簡易檢索 / 詳目顯示

回結果列表
研究生： 謝坤霖
Kun-Lin Hsieh
論文名稱： 褐藻膠共聚生物相容性高分子奈米疫苗載體之合成
Synthesis of vaccine nanocarrier of fucoidan hybrid biocompatible polymer
指導教授： 蘇舜恭
Shuenn-kung Su
口試委員: 陳建光
Jem-Kun Chen
鄭智嘉
Chih-Chia Cheng
許蕙玲
Hui-Ling Hsu
學位類別： 碩士
Master
系所名稱： 工程學院 - 材料科學與工程系
Department of Materials Science and Engineering
論文出版年： 2017
畢業學年度： 105
語文別： 中文
論文頁數： 124
中文關鍵詞： 明膠 、生物相容性高分子 、褐藻膠 、藥物載體 、化學交聯 、兩親分子 、聚己內酯
外文關鍵詞： Gelatin, Biocompatible polymers, Fucoidan, vaccine carrier, Chemical crosslink, Amphiphilic polymer, Polycaprolactone
相關次數： 點閱：267  下載：0 
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

    • 本研究目的是利用褐藻膠(Fucoidan)合成生物相容性疫苗載體，分 為兩個部份，第一部份將天然高分子明膠(Gelatin)經化學交聯 (Chemical crosslinking method) 褐 藻 膠 製 備 天 然 奈 米 粒 子 (Gelatin@Fucoidan nanoparticles，GNFPs)。由 IR 證實氨基交聯結構， 並用電子顯微鏡 SEM 及粒徑分析儀 DLS 分析形貌，得 200~400nm 均 勻粒徑分布。由 UV-vis 測量得 1mg/ml (1FD)組合具有高藥物包覆率 (45%)，並且在兩週內僅損失低於 10%藥物量之高穩定性，藉由 CLSM 我們可以觀察到螢光包覆影像。
    第二部分則是進行人工高分子聚己內酯與褐藻膠之點擊化學 (Click Reaction)合成褐藻膠及聚己內酯兩親高分子(FD@PCL， Amphiphilic polymer)，由 IR 得到疊氮以及炔基的改質訊號，經 NMR 測量褐藻膠與聚己內酯 1:50 比例中，證實三唑環於 8.0ppm 的 1H 訊 號，表示點擊反應成功。在 SEM 觀察油、水相型態轉換，並由 DLS 以及 UV-vis 測得 200nm 之粒徑分佈，與包覆藥物量呈正向關係，具 有高達 86%的包覆率，兩週僅損失 10%蛋白藥物之高穩定性，藉由 CLSM 我們可以觀察兩週後之螢光包覆影像。

    In this study, we synthesized biocompatible vaccine nanocarrier hybrid polysaccride Fucoidan. Our research including two parts:
    In the first part, Gelaitn was hybrided with Fucoidan by chemical crosslinking method, a mean size was observed by DLS & SEM images, which located between 200~400nm nanoparticle, crosslinking structure has been comfirmed by IR spectrum. A high loading efficiency (45%) and high stability carrier (only 10% of drug were loss during 2 weeks) was prepared, which was measured by UV-vis spectrum. Furthermore, we observed drug loading image by CLSM after stability test.
    In the second part, we utilized Click chemistry to combine Fucoidan and Polycaprolactone, which created Fucoidan-graft-Polycaprolactone amphiphilic polymer(FD@PCL), we comfirmed azide and alkynyl group IR signal at 2100cm-1, and then we identified Triazole ring signal around 8.0ppm of 1H NMR, under FD: PCL=1:50 synthesis condition.
    Moreover, we produced high stability, high drug loading efficiency carrier transforming from THF to water condition, surprisingly we discovered that size distribution approximately located at 200nm and increased while drug loading, eventually demonstrated 86% encapsulation efficiency, which maintain below 10% loss during one month, measuring by UV-vis spectrum. At last, we observed nanoparticles containing green fluorescence images by CLSM.
    Keywords:Gelatin、Biocompatible polymers、Fucoidan、vaccine carrier、 Chemical crosslink、Amphiphilic polymer、Polycaprolactone.

