Title

具光裂解與螢光特性之高分子微胞:合成、性質鑑定與在藥物包覆的應用

Translated Titles

Photocleavable and Fluorescent Polymeric Micelles: Synthesis, Characterization, and Application in Drug Encapsulation

DOI

10.6844/NCKU.2012.02159

Authors

陳正穎

Key Words

雙親性嵌段共聚高分子 ; 聚集誘發螢光 ; 藥物載體 ; amphiphilic block copolymers ; aggregation-induced emission ; drug carriers

PublicationName

成功大學化學工程學系學位論文

Volume or Term/Year and Month of Publication

2012年

Academic Degree Category

碩士

Advisor

吳文中

Content Language

繁體中文

Chinese Abstract

此論文針對一系列新穎雙親性嵌段共聚高分子--- poly(ethylene glycol)-b-[polystyrene-co-poly(2-(1,2,3,4,5-pentaphenyl-1H-silol-1-yloxy)ethyl methacrylate)] [PEG-b-(PS-co-PAIE), P3]與poly(ethylene glycol)-b -[poly(2-nitrobenzyl methacrylate)-co-poly(2-(1,2,3,4,5-pentaphenyl-1H-silol-1 -yloxy)ethyl methacrylate)] [PEG-b-(PNBMA-co-PAIE), P4] 所自組裝形成的高分子微胞之奈米結構和光物理性質進行研究。我們以PEG做為親水鏈段,將一種具有Aggregation-Induced Emission (AIE) 性質的螢光側鏈基團引進高分子的疏水鏈段。在高分子側鏈的AIE基團可以克服傳統螢光染料在高分子聚集形成微胞時螢光被淬滅的問題。因此,具AIE特性之高分子所自組裝形成之微胞可作為螢光探針,用於追蹤微胞的位置,顯示其在生物標記具應用潛力。此外,P4具光裂解單體2- nitrobenzyl methacrylate (NBMA),利用NBMA照光會裂解並從疏水性變為親水性的特性可將其應用於藥物控制釋放。 AIE基團在微胞核心的螢光強度高於溶解於有機溶劑中的螢光強度。證明微胞核心的狹小空間可以造成AIE基團的聚集,使AIE基團產生聚集誘發螢光。其中P3微胞的螢光比P4微胞的螢光強,因為NBMA的硝基會淬滅AIE螢光。藉由DLS測出P3與P4系列之高分子微胞粒徑約33.0 ~ 43.9 nm。另外,利用AIE特性可算出這兩系列高分子的臨界微胞濃度(Critical Micelle Concentration, CMC)約4.34×10-6至4.19×10-7 M。 P3與P4系列之高分子微胞進一步被用來包覆藥物 Doxorubicin (Dox)。由於AIE基團的螢光放射波長與Dox的吸收光譜重疊,當兩者之間距離小於10 nm時會產生Föster Resonance Energy Transfer (FRET)。此現象可確認Dox是否成功進入高分子微胞的核心。 經由在37℃ PBS水溶液中的藥物釋放實驗發現照光可促進P4/Dox微胞的Dox釋放。而in vitro實驗的部份則是以HT-29細胞株為對象,初步證實P3高分子微胞的生物相容性良好。未來期望能將P3與P4兩系列之高分子微胞都應用至in vitro的實驗,測試其在細胞內的生物標記與藥物釋放作用情形。

