跳到主要內容

臺灣博碩士論文加值系統

(44.210.149.218) 您好!臺灣時間:2024/11/07 21:29
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:顏修哲
研究生(外文):Yen, Hsiu-Che
論文名稱:新穎單分子鏈微胞:結構設計及功能性應用
論文名稱(外文):Novel Single-chain Polymeric Micelles: From structural design to emerging functions.
指導教授:張豐志孫建文孫建文引用關係
指導教授(外文):Chang, Feng-ChihSun,Chien-Wen
學位類別:碩士
校院名稱:國立交通大學
系所名稱:應用化學系碩博士班
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2013
畢業學年度:102
語文別:中文
論文頁數:89
中文關鍵詞:單分子鏈微胞甲基丙烯酸(寡(乙二醇))酯最高臨界溫度最低臨界溫度氫鍵
外文關鍵詞:SCPNsOEGMAUCSTLCSTHYDROGEN BONDING
相關次數:
  • 被引用被引用:0
  • 點閱點閱:152
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
最近我們已經能成功的製備一種新穎的水溶性奈米粒子,通過共價和非共價相互作用,模仿天然蛋白質的折疊,產生新的“單鏈高分子納米粒子”(SCPNs)其具有獨特的結構和優異性能。在本研究中,透過活性聚合的方式將已官能基化的甲基丙烯酸(寡(乙二醇))酯單體摻入能自組裝鍵結的多點式氫鍵組共聚物。這種材料是透過多點式氫鍵相互作用自組裝成物理交聯的聚合物網絡,由親水性的聚乙二醇(PEG)鏈段作為外殼可以自組裝在水溶液中形成球形SCPNs。所製備的SCPNs從應用的角度來看是非常有吸引力的,因為它們具有非常低的臨界微胞濃度(<10-4 g/L)和均勻的直徑(約25nm),這使得它們非常穩定和顯著降低比黏度。另外,在不同溫度和濃度測試中,能維持均一且穩定的粒徑,而且在介面活性劑的存在下SCPNs和載藥的SCPNs也都能維持動力學穩定。此外,我們還觀察到,在包覆葉酸後會影響SCNPs微胞在水溶液中的形成且與以往的結果相比,有顯著高藥物附載率(19.6%)。在高於最低臨界溫度時,pH值敏感的氫鍵網絡允許在溫和的酸性條件下(pH = 4)的促進釋放附載的藥物,在24 h後可達66.7%的釋放。由以上結果,我們所開發的新一代SCNPs具有很大的潛力可以作為下一代以超分子聚合物設計成的功能性奈米材料。
Recent innovation in water-based polymeric nanoparticle has shown significant promise to mimic the folding of natural proteins by generating novel “single-chain polymeric nanoparticles” (SCPNs) through covalent and non-covalent interactions, which have gained prominence in nanotechnology and nanomedicine due to their unique structures and exceptional properties. In this study, a practical approach to the living polymerization of functionalized oligo(ethylene glycol) methacrylate monomer allows for incorporation of self-constituted multiple hydrogen bonded groups into homopolymer. This material is able to self-assemble through multiple hydrogen bonding interactions into physically core-crosslinked polymeric networks, which by hydrophilic poly(ethylene glycol) segments as the outer shell can self-assemble in aqueous solutions to form spherical SCPNs. The resulting SCPNs are very attractive from a practical point of view, since they have a very low critical micellization concentration (< 10-4 g/L) with an almost uniform diameter of about 25 nm, which makes them extremely stable with a significant reduction in the specific viscosity. In addition, the mean value of the particle size is not only significantly stabled by variables such as temperature and concentration, but also improved kinetic stability of SCPNs and drug-loaded SCPNs in the presence of a destabilizing agent. Moreover, we also observed that the incorporation of anticancer drug affected the micellization process of SCPNs in aqueous solution and enabled significantly higher loading of the drug (19.6 %), compared with previous results. Above the lower critical solution temperature, the pH-sensitive hydrogen bonded network allows the facilitated release of entrapped drug under mildly acidic conditions (pH= 4), with a release of up to 66.7 % of bound drug in 24 h. Thus, these results suggest that this newly developed SCPN is a potential architecture in future supramolecular polymer designs for next-generation functional nano-materials.