    目錄 指導教授推薦書......................................................................................... I 學位考委審定書....................................................................................... II 摘要.......................................................................................................... III Abstract .................................................................................................... IV 致謝........................................................................................................... V 第 1 章 前言.............................................................................................. 1 1.1 研究背景 ........................................................................................ 1 1.2 研究動機與目的 ............................................................................ 3 第 2 章 理論與文獻回顧.......................................................................... 4 2.1 奈米載體 ........................................................................................ 4 2.1.1 奈米載體簡介...........................................................................4 2.1.2 奈米載體種類...........................................................................6 2.2 奈米載體應用於疫苗載體研究 .................................................. 12 2.2.1 奈米載體材料與疫苗的結合.................................................12 2.2.2 疫苗注射路徑對免疫系統機制之影響.................................14 2.2.3 疫苗載體大小對粘膜系統吸收路徑之變化.........................16 2.3 生物相容性高分子 ...................................................................... 18 VII 2.3.1 明膠(Gelatin)簡介與應用......................................................19 2.3.2 褐藻膠(Fucoidan)簡介與應用...............................................20 2.3.3 聚己內酯(Polycaprolactone)簡介與應用..............................22 2.4 化學交聯原理及種類 .................................................................. 24 2.4.1 醛類化學交聯法(Crosslinking with Aldehydes) ................... 25 2.4.2 天然交聯劑 Genipin............................................................... 26 2.5 點擊化學反應 .............................................................................. 28 2.5.1 點擊化學反應及簡介.............................................................28 2.5.2 點擊化學的應用.....................................................................30 第 3 章 儀器原理.................................................................................... 33 3.1 傅立葉轉換紅外線光譜儀(Fourier transform infrared spectrometer，FT-IR) ......................................................................... 33 3.2 可見光紫外光分光光譜儀(Ultraviolet-visible spectroscopy，UV- vis) ....................................................................................................... 38 3.3 核磁共振(Nuclear Magnetic Resonance，NMR)........................ 41 3.4 動態光散射粒徑分析儀(Dynamic light scattering，DLS)......... 44 3.5 表面電位分析儀(Zeta-potential) ................................................. 46 3.6 高解析度場發射掃描式電子顯微鏡(Field-emission scanning electron microscope，FE-SEM).......................................................... 48 VIII 3.7 雷射掃描式共軛焦顯微鏡 (Laser scanning confocal microscope，LSCM)........................................................................... 50 第 4 章 實驗流程與方法........................................................................ 52 4.1 實驗流程圖 .................................................................................. 52 4.2 實驗藥品 ...................................................................................... 53 4.3 實驗儀器 ...................................................................................... 56 4.4 實驗步驟 ...................................................................................... 57 4.4.1 明膠混摻褐藻膠奈米粒子的製備.........................................57 4.4.1.1 PBS 緩衝溶液配製............................................................... 