研究生: |
鄭傑 Jheng, Jie |
---|---|
論文名稱: |
mPEG-P(Ala)-P(Asp)可注射溫度敏感型胺基酸水膠性質探討及其於藥物投遞上的應用 Injectable thermosensitive polypeptide hydrogel mPEG-P(Ala)-P(Asp) :Gelation studies and application for drug delivery |
指導教授: |
朱一民
Chu, I-Ming |
口試委員: |
姚少凌
王潔 |
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: | 2016 |
畢業學年度: | 104 |
語文別: | 中文 |
論文頁數: | 61 |
中文關鍵詞: | 胺基酸水膠 、溫度敏感性 、藥物投遞 |
外文關鍵詞: | polypeptide hydrogel, thermosensitive, drug delivery |
相關次數: | 點閱:1 下載:0 |
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本研究探討可注射溫度敏感性胺基酸水膠成膠性質以及應用於藥物投遞上的潛力。甲氧基化聚乙二醇-聚左旋丙胺酸(methoxy-poly(ethylene glycol)-poly(L-alanine), mPEG-P(Ala))為一已知溫度敏感型胺基酸水膠,利用mPEG-NH2和N-carboxy anhydride-alanine(NCA-alanine)開環聚合反應合成;再以N-carboxyl anhydride β-benzyl L-Aspartate開環聚合並去除保護基,再末端接上天門冬胺酸,形成甲氧基化聚乙二醇-聚左旋丙胺酸-聚左旋天門冬胺酸(methoxy-poly(ethylene glycol)-poly(L-alanine), mPEG-P(Ala) -P(Asp)水膠。
實驗結果顯示聚胺基酸高分子水溶液可以形成微胞,臨界微胞濃度約為0.65-0.11 wt% ; 微胞表面電位及粒徑量測顯示,隨著聚合上mPEG-P(Ala)的左旋天門冬胺酸莫耳數不同,其表面電位由20 mV降低至-20 mV,粒徑大小約為100-250 nm;TEM及表面電位觀測顯示微胞表面電位影響微胞的形貌;SEM觀測水膠能夠形成三維網狀結構;由流變儀觀察胺基酸水膠的黏度及機械性質隨著溫度而變化顯示具有溫度敏感性;MTT assay 顯示水膠具有良好的生物相容性;水膠降解實驗顯示胺基酸水膠需透過酵素進行降解;水膠包覆抗癌藥物順鉑的結果顯示藥物的釋放可由接上不同莫耳數的天門冬胺酸比例控制,達到持續的藥物釋放。
由以上實驗結果顯示,mPEG-P(Ala) -P(Asp)胺基酸水膠為一良好的藥物控制釋放載體,具有原位成膠、良好的生物相容性、降解性等特性,對於局部的藥物治療應用上具有相當的優勢。
The Objective of this study was to discuss the thermoresponsive polypeptide hydrogel properties and the potential of hydrogel in drug delivery. methoxy-poly(ethylene glycol)-poly(L-alanine) (mPEG-P(Ala)) is a well-known thermoresponsive polypeptide hydrogel. By using mPEG-NH2 and N-carboxy anhydride-alanine (NCA-alanine) through ring-opening polymerization. Afterwards, using N-carboxyl anhydride β-benzyl L-Aspartate through ring-opening polymerization and removal of the benzyl protecting groups to form the hydrogel.
The experimental results indicated that the polypeptide polymer with hydrophilic and hydrophobic parts can form a micelle structure in water. The critical micelle concentration (CMC) was ranged from 0.65 to 0.11 wt%. Zeta potential and particle size measurements of micelle indicated that the number of different mole L-aspartic acid were conjugated to mPEG-P(Ala), the Zeta potential decreased from 20 mV to -20 mV and particle size is about 100-250 nm. TEM and Zeta potential observations indicated that the morphology of micelle affected by Zeta potential. SEM results showed that hydrogel can form three-dimensional network structure. Rheology results showed that viscoelastic properties of the polypeptide hydrogel varied with temperature, indicative of the formation of a gel.
MTT assay studies suggested acceptable biocompatibility of the hydrogel and the degradation of hydrogel was accelerated in presence of enzyme.