目錄
中文摘要 I
Abstract III
誌謝 iii
圖目錄 viii
表目錄 xi
第一章 研究動機與目的 1
第二章 文獻回顧 3
2-1 生醫材料 (Biomaterials) 3
2-2智慧型高分子(Intelligent Polymers) 4
2-2-1溫度敏感性材料的簡介 5
2-2-2聚甲基丙烯酸寡(乙二醇)酯 (PolyOEGMAs) 8
2-3微胞 (micelles) 11
2-3-1高分子微胞 (polymeric micelles) 13
2-3-2影響微胞穩定性因素 14
2-3-3微胞的製備和包藥方式 15
2-3-4包覆藥物 17
2-4藥物控制釋放 (Controlled drug delivery) 18
2-5超分子化學(Supramolecular chemistry) 20
2-6氫鍵 22
2-7單鏈高分子奈米粒子(Single-chain polymer nanoparticles) 24
第三章 實驗步驟與方法 27
3-1實驗藥品 27
3-2實驗儀器 29
3-3實驗合成步驟 30
3-3-1氫鍵作用力之化合物合成 30
3-3-2高分子單體合成 35
3-3-3主鏈高分子POEGMA-PgMATMS以ATRP進行聚合 39
3-3-4 POEGMA-PgMATMS去保護 40
3-3-5將POEGMA-PA和UPy進行Click反應 41
3-4 產物結構鑑定及性質分析 42
3-4-1產物結構鑑定 42
3-4-2製備微胞奈米粒子 42
3-4-3 最低臨界溶解溫度分析 43
3-4-4微胞粒徑測定 43
3-4-5 臨界微胞濃度測定 (Critical micelles concentration, CMC) 44
3-4-6微胞擴散係數測定(Diffusion-ordered spectroscopy,DOSY) 45
3-5 微胞穩定度測試 47
3-5-1 微胞在加入SDS時的穩定度測試 47
3-5-2 微胞溶液濃度對於穩定度的測試 47
3.6藥物包覆 (Drug loading) 48
3-7 體外藥物釋放模擬 (Drug release) 48
第四章 結果與討論 49
4-1 材料結構性質鑑定 49
4-1-1 1H-NMR化學結構分析 49
4-1-2 GPC分析 52
4-1-3臨界相轉換溫度之分析 53
4-2 新穎之Single-chain polymer nanoparticles (SCPNs) 微胞材料 55
4-3超分子微胞在水溶液中之性質探討 59
4-3-1 微胞在水溶液下之粒徑分析 59
4-3-2 微胞穩定度之CMC測定 61
4-3-3 微胞在不同濃度下之穩定度測定 63
4-3-4微胞在不同溫度下之粒徑測定 66
4-3-5 微胞在SDS下之穩定度測定 67
4-3-6微胞在水溶液中變溫NMR分析 70
4-3-7微胞在水溶液中擴散係數測定 72
4-4超分子微胞在異丙醇溶液中之性質探討 74
4-4-1最高臨界溶解溫度之分析 74
4-4-2 藥微胞在不同溫度下之粒徑測定 75
4-5藥物控制釋放 78
4-5-1 藥物包覆 (Drug Loading) 78
4-5-2 體外藥物釋放模擬 (Drug Release) 82
第五章 結論與未來展望 86
第六章 參考文獻 87

圖目錄
圖2-1 LCST前後相變化圖 6
圖2-2不同種類的甲基丙烯酸寡(乙二醇)酯化學結構 8
圖2-3奈米微胞藥物載體 13
圖2-4利用直接溶解法與透析法製備高分子微胞 16
圖2-5利用乳化法製備高分子微胞 17
圖2-6葉酸化學結構 17
圖2-7藥物時間控制釋放示意圖 19
圖2-8藥物分佈控制釋放示意圖 20
圖2-9分子間利用共價鍵與非共價鍵結合之示意圖 21
圖2-10超分子中可能的分子間氫鍵種類 22
圖2-11多點式氫鍵作用力 23
圖2-11 SCNPs合成示意圖:(a) Homo-functional chain collapse;(b) Hetero-bifunctional chain collapse;(c) Cross-linker-mediated chain collapse;(d) One-block collapse of diblock or triblock copolymer 25
圖3-1 (a) 11-azidoundecanoic acid 和 (b) 11-Bromoundecanoic acid 之 1H NMR 31
圖3-2 (a) 11-azido-N-(6-(3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) propanamido)pyridin-2-yl)undecanamide (UPy) 和 (b) N-(6-aminopyr idine -2-yl)-11- azidoundecanamid 之 1H NMR 34