57 4.4.1.2 明膠混摻交聯合成..............................................................57 4.4.2 明膠混摻褐藻膠奈米載體穩定性測試.................................59 4.4.2.1 檢量線製作..........................................................................59 4.4.2.2 不同交聯劑之穩定性測試..................................................59 4.4.2.3 不同交聯劑在 pH 值穩定性測試 ....................................... 60 4.4.3 褐藻膠疊氮官能基修飾.........................................................61 4.4.4 聚己內酯聚合炔鍵改質.........................................................63 4.4.4.1 起始劑炔鍵改質..................................................................63 4.4.4.2 炔改質聚己內酯聚合..........................................................64 4.4.5 褐藻醣膠與聚己內酯兩親高分子點擊化學鍵結.................65 IX 4.4.6 褐藻膠合聚己內酯奈米載體穩定性測試.............................66 第 5 章 結果與討論................................................................................ 67 5.1 GNFPs 奈米粒子光譜定性分析................................................... 67 5.1.1 FT-IR 光譜分析....................................................................... 67 5.1.2 DLS 粒徑分析 ......................................................................... 68 5.1.3Zeta-potential 表面電位分析.................................................71 5.1.4 UV-vis 光譜分析 ..................................................................... 72 5.1.4.3 GNFPs 載體穩定性測試 ...................................................... 76 5.1.4.4 不同交聯劑在 pH 值穩定性測試....................................... 77 5.2 GNFP 奈米粒子影像型態分析 .................................................... 77 5.2.1 SEM 表面型態分析 ................................................................ 78 5.2.2 CLSM 雷射共軛焦螢光型態分析.......................................... 79 5.3 FD@PCL 奈米粒子定性分析 ...................................................... 81 5.3.1 FT-IR 光譜分析....................................................................... 81 5.3.2 NMR 化學結構分析................................................................ 85 5.3.3 DLS 粒徑分析 ......................................................................... 86 5.3.4 Zeta potential 表面電位分析................................................... 88 5.3.5 UV-vis 光譜分析 ..................................................................... 89 5.4 FD@PCL 奈米載體影像型態分析 .............................................. 92 X 5.4.1 SEM 表面形態分析 ................................................................ 92 5.4.2 CLSM 雷射共軛焦螢光顯微鏡型態分析.............................. 94 第 6 章 結論............................................................................................ 96 XI 圖目錄 圖 1-1 近年疫苗載體的期刊發表數量趨勢圖[1] ................................... 2 圖 2-1 奈米載體於生醫藥物上的應用示意圖[2] ................................... 5 圖 2-2 常見的奈米粒子種類[28] ............................................................. 6 圖 2-3 Mansoor Amiji 等人改質明膠載體之示意圖[33] ........................ 8 圖 2-4 為高滲透延長滯留效應(Enhanced Permeability and Retention effect，EPR)示意圖[34] .................................................................... 8 圖 2-5 Kaur et al.等人藉由甘露糖化(Mannsylated)改質明膠結構[35].. 9 圖 2-6 肝素抗癌型微胞藥物兼載體[38] ............................................... 10 圖 2-7 疫苗注射方式示意圖[8] ............................................................. 14 圖 2-8 奈米載體作用於粘膜部位之免疫反應路徑示意圖[8] ............. 16 圖 2-9 明膠結構示意圖.......................................................................... 20 圖 2-10 褐藻 Macrocystis pyrifera(左)及褐藻膠分子結構(右) ............ 21 圖 2-11 聚己內酯開環聚合反應式........................................................ 22 圖 2-12 交聯法種類概念圖[11].............................................................. 24 圖 2-13 互補鍵結化學交聯法合成路徑[11] ........................................ 25 圖 2-14 戊二醛交聯反應機構................................................................ 