English Abstract

The nanostructures and photophysical properties of the fluorescent polymeric micelles self-assembled from a series of new amphiphilic block copolymers, poly(ethylene glycol)-b-[polystyrene-co-poly(2-(1,2,3,4,5-pentaphenyl-1H-silol-1 -yloxy)ethyl methacrylate)] [PEG-b-(PS-co-PAIE), P3] and poly(ethylene glycol)-b -[poly(2-nitrobenzyl methacrylate)-co-poly(2-(1,2,3,4,5-pentaphenyl-1H-silol-1 -yloxy)ethyl methacrylate)] [PEG-b-(PNBMA-co-PAIE), P4], were investigated in this work. We chose PEG as the hydrophilic block, and a fluorescent pendent group with the special characteristic of aggregation-induced emission (AIE) was introduced in the hydrophobic block of the copolymers. This AIE fluorescent moiety could overcome the problem of aggregation-induced quenching for most conventional dyes when encapsulated in the core of polymeric micelles. The chemical attachment of AIE moiety in the side chain of copolymers enables the emission of AIE moieties as the fluorescent probe to trace the location of polymeric micelles, suggesting its potential application in the bioimaging. In addition, the photocleavable monomers (2-nitrobenzyl methacrylate, NBMA) of P4 would show the transition from hydrophobic to hydrophilic after irradiated by UV light which could be used in the controlled drug release. The photophysical properties of these fluorescent polymeric micelles were studied by the absorption and photoluminescence spectra. The emission from the AIE moieties in the core of micelles was observed with higher fluorescent intensity than the AIE moieties dissolved in the organic solvent. The nano confinement of AIE moieties in the core of micelles provides suitable environment for aggregation-induced emission. Unfortunately, the fluorescence of P4 was quenched by the nitro groups on NBMA, so the fluorescence of P4 was weaker than that of P3. The sizes of P3 and P4 series polymeric micelles were from 33.08 to 43.86 nm. The CMCs could be calculated about 4.34×10-6 to 4.19×10-7 M using the AIE effect. The P3 and P4 series polymer were utilized as nanocarriers for encapsulation of cancer drug, doxorubicin (Dox). Due to the spectral overlap between the emission of AIE moieties and the absorption of Dox, the Föster Resonance Energy Transfer (FRET) from AIE moieties to Dox encapsulated in the micelles indicates the successful encapsulation of Dox in the core of polymeric micelles. According to the release profile of P4/Dox micelles in 37℃ PBS solution, the UV-irradiation could accelerate the release rate of Dox released from P4 micelles. The cytotoxicity test revealed the high biocompatibility of P3 micelles. In the future, we expect both P3 and P4 series polymeric micelles can be applied to in vitro experiments and investigate their application in bioimaging as well as intracellular drug release.

