研究生: |
林千靖 |
---|---|
論文名稱: |
光交聯聚乙二醇-聚乳酸二團聯共聚物之合成及其奈米水膠之研究 The Study of Photocrosslinked Nanogel Based on Methoxy Poly(ethylene glycol)-Poly(L-lactide) Copolymer |
指導教授: | 朱一民 |
口試委員: | |
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: | 2007 |
畢業學年度: | 95 |
語文別: | 中文 |
論文頁數: | 61 |
中文關鍵詞: | 生醫材料 、藥物載體 、光交聯 、奈米水膠 、紫杉醇 |
相關次數: | 點閱:4 下載:0 |
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以生物可分解高分子材料作為藥物載體已被廣為研究,多數的藥物載體皆以微胞形式包覆藥物,然而近年來開發了水膠形式的藥物載體,利用光交聯反應製備水膠,不但製備方法簡單、殘留的單體毒性不高,並可在溫和的環境下合成,加上水膠獨特的性質,會在水中膨潤但不溶於水中,且隨著不同官能基對外在環境會有不同應答,使得水膠的應用範圍已被廣為研究。
本研究使用已被FDA認可通過的mPEG及L-lactide,利用開環聚合方式(ring-opening polymerization)獲得具有生物可分解、生物相容性、有親疏水兩性鏈段的二團聯共聚物mPEG-PLLA,經由GPC、1H-NMR、FT-IR鑑定確定合成物後,針對PLLA末端的OH改質為帶有C=C雙鍵的基團,以便後續作光交聯反應形成水膠粒子。
在添加光起始劑(DMPA)及光交聯劑(EGDMA)照射紫外光形成核中有網狀結構的水膠,未作光交聯反應的微胞為150 nm,有光交聯反應的水膠粒子則約125 ~ 195 nm,隨著膨潤效應影響而有差異。使用3T3細胞作材料MTT assay,僅20% EGDMA光交聯劑在72 hr有較高的毒殺性,存活率剩36.85 ± 1.18 %。
水膠製備完成後,利用透析方式包埋Paclitaxel,包藥後粒徑增加10 ~ 40 nm,包覆效率則以20% EGDMA光交聯劑的奈米水膠粒子最佳。在連續30天觀察累積藥物釋放結果,以0% EGDMA釋放最多,可達73.1 ± 2.2 %,最有長期釋放效果的則是20% EGDMA 30天內僅釋出35.1 ± 0.7 %。最後作了HeLa細胞毒性測試,包了藥的無論是微胞或水膠粒子,在培養72 hr都可看到明顯抑制癌細胞效果。
本研究得到小於200 nm的粒徑,無嚴重生物毒性,藥物可穩定釋放的奈米水膠粒子,是個適合作為藥物載體的選擇。
Use biodegradable and amphiphilic copolymer as drug delivery carrier has been researched widely, most of them are made in micelle form. Recently, there is another method developed. Photo-cross-linked reaction is used to prepare nano-hydrogel particles as drug carriers. This is an easy and low residual toxicity hydrogel preparation. Hydrogel has been widely applied because its unique behaviors, it can swell but not dissolve in water, and have different responses depend on the environment.
This research synthesized mPEG and L-lactide by ring-opening polymerization without solvent, after analysis mPEG-PLLA by GPC, 1H-NMR, FT-IR, then modified as mPEG-PLLA-AC carried C=C double bond at the hydrophobic chain end. By the UV reaction we formulated nano-size photo-cross-linked hydrogel particles.
The UV photo-cross-linking irradiation added photo-initiator(DMPA) and different concentration of photo-crosslinker(EGDMA)to form nano-hydrogel particles. Without cross-linked micelle particle sizes are 150 nm, and cross-linked nano-hydrogel particles are 125 ~ 195 nm, the size range depends crosslinker concentration. MTT assay appears that 20% EGDMA nano-hydrogel has little influence on cell growth, after 72 hr cell culture viability is 36.85 ± 1.18 %.
After nano-hydrogel particles were prepared, Paclitaxel is encapsulated by dialysis method. Particle sizes are increased 10 ~ 40 nm, and 20% EGDMA nano-hydrogel encapsulation efficiency (EE) is the best. During 30 days accumulative drug release, 0% EGDMA has the most amount of release ratio 73.1 ± 2.2 %, and the most stable release is 20% EGDMA hydrogel, 35.1 ± 0.7 %. In HeLa cell cytotoxicity test, after incubate 72 hr all of Paclitaxel-loaded particles have cell inhibition effect.
In this research we obtain an amphiphilic copolymer to prepare hydrogel particles, which have smaller than 200 nm particle size, no serious cytotoxicity and stable drug release results. Provide an optimistic choice as drug delivery carrier.