26 圖 2-15 Genipine 京尼丁交聯反應機構 ................................................. 27 圖 2-16 屬於點擊化學之化學反應........................................................ 28 XII 圖2-17 為加熱環加成產生約1:1的1,4和1,5取代之1,2,3-三唑 立體異構物:銅(I)催化的 Huisgen 速接合化學僅產生 1, 4-取代的 1, 2, 3-三唑........................................................................................ 29 圖 2-18 密度泛函理論推測的疊氮與炔經銅催化速配接合反應機構 30 圖 2-19 Giovanni Maglio 及 Fabiana Quaglia 等人製作的 Y、H 型高分 子示意圖[71] .................................................................................... 31 圖 3-1 XPS(ESCA)光電子產生示意圖 ................... 錯誤! 未定義書籤。 圖 3-2 雙原子分子伸縮振動示意圖...................................................... 34 圖 3-3 多原子分子的振動模式.............................................................. 34 圖 3-4 伸縮振動偶級矩變化示意圖...................................................... 35 圖 3-5 干涉型紅外線光譜儀工作原理圖.............................................. 36 圖 3-6 干涉型基本方程式示意圖.......................................................... 37 圖 3-7 各光線波長與能量對照圖.......................................................... 39 圖 3-8 紫外光/可見光光譜儀工作原理圖 ............................................ 40 圖 3-9 原子核於磁場自旋示意圖.......................................................... 41 圖 3-10 核磁共振儀器系統示意圖........................................................ 43 圖 3-11 動態光散射儀基本架構圖 ........................................................ 45 圖 3-12 表面電位圖................................................................................ 47 圖 3-13 高解析度場發射掃描式電子顯微鏡構造示意圖.................... 49 XIII 圖 3-14 雷射掃描式共軛焦顯微鏡工作原理圖.................................... 51 圖 4-1 實驗流程圖.................................................................................. 52 圖 4-2 疊氮官能基修飾流程.................................................................61 圖 4-3 褐藻膠氫氧基改質形成離去基.................................................62 圖 4-4 褐醣藻膠疊氮化合物親和取代反應.........................................62 圖 4-5 聚己內酯聚合炔鍵改質.............................................................. 63 圖 4-6 炔鍵結構修飾反應.....................................................................64 圖 4-7 炔鍵改質聚己內酯聚合.............................................................64 圖 4-8 兩親高分子點擊反應流程.........................................................65 圖 5-1 (A)Gelatin;(b)Fucoidan;(c)FITC-BSA;(d)GNFPs- Glutaraldehyde;(e)GNFPs-Genipin................................................ 67 圖 5-2 (A)明膠濃度變化;(B)戊二醛交聯劑劑量變化之 GNFPS 粒子 DLS 粒徑分布比較圖 ...................................................................... 69 圖 5-3 (A)褐藻膠濃度變化經 Glutaraldehyde 交聯;(B)褐藻膠濃度變 化經 Genipine 交聯聚合之 DLS 粒徑分布比較圖 ........................ 71 圖 5-4 不同交聯劑之粒子表面電位.....................................................71 圖 5-5 各濃度 FITC-BSA 在吸收波長為 460NM 之 UV-VIS 吸收光譜圖 ........................................................................................................... 73 圖 5-6 為各濃度 FITC-BSA 標準液之線性回歸圖 ............................. 74 XIV 圖 5-7 載體穩定性測試:(A)為戊二醛交聯組合(1FD-GA);(B)為京尼 丁交聯組合(1FD-GP) ...................................................................... 76 圖 5-8 1FD-GA(左)1FD-GP(右)於不同 PH 值變化之穩定度............... 77 圖 5-9 GNFPS 粒子使用戊二醛交聯不同褐藻膠濃度包覆 BSA 之粒子 型態圖:(A) 0FD (純明膠粒子);(B) 1FD;(C) 3FD;(D) 5FD .... 78 圖 5-10 GNFPS 粒子使用京尼丁交聯不同褐藻膠濃度包覆 BSA 之粒 子型態圖:(A) 0FD (純明膠粒子);(B) 1FD;(C) 3FD;(D) 5FD 79 圖 5-11 0FD GNFPS(純明膠粒子)包覆 FITC-BSA 於雷射共軛焦顯微 鏡之影像(A)Fluorescence Image;(b)Bright Image;(c)Merge ..... 80 圖 5-12 1FD GNFPS 包覆 FITC-BSA 於雷射共軛焦顯微鏡之影像(A) Fluorescence Image;(b)Bright Image;(c)Merge 及包覆影像(箭 號) ..................................................................................................... 80 圖 5-13 褐藻膠改質各步驟之 FT-IR 圖譜，(A)褐藻膠，FD; (B)改質接 上 p-toluenesulfonyl，FD-OTS; (C)親和取代形成疊氮化物，FD- N3。 .................................................................................................. 