簡易檢索 / 詳目顯示

回結果列表
研究生： 楊凱翔
Kai-Shiang Yang
論文名稱： 雙性接枝高分子之合成及鑑定
Synthesis and Characterization of Amphiphilic Graft Copolymer
指導教授： 陳崇賢
Chorng-Shyan Chern
口試委員: 李振綱
Cheng-Kang Lee
邱信程
Hsin-Cheng Chiu
學位類別： 碩士
Master
系所名稱： 工程學院 - 化學工程系
Department of Chemical Engineering
論文出版年： 2006
畢業學年度： 94
語文別： 中文
論文頁數： 133
中文關鍵詞： 雙性高分子 、高分子微胞 、微脂粒 、膠體穩定性
外文關鍵詞： polymeric micelle, liposomes, colloidal stability, amphiphilic polymers
相關次數： 點閱：335  下載：1 
分享至:
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報
  •  上一筆

    • 本研究以酯交換反應來合成含有聚乙二醇與二硬脂酸甘油(或正十八醇)之雙性高分子，並由1H-NMR、GPC計算接枝效率與相對平均分子量。此雙性高分子能在不同pH水溶液中形成微胞，由螢光光譜、動態光散射光譜儀(DLS)與電子順磁共振光譜儀(EPR)分析高分子微胞之結構形態與親疏水性。在pH 4的緩衝溶液中，微胞有較低的CAC (1.87~24.4 mg/l)、較高的焦油腦分配係數(9588~8272)、較大的粒徑(100~150 nm)、較高的τ (2.46~3.09 × 10-10 s)與較低的aN (15.42~15.48 G)。在pH 7的緩衝溶液中，則呈現相反之性質。在微脂粒的改質實驗上，以DLS觀察在30天內之粒徑，經改質的微脂粒呈現較佳的膠體穩定性，且嵌入Distearin側鏈的微脂粒具有較高的嵌入效率、較高的結晶溫度、較低的螢光滲透率以及較高的螢光強度比(I3/I1)。又以DLS測量微胞之粒徑，發現含Distearin側鏈的高分子較容易形成緻密且體積小之微胞。由EPR實驗觀察微胞核心內之微環境親疏水性，發現含Distearin側鏈的高分子能形成結構較為緻密且疏水性較高之核心。由以上結果得知，此類型高分子能有效的改善微脂粒之膠體穩定性，且具有pH敏感性。在不同pH水溶液中，微胞可以改變親疏水性與結構形態，能有效的控制藥物的傳遞與釋放，以達到作為良好的藥物載體之目標。

    In this study, amphiphilic polymers comprising both PEG and distearin (or stearyl alcohol) side chains were synthesized and characterized. Grafting efficiency and relative average molecular weight were determined by 1H-NMR and GPC, respectively. Amphiphilic graft copolymer is capable of forming micelles in the aqueous solutions with different pH values. Characteristic properties of polymeric micelles were analyzed by fluorescence spectroscopy and dynamic light scattering (DLS). The colloidal system has lower CAC values (1.87~24.4 mg/l), higher partitioning coefficients (9588~8272), larger particle sizes (100~150 nm), higher rotational correlation time (2.46~3.09 × 10-10 s) and lower hyperfine coupling constant (15.42~15.48 G) in pH 4 buffer. On the other hand, these copolymers show opposite results in pH 7 buffer. For the copolymer-modified liposomes, the liposome complex shows good colloidal stability, as shown by the DLS data. Liposomes encapsulated by distearin side chains have higher encapsulation efficiency, higher crystallization temperature, lower fluorescence permeability and higher fluorescence intensity ratio (I3/I1). The copolymer with distearin side chains forms more compact and smaller micelles compared to the stearyl alcohol counterpart. These results indicate that the graft copolymers can effectively improve the colloidal stability of liposomes and are pH sensitive. These graft copolymers find potential application as the pH-sensitive drug delivery carrier.