Topic Category 工學院 > 化學工程學系
工程學 > 化學工業
Reference
  1. 4. Ahmed, F.; Discher, D. E. Journal of Controlled Release 2004, 96, (1), 37-53.
    連結:
  2. 8. Gil, E. S.; Hudson, S. M. Progress in Polymer Science 2004, 29, (12), 1173-1222.
    連結:
  3. 10. Hoffman, A. S. J Biomed Mater Res 2000, 52, 577-586.
    連結:
  4. 11. L.Y. Galaev, B. M. Trends Biotechnol 2000, 17, 335-340.
    連結:
  5. 15. Jiang, H. J.; Gao, Z. Q.; Deng, X. Y.; Chen, R. F.; Huang, W. Journal of Applied Polymer Science 2012, 124, (5), 3921-3929.
    連結:
  6. 19. Akcelrud, L. Progress in Polymer Science 2003, 28, (6), 875-962.
    連結:
  7. 25. Adhikari, B.; Majumdar, S. Progress in Polymer Science 2004, 29, (7), 699-766.
    連結:
  8. 28. Ercole, F.; Davis, T. P.; Evans, R. A. Polymer Chemistry 2010, 1, (1), 37-54.
    連結:
  9. 41. Rurack, K.; Resch-Genger, U., Fluorescence Quantum Yields: Methods of Determination and Standards
    連結:
  10. Standardization and Quality Assurance in Fluorescence Measurements I. In Springer Berlin Heidelberg: 2008; Vol. 5, pp 101-145.
    連結:
  11. 47. Yu, Y.; Feng, C.; Hong, Y.; Liu, J.; Chen, S.; Ng, K. M.; Luo, K. Q.; Tang, B. Z. Advanced Materials 2011, 23, (29), 3298-3302.
    連結:
  12. 49. Wu, W.-C.; Chen, C.-Y.; Tian, Y.; Jang, S.-H.; Hong, Y.; Liu, Y.; Hu, R.; Tang, B. Z.; Lee, Y.-T.; Chen, C.-T.; Chen, W.-C.; Jen, A. K. Y. Advanced Functional Materials 2010, 20, (9), 1413-1423.
    連結:
  13. 52. Ren, Y.; Lam, J. W. Y.; Dong, Y.; Tang, B. Z.; Wong, K. S. The Journal of Physical Chemistry B 2005, 109, (3), 1135-1140.
    連結:
  14. 54. Luo, J.; Xie, Z.; Lam, J. W. Y.; Cheng, L.; Chen, H.; Qiu, C.; Kwok, H. S.; Zhan, X.; Liu, Y.; Zhu, D.; Tang, B. Z. Chemical Communications 2001, (18), 1740-1741.
    連結:
  15. 59. Yoon, S.-J.; Chung, J. W.; Gierschner, J.; Kim, K. S.; Choi, M.-G.; Kim, D.; Park, S. Y. Journal of the American Chemical Society 2010, 132, (39), 13675-13683.
    連結:
  16. 64. Xie, Z.; Yang, B.; Cheng, G.; Liu, L.; He, F.; Shen, F.; Ma, Y.; Liu, S. Chemistry of Materials 2005, 17, (6), 1287-1289.
    連結:
  17. 67. Fang, J.; Nakamura, H.; Maeda, H. Advanced Drug Delivery Reviews 2010, 63, (3), 136-151.
    連結:
  18. 68. Maeda, H.; Bharate, G. Y.; Daruwalla, J. European Journal of Pharmaceutics and Biopharmaceutics 2009, 71, (3), 409-419.
    連結:
  19. 1. P. Bahadur, N. V. S., Principles of Polymer Science. Alpha Science International Ltd.: Oxford, U.K., 2005.
  20. 2. Paschalis Alexandridis, B. L., Amphiphilic Block Copolymers:Self-Assembly and Applications. ELSEVIER: 2000.
  21. 3. Discher, D. E.; Eisenberg, A. Science 2002, 297, (5583), 967-973.
  22. 5. Thambi, T.; Deepagan, V. G.; Yoo, C. K.; Park, J. H. Polymer 2011, 52, (21), 4753-4759.
  23. 6. Shuai, X.; Ai, H.; Nasongkla, N.; Kim, S.; Gao, J. Journal of Controlled Release 2004, 98, (3), 415-426.
  24. 7. Kataoka, K.; Harada, A.; Nagasaki, Y. Advanced Drug Delivery Reviews 2001, 47, (1), 113-131.
  25. 9. Kikuchi, A.; Okano, T. Progress in Polymer Science 2002, 27, (6), 1165-1193.
  26. 12. Sugiyama, K.; Hirao, A.; Hsu, J.-C.; Tung, Y.-C.; Chen, W.-C. Macromolecules 2009, 42, (12), 4053-4062.