82 圖 5-14 褐藻膠改質各步驟之 FT-IR 圖譜:(A)起始劑 4- Hydroxybenzyl alcohol;(B)改質炔鍵(Alkyne group)後的起始劑; (C)為最終聚合之 Alkyne PCL。 ..................................................... 83 XV 圖 5-15 (A)為改質疊氮化物之 FD-N3;(B)為修飾過參鍵之 Alkyne- PCL;(C)為點擊反應後的最終產物 FD@PCL。 ......................... 84 圖 5-16 不同 PCL 之莫耳組成之 1H-NMR 光譜圖(由上至下分別為 1:50、30、10) ............................................................................... 85 圖 5-17 不同 FD 與 PCL 比例於不同溶劑之 DLS 粒徑比較圖:左圖 為 THF 環境下之粒徑;右圖則為進入 PBS 時的粒徑 ................ 87 圖 5-18 FD@PCL 包覆藥物後的粒徑分佈圖 ....................................... 88 圖 5-19 不同溶劑下之表面電位變化.................................................... 89 圖 5-20 對不同的交聯劑條件進行兩週穩定性測試............................ 91 圖 5-21 各別 FD@PCL 兩親奈米載體不同溶劑之倍率表面型態圖: (A)、(D)為 FD@PCL=1:10;(B)、(E) FD@PCL=1:30;(C)、 (F)1:50，分別分散於水相及 THF 相(上排圖放大倍率為 X20K、 下排圖放大率為 X5K) ...................................................................... 92 圖 5-22 為 1:50 之 FD@PCL@FITC-BSA 奈米載體結構型態圖 (X5K):由左至右分別為沒加入交聯劑(左)、加入戊二醛 GA(中)、加入京尼丁 GP(右)之藥物包覆後的影像 ..................... 93 圖 5-23 FD@PCL50 奈米粒子未交聯包覆螢光藥物之 CLSM 影像 (a)Fluorescence Image; (b)Bright Image; (c)Merge ......................... 94 XVI 圖 5-24 FD@PCL50 奈米粒子為加入 Glutaraldehyde 交聯包覆螢光藥 物之 CLSM 影像(A) Fluorescence Image; (b)Bright Image; (c)Merge ........................................................................................................... 95 圖 5-25 FD@PCL50 奈米粒子為加入 GENIPIN 交聯包覆螢光藥物之 CLSM 影像，黃色表示沈積或團聚現象(A)Fluorescence Image; (B)Bright Image; (c)Merge................................................................ 95

    1. Zhao, L., et al., Nanoparticle vaccines. Vaccine, 2014. 32(3): p. 327- 337.
    2. Chen, G., et al., Nanochemistry and Nanomedicine for Nanoparticle-based Diagnostics and Therapy. Chemical Reviews, 2016. 116(5): p. 2826-2885.
    3. Mura, S., J. Nicolas, and P. Couvreur, Stimuli-responsive nanocarriers for drug delivery. Nat Mater, 2013. 12(11): p. 991- 1003.
    4. Ghosh Chaudhuri, R. and S. Paria, Core/Shell Nanoparticles: Classes, Properties, Synthesis Mechanisms, Characterization, and Applications. Chemical Reviews, 2012. 112(4): p. 2373-2433.
    5. Ma, W., et al., Genipin-crosslinked gelatin films as controlled releasing carriers of lysozyme. Food Research International, 2013. 51(1): p. 321-324.
    6. Tan, H., et al., Gelatin Particle-Stabilized High Internal Phase Emulsions as Nutraceutical Containers. ACS Applied Materials & Interfaces, 2014. 6(16): p. 13977-13984.
    7. Matteo Conti, V.T., Cesare Baccini, Gianni Pertici, Lorenzo Pio Serino and Ugo De Giorgi, Anticancer Drug Delivery with Nanoparticles. In Vivo, 2006. 20(6A): p. 697-701.
    8. Sharma, R., et al., Polymer nanotechnology based approaches in mucosal vaccine delivery: Challenges and opportunities. Biotechnology Advances, 2015. 33(1): p. 64-79.
    9. Ahmed, A., et al., Multicomponent Polymeric Nanoparticles Enhancing Intracellular Drug Release in Cancer Cells. ACS applied materials & interfaces, 2014. 6(23): p. 21316-21324.
    10. Hamid Akash, M.S., K. Rehman, and S. Chen, Natural and synthetic polymers as drug carriers for delivery of therapeutic proteins. Polymer Reviews, 2015. 55(3): p. 371-406.
    11. Das, D. and S. Pal, Modified biopolymer-dextrin based crosslinked hydrogels: application in controlled drug delivery. RSC Advances, 2015. 5(32): p. 25014-25050.
    12. Strebhardt, K. and A. Ullrich, Paul Ehrlich's magic bullet concept: 100 years of progress. Nat Rev Cancer, 2008. 8(6): p. 473-480.
    13. Kreuter, J., Nanoparticles—a historical perspective. International Journal of Pharmaceutics, 2007. 331(1): p. 1-10.
    97
    14. Birrenbach, G. and P.P. Speiser, Polymerized Micelles and Their Use as Adjuvants in Immunology. Journal of Pharmaceutical Sciences. 65(12): p. 1763-1766.