    中文摘要.....................................................i 英文摘要....................................................ii 誌謝.......................................................iii 目錄........................................................iv 圖目錄.....................................................vii 表目錄.....................................................xi 第一章 緒論.................................................1 第二章 文獻回顧.............................................3 2-1 雙性高分子...........................................3 2-2 雙性高分子之合成.....................................4 2-3 高分子微胞在藥物控制釋放上之應用.....................4 2-4 聚乙二醇之特性.......................................5 2-5 聚丙烯酸之特性.......................................6 2-6 高分子微胞系統之分析方法.............................7 2-7 螢光方法.............................................8 2-8 微脂粒...............................................9 2-9 微脂粒之物理結構....................................10 2-10 膽固醇............................................11 2-11 微脂粒脂質雙層之特性...............................12 2-12 電子順磁共振原理................................13 第三章 實驗部分............................................23 3-1 實驗原料............................................23 3-2 實驗儀器及設備......................................26 3-3 合成步驟............................................28 3-3-0 雙性高分子合成................................28 3-3-1 N-acryloxysuccinimide之合成......................30 3-3-2 Poly N-acryloxysuccinimide之合成.................30 3-3-3 Distearin與Stearyl alcohol之接枝合成..............32 3-3-4 PEG之接枝合成................................33 3-3-5 PAAc-Distearin-PEG與PAAc-SA-PEG之合成........34 3-4 原料及雙性高分子性質之分析..........................36 3-4-1 1H-NMR核磁共振光譜分析.......................36 3-4-2 雙性高分子之相對平均分子量之測量..............36 3-4-3 高分子微胞之製備...........................36 3-4-4 臨界聚集濃度之測量........................37 3-4-5 焦油腦消光實驗............................37 3-4-6高分子微胞粒徑之測量.........................37 3-5 雙性高分子－微脂粒複合物之製備與性質探討............38 3-5-1 雙性高分子－微脂粒複合物之製備................38 3-5-2 雙性高分子嵌入效率............................38 3-5-3 微脂粒粒徑對時間的變化........................38 3-5-4 滲透實驗......................................38 3-5-5 微脂粒相轉移溫度之測量.......................39 3-5-6 微脂粒薄膜之焦油腦螢光實驗....................39 3-6 電子順磁共振實驗....................................39 第四章 結果與討論..........................................40 4-1 1H-NMR光譜分析...................................40 4-1-1 反應單體之1H-NMR光譜分析.................40 4-1-2 雙性高分子之1H-NMR光譜分析..............41 4-2 臨界聚集濃度(CAC) ..................................53 4-3 高分子親疏水性之分析...............................55 4-4 焦油腦消光實驗.....................................65 4-5 高分子微胞粒徑.....................................76 4-6 雙性高分子-微脂粒複合物性質分析....................81 4-6-1 雙性高分子崁入效率............................82 4-6-2 5(6)-CF滲透實驗................................85 4-6-3 微脂粒DSC實驗................................86 4-6-4 微脂粒焦油腦螢光實驗..........................88 4-6-5 Distearin與SA差異性之分析..................89 4-7 EPR光譜分析........................................91 4-7-1 高分子微胞EPR實驗............................91 4-7-2 雙性高分子-微脂粒複合物EPR實驗...............94 第五章 結論與建議..........................................98 5-1 結論................................................98 5-2 建議...............................................100 第六章 參考資料...........................................101 附錄 A....................................................107 附錄 B...................................................114 附錄 C...................................................126

    1. Y. Yu, C. Allen, S. Chijiwa, D. Maysinger, A. Eisenberg, Macromolecules, submitted for publication.
    2. G. S. Kwon, T. Okano, Advan. Drug Delivery Rev. 21, 107 (1996).
    3. S. Creutz, J. van Stam, F.C. De Schryver, R. Jerome, Macromolecules 31, 681 (1998).
    4. M. Yokoyama, S. Fukushima, R. Uehara, K. Okamoto, K. Kataoka, Y. Sakurai, T. Okano, J. Controlled Release 50, 79 (1998).
    5. T. Cao, P. Munk, C. Ramireddy, Z. Tuzar, S. E. Webber, Macromolecules, 24, 6300 (1991).
    6. Barrett, K. E. J., Dispersion Polymerization in Organic Media. Wiley, London (1975).
    7. C. Bo, B. Wesslen, K. B. Wesslen, Journal of Polymer Science : Part A : Polymer Chemistry, 30, 1799 (1992).
    8. M. A. Twaik, M. Tahan, A. Zilkha, J. Polym. Sci. A, 7, 2469 (1969).
    9. A. Thierry, A. Skoulios, Makromol. Chem., 177, 319 (1977).
    10. B. Wesslen, K. B. Wesslen, Journal of Polymer Science : Part A : Polymer Chemistry, 27, 3915 (1989).
    11. Z. Yue, M. E. Eccleston, N. K.H. Slater, Biomaterials, 26, 6357–6366 (2005).
    12. X. M. Liu, K.P. Pramoda, Y. Y. Yang, S. Y. Chow, C. He, Biomaterials, 25, 2619 (2004).
    13. Bader H., Ringsdorf H. Schmidt B., Angew. Chem., 123/124, 457 (1984).
    14. Pratten M. K., Lioyd J. B., Horpel G., Ringsdorf H., Makromol. Chem., 186, 725 (1985).
    15. R. M. Ottenbrite, "Polymeic Drugs and Drug Aministration", Chapter 10, (1992).
    16. Masayuki Yokoyama, Shohei Inoue, Makromol. chem., 190, 2041-2054 (1989).
    17. G. Gregoriadis, B. E. Ryman, Eur. J. Biochem., 24, 485 (1972).
    18. J. H. Senior, CRC Crit. Rev. Ther. Drug Carrier Syst., 3 : 123 (1987).
    19. D. Lin, A. Mori, and L. Huang, Biochimica et Biophysica Acta, 1104, 95 (1992).
    20. 常慧芳, 碩士論文, 台灣工業技術學院 (1996).
