簡易檢索 / 詳目顯示

回結果列表
研究生： 李亞宸
Li, Ya-Chen
論文名稱： 雙重響應特性接枝高分子微胞於藥物釋放上之應用
The Application of Graft Polymeric Micelles with Dual Stimuli-Responsive Characteristics in Drug Release
指導教授： 吳文中
Wu, Wen-Chung
學位類別： 碩士
Master
系所名稱： 工學院 - 化學工程學系
Department of Chemical Engineering
論文出版年： 2021
畢業學年度： 109
語文別： 中文
論文頁數： 84
中文關鍵詞： 雙親性嵌段共聚高分子 、溫度響應性高分子 、酸鹼響應性高分子 、藥物載體 、藥物釋放 、高分子-藥物結合物
外文關鍵詞： amphiphilic block copolymer polymer, pH-responsive polymer, drug release, drug carrier, temperature responsive polymer, polymer-drug conjugate
相關次數： 點閱：131  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

    • 本研究開發出雙親性嵌段共聚高分子 Poly[tert-butyl 7-oxooxepane-4-carboxylate-co-caprolactone]-b-poly[triethylene glycol methacrylate-co-folic acid ] [(PCL-co-PTCL)-b-p(TEGMA-co-FA)](PTFA) 以及[PCL-b-P(TEGMA-co-AHA)](PTAHA)，使其作為具有主動標靶能力與環境響應性之藥物載體，並在其高分子側鏈修飾上癌症化療藥物 doxorubicin (DOX)，構成高分子-藥物結合物。此共聚高分子在水溶液中自組裝形成微胞後，進一步對其奈米結構、微胞性質、環境響應性與藥物釋放結果進行分析與探討。
    將 poly(ε-caprolactone) (PCL)與經側鏈修飾後 Poly[tert-Butyl ε-Caprolactone carboxylate-co-Caprolactone] (PTCL)共聚作為雙親性高分子微胞的疏水內核，可在內核包覆疏水性藥物 doxorubicin (DOX)，亦可同時在高分子側鏈利用醯胺鍵與疏水性藥物 DOX 連接，並以 triethylene glycol methacrylate (TEGMA)與 Folic acid (FA)作為具溫度響應性及酸鹼響應性的親水性外殼，使其具有特定響應功能。藉由調整溫度響應性單體 TEGMA 與酸鹼響應性單體 FA 的聚合度，不但可以調控高分子微胞的最低臨界微胞溫度(lower critical solution temperature, LCST)，且可使此臨界溫度在不同酸鹼度下產生變化。為了觀察藥物釋放情形，引入高分子 PCL-b-P(TEGMA-co-PPSEMA) (PTAIE)來製備混合微胞，使最低臨界溶液溫度於酸性環境下低於人體體溫 37 °C，而在中性環境時則高於 37 °C，因此混合微胞能穩定存在於血液循環中並能於細胞溶酶體釋放藥物，並以緩衝溶液來模擬人體血液與溶酶體內之 pH 值來進行藥物釋放行為測試，將其結果做為混合微胞具有作為藥物載體的潛力之依據。

    In this research, we developed an amphiphilic block copolymer (PCL-co-PTCL)-b-p(TEGMA-co-FA) (PTFA) and [PCL-b-P(TEGMA-co-AHA)] (PTAHA) as a drug carrier with the characteristics of active-targeting and environmental responsiveness. The polymer chain was functionalized to conjugate with doxorubicin (DOX) as pendent groups by covalent bond to form polymer-drug conjugates. These copolymers self-assembled into micelles in aqueous solution, and their structure, characteristics, stimuli-responsive properties, and drug release results were further analyzed and discussed.

    The poly(ε-caprolactone) (PCL) and poly[(tert-butyl ε-caprolactone carboxylate)-co-caprolactone] (PTCL) copolymer formed the hydrophobic core of micelles, which can be used for encapsulating with hydrophobic drug, Doxorubicin (DOX), it can also be connected to the hydrophobic drug DOX with an amide bond on the side chain of the polymer. The hydrophilic shell consisted of poly[(triethylene glycol methacrylate)-co-(folic acid)] (p[TEGMA-co-FA]) as temperature-responsive and pH-responsive polymers with promising response for environment.