    15. Gurny, R., et al., Development of Biodegradable and Injectable Latices for Controlled Release of Potent Drugs. Drug Development and Industrial Pharmacy, 1981. 7(1): p. 1-25.
    16. Khanna, S.C., T. Jecklin, and P. Speiser, Bead Polymerization Technique for Sustained-Release Dosage Form. Journal of Pharmaceutical Sciences. 59(5): p. 614-618.
    17. Perrault, S.D. and W.C.W. Chan, Synthesis and Surface Modification of Highly Monodispersed, Spherical Gold Nanoparticles of 50−200 nm. Journal of the American Chemical Society, 2009. 131(47): p. 17042-17043.
    18. Nikoobakht, B. and M.A. El-Sayed, Preparation and Growth Mechanism of Gold Nanorods (NRs) Using Seed-Mediated Growth Method. Chemistry of Materials, 2003. 15(10): p. 1957-1962.
    19. Cui, Y., et al., Nanowire Nanosensors for Highly Sensitive and Selective Detection of Biological and Chemical Species. Science, 2001. 293(5533): p. 1289-1292.
    20. Altintas, O., et al., Constructing star polymersvia modular ligation strategies. Polymer Chemistry, 2012. 3(1): p. 34-45.
    21. Prasad, P.N., Nanophotonics. 2004: John Wiley & Sons.
    22. Burda, C., et al., Chemistry and Properties of Nanocrystals of
    Different Shapes. Chemical Reviews, 2005. 105(4): p. 1025-1102.
    23. Allen, T.M. and P.R. Cullis, Drug Delivery Systems: Entering the
    Mainstream. Science, 2004. 303(5665): p. 1818-1822.
    24. Riehemann, K., et al., Nanomedicine – challenge and perspectives. Angewandte Chemie (International ed. in English), 2009. 48(5): p.
    872-897.
    25. Müller, R.H., K. Mäder, and S. Gohla, Solid lipid nanoparticles
    (SLN) for controlled drug delivery – a review of the state of the art.
    European Journal of Pharmaceutics and Biopharmaceutics, 2000.
    50(1): p. 161-177.
    26. Nicolas, J., et al., Design, functionalization strategies and
    biomedical applications of targeted biodegradable/biocompatible polymer-based nanocarriers for drug delivery. Chemical Society Reviews, 2013. 42(3): p. 1147-1235.
    27. McCarthy, J.R. and R. Weissleder, Multifunctional magnetic 98

    nanoparticles for targeted imaging and therapy. Advanced Drug
    Delivery Reviews, 2008. 60(11): p. 1241-1251.
    28. Conniot, J., et al., Cancer immunotherapy: nanodelivery approaches
    for immune cell targeting and tracking. Frontiers in Chemistry, 2014.
    2(105).
    29. Uhrich, K.E., et al., Polymeric Systems for Controlled Drug Release.
    Chemical Reviews, 1999. 99(11): p. 3181-3198.
    30. Jain, A.K., et al., Synthesis, characterization and evaluation of novel
    triblock copolymer based nanoparticles for vaccine delivery against
    hepatitis B. Journal of Controlled Release, 2009. 136(2): p. 161-169.
    31. Jain, A.K., et al., PEG–PLA–PEG block copolymeric nanoparticles for oral immunization against hepatitis B. International Journal of
    Pharmaceutics, 2010. 387(1): p. 253-262.
    32. Matsumura, Y. and H. Maeda, A New Concept for Macromolecular
    Therapeutics in Cancer Chemotherapy: Mechanism of Tumoritropic Accumulation of Proteins and the Antitumor Agent Smancs. Cancer Research, 1986. 46(12 Part 1): p. 6387-6392.
    33. Xu, J., F. Gattacceca, and M. Amiji, Biodistribution and Pharmacokinetics of EGFR-Targeted Thiolated Gelatin Nanoparticles Following Systemic Administration in Pancreatic Tumor-Bearing Mice. Molecular Pharmaceutics, 2013. 10(5): p. 2031-2044.
