臺灣博碩士論文加值系統

雙親性嵌段高分子近年來應用在生醫藥物載體材料是相當熱門的研究議題，雙親性嵌段高分子可以在水溶液中自組裝形成親水段為外殼，疏水段為內核的微胞，疏水的內核可用於包覆疏水性的抗癌藥物，增加藥物在生物體中的溶解性，微胞應用於藥物傳輸系統中有相當好的成效，能延長藥物在體內循環時間和低臨界微胞濃度的穩定性，還能具備靶向功能是相當安全長效的抗癌藥物載體。
此論文針對一系列新的雙親性嵌段共聚高分子[PEG-b-P(S-co-SFl3), P3] 與[PEG-b-P(S-co-SFlBT), P4] 所自組裝形成具有螢光特性的微胞進行奈米結構和光物理性質的研究。微胞內含有化學連接的螢光基團，藉由寡聚芴的特徵螢光放射可追蹤其微胞。此外，因寡聚芴基團P3與P4的放射波長分別和抗癌藥物薑黃素(Curcumin)及阿黴素(Doxorubicin)的吸收波長有所重疊，由寡聚芴基團和薑黃素及阿黴素所形成的福斯特共振能量轉移(Förster Resonance Energy Transfer, FRET)效應而有不同螢光性質表現，有利於判斷抗癌藥物成功的被包覆於微胞中，由於包覆薑黃素及阿黴素之微胞的增強生物相容性和光譜特性，使其螢光微胞在光學成像的應用具有發展潛力。
此兩系列微胞的直徑皆小於100 nm，大小均一且具穩定性，可利用Enhanced Permeation and Retention (EPR) 效應增加藥物對癌症細胞的選擇性，另外，P3與P4系列高分子臨界微胞濃度(Critical Micelle Concentration, CMC)相當低約4.4×10-6 M與5.58×10-6 M，在37℃水溶液進行藥物釋放實驗發現經24小時後僅有10% 的藥物釋放，此兩系列微胞是相當穩定的藥物載體，在光學成像和癌症治療上有相當好的發展前景。

In recent years, polymeric micelles formed from amphiphilic block copolymers have found a rich variety of applications in nanotechnology as drug delivery vehicles. Amphiphilic block copolymers can self-assemble into core-shell micelles with hydrophobic block as the core and hydrophilic as the shell in water. They can efficiently load hydrophobic drugs into its hydrophobic core and significantly improve its solubility. For drug delivery system, Polymeric micelles have several advantages of improving bioavailability of hydrophobic drugs and low critical micelle concentration and drug targeting to solid tumors. Thus, the polymeric micelle carrier system as a drug carrier is very safe and sustained release.
The nanostructures and photophysical properties of the fluorescent polymeric micelles self-assembled from a series of new amphiphilic block copolymers, [PEG-b-P(S-co-SFl3), P3] and [PEG-b-P(S-co-SFlBT), P4], were investigated in this work. The chemical attachment of fluorescent moieties enables the tracing of micelles by the emission of oligofluorene. Furthermore, due to the spectral overlap between the emission of the oligofluorene moieties of P3 and P4 series polymer and the absorption of curcumin (CUM) and doxorubicin (DOX), the Föster Resonance Energy Transfer (FRET) from oligofluorene moieties to curcumin and doxorubicin encapsulated in the micelle facilitates the indication of successful encapsulation of curcumin and doxorubicin in the core of polymeric micelles. In consideration of the enhanced biocompatibility and spectral characteristics of the CUM-loaded and DOX-loaded micelles, the fluorescent micelles may find potential application in optical imaging.
The micelles are very uniform in size and the distance of inter-micelle all less than 100 nm. The condition is favorable for polymeric micelles are accumulated in tumor tissue by EPR effect. In addition, the Critical Micelle Concentration (CMC) values of P3 and P4 series polymer are very low about 4.4×10-6 M and 5.58×10-6 M. The release rate of drug-loaded micelles in 37℃ water solution is about 10% in the 24 hour, indicating that the micelles are stabilized and sustained release. As the results, these drug-loaded micelles have great potential for application in optical imaging and drug delivery system.