    By adjusting the degree of polymerization of the temperature-responsive monomer TEGMA and pH-responsive FA moieties, the lower critical solution temperature (LCST) of the polymer micelles can be controlled. To obtain promising responsive properties, another type of polymer, PCL-b-P (TEGMA-co-PPSEMA) (PTAIE), is chosen as one component in mixed micelles, so that the resulting LCST of these mixed micelles was lower than human body temperature in an acidic environment, while in a neutral environment the temperature is higher than 37 °C. The mixed micelles can stably exist in the blood circulation and can release the drugs in the lysosomes. The buffer solution is used to simulate the pH value of human blood and lysosomes for in-vitro drug release study. The result suggests that these mixed micelles possess the potential as drug delivery system with controlled drug release.

    摘要 I Abstract II 誌謝 XIII 目錄 XIV 流程圖目錄 XVIII 表目錄 XIX 圖目錄 XX 公式目錄 XXIII 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 1.1.1.1雙親性嵌段共聚高分子於水溶液中之奈米結構 2 1.1.1.2原子轉移自由基聚合反應合成雙親性嵌段共聚高分子 4 1.1.2 功能性高分子 5 1.1.2.1 刺激響應性高分子 5 1.1.2.2 多重響應性高分子 11 1.1.3雙親性嵌段共聚高分子於藥物傳遞之應用 13 1.1.3.1藥物傳遞 15 1.1.4 微胞製備 23 1.2 研究動機與目的 24 第二章、實驗 26 2.1實驗藥品(Chemicals) 26 2.2實驗方法(Experiments) 29 2.2.1單體合成(Synthesis of monomer) 29 2.2.1.1 Hydroxyethl 2-bromoisobutyrate (HEBib) 29 2.2.1.2 N-hydroxysuccinimide methacrylate (NSMA)合成 30 2.2.1.3 4-oxocyclohexanecarboxylic acid (Cy-acid) 31 2.2.1.4 tert-Butyl 4-Ketocyclohexanecarboxylate (Cy-OBu) 31 2.2.1.5 tert-Butyl ε-Caprolactone carboxylate (t-BuCL) 32 2.2.2高分子聚合(Polymerization) 33 2.2.2.1 poly(ε-caprolactone) (PCL) 33 2.2.2.2Poly(ɛ-caprolactone)-b-poly[triethylene glycol methacrylate-co- N-hydroxysuccinimide methacrylate] [PCL-b-P(TEGMA-co-NSMA)] 34 2.2.2.3Poly(ɛ-caprolactone)-b-poly[triethylene glycol methacrylate-co- 6-(methacrylamino)hexanoic acid] [PCL-b-P(TEGMA-co-AHA)] 35 2.2.2.4 Poly[tert-Butyl ε-Caprolactone carboxylate-co-Caprolactone] [PCL-co-PTCL] 35 2.2.2.5 Poly[tert-Butyl ε-Caprolactone carboxylate-co-Caprolactone]-b-poly[triethylene glycol methacrylate-co-N-hydroxysuccinimide methacrylate ] [(PCL-co-PTCL)-b-p(TEGMA-co-NSMA)] 36 2.2.2.6 Poly[tert-Butyl ε-Caprolactone carboxylate-co-Caprolactone]-b-poly[triethylene glycol methacrylate-co-N-(2-aminoethyl)pivalamide ] [(PCL-co-PTCL)-b-p(TEGMA-co-EDA)] 37 2.2.2.7 Poly[tert-Butyl ε-Caprolactone carboxylate-co-Caprolactone]-b-poly[triethylene glycol methacrylate-co-folic acid ] [(PCL-co-PTCL)-b-p(TEGMA-co-FA)] 38 2.2.2.8 Deprotection of Poly[tert-Butyl ε-Caprolactone carboxylate-co-Caprolactone] 39 2.2.2.9 Deprotected Poly[tert-Butyl ε-Caprolactone carboxylate-co-Caprolactone] conjugate with doxorubicin 40 2.2.3 微胞製備 40 2.2.4 Lower Critical Solution Temperature, LCST 測試 41 2.2.5臨界微胞濃度(Critical micelle concentration, CMC)檢測 41 2.2.6藥物包覆與釋放 43 2.2.6.1藥物包覆 43 2.2.6.2藥物釋放 44 2.3 儀器鑑定 44 第三章、結果與討論 48 3.1聚合與鑑定 48 3.1.1 2-Hydroxyethl 2-bromoisobutyrate (HEBib)起始劑合成 49 3.1.2 N-hydroxysuccinimide methacrylate (NSMA)合成 49 3.1.3 4-oxocyclohexanecarboxylic acid (Cy-acid)合成 50 3.1.4 tert-Butyl 4-Ketocyclohexanecarboxylate (Cy-OBu)合成 52 3.1.5 tert-Butyl ε-Caprolactone carboxylate (t-BuCL)合成 53 3.1.6 Poly[tert-Butyl ε-Caprolactone carboxylate-co-Caprolactone] [PCL-PTCL]、 poly(ε-caprolactone) (PCL)合成 54 3.1.7 [(PCL-co-PTCL)-b-p(TEGMA-co-NSMA)] (PCTN)、[PCL-b-P(TEGMA-co-NSMA)]合成 56 3.1.8[PCL-b-P(TEGMA-co-AHA)]、[(PCL-co-PTCL)-b-p(TEGMA-co-EDA)]合成 59 3.1.9 Poly[tert-Butyl ε-Caprolactone carboxylate-co-Caprolactone]-b-poly[triethylene glycol methacrylate-co-folic acid ] [(PCL-co-PTCL)-b-p(TEGMA-co-FA)] (PTFA) 61 3.1.10 Deprotection of Poly[tert-Butyl ε-Caprolactone carboxylate-co-Caprolactone] 64 3.1.11 Deprotected Poly[tert-Butyl ε-Caprolactone carboxylate-co-Caprolactone] conjugate with doxorubicin 65 3.2微胞的製備與性質檢測 67 3.2.1溫度響應性 68 3.2.2 CMC性質測試 74 3.2.3藥物包覆 76 3.2.4藥物釋放 77 第四章、結論與未來工作 79 第五章、參考文獻 80

