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研究生： 陳佑如
論文名稱： 以聚乙二醇-聚酸酐共聚物自組裝形成之混合微胞作為包覆薑黃素載體及其藥物傳送研究
Self-assembled Mixed Micelles of Methoxy Poly(ethylene glycol-polyanhydride) for Curcumin Delivery
指導教授： 朱一民
口試委員: 郭勇志
姚少凌
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： 2012
畢業學年度： 100
語文別： 中文
論文頁數： 78
中文關鍵詞： 聚酸酐 、奈米載體 、混合微胞 、薑黃素
相關次數： 點閱：3  下載：0 
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    • 兩性團聯共聚物能在水中自組裝形成核殼結構的微胞，藉此包覆疏水性藥物，提升藥物的療效，因此高分子微胞受到學者的重視。微胞依其組成與結構可分為許多類型，其中混合型微胞是將兩種以上的團聯共聚物混合形成一微胞系統，藉以彌補單一微胞功能性的不足，或同時具有兩種團聯共聚物的優點，此特性為本研究之探討的重點。
    本研究利用親水性高的甲基聚乙二醇(methoxy poly(ethylene glycol，mPEG)和疏水性高的癸二酸(sebacic acid，SA) 、1,3-雙(對羧基苯氧基)丙烷(1,3-bis(carboxyphenoxy)propane，CPP)，經熔融縮合聚合反應後，可得到mPEG-SA與mPEG-CPP的生物可降解性兩性高分子材料，再將以上兩種兩性高分子依比例混合，以溶劑揮發法製備具有自組裝性質的微胞。Mixed micelles的臨界微胞測定結果介於單一微胞系統之間，可證明確實有形成一微胞系統。Mixed micelles粒徑約為133.5nm，小於單一組成的微胞粒徑，在八天內粒徑維持在200nm以下，顯示有良好的穩定性。並透過穿透電子顯微鏡觀察，粒徑與DLS的結果是相符合的，其結構為圓形的顆粒狀。
    薑黃素(Curcumin)是一種多酚類的古老藥材，文獻指出有抗癌的功效，不過對水的溶解度極低(約2.99x10-8 mole/L)且容易降解，造成在臨床上不便於應用，因此我們藉由混合型微胞當作薑黃素的載體，改善上述之缺點。微胞在包覆後薑黃素的粒徑仍能維持在200nm以下，mixed micelles包覆效率(約40.3%)比mPEG-SA micelle(約35.6%) 和 mPEG-CPP micelle(約13.6%)還高，不過隨著薑黃素載入的量越高，包覆效率也隨之降低，在藥物/高分子比為0.1時，mixed micelles依然可包覆薑黃素而呈黃色澄清溶液，其餘則呈混濁狀態表示過多薑黃素無法被包覆而析出。藥物釋放結果顯示mixed micelles具有以階段性釋放，且突然釋放(initial burst)有減緩的現象。細胞毒殺實驗以HeLa cells為目標細胞，細胞存活率與薑黃素濃度相關，隨著薑黃素濃度增加，細胞存活率下降。
    從以上結果得知，mixed micelles具有多種優勢，如降低粒徑、提升藥物包覆、提供階段性藥物釋放及促進細胞吞噬等，可提高薑黃素的利用率，顯示出具有相當良好的發展潛力。

    摘要 I Abstract III 目錄 IV 圖目錄 VII 表目錄 IX 第一章 文獻探討 1 1-1 醫用高分子材料 1 1-2 生物可分解性高分子材料的簡介 2 1-2-1 天然生物可分解性高分子 3 1-2-2 合成生物可分解性高分子 4 1-3 聚酸酐 7 1-3-1 聚酸酐的簡介 7 1-3-2 聚酸酐的製備 9 1-3-3 聚酸酐的種類 11 1-3-4 聚酸酐的降解與侵蝕 12 1-3-5 聚酸酐的生物相容性 14 1-4 藥物制放系統 16 1-4-1 藥物控制釋放系統之機制 17 1-4-2 常見藥物制放載體之類型 17 1-5 高分子奈米微胞 19 1-5-1 高分子微胞的形成 20 1-5-2 高分子奈米微胞的製備 21 1-5-3 影響奈米微胞穩定性的因素 22 1-5-4 高分子微胞的應用 23 1-6 混合型微胞 24 1-7 抗癌藥物之薑黃素 25 第二章 研究動機與目的 27 第三章 實驗架構、藥品與儀器 29 3-1實驗架構 29 3-2 實驗藥品 