摘要 I
Abstract II
誌謝 IV
流程目錄 VII
表目錄 VIII
圖目錄 IX
第一章、緒論 1
1.1 研究背景與文獻回顧 1
1.1.1雙親性嵌段共聚高分子 1
1.1.2高分子微胞發展與設計 2
1.1.2.1 雙親性嵌段共聚高分子微胞 2
1.1.2.2 用於醫療的雙親性嵌段共聚高分子材料 5
1.1.2.3高分子微胞穩定性 6
1.1.3藥物傳輸與癌症治療 7
1.1.4 藥物靶向載體 8
1.1.4.1被動靶向(Passive drug targeting) 8
1.1.4.2主動靶向(Active drug targeting) 9
1.1.5芴類螢光高分子 10
1.1.6 螢光 12
1.1.6.1螢光與磷光產生機制 12
1.1.6.2影響螢光強度的因素 13
1.1.6.3 Förster Resonance Energy Transfer（FRET） 14
1.1.6.4量子產率 16
1.2 研究動機與目的 17
第二章、實驗 19
2.1 實驗藥品 19
2.2 實驗方法 21
2.2.1 單體合成 21
2.2.2 高分子聚合 27
2.2.3 微胞製備與CMC測量 33
2.2.4 藥物包覆 34
2.2.5 藥物釋放 36
2.3 儀器鑑定 36
2.3.1 Gel permeation chromatography (GPC) 36
2.3.2 Nuclear Magnetic Resonance (NMR) 37
2.3.3 Dynamic Light Scattering (DLS) 38
2.3.4 Transmission Electron Microscopy (TEM) 38
2.3.5 Ultraviolet-visible spectra (UV-vis. spectra) 39
2.3.6螢光光譜與量子效率 39
第三章、結果與討論 40
3.1 聚合和鑑定 40
3.2 奈米微胞之性質分析 49
3.2.1高分子微胞粒徑分析 49
3.2.2高分子臨界微胞濃度 (CMC) 51
3.3 光學性質分析 53
3.3.1 UV/Vis 吸收光譜和 PL發射光譜 53
3.3.2相對量子效率 63
3.4 藥物包覆效率 64
3.5 藥物釋放 65
第四章、結論與未來工作 68
第五章、參考文獻 70

(1)Förster, S. A., Markus Advanced Materials 1998, 10, 195.
(2)Paschalis Alexandridis, B. L. ELSEVIER 2000.
(3)Bernard, J.; Favier, A.; Zhang, L.;Barner-Kowollik C. ; Davis, T. P.; Stenzel, M. H. Macromolecules, 2005(38), 5475-5484 .
(4)Vosloo JJ, Tonge MP, Fellows CM, D'Agosto F, Sanderson RD, Gilbert RG. Macromolecules, 2004(37),2371–2382.
(5)Wang Z M, He J P , Yang YL , et al . Macromolecules , 2003 , 36(20) : 7446 -7452.
(6)Hu, Y.-HU. National Cheng Kung University, Department of Chemical Engineering 2005.
(7)T. E. Patten, K. M., Advanced Materials, 10, 901 (1998).
(8)Zetterlund, P. B. Polym.Chem., 2011, 2, 534–549.
(9)Zhang L, Eisenberg A. Science, 1995, 268(5218): 1728 -1731.
(10)Yu, Kui; Zhang, Lifeng; Eisenberg, Adi. Langmuir (1996), 12(25), 5980-5984.
(11)Zhang, L.; Eisenberg, A. Macromolecules 1996, 29, 8805-8815.
(12)Andrew R. Eckert, S. E. Webber.. Macromolecules, 1996, 29: 560 - 567.
(13)Xiaohu Yan, Guojun Liu, Zhao Li. Journal: Journal of The American Chemical Society, 2004, 126 (32): 10059 - 10066.