圖3-3 PgMA 之 1H NMR 36
圖3-4 PgMATMS 之 1H NMR 38
圖4-1 Poegma-PgMATMS 之 1H-NMR 結構鑑定 50
圖4-2 Poegma-PgMA 之 1H-NMR 結構鑑定 51
圖4-3 Poegma-UPy 之 1H-NMR 結構鑑定 52
圖4-4高分子材料在 DI water 中LCST 溫度分析圖 54
圖4-5各高分子材料之黏度測試 57
圖4-6各高分子材料之Count rate測試 57
圖4-7不同比例高分子材料之小角度X射線散射圖(saxs) 61
圖4-8各高分子材料之臨界微胞濃度 65
圖4-9各高分子材料在不同濃度下之粒徑大小 65
圖4-10不同濃度下之粒徑大小SEM圖 66
圖4-11 Poegma-UPy之TEM圖 66
圖4-12各高分子材料在不同溫度下之粒徑大小 67
圖4-13 Sodium dodecyl sulfate (SDS) 之化學結構 68
圖4-14各高分子材料在加入 SDS 後之粒徑穩定度 69
圖4-15 Poegma-PgMA 和Poegma-UPy 之變溫1H NMR 70
圖4-16 Poegma-PgMA 之高分子鏈型態變化示意圖 71
圖4-17 Poegma-UPy 之高分子鏈型態變化示意圖 72
圖4-18各高分子材料之擴散係數 73
圖4-19高分子材料在 IPA 中UCST 溫度分析圖 75
圖4-20各高分子材料在異丙醇容易中之粒徑變化圖 77
圖4-21 Folic acid 溶在 DMF 中之減量線 78
圖4-22各組成Poymer之藥物負載前後粒徑變化圖 79
圖4-23 Poegma-UPy負載藥物對微胞粒徑及DLC之分析圖 80
圖4-24 Poegma-UPy微胞在包覆藥物後加入SDS下之粒徑穩定度 82
圖4-25 Poegma-UPy微胞藥物模擬釋放 84


1. Liu, M.; Fre´chet, J. M. J. Pharm. Sci. Technol. Today 1999, 2, 393.
2. Hedrick, J. L.; Miller, R. D.; Hawker, C. J.; Carter, K. R.; Volksen, W.; Yoon, D. Y.; Trollsas, M. AdV. Mater. 1998, 10, 1049.
3. Landfester, K. AdV. Mater. 2001, 13, 765
4. Liu, S.; Armes, S. P. J. Am. Chem. Soc.2001, 123, 9910
5. Mecerreyes, D.; Lee, V.; Hawker, C. J.; Hedrick, J. L.; Wursch, A.; Volksen,W.; Magbitang, T.; Huang, E.; Miller, R. D. AdV. Mater. 2001, 13, 204.
6. Joon B. Park and Ruderic S. Lakes“BIOMATERIALS An Introduction 2nded.”Plenum Press, New York, P.2-3, 1992.
7. Park, Joon Bu.Biomaterials science and engineering. N.p.: Plenum Press, 1984. 1-459. Print.
8. Guo, B. L., Yuan, J. F., Yao, L., Gao, Q. Colloid Polym. Sci. 2007,285, 665-671.
9. Guo, B. L., Yuan, J. F., Yao, L., Gao, Q.Coll.Surfaces B: Biointerfaces. 2007,58, 151-156.
10. Fundueanu, G., Constantin, M., Ascenzi, P. Biomaterials. 2008,29,2767-2775.
11. J. Chung, M. Yokoyama, M. Yamato, T. Aoyagi, Y. Sakurai and T. Okano, Journal of Controlled Release 1999, 62, 115-127
12. S. Sugihara , K. Hashimoto , S. Okabe , M. Shibayama , S. Kanaoka ,S.Aoshima , Macromolecules 2004 , 37 , 336 – 343 .