    21. G. Gregoriadis and B. E. Ryaman, Eur. J. Biochem., 24, 485 (1972).
    22. S. E. Dunn, A. Brindley, S. S. Davis, M. C. Davies, and L. Illum, Pharmacentical Research, 11 (7) (1994).
    23. J. Milton Harris, Poly(eyhylene glycol) Chemistry : Biotechnical and Biomedical Applications, Plenum Press, New York, 1992.
    24. A. Abuchowski, J. R. McCoy, N. C. Palczuk, T. V. Es, and F. F. Davis, The Journal of Biological Chemistry, Vol. 252, NO. 11, 3582 (1977).
    25. 諸亞儂, 呂理福, 溫永福, 曾文雄, 生物學, 環球書社 (1979).
    26. H. Yang, J. J. Morris, and S. T. Lopina, Journal of Colloid and Interface Science, 273, 148 (2004).
    27. A. A. Gabizon, Y. Barenholz, M. Bialer, Pharmaceutical Research, 10 (5) (1993).
    28. Z. Tuzar, Iranian J. of Polymer Science and Technology, 4 (1) (1995).
    29. B. Lindman, H. Wennerstrom, H. F. Eicke, Micelles, Springer–Verlag, Heidelberg (1980).
    30. K. N.Prasad, T. T. Luong, A. T. Florence, J. Pharis, C. Vaution, M. Seiller, F. Puisieux, Journal of Colloid and Interface Science, 69 (2), 225 (1979).
    31. Koichi I., Kazuo T., Hiroshige T., Genji I., Seiqou K., Shinichi I., Macromolecules, 24, 2348 (1991).
    32. Kanehiro N., Ryuichi E., Mastami T., Journal of Polymer Scicnce : Polymer Physics Edition, 14, 1287 (1976).
    33. K. Kalyanasundaram and J. K. Thomas, J. Amer. Chem. Soc. 99 (7), 2039 (1977).
    34. T. S. Chen, J.K. Thomas, J. Polymer Science:Polymer Chem. Ed., 17, 1103 (1979).
    35. G. Kwon, M. Naito, M. Yokoyama, T. Okano, Y. Sakurai, K. Kataoka, Langmuir, 9, 945 (1993).
    36. Nakamura K., Endo R., Takeda M., J. Polym. Sci., Polym. Phys. Ed., 14, 135 (1976).
    37. Nakamura K., Endo R., Takeda M., J. Polym. Sci., Polym. Phys. Ed., 14, 1287 (1976).
    38. E. L. Wehry, Pleum Press. New York and London, 1976.
    39. (a)P. Lianos, J. Lang, J. Sturm, and R. Zana, J.Phys. Chem. 88, 17, 1103 (1979).
    40. M. J. Ostro and P. R. Cullis, American Journal of Hospital Pharmacy, 46, 1576 (1989).
    41. S. M. Sullivan, J. Connor and L. Huang, Medicinal Research Reviews, 6(2), 171 (1986).
    42. A. D. Bangham, M. M. Standish and J. C. Watkins, J. Mol. Biol., 13, 238 (1965).
    43. F. Frezard and A. Garniersuillerot, Biochimica et Biophysica Acta – Lipids and Lipid Metabolism, 1389, 13 (1998).
    44. D. Papahadjopoulos, Ann. N.Y. Acad. Sci., 308, 1 (1978).
    45. G. Greoriadis, New Engl. J. Med., 295, 704-710; 765-770, 1976.
    46. J. Freise and P. Magerstedt, Georg Thieme Verlag Stuttgart. New York, 1986.
    47. X. M. Zeng, G. P. Martin and C. Marriott, “The Controlled Delivery of Drugs to the Kung”, International Journal of Pharmaceutics, 124, 149 (1995).