30 3-3 實驗儀器 31 第四章 實驗步驟 33 4-1 兩性高分子製備及鑑定 33 4-1-1 甲基聚乙二醇 (mPEG-OH)改質 33 4-1-2 酸酐化Sebacic acid (pre-SA) 34 4-1-3 合成1,3-雙(對羧基苯氧基)丙烷(1,3bis(p-carboxyphenoxy)propane, CPP)單體 35 4-1-4 酸酐化CPP (CPPa) 36 4-1-5 mPEG-SA團聯共聚物熔融縮合聚合反應 37 4-1-6 mPEG-CPP團聯共聚物熔融縮合聚合反應 38 4-1-7高分子性質鑑定 39 4-2 臨界微胞濃度(CMC)量測 40 4-3 高分子微胞製備及性質測定 41 4-3-1 製備高分子奈米微胞與穩定度測試 41 4-3-2 高分子微胞外觀型態(morphology)的觀測 42 4-4 高分子微胞包覆藥物的製備與藥物釋放實驗 42 4-4-1 高分子微胞包覆薑黃素(Curcumin)的製備 42 4-4-2 藥物包覆效率與藥物含量的測試 43 4-4-3 微胞藥物釋放實驗 44 4-5 含藥物微胞之細胞毒性測試 44 4-6 細胞吞噬微胞實驗 45 第五章 實驗結果與討論 47 5-1 mPEG-SA、mPEG-CPP二團聯共聚物結構鑑定 47 5-1-1 甲基聚乙二醇改質醇基為酸基(mPEG5000) 47 5-1-2 酸酐化Sebacic acid (pre-SA) 49 5-1-3 合成CPP單體 50 5-1-4 酸酐化CPP 52 5-1-5 mPEG-SA、mPEG-CPP結構鑑定 53 5-2 臨界微胞濃度(CMC)的測定 55 5-3 高分子微胞粒徑及其穩定度測試 58 5-3-1 微胞冷凍乾燥後的粒徑分析 58 5-3-2 奈米微胞穩定度測試 59 5-3-3 奈米微胞酸鹼值的變化 60 5-4 高分子微胞外觀型態(morphology)的觀測 61 5-5 高分子微胞包覆薑黃素(Curcumin)之粒徑分析 61 5-6 高分子微胞包覆薑黃素(Curcumin)之效率與含量 63 5-6-1 包覆藥物效率的比較 63 5-6-2 藥物含量的比較 64 5-7 高分子微胞包覆薑黃素(Curcumin)的釋放實驗 65 5-8 高分子微胞包覆薑黃素(Curcumin)之熱分析 68 5-9 高分子微胞包覆薑黃素(Curcumin)的細胞毒殺實驗 69 5-10 細胞吞噬實驗 72 第六章 結論與未來展望 73 參考文獻 75 附錄 78

    1. Pillai, O.; Panchagnula, R., Polymers in drug delivery. Current Opinion in Chemical Biology 2001, 5, (4), 447-451.
    2. Sipe, J. D., Tissue engineering and reparative medicine. Annals of the New York Academy of Sciences 2002, 961, (1), 1-9.
    3. Vacanti, J. P.; Langer, R.; Upton, J.; Marler, J. J., Transplantation of cells in matrices for tissue regeneration. Advanced drug delivery reviews 1998, 33, (1-2), 165.
    4. Langer, R., Drug delivery and targeting. Nature 1998, 392, (6679), 5-10.
    5. Uhrich, K. E.; Cannizzaro, S. M.; Langer, R. S.; Shakesheff, K. M., Polymeric systems for controlled drug release. Chemical Reviews 1999, 99, (11), 3181-3198.
    6. Kumar, M.; Kumar, N.; Domb, A.; Arora, M., Pharmaceutical polymeric controlled drug delivery systems. Filled elastomers drug delivery systems 2002, 45-117.