    [1] Raval, N.; Kalyane, D.; Maheshwari, R.; Tekade, R. K., Copolymers and Block Copolymers in Drug Delivery and Therapy. In Basic Fundamentals of Drug Delivery, 2019; pp 173-201.

    [2] Karimi, M.; Sahandi Zangabad, P.; Ghasemi, A.; Amiri, M.; Bahrami, M.; Malekzad, H.; Ghahramanzadeh Asl, H.; Mahdieh, Z.; Bozorgomid, M.; Ghasemi, A., Temperature-responsive smart nanocarriers for delivery of therapeutic agents: applications and recent advances. ACS applied materials & interfaces 2016, 8 (33), 21107-21133.

    [3] Miyata, K.; Christie, R. J.; Kataoka, K., Polymeric micelles for nano-scale drug delivery. Reactive and Functional Polymers 2011, 71 (3), 227-234.

    [4] Van Vlerken, L. E.; Amiji, M. M., Multi-functional polymeric nanoparticles for tumour-targeted drug delivery. Expert opinion on drug delivery 2006, 3 (2), 205-216.

    [5] Chen, C.-Y.; Kim, T. H.; Wu, W.-C.; Huang, C.-M.; Wei, H.; Mount, C. W.; Tian, Y.; Jang, S.-H.; Pun, S. H.; Jen, A. K.-Y., pH-dependent, thermosensitive polymeric nanocarriers for drug delivery to solid tumors. Biomaterials 2013, 34 (18), 4501-4509.

    [6] Anarjan, F. S., Active targeting drug delivery nanocarriers: Ligands. Nano-Structures & Nano-Objects 2019, 19, 100370.