(14)Soo P L, Eisenberg J. Polym. Sci., Part B: Polym.Phys., 2004, 42(6): 923 - 938.
(15)Yanhui Ma; Ti Cao; S. E. Webber,. Macromolecules . 31 ( 6): 1773- 1778.
(16)Themistou E, Costas S. European Polymer Journal , 2007,43(1): 84 - 92.
(17)Letchford, K.; Burt, H. European Journal of Pharmaceutics and Biopharmaceutics 2007, 65, 259.
(18)Shimizu, H. Fujita, T.Nat. Rev. Nephrol.7, 2001 , 407-415.
(19)Torchilin V P. J . Controlled Release , 2001 , 73 : 137-172.
(20)Li, Z. B.; Kesselman, E.; Talmon, Y.; Hillmyer, M. A.; Lodge, T. P. Science 2004, 306, 98- 101.
(21)Kubowicz S , Baussard J F , Lutz J F . Chem. Int . Ed. , 2005 ,44 : 5262 -5265.
(22)Kubowicz S , Thünemann A F , Weberskirch R , Möhwald H . Langmuir ,2005 , 21, 7214-7219.
(23)Z. Li, M. A. Hillmyer, T. P. Lodge, Macromolecules 2004, 37,6680-6682.
(24)Z. Zhou, Z. Li, Y. Ren, M. A. Hillmyer, T. P. Lodge, J. Am. Chem. Soc., 2003, 125, 10182-10183.
(25)Tyrrell, Z. L.; Shen, Y.; Radosz, M. Progress in Polymer Science 2010, 35, 1128.
(26)Sutton D, Nasongkla N, Blanco E, Gao J AM. Pharm. Res. , 2007 , 24(6) , 1029-1046.
(27)R.K. Jain, Cancer Research, 47(1987), 3039.
(28)R.K. Jain, Journal of Controlled Release, 74(2001),7.
(29)Allen C , Maysinger D , Eisenberg A. . Colloids Surfaces B : Biointerfaces , 1999 , 16 (1 - 4),3 -27.
(30)Allen, C.; Maysinger, D.; Eisenberg, A. Colloids and Surfaces B: Biointerfaces 1999, 16, 3.
(31)Kumar N , Ravikumar MN , Domb AJ . Adv Drug Deliv Rev , 2001 , 53 (1),23 -44.
(32)Uhrich K.E, Cannizzaro S.M, Langer R.S, Shakesheff K.M. Chem Rev.1999;99:3181-3198.
(33)Bader H, Ringsdorf H, Schmidt B.Angew. Makromol. Chem. , 1984, 123(1), 457-485.
(34)X. Gao, Y. Cui, R. M. Levenson, L. W. K. Chung, S. Nie, Nature biotech., 22(2004), 969.
(35)K. Ulbrich, V. Subr, Advanced Drug Delivery Reviews, 56(2004),1023.
(36)Fang, J.; Nakamura, H.; Maeda, H. Advanced Drug Delivery Reviews 2010, 63, 136.
(37)Lavasanifar A , Samuel J, Kwon GS. Advanced Drug Delivery Reviews 54 (2002) 169-190.
(38)Yoo, H. S.; Park, T. G. J. Controlled Release 2004, 96, 273–283.
(39)Pei, J.; Liu, X. L.; Huang, W. Macromolecules 2003, 36, 323.
(40)Liu, B.; Yu, W. L.; Huang, W. Macromolecules 2002, 35, 4975.
(41)Burroughes, J. H.; Bradley, D. D. C.; Brown, A. R.; Marks, R. N.; Mackay, K.; Friend, R. H.; Burns, P. L.; Holmes, A. B. Nature 1990, 347, 539.
(42)Grimsdale, A. C.; Leok Chan, K.; Martin, R. E.; Jokisz, P. G.; Holmes, A. B. Chemical Reviews 2009, 109, 897.
(43)Akcelrud, L. Progress in Polymer Science 2003, 28, 875.