13. S. Han , M. Hagiwara , T. Ishizone , Macromolecules 2003 , 26 ,8312 – 8319 .
14. Xuejuan, W.; Shiyong, L. J. Mater. Chem. 2011, 21, 10321–10329.
15. Magnusson, J. P.; Khan, A.; Pasparakis, G.; Saeed, A. O.;Wang, W.; Alexander, C. J. Am. Chem. Soc. 2008, 130, 10852–10853.
16. Yamamoto, S.-I.; Pietrasik, J.; Matyjaszewski, K. J. Polym. Sci. Part A: Polym. Chem. 2008, 46, 194–202.
17. Becer, C. R.; Hahn, S.; Fijten, M. W. M.; Thijs, H. M. L.; Hoogenboom, R.; Schubert, U. S. J. Polym. Sci. Part A: Polym. Chem. 2008, 46, 7138–7147.
18. Bebis, K.; Jones, M. W.; Haddleton, D. M.; Gibson, M. I. Polym. Chem. 2011, 2, 975–982.
19. Roth, P. J.; Jochum, F. D.; Theato, P. Soft Matter 2011, 7, 2484
20. Heskins, M.; Guillet, J. E. J. Macromol. Sci. Chem. 1968, 2,1441–1455.
21. Dowson, K. A.; Gorelov, A. V.; Timoshenko, E. G.; Kuznetsov, Y. A. Phys. A 1997, 244, 68–80.
22. Timoshenko, E. G.; Kuznetsov, Y. A.; Dawson, K. A. Phys. A 1997, 240, 432–442.
23. M. Sugimoto, T. Okagaki, S. Narisawa, Y. Koida, K. Nakaji-ma, , Int. J. Pharm. 1998, 160, 11–19
24. A.W. Basit, J.M. Newton, M.D. Short, W.A. Waddington,
P.J. Ell, L.F. Lacey, Pharm. Res. 2001, 18,1146–1150.
25. Xiaojie Li, Yinfeng Qian, Tao Liu, Xianglong Hu, Guoying Zhang, Yezi You, Shiyong Liu. Biomaterials, 32, 2011, 6595-6605
26. V.P. Torchilin, Pharmaceutical Research 24,2007,1-16.
27. Y. Matsumura, K. Kataoka, Cancer Science 100 ,2009, 572-579.
28. D. Sutton, N. Nasongkla, E. Blanco, J.M. Gao, Pharmaceutical Research ,24, 2007,1029-1046.
29. N. Nasongkla, E. Bey, J. Ren, H. Ai, C. Khemtong, J.S. Guthi, S.-F. Chin,
A.D. Sherry, D.A. Boothman, J. Gao. Nano Letters,6,2006,2427-2430.
30. Woodle M.C., and Lasic D.D. Biochimica et Biophysica Acta, 1113 ,1992, 171-199
31. Yokoyama M., Fukushima S., Uehara R., Okamoto K., Kataoka K.,Sakurai Y., and Okano T., Journal of Controlled Release, 50 ,1998, 79-92.
32. Allen C., Maysinger D., and Eisenberg A. Colloids and Surfaces B:Biointerfaces, 16 ,1999, 3-27.
33. Torchilin V.P. Journal of Controlled Release, 73,2001,137-172
34. Kwon G.S., and Okano T. 21,1996,107-116
35. Langer R. Drug delivery and targeting. Nature 1998,392,5-10.
36. J Byeongmoon, W K Sung, H B You. Adv. Drug Del. Rev. 54,2002,37-51.
37. K E Uhrich, S M Cannizzaro, R S Langer et al. Chem. Rev. 99,1999, 3181-3198.
38. Lehn, J. M., Angew. Chem. Int. Ed. 1998, 27,90-112.
39. Hideo N. , Z. L., Nature 2000, 404, 625.
40. Ilhan F. , G. M., Rotello V. M., Macromolecules 2001, 34, 2597.
41. Rint P. Sijbesma, Felix H. Beijer, Luc Brunsveld, Brigitte J. B. Folmer, J. H. K. Ky Hirschberg, Ronald F. M. Lange, Jimmy K. L. Lowe, and E. W. Meijer. Scince 1997,278,1601.