  27. 13. Lin, P.-H.; Lee, W.-Y.; Wu, W.-C.; Chen, W.-C. Polymer Bulletin 2011, 1-19.
  28. 14. Onimura, K.; Matsushima, M.; Nakamura, M.; Tominaga, T.; Yamabuki, K.; Oishi, T. Journal of Polymer Science Part A: Polymer Chemistry 2011, 49, (16), 3550-3558.
  29. 16. Huang, W.; Wu, W. Journal of Applied Polymer Science 2012, 124, (3), 2055-2061.
  30. 17. 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, (6293), 539-541.
  31. 18. Grimsdale, A. C.; Leok Chan, K.; Martin, R. E.; Jokisz, P. G.; Holmes, A. B. Chemical Reviews 2009, 109, (3), 897-1091.
  32. 20. Kim, D. Y.; Cho, H. N.; Kim, C. Y. Progress in Polymer Science 2000, 25, (8), 1089-1139.
  33. 21. Shimizu, M.; Hiyama, T. Chemistry – An Asian Journal 2010, 5, (7), 1516-1531.
  34. 22. McGehee, M. D.; Heeger, A. J. Advanced Materials 2000, 12, (22), 1655-1668.
  35. 23. Kozlov, V. G.; Forrest, S. R. Current Opinion in Solid State and Materials Science 1999, 4, (2), 203-208.
  36. 24. Thomas, S. W.; Joly, G. D.; Swager, T. M. Chemical Reviews 2007, 107, (4), 1339-1386.
  37. 26. Dai, S.; Ravi, P.; Tam, K. C. Soft Matter 2009, 5, (13), 2513-2533.
  38. 27. Schumers, J.-M.; Fustin, C.-A.; Gohy, J.-F. Macromolecular Rapid Communications 2010, 31, (18), 1588-1607.
  39. 29. Schumers, J.-M.; Bertrand, O.; Fustin, C.-A.; Gohy, J.-F. Journal of Polymer Science Part A: Polymer Chemistry 2012, 50, (3), 599-608.
  40. 30. Yang, P.-C.; Wang, Y.-H.; Wu, H. Journal of Applied Polymer Science 2012, 124, (5), 4193-4205.
  41. 31. Li, L.; Xing, X.; Liu, Z. Journal of Applied Polymer Science 2012, 124, (2), 1128-1136.
  42. 32. Bochet, C. G. Journal of the Chemical Society, Perkin Transactions 1 2002, (2), 125-142.
  43. 33. Bertrand, O.; Schumers, J.-M.; Kuppan, C.; Marchand-Brynaert, J.; Fustin, C.-A.; Gohy, J.-F. Soft Matter 2011, 7, (15), 6891-6896.
  44. 34. Zhao, Y. Journal of Materials Chemistry 2009, 19, (28), 4887-4895.
  45. 35. Zhao, H.; Gu, W.; Sterner, E.; Russell, T. P.; Coughlin, E. B.; Theato, P. Macromolecules 2011, 44, (16), 6433-6440.
  46. 36. Tian, H.; Tang, Z.; Zhuang, X.; Chen, X.; Jing, X. Progress in Polymer Science 2012, 37, (2), 237-280.
  47. 37. Lutz, J.-F.; Weichenhan, K.; Akdemir, z.; Hoth, A. Macromolecules 2007, 40, (7), 2503-2508.
  48. 38. Lutz, J.-F.; Akdemir, z.; Hoth, A. Journal of the American Chemical Society 2006, 128, (40), 13046-13047.
  49. 39. Moliton, A.; Hiorns, R. C. Polymer International 2004, 53, (10), 1397-1412.
  50. 40. Moliton, A.; Nunzi, J.-M. Polymer International 2006, 55, (6), 583-600.
  51. 42. Bera, D.; Qian, L.; Tseng, T.-K.; Holloway, P. H. Materials 2010, 3, (4), 2260-2345.
  52. 43. Faisal, M.; Hong, Y.; Liu, J.; Yu, Y.; Lam, J. W. Y.; Qin, A.; Lu, P.; Tang, B. Z. Chemistry – A European Journal 2010, 16, (14), 4266-4272.
  53. 44. Resch-Genger, U.; Grabolle, M.; Cavaliere-Jaricot, S.; Nitschke, R.; Nann, T. Nat Meth 2008, 5, (9), 763-775.
  54. 45. Sapsford, K. E.; Berti, L.; Medintz, I. L. Angewandte Chemie International Edition 2006, 45, (28), 4562-4589.
  55. 46. Jenekhe, S. A.; Osaheni, J. A. Science 1994, 265, (5173), 765-768.
  56. 48. Lu, H.; Xu, B.; Dong, Y.; Chen, F.; Li, Y.; Li, Z.; He, J.; Li, H.; Tian, W. Langmuir 2010, 26, (9), 6838-6844.