    [7] L.Adams, M.; AfsanehLavasanifar; S.Kwon, G., Amphiphilic block copolymers for drug delivery. Journal of Pharmaceutical Sciences 2003, 1343-1355.

    [8] Varlas, S.; Lawrenson, S. B.; Arkinstall, L. A.; O’Reilly, R. K.; Foster, J. C., Self-assembled nanostructures from amphiphilic block copolymers prepared via ring-opening metathesis polymerization (ROMP). Progress in Polymer Science 2020, (101), 1-41.

    [9] Patten, T. E.; Matyjaszewski, K., Atom Transfer Radical Polymerization and the Synthesis of Polymeric Materials. Advanced Materials 1999, 901-915.

    [10] VeerleCoessens; TomislavPintauer; KrzysztofMatyjaszewski, Functional polymers by atom transfer radical polymerization. Progress in Polymer Science 2001, 26 (3), 337-377.

    [11] Rao, K. S. V. K.; Rao, K. M., A Review on Radical Polymerization Used for Design and Development of Biomaterials. In Radical Polymerization, 2011; pp 175-198.

    [12] Hu, J.; Meng, H.; Li, G.; Ibekwe, S. I., A review of stimuli-responsive polymers for smart textile applications. Smart Materials and Structures 2012.

    [13] Cabane, E.; Zhang, X.; Palivan, C. G.; Langowska, K.; Meier, W., Stimuli-Responsive Polymers and Their Applications in Nanomedicine. Biointerphases 2012, 7 (1).

    [14] Mohammed, M. N.; Yusoh, K. B.; Shariffuddin, J. H. B. H., Poly (N-vinyl caprolactam) thermoresponsive polymer in novel drug delivery systems: a review. Materials Express 2018, 8 (1), 21-34.

    [15] Fitzpatrick, S. D.; Fitzpatrick, L. E.; Thakur, A.; Mazumder, M. A. J.; Sheardown, H., Temperature-sensitive polymers for drug delivery. Expert review of medical devices 2012, 9 (4), 339-351.

    [16] Crespy, D.; Rossi, R. M., Temperature‐responsive polymers with LCST in the physiological range and their applications in textiles. Polymer International 2007, 56 (12), 1461-1468.

    [17] Kocak, G.; Tuncer, C.; Bütün, V., pH-Responsive polymers. Polymer Chemistry 2017, 8 (1), 144-176.

    [18] Augustine, R.; Kim, D.-K.; Kalva, N.; Eom, K. H.; Kim, J. H.; Kim, I., Multi-stimuli-responsive nanomicelles fabricated using synthetic polymer polylysine conjugates for tumor microenvironment dependent drug delivery. Journal of Materials Chemistry B 2020, 8 (26), 5745-5755.

    [19] Hao, Y.; Meng, J.; Wang, S., Photo-responsive polymer materials for biological applications. Chinese Chemical Letters 2017, 28 (11), 2085-2091.

    [20] Gohy, J.-F.; Zhao, Y., Photo-responsive block copolymer micelles: design and behavior. Chemical Society Reviews 2013, 42 (17), 7117-7129.

    [21] Rahoui, N.; Jiang, B.; Taloub, N.; Hegazy, M.; Huang, Y. D., Synthesis and evaluation of water soluble pH sensitive poly (vinyl alcohol)-doxorubicin conjugates. Journal of Biomaterials science, Polymer edition 2018, 29 (12), 1482-1497.

    [22] Liang, J.; Zhang, Z.; Zhao, H.; Wan, S.; Zhai, X.; Zhou, J.; Liang, R.; Deng, Q.; Wu, Y.; Lin, G., Simple and rapid monitoring of doxorubicin using streptavidin-modified microparticle-based time-resolved fluorescence immunoassay. RSC advances 2018, 8 (28), 15621-15631.

    [23] Li, S.; Wu, W.; Xiu, K.; Xu, F.; Li, Z.; Li, J., Doxorubicin loaded pH-responsive micelles capable of rapid intracellular drug release for potential tumor therapy. Journal of biomedical nanotechnology 2014, 10 (8), 1480-1489.