42. Beatty A. M. , C. E., Comm. 2001, 51, 1.
43. Felix H. Beijer, Huub Kooijman, Anthony L. Spek, Rint P. Sijbesma, E. W. Meijer. Angew. Chem. Int. Ed. 1998, 37,75-78.
44. Schmidt, J. S., R.;Wu¨rthner, F.J. Org. Chem.2008, 73, 6355.
45. Bertin, P. A.; Gibbs, J. M.; Shen, C. K.-F.; Thaxton, C. S.; Russin, W. A.;
Mirkin, C. A.; Nguyen, S. T. J. Am. Chem. Soc. 2006, 128, 4168–4169.
46. Hawker, C. J.; Wooley, K. L. Science 2005, 309, 1200–1205.
47. Rodriguez-Hernandez, J.; Checot, F.; Gnanou, Y.; Lecommandoux, S. Prog. Polym. Sci. 2005, 30, 691–724.
48. Pochan, D. J.; Chen, Z.; Cui, H.; Hales, K.; Qi, K.; Wooley, K. L. Science
2004, 306, 94–97.
49. Harth, E.; Horn, B. V.; Lee, V. Y.; Germack, D. S.; Gonzales, C. P.; Miller,
R. D.; Hawker, C. J. Am. Chem. Soc. 2002, 124, 8653–8660.
50. Luzuriaga, A. R. d.; Ormategui, N.; Grande, H. J.; Odriozola, I.; Pomposo,
J. A.; Loinaz, I. Macromol. Rapid Commun. 2008, 29, 1156–1160.
51. Croce, T. A.; Hamilton, S. K.; Chen, M. L.; Muchalski, H.; Harth, E. Macromolecules 2007, 40, 6028–6031.
52. Cherian, A. E.; Sun, F. C.; Sheiko, S. S.; Coates, G. W. J. Am. Chem. Soc.
2007, 129, 11350–11351.
53. Malkoch, M.; Thibault, R. J.; Drockenmuller, E.;Messerschmidt, M.; Voit, B.; Russell, T. P.;Hawker, C. J. J Am Chem Soc 2005, 127, 14942.
54. Ladmiral, V.; Mantovani, G.; Clarkson, G. J.; Cauet, S.; Irwin, J. L.; Haddleton,
D. M. J. Am. Chem. Soc. 2006, 128, 4823.
55. C. L. Zhao, M. A. Winnik, G. Riess and M. D. Croucher, Langmuir 1990, 6, 514.
56. Chien, W. J.; Lin, S. C.; Chang, D. K.. Bull. Inst. Chem., Acad. Sinica,1996 ,43, 53.
57. Chien, W. J.; Cheng, S. F.; Chang, D. K.. Anal. Biochem.1998, 264, 211.
58. N. Kang, M. È. Perron, R. E. Prud'Homme, Y. Zhang, G. Gaucher and J. C. Leroux, Nano letters 2005, 5, 315.
59. H. J. Lee and Y. Bae. Biomacromolecules 2011.
60. Minchin R. Nat Nanotechno , 2008, 3,12.
61. Hamilton SK, Harth E. ACS Nano, 2009,3,42.
62. C. C. Cheng, Y. C. Yen and F. C. Chang, RSC Advances 2011.
63. P. L. Ritger and N. A. Peppas, Journal of Controlled Release 1987, 5, 37-42.
64. S. H. Kim, J. P. K. Tan, F. Nederberg, K. Fukushima, J. Colson, C. Yang, A. Nelson, Y. Y. Yang and J. L. Hedrick, Biomaterials 2010, 31, 8063-8071.

連結至畢業學校之論文網頁點我開啟連結
註: 此連結為研究生畢業學校所提供,不一定有電子全文可供下載,若連結有誤,請點選上方之〝勘誤回報〞功能,我們會盡快修正,謝謝!
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top