  57. 50. Lu, H.; Su, F.; Mei, Q.; Zhou, X.; Tian, Y.; Tian, W.; Johnson, R. H.; Meldrum, D. R. Journal of Polymer Science Part A: Polymer Chemistry 2012, 50, (5), 890-899.
  58. 51. Yuan, W. Z.; Zhao, H.; Shen, X. Y.; Mahtab, F.; Lam, J. W. Y.; Sun, J. Z.; Tang, B. Z. Macromolecules 2009, 42, (24), 9400-9411.
  59. 53. Qin, A.; Lam, J. W. Y.; Tang, B. Z. Progress in Polymer Science 2012, 37, (1), 182-209.
  60. 55. Liu, Y.; Tang, Y.; Barashkov, N. N.; Irgibaeva, I. S.; Lam, J. W. Y.; Hu, R.; Birimzhanova, D.; Yu, Y.; Tang, B. Z. Journal of the American Chemical Society 2010, 132, (40), 13951-13953.
  61. 56. Chen, J.; Xu, B.; Ouyang, X.; Tang, B. Z.; Cao, Y. The Journal of Physical Chemistry A 2004, 108, (37), 7522-7526.
  62. 57. Chen, J.; Xie, Z.; Lam, J. W. Y.; Law, C. C. W.; Tang, B. Z. Macromolecules 2003, 36, (4), 1108-1117.
  63. 58. Chen, J.; Law, C. C. W.; Lam, J. W. Y.; Dong, Y.; Lo, S. M. F.; Williams, I. D.; Zhu, D.; Tang, B. Z. Chemistry of Materials 2003, 15, (7), 1535-1546.
  64. 60. Lim, C.-K.; Kim, S.; Kwon, I. C.; Ahn, C.-H.; Park, S. Y. Chemistry of Materials 2009, 21, (24), 5819-5825.
  65. 61. An, B.-K.; Kwon, S.-K.; Jung, S.-D.; Park, S. Y. Journal of the American Chemical Society 2002, 124, (48), 14410-14415.
  66. 62. Oelkrug, D.; Tompert, A.; Gierschner, J.; Egelhaaf, H.-J.; Hanack, M.; Hohloch, M.; Steinhuber, E. The Journal of Physical Chemistry B 1998, 102, (11), 1902-1907.
  67. 63. Li, Y.; Li, F.; Zhang, H.; Xie, Z.; Xie, W.; Xu, H.; Li, B.; Shen, F.; Ye, L.; Hanif, M.; Ma, D.; Ma, Y. Chemical Communications 2007, (3), 231-233.
  68. 65. Chien, R.-H.; Lai, C.-T.; Hong, J.-L. The Journal of Physical Chemistry C 2011, 115, (13), 5958-5965.
  69. 66. Xiao, Y.; Hong, H.; Javadi, A.; Engle, J. W.; Xu, W.; Yang, Y.; Zhang, Y.; Barnhart, T. E.; Cai, W.; Gong, S. Biomaterials 2012, 33, (11), 3071-3082.
  70. 69. Bisht, S.; Maitra, A. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology 2009, 1, (4), 415-425.
  71. 70. Rijcken, C. J. F.; Soga, O.; Hennink, W. E.; Nostrum, C. F. v. Journal of Controlled Release 2007, 120, (3), 131-148.
  72. 71. Khandare, J.; Minko, T. Progress in Polymer Science 2006, 31, (4), 359-397.
  73. 72. Liu, X.-M.; Quan, L.-d.; Tian, J.; Laquer, F. C.; Ciborowski, P.; Wang, D. Biomacromolecules 2010, 11, (10), 2621-2628.
  74. 73. Dougherty, T. J.; Gomer, C. J.; Jori, G.; Kessel, D.; Korbelik, M.; Moan, J.; Peng, Q. Journal of the National Cancer Institute 1998, 90, (12), 889-905.
  75. 74. Dolmans, D. E. J. G. J.; Fukumura, D.; Jain, R. K. Nat Rev Cancer 2003, 3, (5), 380-387.
  76. 75. Doh, J.; Irvine, D. J. Journal of the American Chemical Society 2004, 126, (30), 9170-9171.
  77. 76. Tang, B. Z.; Zhan, X.; Yu, G.; Sze Lee, P. P.; Liu, Y.; Zhu, D. Journal of Materials Chemistry 2001, 11, (12), 2974-2978.
  78. 77. Kim, C.; Hsieh, Y.-L. Colloids and Surfaces A: Physicochemical and Engineering Aspects 2001, 187–188, (0), 385-397.
  79. 78. Jiang, J.; Tong, X.; Morris, D.; Zhao, Y. Macromolecules 2006, 39, (13), 4633-4640.
  80. 79. Xie, Z.; Hu, X.; Chen, X.; Mo, G.; Sun, J.; Jing, X. Advanced Engineering Materials 2009, 11, (3), B7-B11.