    34. Duncan, R., The dawning era of polymer therapeutics. Nat Rev Drug Discov, 2003. 2(5): p. 347-360.
    35. Jain, S.K., et al., Mannosylated gelatin nanoparticles bearing an anti-HIV drug didanosine for site-specific delivery. Nanomedicine: Nanotechnology, Biology and Medicine, 2008. 4(1): p. 41-48.
    36. Zwiorek, K., et al., Delivery by Cationic Gelatin Nanoparticles Strongly Increases the Immunostimulatory Effects of CpG Oligonucleotides. Pharmaceutical Research, 2008. 25(3): p. 551-562.
    37. Leibler, L., H. Orland, and J.C. Wheeler, Theory of critical micelle concentration for solutions of block copolymers. The Journal of chemical physics, 1983. 79(7): p. 3550-3557.
    38. Mei, L., et al., Antitumor and Antimetastasis Activities of Heparin- based Micelle Served As Both Carrier and Drug. ACS Applied Materials & Interfaces, 2016. 8(15): p. 9577-9589.
    39. Singh, J., et al., Diphtheria toxoid loaded poly-(ε-caprolactone) nanoparticles as mucosal vaccine delivery systems. Methods, 2006.
    99
    38(2): p. 96-105.
    40. Florindo, H.F., et al., New approach on the development of a mucosal
    vaccine against strangles: Systemic and mucosal immune responses
    in a mouse model. Vaccine, 2009. 27(8): p. 1230-1241.
    41. Florindo, H.F., et al., The enhancement of the immune response against S. equi antigens through the intranasal administration of
    poly-ɛ-caprolactone-based nanoparticles. Biomaterials, 2009. 30(5):
    p. 879-891.
    42. Emoto, K., Y. Nagasaki, and K. Kataoka, A Core−Shell Structured
    Hydrogel Thin Layer on Surfaces by Lamination of a Poly(ethylene glycol)-b-poly(d,l-lactide) Micelle and Polyallylamine. Langmuir, 2000. 16(13): p. 5738-5742.
    43. Rösler, A., G.W.M. Vandermeulen, and H.-A. Klok, Advanced drug delivery devices via self-assembly of amphiphilic block copolymers. Advanced Drug Delivery Reviews, 2012. 64: p. 270-279.
    44. Atashrazm, F., et al., Fucoidan and Cancer: A Multifunctional Molecule with Anti-Tumor Potential. Marine Drugs, 2015. 13(4): p. 2327.
    45. Jin, J.-O., et al., Fucoidan Can Function as an Adjuvant In Vivo to Enhance Dendritic Cell Maturation and Function and Promote Antigen-Specific T Cell Immune Responses. PLOS ONE, 2014. 9(6): p. e99396.
    46. Kwak, J.-Y., Fucoidan as a Marine Anticancer Agent in Preclinical Development. Marine Drugs, 2014. 12(2): p. 851.
    47. Yang, M., et al., Fucoidan stimulation induces a functional maturation of human monocyte-derived dendritic cells. International Immunopharmacology, 2008. 8(13): p. 1754-1760.
    48. Jiang, Y., et al., PEGylated Albumin-Based Polyion Complex Micelles for Protein Delivery. Biomacromolecules, 2016. 17(3): p. 808-817.
    49. Ghosh, S., Recent research and development in synthetic polymer- based drug delivery systems. Journal of Chemical Research, 2004. 2004(4): p. 241-246.
    50. Asghar, A. and R.L. Henrickson, Chemical, Biochemical, Functional, and Nutritional Characteristics of Collagen in Food Systems. Advances in Food Research, 1982. 28: p. 231-372.
    51. Wormall, A., Non-antigenicity of Gelatin. Nature, London, 1944. 154: p. 3X2.
    100
    52. Olsen, D., et al., Recombinant collagen and gelatin for drug delivery. Advanced Drug Delivery Reviews, 2003. 55(12): p. 1547-1567.
    53. Mao, J.S., et al., Structure and properties of bilayer chitosan–gelatin scaffolds. Biomaterials, 2003. 24(6): p. 1067-1074.