    [24] Tiwari, G.; Tiwari, R.; Sriwastawa, B.; Bhati, L.; Pandey, S.; Pandey, P.; Bannerjee, S. K., Drug delivery systems: An updated review. International journal of pharmaceutical investigation 2012, 2 (1), 2.

    [25] Kumari, A.; Yadav, S. K.; Yadav, S. C., Biodegradable polymeric nanoparticles based drug delivery systems. Colloids and surfaces B: biointerfaces 2010, 75 (1), 1-18.

    [26] Patra, J. K.; Das, G.; Fraceto, L. F.; Campos, E. V. R.; del Pilar Rodriguez-Torres, M.; Acosta-Torres, L. S.; Diaz-Torres, L. A.; Grillo, R.; Swamy, M. K.; Sharma, S., Nano based drug delivery systems: recent developments and future prospects. Journal of nanobiotechnology 2018, 16 (1), 1-33.

    [27] Gullotti, E.; Yeo, Y., Extracellularly activated nanocarriers: a new paradigm of tumor targeted drug delivery. Molecular pharmaceutics 2009, 6 (4), 1041-1051.

    [28] Cho, K.; Wang, X.; Nie, S.; Shin, D. M., Therapeutic nanoparticles for drug delivery in cancer. Clinical cancer research 2008, 14 (5), 1310-1316.

    [29] Yokoyama, M., Clinical applications of polymeric micelle carrier systems in chemotherapy and image diagnosis of solid tumors. Journal of Experimental & Clinical Medicine 2011, 3 (4), 151-158.

    [30] Jones, M.-C.; Leroux, J.-C., Polymeric micelles–a new generation of colloidal drug carriers. European journal of pharmaceutics and biopharmaceutics 1999, 48 (2), 101-111.

    [31] Croy, S.; Kwon, G., Polymeric micelles for drug delivery. Current pharmaceutical design 2006, 12 (36), 4669-4684.

    [32] Rapoport, N., Physical stimuli-responsive polymeric micelles for anti-cancer drug delivery. Progress in Polymer Science 2007, 32 (8-9), 962-990.

    [33] Kwon, G. S.; Forrest, M. L., Amphiphilic block copolymer micelles for nanoscale drug delivery. Drug development research 2006, 67 (1), 15-22.

    [34] Lee, M.-K., Liposomes for enhanced bioavailability of water-insoluble drugs: In Vivo evidence and recent approaches. Pharmaceutics 2020, 12 (3), 264.

    [35] Danhier, F.; Feron, O.; Préat, V., To exploit the tumor microenvironment: passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. Journal of controlled release 2010, 148 (2), 135-146.

    [36] Yin, H.; Liao, L.; Fang, J., Enhanced permeability and retention (EPR) effect based tumor targeting: the concept, application and prospect. JSM Clin Oncol Res 2014, 2 (1), 1010.

    [37] Nakamura, Y.; Mochida, A.; Choyke, P. L.; Kobayashi, H., Nanodrug delivery: is the enhanced permeability and retention effect sufficient for curing cancer? Bioconjugate chemistry 2016, 27 (10), 2225-2238.

    [38] Kedar, U.; Phutane, P.; Shidhaye, S.; Kadam, V., Advances in polymeric micelles for drug delivery and tumor targeting. Nanomedicine: Nanotechnology, Biology and Medicine 2010, 6 (6), 714-729.

    [39] Behera, A.; Padhi, S., Passive and active targeting strategies for the delivery of the camptothecin anticancer drug: a review. Environmental Chemistry Letters 2020, 1-11.

    [40] Son, G.-H.; Lee, B.-J.; Cho, C.-W., Mechanisms of drug release from advanced drug formulations such as polymeric-based drug-delivery systems and lipid nanoparticles. Journal of Pharmaceutical Investigation 2017, 47 (4), 287-296.

    [41] Li, C.; Wallace, S., Polymer-drug conjugates: recent development in clinical oncology. Advanced drug delivery reviews 2008, 60 (8), 886-898.