    48. T. W. Chung and I. H. Peng, Artifical Cell. Blood Substitutes, and Immobilization Biotechnology, 26, 389 (1998).
    49. H. Farhood, N. Serbina and L. Huang, Biochimica et Biophysica Acta, 289, 1235 (1995).
    50. Jacob Israelachvili, Academic Press, London (1991).
    51. R. J. M. Tausk, J. Karmiggelt, C. Oudshoorn and J. Th. G. Overbeek, Biophysical Chemistry, 1, 175 (1974).
    52. R. J. M. Tausk, J. Karmiggelt, C. Oudshoorn and J. Th. G. Overbeek, Biophysical Chemistry, 1, 184 (1974).
    53. J. J. Collins and M. C. Phillips, J. Lipid Res., 23, 291 (1982).
    54. S. Bhattacharya and S. Haldar, Biochim. Biophys. Acta, 39, 1467 (2000).
    55. M. Cócera, O. López, L. Coderch, J. L. Parra and A. de la Maza, Colloids and Surfaces A, 9, 221 (2003).
    56. 莊宜靜, 碩士論文, 國立台灣科技大學(2001).
    57. 張富雄, 碩士論文, 國立台灣科技大學(2002).
    58. R. R. C. New, IRL Press , Oxford University Press, New York, 1990.
    59. S.R. Tonge, B.J. Tighe, Advanced Drug Delivery Reviews, 53, 109 (2001).
    60. J. Rička and T. Tanaka, Macromolecules, 17, 2916 (1984).
    61. L. S. Choi and O. K. Kim, Langmuir, 10(1), 57 (1995).
    62. Y. Wang and M. A. Winnik, Langmuir, 16(9), 1473 (1990).
    63. F. M. Winnik, H. Ringsdorf and J. Venzmer, Langmuir, 7(5), 912 (1991).
    64. J. R. Lakowicz, “Principle of Fluorescence Spectroscopy” (1983).
    65. J. E. Wertz, J. R. Bolton, Electron Spin Resonance, Ele-mentary Theory and Practical Applications, McGraw-Hill Book Co., New York, 1972.
    66. W. A. Pryor, Free Radicals in Biology, Vol. 1~6, Academic Press, New York, 1976~1984.
    67. B. Rånby and J. R. Rabek, “ESR Spectroscopy in Polymer Research”, Springer-Verlag, New York, 1977.
    68. N. Deo, P. Somasundaran, Colloids and Surfaces B, 25, 225 (2002).
    69. Fedors, R. F. Polym Eng Sci, 14, 147 (1974).
    70. J. T. Davies and E. K. Rideal, “Interfacial Phenomena”, Academic Press, London (1963).
    71. C. S. Chern, H. C.Chiu and Y. C. Chuang, Polymer International, 53, 420 (2004).
    72. G. S. Kwon, M. Naito, K. Kataoka, M. Yokoyama, Y. Sakurai, T. Okano, Colloids and Surfaces B : Biointerfaces, 2, 429 (1994).
    73. T. Sato and R. Ruch, “Stabilizaiton of Colloidal Dispersions By Polymer Adsorption”, Chapter 3, New York, 1980.
    74. W. F. Polikt and W. Burchard, Macromolecules, 16, 978 (1983).
    75. R. Xu and M. A. Winnik, Macromolecules, 24, 87 (1991).
    76. H. Arimura, Y. Ohya and T. Ouchi, Biomacromolecules, 6, 720 (2005).
    77. N. Deo, P. Somasundaran, Colloids and Surfaces B, 25, 225 (2002).
    78. V. P. Torchilin, T. S. Levchenko, K. R. Whiteman, A. A. Yaroslavov, A. M. Tsatsakis, A. K. Rizos, E. V. Michailova, M. I. Shtilman, Biomaterials, 22, 3035 (2001).
    79. A. M. Wasserman, V. A. Kasaikin, Y. A. Zakharova, I. I. Aliev, V. Y. Baranovsky, V. Doseva, L. L. Yasina, Spectrochimica Acta Part A, 58, 1241 (2002).
    80. D. A. Skoog, D. M. West, F. J. Holler, “Fundamentals of Analytical Chemistry”, 1996.
    81. J. Martinie, J. Michon and A. Rassat, J. Amer. Chem. Soc., 97, 1818 (1975).
    82. J. Seelig, J. Am. Chem. Soc., 92, 3881 (1970).
    83. H. Fukuda, A. Goto, H. Yoshioka, R. Goto, K. Morigaki and P. Walde, Langmuir, 17, 4223 (2001).
    84. D. J. Hemker, V. Garza, and C. W. Frank, Macromolecules, 23, 4411 (1990).
    85. V. V. Khutoryanskiy, A. V. Dubolazov, Z. S. Nurkeeva and G. A. Mun, Langmuir, 20, 3785 (2004).
    86. D. Y. Chu and J. K. Thomas, Macromolecules, 20, 2133 (1987).

    QR CODE