    54. Li, B., et al., Fucoidan: Structure and Bioactivity. Molecules, 2008. 13(8): p. 1671.
    55. Zhang, W., et al., Fucoidan from Macrocystis pyrifera Has Powerful Immune-Modulatory Effects Compared to Three Other Fucoidans. Marine Drugs, 2015. 13(3): p. 1084.
    56. Ponsart, S., J. Coudane, and M. Vert, A Novel Route To Poly(ε- caprolactone)-Based Copolymers via Anionic Derivatization. Biomacromolecules, 2000. 1(2): p. 275-281.
    57. Coombes, A.G.A., et al., Precipitation casting of polycaprolactone for applications in tissue engineering and drug delivery. Biomaterials, 2004. 25(2): p. 315-325.
    58. Bahadori, F., et al., Synthesis and Characterization of Biodegradable Amphiphilic Star and Y-Shaped Block Copolymers as Potential Carriers for Vinorelbine. Polymers, 2014. 6(1): p. 214.
    59. Dai, W.S. and T.A. Barbari, Hydrogel membranes with mesh size asymmetry based on the gradient crosslinking of poly(vinyl alcohol). Journal of Membrane Science, 1999. 156(1): p. 67-79.
    60. Peppas, N.A. and R.E. Berner, Proposed method of intracopdal injection and gelation of poly (vinyl alcohol) solution in vocal cords: polymer considerations. Biomaterials, 1980. 1(3): p. 158-162.
    61. Tabata, Y. and Y. Ikada, Synthesis of gelatin microspheres containing interferon. Pharmaceutical Research, 1989. 6(5): p. 422-427.
    62. Yamamoto, M., et al., Bone regeneration by transforming growth
    factor β1 released from a biodegradable hydrogel. Journal of
    Controlled Release, 2000. 64(1): p. 133-142.
    63. Jameela, S.R. and A. Jayakrishnan, Glutaraldehyde cross-linked
    chitosan microspheres as a long acting biodegradable drug delivery vehicle: studies on the in vitro release of mitoxantrone and in vivo degradation of microspheres in rat muscle. Biomaterials, 1995. 16(10): p. 769-775.
    64. Draye, J.-P., et al., In vitro release characteristics of bioactive molecules from dextran dialdehyde cross-linked gelatin hydrogel films. Biomaterials, 1998. 19(1): p. 99-107.
    65. Draye, J.-P., et al., In vitro and in vivo biocompatibility of dextran 101

    dialdehyde cross-linked gelatin hydrogel films. Biomaterials, 1998.
    19(18): p. 1677-1687.
    66. Lee, K.Y., K.H. Bouhadir, and D.J. Mooney, Degradation Behavior
    of Covalently Cross-Linked Poly(aldehyde guluronate) Hydrogels.
    Macromolecules, 2000. 33(1): p. 97-101.
    67. Nandivada, H., X. Jiang, and J. Lahann, Click chemistry: versatility
    and control in the hands of materials scientists. Advanced Materials,
    2007. 19(17): p. 2197-2208.
    68. Bock, V.D., H. Hiemstra, and J.H. Van Maarseveen, CuI-Catalyzed
    Alkyne–Azide “Click” Cycloadditions from a Mechanistic and Synthetic Perspective. European Journal of Organic Chemistry, 2006. 2006(1): p. 51-68.
    69. Moses, J.E. and A.D. Moorhouse, The growing applications of click chemistry. Chemical Society Reviews, 2007. 36(8): p. 1249-1262.
    70. Angell, Y.L. and K. Burgess, Peptidomimetics via copper-catalyzed azide-alkyne cycloadditions. Chemical Society Reviews, 2007. 36(10): p. 1674-1689.
    71. Tirino, P., et al., Y-and H-Shaped Amphiphilic PEG–PCL Block Copolymers Synthesized Combining Ring-Opening Polymerization and Click Chemistry: Characterization and Self-Assembly Behavior. Macromolecular Chemistry and Physics, 2014. 215(12): p. 1218- 1229.

    無法下載圖示 全文公開日期 2022/07/13 (校內網路)
    全文公開日期 本全文未授權公開 (校外網路)
    全文公開日期 本全文未授權公開 (國家圖書館：臺灣博碩士論文系統)
    QR CODE