    [42] Ringsdorf, H. In Structure and properties of pharmacologically active polymers, Journal of Polymer Science: Polymer Symposia, Wiley Online Library: 1975; pp 135-153.

    [43] Larson, N.; Ghandehari, H., Polymeric conjugates for drug delivery. Chemistry of Materials 2012, 24 (5), 840-853.

    [44] Cholkar, K.; Patel, A.; Dutt Vadlapudi, A.; K Mitra, A., Novel nanomicellar formulation approaches for anterior and posterior segment ocular drug delivery. Recent patents on nanomedicine 2012, 2 (2), 82-95.

    [45] Yang, L.; Wu, X.; Liu, F.; Duan, Y.; Li, S., Novel biodegradable polylactide/poly (ethylene glycol) micelles prepared by direct dissolution method for controlled delivery of anticancer drugs. Pharmaceutical research 2009, 26 (10), 2332-2342.

    [46] Kohori, F.; Yokoyama, M.; Sakai, K.; Okano, T., Process design for efficient and controlled drug incorporation into polymeric micelle carrier systems. Journal of controlled release 2002, 78 (1-3), 155-163.

    [47] Le Garrec, D.; Gori, S.; Luo, L.; Lessard, D.; Smith, D.; Yessine, M.-A.; Ranger, M.; Leroux, J.-C., Poly (N-vinylpyrrolidone)-block-poly (D, L-lactide) as a new polymeric solubilizer for hydrophobic anticancer drugs: in vitro and in vivo evaluation. Journal of controlled release 2004, 99 (1), 83-101.

    [48] Asyikin binti Abdul Aziz, Z.; Ahmad, A.; Hamidah Mohd-Setapar, S.; Hassan, H.; Lokhat, D.; Amjad Kamal, M., Recent advances in drug delivery of polymeric nano-micelles. Current drug metabolism 2017, 18 (1), 16-29.

    [49] Ai, X.; Zhong, L.; Niu, H.; He, Z., Thin-film hydration preparation method and stability test of DOX-loaded disulfide-linked polyethylene glycol 5000-lysine-di-tocopherol succinate nanomicelles. asian journal of pharmaceutical sciences 2014, 9 (5), 244-250.

    [50] Salvage, J. P.; Thom, C.; Lewis, A. L.; Phillips, G. J.; Lloyd, A. W., Nanoprecipitation of polymeric nanoparticle micelles based on 2-methacryloyloxyethyl phosphorylcholine (MPC) with 2-(diisopropylamino) ethyl methacrylate (DPA), for intracellular delivery applications. Journal of Materials Science: Materials in Medicine 2015, 26 (3), 1-14.

    [51] Chang, L.; Liu, J.; Zhang, J.; Deng, L.; Dong, A., pH-sensitive nanoparticles prepared from amphiphilic and biodegradable methoxy poly (ethylene glycol)-block-(polycaprolactone-graft-poly (methacrylic acid)) for oral drug delivery. Polymer Chemistry 2013, 4 (5), 1430-1438.

    [52] Sarbu, T.; Lin, K.-Y.; Spanswick, J.; Gil, R. R.; Siegwart, D. J.; Matyjaszewski, K., Synthesis of hydroxy-telechelic poly (methyl acrylate) and polystyrene by atom transfer radical coupling. Macromolecules 2004, 37 (26), 9694-9700.

    [53] Batz, H.-G.; Franzmann, G.; Ringsdorf, H., Model reactions for synthesis of pharmacologically active polymers by way of monomeric and polymeric reactive esters. Angewandte Chemie (International ed. in English) 1972, 11 (12), 1103-1104.

    [54] Trollsås, M.; Lee, V. Y.; Mecerreyes, D.; Löwenhielm, P.; Möller, M.; Miller, R. D.; Hedrick, J. L., Hydrophilic aliphatic polyesters: design, synthesis, and ring-opening polymerization of functional cyclic esters. Macromolecules 2000, 33 (13), 4619-4627.

    下載圖示
    2026-09-22公開
    QR CODE