The results of cisplatin encapsulated in hydrogel indicated that the continuous drug release can be controlled by the number of different mole L-aspartic acid were conjugated.
From the above results, mPEG-P(Ala) -P(Asp) is a good drug controlled release carriers. It has In-Situ gelling, biocompatibility and biodegradability properties. For the local application of drugs has a considerable advantage.
參考文獻
[1] Holling J. O. Biomedical applications of synthetic biodegradable polymers, CRC press, Inc., Boca Raton. 1995.
[2] Gopferich, A.; Tesmar, J. Polyanhydride degradation and erosion. Advanced Drug Delivery Reviews. 2002, 54, 7, 911-931.
[3] Uhrich, K. E.; Cannizzaro, S. M.; Langer, R. S.; Shakesheff, K. M. Polymeric systems for controlled drug release. Chemical reviews. 1999, 99, 11, 3181-3198.
[4] Ward, M. A.; Georgiou, T. K. Thermoresponsive polymers for biomedical applications. Polymers, 2011, 3, 3, 1215-1242.
[5] Treiser, M.; Abramson, S.; Langer, R.; Kohn J. Degradable and Resorbable Biomaterials In Biomaterials Science: An Introduction to Materials in Medicine: Elsevier Academic Press; 2004.
[6] Winzenburg, G.; Schmidt, C.; Fuchs, S.; Kissel, T. Biodegradable polymers and their potential use in parenteral veterinary drug delivery systems. Advanced drug delivery reviews, 2004, 56, 1453-1466.
[7] Jeong, B.; Bae, Y. H.; Lee, D. S.; Kim, S. W. Biodegradable block copolymers as injectable drug-delivery systems. Nature, 1997, 388(6645), 860-862.
[8] Jeong, B.; Bae, Y. H.; Kim, S. W. Thermoreversible gelation of PEG-PLGA-PEG triblock copolymer aqueous solutions. Macromolecules, 1999, 32(21), 7064-7069.
[9] Lee, D. S.; Shim, M. S.; Kim, S. W.; Lee, H.; Park, I.; Chang, T. Novel Thermoreversible Gelation of Biodegradable PLGA‐block‐PEO‐block‐PLGA Triblock Copolymers in Aqueous Solution. Macromolecular rapid communications, 2001, 22(8), 587-592.
[10] Lai, P. L.; Lin, C. T. Y.; Hong, D. W.; Yang, S. R.; Chang, Y. H.; Chen, L. H.; Chu, I. M. Development of bioactive thermosensitive polymer–ceramic composite as bone substitute. Chemical Engineering Science, 2013, 89, 133-141.
[11] Kim, M. S.; Seo, K. S.; Khang, G.; Cho, S. H.; Lee, H. B. Preparation of poly (ethylene glycol)-block-poly(caprolactone) copolymers and their applications as thermos-sensitive materials. Journal of Biomedical Materials Research Part A, 2004, 70(1), 154-158.
[12] Bae, S. J.; Suh, J. M.; Sohn, Y. S.; Bae, Y. H.; Kim, S. W.; Jeong, B. Thermogelling poly (caprolactone-b-ethylene glycol-b-caprolactone) aqueous solutions. Macromolecules, 2005, 38(12), 5260-5265.
[13] Hwang, M. J.; Suh, J. M.; Bae, Y. H.; Kim, S. W.; Jeong, B. Caprolactonic Poloxamer Analog: PEG-PCL-PEG. Biomacromolecules, 2005, 6(2), 885-890.
[14] Huynh, C. T.; Nguyen, M. K.; Lee, D. S. Injectable block copolymer hydrogels: achievements and future challenges for biomedical applications. Macromolecules, 2011, 44(17), 6629-6636.
[15] Choi, Y. Y.; Joo, M. K.; Sohn, Y. S.; Jeong, B. Significance of secondary structure in nanostructure formation and thermosensitivity of polypeptide block copolymers. Soft Matter, 2008, 4(12), 2383-2387.
[16] Oh, H. J.; Joo, M. K.; Sohn, Y. S.; Jeong, B. Secondary structure effect of polypeptide on reverse thermal gelation and degradation of L/DL-poly (alanine)–poloxamer–L/DL-poly (alanine) copolymers. Macromolecules, 2008, 41(21), 8204-8209.