    7. Kopecek, J.; Ulbrich, K., Biodegradation of biomedical polymers. Progress in polymer science 1983, 9, (1), 1-58.
    8. Chadra, R.; Rustgi, R., Biodegradable polymers. Prog. Polym. Sci 1998, 23, 1273-1335.
    9. Cook, A. D.; Hrkach, J. S.; Gao, N. N., IM Johnson, U. B. Pajvani. SM Cannizzaro. R. Langer. Characterization and development of RGD-peptide-modified poly-(lactic acid-co-lysine) as an interactive, resorbable biomaterial. J. Biomed. Mater. Res 1997, 35, (4), 513-523.
    10. Heath, C. A., Cells for tissue engineering. Trends in biotechnology 2000, 18, (1), 17-19.
    11. Jain, J. P.; Modi, S.; Domb, A. J.; Kumar, N., Role of polyanhydrides as localized drug carriers. Journal of controlled release 2005, 103, (3), 541-563.
    12. Bucher, J. E.; Slade, W. C., The anhydrides of isophthalic and terephthalic acids. Journal of the American Chemical Society 1909, 31, (12), 1319-1321.
    13. Carothers, W. H.; Hill, J. W., Studies of polymerization and ring formation. XV. Artificial fibers from synthetic linear condensation superpolymers. Journal of the American Chemical Society 1932, 54, (4), 1579-1587.
    14. Conix, A., Aromatic polyanhydrides, a new class of high melting fiber forming polymers. Journal of Polymer Science 1958, 29, (120), 343-353.
    15. Yoda, N., Syntheses of polyanhydrides. XII. Crystalline and high melting polyamidepolyanhydride of methylenebis (p carboxyphenyl) amide. Journal of Polymer Science Part A: General Papers 1963, 1, (4), 1323-1338.
    16. Leong, K. W.; Brott, B. C.; Langer, R., Bioerodible polyanhydrides as drug carrier matrices. I: Characterization, degradation, and release characteristics. Journal of biomedical materials research 1985, 19, (8), 941-955.
    17. Domb, A. J.; Langer, R., Polyanhydrides. I. Preparation of high molecular weight polyanhydrides. Journal of Polymer Science Part A: Polymer Chemistry 1987, 25, (12), 3373-3386.
    18. Albertsson, A. C.; Lundmark, S., Synthesis, characterization and degradation of aliphatic polyanhydrides. British Polymer Journal 1990, 23, (3), 205-212.
    19. Gopferich, A.; Tesmar, J., Polyanhydride degradation and erosion. Advanced drug delivery reviews 2002, 54, (7), 911-931.
    20. Teomim, D.; Nyska, A.; Domb, A. J., Ricinoleic acid based biopolymers. Journal of biomedical materials research 1999, 45, (3), 258-267.
    21. Gopferich, A., Polymer bulk erosion. Macromolecules 1997, 30, (9), 2598-2604.
    22. Gopferich, A.; Langer, R., Modeling of polymer erosion in three dimensions: rotationally symmetric devices. AIChE Journal 1995, 41, (10), 2292-2299.
    23. Laurencin, C.; Domb, A.; Morris, C.; Brown, V.; Chasin, M.; McConnell, R.; Lange, N.; Langer, R., Poly (anhydride) administration in high doses in vivo: studies of biocompatibility and toxicology. Journal of biomedical materials research 1990, 24, (11), 1463-1481.
    24. Tamargo, R. J.; Epstein, J. I.; Reinhard, C. S.; Chasin, M.; Brem, H., Brain biocompatibility of a biodegradable, controlled release polymer in rats. Journal of biomedical materials research 1989, 23, (2), 253-266.
    25. Brem, H.; Kader, A.; Epstein, J. I.; Tamargo, R. J.; Domb, A.; Langer, R.; Leong, K. A. M. W., Biocompatibility of a biodegradable, controlled-release polymer in the rabbit brain. Selective Cancer Therapeutics 1989, 5, (2), 55-65.
    26. Uhrich, K. E.; Cannizzaro, S. M.; Langer, R. S.; Shakesheff, K. M., Polymeric systems for controlled drug release. Chemical Reviews-Columbus 1999, 99, (11), 3181-3198.
    27. Weiner, N.; Martin, F.; Riaz, M., Liposomes as a drug delivery system. Drug Development and Industrial Pharmacy 1989, 15, (10), 1523-1554.
