本研究利用一含PEG 與十八烷基之梳狀高分子來修飾微脂粒，以同時增加微脂粒物理與生物穩定性的方法。此雙性共聚合高分子係由 stearyl methacrylate, acrylic acid 與polyethylene glycol acrylate ，以偶氮二異丁 （AIBN）為起始劑，甲苯為溶劑，於 70 ℃ 下進行自由基加成聚合反應，合成具親水基及疏水基之雙性高分子。
經沉澱與超過濾純化步驟後，所得之梳狀高分子，以IR、1H-NMR、GPC 檢測其純化效果，並以 GPC 測量梳狀高分子之相對分子量（標準品為聚苯乙烯），由1H-NMR 圖譜積分值計算組成，螢光圖譜檢測臨界微胞濃度。將此雙性 PEG 接枝壓克力高分子以其十八烷基嵌入微脂粒中，而可改變微脂質的性質。其中 stearyl methacrylate 單元係藉由與微脂粒的脂肪鏈部分相溶而可嵌入微脂粒中，此即為定錨 (anchored) 作 用。再由線與平面方式的高分子主鏈相連重疊，以提高微脂粒的型態穩定性。除此之外，高分子的 PEG 側鏈部份則可站立於微脂粒表面，並且伸展於水相中，藉由 PEG 在水相中對生物分子或細胞的高度排斥作用，以大幅提高微脂粒於體內的穩定性，並增加微脂粒所包覆藥物的洩漏量，其他探討之主題尚包括經雙性 PEG 接枝高分子改質之微脂粒薄膜的結構分析、微脂粒粒徑與其對時間變化關連性、水溶性與非水溶性藥物之釋放行為等。

In this study, a novel polymer modifier designed to improve the physical and biological stability of liposomes was proposed. A series of polymeric modifiers comprising monomeric units of stearyl methacrylate, acrylic acid, and PEG acrylate was synthesized using AIBN as initiator at 70 ℃. The compositions and molecular weights of these comb copolymers were determined by IR and 1H-NMR and GPC,respectively.The fluorimetric techniques were used to characterize the properties of the aqueous solutions of comb copolymer micelles. This method is based on the measurements of the ratio of intensities of the third and first vibrational bands, I3/I1, in the emission spectra of pyrene solubilized in a polymer solution as a function of micellar concentration. The strong perturbation of the vibronic band intensities was used as a probe to accurately determine the CMC of these comb copolymers.
While stearyl methacrylate acts as an anchor by being dissolved in the phospholipid part of liposomes, the polymeric main chain further enhances the stability of liposomes by unlocalization of the PEG-grafted copolymer through liposomal surface area. PEG on the liposome surface exerts its aqueous repulsion effect on approaching macromolecules and/or cells and elevates the biological stability of the modified liposomes. In addition, the membrane structure of these polymer-coated liposomes, the dependence of liposome diameter versus time, and release behavior of water-insoluble and water-soluble model compounds were also investigated.

第一章 緒論1
1-1 研究背景與目的1
1-2 研究內容簡介2
第二章 文獻回顧4
2-1 微脂粒4
2-1-1 前言4
2-1-2 簡介5
2-1-3 微脂粒的組成5
2-2 微脂粒的製備與安定性13
2-2-1 微脂粒的製備13
2-2-2 微脂粒的安定性16
2-3 微脂粒之藥物動力學之影響18
第三章 實驗方法及設備25
3-1 實驗原料25
3-2 實驗儀器及設備26
3-3 合成步驟28
3-3-1 PEG Acrylate 之合成28
3-3-2 梳狀高分子之合成31
3-3-3 原料及梳狀高分子產品之分析37
3-3-3-1 紅外光光譜分析37
3-3-3-2 1H-NMR核磁共振光譜分析37
3-3-4 梳狀高分子之重量平均分子量38
3-3-5 臨界微胞濃度之測量38
3-3-6 雙性梳狀高分子-微脂粒複合物的製備39
3-3-7 微脂粒粒徑對時間的變化41
3-3-8 測量微脂粒相變化溫度41
3-3-9 微脂粒之藥物包覆與釋放42
3-3-10 pH 值對微脂粒表面電位之效應43
3-3-11 微脂粒之電子顯微鏡照相43
第四章 結果與討論44
4-1 梳狀高分子之鑑定44
4-1-1 IR光譜圖44
4-1-2 反應單體之1H-NMR光譜圖51
4-1-3 梳狀高分子之相對重量平均分子量58
4-1-4 臨界微胞濃度(CMC)60
4-1-5 聚合反應配方對高分子產物性質之影響62
4-2 微脂粒安定性探討63
4-2-1 梳狀高分子在微脂粒表面上之塗佈效率63
4-2-2 微脂粒粒徑與時間之關係67
4-2-3 溫度對微脂粒安定性之影響70
4-2-4 pH 對微脂粒電氣性質之影響73
4-2-5 微脂粒之結構75
4-2-6 微脂粒之藥物釋放77
4-2-7 含PEG梳狀高分子修飾微脂粒在藥物傳遞應 用上之潛力80
第五章 結論與建議81
5-1 結論81
5-2 建議82
參考文獻84
附錄87