[17] Choi, Y. Y.; Jang, J. H.; Park, M. H.; Choi, B. G.; Chi, B.; Jeong, B. Block length affects secondary structure, nanoassembly and thermosensitivity of poly (ethylene glycol)-poly (L-alanine) block copolymers. Journal of Materials Chemistry, 2010, 20(17), 3416-3421.
[18] Jeong, Y.,; Joo, M. K.; Bahk, K. H.; Choi, Y. Y.; Kim, H. T.; Kim, W. K.; Jeong, B. Enzymatically degradable temperature-sensitive polypeptide as a new in-situ gelling biomaterial. Journal of Controlled Release, 2009 137(1), 25-30.
[19] Moon, H. J.; Choi, B. G.; Park, M. H.; Joo, M. K.; Jeong, B. Enzymatically degradable thermogelling poly (alanine-co-leucine)-poloxamer-poly (alanine-co-leucine). Biomacromolecules, 2011, 12(4), 1234-1242.
[20] Park, S. H.; Choi, B. G.; Moon, H. J.; Cho, S. H.; Jeong, B. Block sequence affects thermosensitivity and nano-assembly: PEG-L-PA-DL-PA and PEG-DL-PA-L-PA block copolymers. Soft Matter, 2011, 7(14), 6515-6521.
[21] Joo, M. K.; Jeong, S. J.; Park, M. H.; Shinde, U. P.; Jeong, B. Incorporation of D-alanine into poly (ethylene glycol) and L-poly (alanine-co-phenylalanine) block copolymers affects their nanoassemblies and enzymatic degradation. Soft Matter, 2013, 9(33), 8014-8022.
[22] Cheng, Y.; He, C.; Xiao, C.; Ding, J.; Zhuang, X.; Huang, Y.; Chen, X. Decisive role of hydrophobic side groups of polypeptides in thermosensitive gelation. Biomacromolecules, 2012, 13(7), 2053-2059.
[23] Cheng, Y.; He, C., Ding, J.; Xiao, C.; Zhuang, X.; Chen, X. Thermosensitive hydrogels based on polypeptides for localized and sustained delivery of anticancer drugs. Biomaterials, 2013, 34(38), 10338-10347.
[24] Huang, J.; Hastings, C. L.; Duffy, G. P.; Kelly, H. M.; Raeburn, J.; Adams, D. J.; Heise, A. Supramolecular hydrogels with reverse thermal gelation properties from (oligo) tyrosine containing block copolymers. Biomacromolecules, 2012, 14(1), 200-206.
[25] B. E. Tropp. Biochemistry: Concepts and Applications, First edition. Brooks/Cole Publishing Company, 1997.
[26] Dooling, L. J.; Tirrell, D. A. Peptide and protein hydrogels. Polymeric and Self Assembled Hydrogels: From Fundamental Understanding to Applications, 2013, 93-124.
[27] Dasari, S.; Tchounwou, P. B. Cisplatin in cancer therapy: Molecular mechanisms of action. European journal of pharmacology, 2014, 740, 364-378.
[28] Oberoi, H. S.; Nukolova, N. V.; Kabanov, A. V.; Bronich, T. K. Nanocarriers for delivery of platinum anticancer drugs. Adv. Drug Deliv. Rev, 2013, 65, 1667-1685.
[29] Cubells, Montserrat Pujol, et al. Stability of cisplatin in sodium chloride 0.9% intravenous solution related to the container's material. Pharmacy World and Science, 1993, 15.1,34-36.
[30] 衛生福利部國民健康署. Health Promotion Administration of Health and Welfare. 2014.
[31] Thun, M. J.; Hannan, L. M.; Adams-Campbell, L. L.; Boffetta, P.;Buring, J. E.; Feskanich, D.; Samet, J. M. Lung cancer occurrence in never-smokers: an analysis of 13 cohorts and 22 cancer registry studies. PLoS medicine, 2008, 5(9), e185.
[32] Pisters, K. M.; Evans, W. K.; Azzoli, C. G.; Kris, M. G.; Smith, C. A.; Desch, C. E.; Shepherd, F. A. Cancer Care Ontario and American Society of Clinical Oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non–small-cell lung cancer guideline. Journal of Clinical Oncology, 2007, 25(34), 5506-5518.