PBAsp之組成比與性質分析...................58
表4- 4. PEOz-b-PAsp之產率與性質分析......................62
表4-5 PEOz-b-PAsp PIC micelles之粒徑與分佈...............76

                                

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