1. A. D. Bangham, M. M. Standish and J. C. Watkins, Diffusion of Unrelevant Ions Across the Lamellae of Swollen Phospholipids. J. Mol. Biol., 1965, 13:238-252.
2. D, Papahadjopoulos, Liposomes and Their Use in Biology and Medicine. Ann. N.Y. Acad. Sci., 1978, 308:1,
3. G. Greoriadis, Preparation of Liposome in : Liposome Technology Volume I Prearation of Liposome, CRC Press, Inc., Boca Raton, Florida, 1983, pp. 31-33.
4. J. Freise and P. Magerstedt, How Does Liposome Entrapment Change the Pharmackinetics of Drug in : Liposome as Drug Carriers, Georg Thieme Verlag Stuttgart., New York, 1986, pp. 182-210.
5. (a) G. V. Betageri, S. A. Jenkins and D. L. Parson, Pharmaceutical Applications of Liposomes in : Liposome Drug Delivery Systems, Technomic Pubilshing Co., Inc., Lancaster. Basel, 1993, pp. 65-81; (b) ibid., pp. 7-18; (c) ibid., pp. 27-44; (d) ibid., pp. 47-55.
6. M. J. Ostro and P. R. Cullis, Use of Liposomes as Injectable-Drug Delivery Systems. American Journal of Hospital Pharmacy, 1989, 46: 1576-1587.
7. S. M. Sullivan, J. Connor and L. Huang, Immunoliposomes : Preparation, Properties, and Applications. Medicinal Research Reviews, 1986, 6(2), 171-195.
8. (a) R. R. C. New, Introductuon in : Liposome : a Practical Approach, IRL Press Oxford University Press, New York, 1990, pp. 2-4; (b). ibid., pp. 15-22; (c) ibid., pp. 221-234.
9. D. D. Lasic, N. Weiner, M. Riaz and F. Martin, Loiposome in : Pharmaceutical Dosage Forms: Disperse System , Marcel Dekker, Inc., New York, (3), 1998, p. 44.
10. H. C. Korting, P. Blecher, M. Schafer-Korting, A. Wendel. Topical Liposome Drugs to Come : What the Patent Literature Tells us. Journal of the American Academy of Dermatology. 1991, 25: 1068-1071.
11. V. Rhoden, S. M. Goldin, Formation of Unilamellar Lipid Vesicles of Controllable dimensions by detergent dialysis. Biochemistry, 1979, 18: 4173-4176.
12. H. G. Enoch, P. Strittmatter, Formation and Properties of 1000A Diameter Single Bilayer Phospholipid Vesicles. Proc. Natl. Acad. Sci., U. S. A., 1979, 76: 145-149.
13. G. B. Warren, A. Penelope, P. A. Poon, N. J. Birdsall, A. G. Lee and J. C. Metcalfe, Reconstitution of a Calcium Pump Using Defined Membrane Components. Proc. Natl. Acad. Sci., U. S. A., 1974, 71: 622-626.
14. R. Fraley, S. Subramani, P. Berg and D. Papahadjopoulos, Introduction of Liposome-Encapsulated SV40 DNA into Cells. J. Biol. Chem., 1980, 255: 10431-10438.
15. Y. W. Chien, Novel Drug Delivery Systems, Second Edition, Marcel Dekker, Inc. 1992.
16. G. Gregoriadis and B. E. Ryman, Eur. J. Biochem., 1972, 24, 485
17. J. H. Senior, CRC Crit. Rev. Ther. Drug Carrier Syst., 1987, 3: 123.
18. D. Lin, A. Mori and L. Huang, Biochimica et Biophysica Acta., 1992, 1104, 95.
19 D. Lin, A. Mori and L. Huang, Biochimica et Biophysica Acta., 1991, 1066, 159.
20. M. Yokoyama and Shohei Inoue, Makromol. Chem., 1989, 190: 2041-2054.