(44)Kim D. Y., Cho H. N., KimC. Y. Progress in Polymer Science 2000, 25, 1089.
(45)Shimizu, M.; Hiyama, T. Chemistry An Asian Journal 2010, 5, 1516.
(46)McGehee, M. D.; Heeger, A. J. Advanced Materials 2000, 12, 1655.
(47)Kozlov, V. G.; Forrest, S. R. Current Opinion in Solid State and Materials Science 1999, 4, 203.
(48)Setayesh S, Mullen K. J. Am. Chem. Soc. ,2001, 123 , 946-953
(49)Anthony, J. E. Chem. Rev. 2006, 106, 5028.
(50)Okamoto, T.; Bao, Z. J. Am. Chem. Soc. 2007, 129, 10308.
(51)M. Svensson, F. Zhang, S. C. Veenstra, W. J. H. Verhees, J. C. Hummelen, J. M. Kroon, O. Inganäs, and M. R. Andersson, Adv. Mater. (Weinheim, Ger.) 15, 988 (2003).
(52)Feng F, Tang Y, He F, Yu M, Duan X, Wang S, Li Y, Zhu D B. Adv. Mater. 2007, 3490.
(53)Thomas, S. W.; Joly, G. D.; Swager, T. M. Chemical Reviews 2007, 107, 1339.
(54)Adhikari, B.; Majumdar, S. Progress in Polymer Science 2004, 29, 699.
(55)Werts, M. H. W.; Gmouh, S.; Mongin, O.; Pons, T.; Desce, M. J. Am. Chem. Soc. 2004, 126 (50): 16294.
(56)Zhou, X. H.; Yan, J. C.; Pei, J. Macromolecules 2004, 37, 7078.
(57)Dingyi Yu, Yong Zhang, and Bin Liu. Macromolecules 2008, 41, 4003-4011.
(58)Alma R. Morales, C. O. Y., Katherine J. Schafer-Hales, Adam I. Marcus, and Kevin D. Belfield Bioconjugate Chem. 2009, 20, 1992–2000.
(59)Shimizu, M.; Hiyama, T. Chemistry . An Asian Journal 2010, 5, 1516.
(60)Bernard Valeur,Molecular Fluorescence Principles and Applications;WILEY-VCH, 2002.
(61)Sapsford, K. E.; Berti, L.; Medintz, I. L. Angewandte Chemie International Edition 2006, 45, 4562.
(62)圖片來自:http://ppt.cc/W3Tj.
(63)G. Jones Ⅱ,W. R. Jackson, C. Y. Chio, W. R. Bergmark, J. Phys. Chem. 1985, 89, 294.
(64)Kataoka K, Matsumoto T, Yokoyama M . Journal of Controlled Release ,2000 , 64(1 - 3) :143 - 153.
(65)Yokoyama M, Miyauchi M, Yamada N, Okano T, Sakurai Y, Kataoka K, Inoue S. J Controlled. Release 1990;11(1-3):269-278.
(66)Andrade, C. D.; Yanez, C. O.; Rodriguez, L.; Belfield, K. D. J. Org. Chem. 2010, 75, 3975.
(67)Kim K R, Liu M J, Choi YK , Wong YS, Biol Chem 277, 38930–38938.
(68)Lemgwehastit I. and Dickson A. J. , Biotechnol Bioeng, Vol. 80, 2002, 719-730.
(69)Jung-Ching Hsu, Y.-C. T., Wen-Chang Chen Macromolecules, Vol. 42, No. 12, 2009.
(70)Alexander L. Kanibolotsky, Rorry Berridge, Peter J. Skabara, Igor F. Perepichka, Donal D. C. Bradley, Mattijs Koeberg. J. AM. CHEM. SOC. 2004, 126, 13695-13702.
(71)Berlman, I. B. Academic Press, N.Y. 1971.
(72)Eaton, D. F. , Pure Appl. Chem. 60, 1988, 1107-1114.