    28. Torchilin, V. P., Structure and design of polymeric surfactant-based drug delivery systems. Journal of controlled release 2001, 73, (2-3), 137-172.
    29. Kumar, N.; Ravikumar, M. N. V.; Domb, A. J., Biodegradable block copolymers. Advanced drug delivery reviews 2001, 53, (1), 23-44.
    30. Kabanov, A. V.; Nazarova, I. R.; Astafieva, I. V.; Batrakova, E. V.; Alakhov, V. Y.; Yaroslavov, A. A.; Kabanov, V. A., Micelle formation and solubilization of fluorescent probes in poly (oxyethylene-b-oxypropylene-b-oxyethylene) solutions. Macromolecules 1995, 28, (7), 2303-2314.
    31. Allen, C.; Maysinger, D.; Eisenberg, A., Nano-engineering block copolymer aggregates for drug delivery. Colloids and Surfaces B: Biointerfaces 1999, 16, (1-4), 3-27.
    32. Nagarajan, R.; Ganesh, K., Block copolymer self-assembly in selective solvents: theory of solubilization in spherical micelles. Macromolecules 1989, 22, (11), 4312-4325.
    33. Shim, D. F. K.; Marques, C.; Cates, M. E., Diblock copolymers: comicellization and coadsorption. Macromolecules 1991, 24, (19), 5309-5314.
    34. Borovinskii, A. L.; Khokhlov, A. R., Micelle formation in the dilute solution mixtures of block-copolymers. Macromolecules 1998, 31, (22), 7636-7640.
    35. Lo, C. L.; Lin, S. J.; Tsai, H. C.; Chan, W. H.; Tsai, C. H.; Cheng, C. H. D.; Hsiue, G. H., Mixed micelle systems formed from critical micelle concentration and temperature-sensitive diblock copolymers for doxorubicin delivery. Biomaterials 2009, 30, (23-24), 3961-3970.
    36. Yang, L.; Wu, X.; Liu, F.; Duan, Y.; Li, S., Novel biodegradable polylactide/poly (ethylene glycol) micelles prepared by direct dissolution method for controlled delivery of anticancer drugs. Pharmaceutical research 2009, 26, (10), 2332-2342.
    37. Alakhov, V.; Klinski, E.; Li, S.; Pietrzynski, G.; Venne, A.; Batrakova, E.; Bronitch, T.; Kabanov, A., Block copolymer-based formulation of doxorubicin. From cell screen to clinical trials. Colloids and Surfaces B: Biointerfaces 1999, 16, (1-4), 113-134.
    38. Yoo, H. S.; Park, T. G., Folate receptor targeted biodegradable polymeric doxorubicin micelles. Journal of controlled release 2004, 96, (2), 273-283.
    39. Huang, C. K.; Lo, C. L.; Chen, H. H.; Hsiue, G. H., Multifunctional micelles for cancer cell targeting, distribution imaging, and anticancer drug delivery. Advanced Functional Materials 2007, 17, (14), 2291-2297.
    40. Lin, Y. G.; Kunnumakkara, A. B.; Nair, A.; Merritt, W. M.; Han, L. Y.; Armaiz-Pena, G. N.; Kamat, A. A.; Spannuth, W. A.; Gershenson, D. M.; Lutgendorf, S. K., Curcumin inhibits tumor growth and angiogenesis in ovarian carcinoma by targeting the nuclear factor-κB pathway. Clinical cancer research 2007, 13, (11), 3423-3430.
    41. Letchford, K.; Liggins, R.; Burt, H., Solubilization of hydrophobic drugs by methoxy poly (ethylene glycol)-block-polycaprolactone diblock copolymer micelles: Theoretical and experimental data and correlations. Journal of pharmaceutical sciences 2008, 97, (3), 1179-1190.
    42. Zhao, L.; Du, J.; Duan, Y.; Zang, Y.; Zhang, H.; Yang, C.; Cao, F.; Zhai, G., Curcumin loaded mixed micelles composed of Pluronic P123 and F68: Preparation, optimization and in vitro characterization. Colloids and Surfaces B: Biointerfaces 2012, 97, (1), 101-108.

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