1. Clemson Advisory Board for Biomaterials , Definition of the word biomaterial , Thc 6th Annnal Intermalionel Biomaterial Symposium , April 20-24 (1974)
2. Shikanov A. , Kumar D. , Domb A. J. , Biodegradable polymers : an update, Israel Journal of Chemistry 45, 393-399 (2005)
3. Choi S. K. , Kim D. , Drug-releasing behavior of MPEG-PLA block copolymer micelles and solid particles controlled by component block length, Journal of Applied Polymer Science, 83, 435-445 (2002)
4. Uhrich K. E. , Cannizzaro S. M. , Langer R. S. , Shakesheff K. M. , Polymeric systems for controlled drug release, Chemical Reviews 99, 3181-3198 (1999)
5. Langer R. , New methods of drug delivery, Science, 249, 1527-1533 (1990)
6. Ghosh S. , Recent research and development in synthetic polymer -based drug delivery systems, Journal of Chemical Research, APRIL, 241-246 (2004)
7. Sodergard A. , Stolt M. , Properties of lactic acid based polymers and their correlation with composition, Progress in Polymer Science, 27, 1123-1163 (2002)
8. Winzenburg G. , Schmidt C. , Fuchs S. , Kissel T. , Biodegradable polymers and their potential use in parenteral veterinary drug delivery systems, Advanced Drug Delivery Reviews , 56, 1453-1466 (2004)
9. Domb A. J. , Kost J. , Wiseman D. M. , Handbook of biodegradable polymers, Amsterdam :Harwood Academic Publishers (1997)
10. Kumar N. , Ravikumar M. N. V. , Domb A.J. , Biodegradable block copolymers, Advanced Drug Delivery Reviews, 53, 23-44 (2001)
11. Gaucher G. , Dufresne M. H. , Sant V. P. , Kang N. , Maysinger D. , Leroux J. C. , Block copolymer micelles – preparation, characterization and application in drug delivery, Journal of Controlled Release, 109, 169-188 (2005)
12. Kopeček J. , Swell gels, Nature, 417, 388-391 (2002)
13. Hoffman A. S. , Hydrogels for biomedical applications, Advanced Drug Delivery Reviews, 43, 3-12 (2002)
14. Lee K. Y. , Mooney D. J. , Hydrogels for Tissue Engineering, Chemical Reviews, 101, 1869-1879 (2001)
15. Bos G. W. , Verrijk R. , Franssen O. , Bezemer J. M. , Hennink W. E. , Crommelin D. J. A. , Hydrogels for the controlled release of pharmaceutical proteins, Pharmaceutical Technology, 25, 110-120 (2001)
16. Hennink W. E. , Nostrum C. F. , Novel crosslinking methods to design hydrogels, Advanced Drug Delivery Reviews, 54, 13-36 (2002)
17. Rosler A. , Vandermeulen G. W. M. , Klok H. A. , Advanced drug delivery devices via self-assembly of amphiphilic block copolymers, Advanced Drug Delivery Reviews, 53, 95-108 (2001)
18. Peppas N. A. , Hilt J. Z. , Khademhosseini A. , Langer R. , Hydrogels in biology and medicine-From molecular principles to bionanotechnology, Advanced Materials, 18, 1345-1360 (2006)
19. Qiu Y. , Park K. , Environment-sensitive hydrogels for drug delivery, Advanced Drug Delivery Reviews, 53, 321-339 (2001)
20. Peppas N. K. , Khare A. R. , Preparation , structure and diffusional behavior of hydrogels in controlled release, Advanced Drug Delivery Reviews, 11, 1-35 (1993)
21. Nguyen K. T. , West J. L. , Photopolymerizable hydrogels for tissue engineering applications, Biomaterials, 23, 4307-4314 (2002)
22. Baroli B. , Photopolymerization of biomaterials-issues and potentialities in drug delivery, tissue engineering, and cell encapsulation applications, Journal of Chemical Technology and Biotechnology, 81, 491-499 (2006)
23. Fisher J. P. , Dean D. , Engel P. S. , Mikos A. G. , Photoinitiated Polymerization of Biomaterials, Annual Review of Materials Research, 31, 171-181 (2001)
24. Brown C. D. , Stayton P. S. , Hoffman A. S. , Semi-interpenetrating network of poly(ethylene glycol) and poly(D,L-lactide) for the controlled delivery of protein drugs, Journal of Biomaterials Science -- Polymer Edition, 16, 189-201 (2005)
25. Missirlis D. , Tirelli N. , Hubbell J. A. , Amphiphilic Hydrogel Nanoparticales.Preparation, Characterization, and Preliminary Assessment as New Colloidal Drug Carriers, Langmuir, 21, 2605-2613 (2005)
26. Kim J. H. , Emoto K. , Iijima M. , Nagasaki Y. , Aoyagi T. , Okano T. , Sakurai Y. , Kataoka K. , Core-stabilized Polymeric Micelle as Potential Drug Carrier Increased Solubilization of Taxol, Polymers For Advanced Technologies, 10, 647-654 (1999)
27. Lee S. C. , Kim C. , Kwon I. C. , Chung H. , Jeong S. Y. , Polymeric micelles of poly(2-ethyl-2-oxazoline)–block-poly(ε-caprolactone) copolymer as a carrier for paclitaxel, Journal of Controlled Release, 89, 437-446 (2003)
28. Gueritte-Voegelein F. , Guenard D. , Lavelle F. , Goff M. T. L. , Mangatal L. , Potier P. , Relationships between the structure of Taxol analogues and their antimitotic activity, Journal of Medicinal Chemistry, 34, 992-998 (1991)
29. Panchagnula R. , Pharmaceutical aspects of paclitaxel, International Journal of Pharmaceutics, 172, 1-15 (1998)
30. Zhang Z. , Feng S. S. , In vitro investigation on poly(lactide)-Tween 80 copolymer nanoparticles fabricated by dialysis method for chemotherapy, Biomacromolecules, 7, 1139-1146 (2006)
31. Deng L. , Li A. , Yao C. , Sun D. , Dong A. , Methoxy poly(ethylene glycol)-b-poly(L-lactic acid) copolymer nanoparticles as delivery vehicles for paclitaxel, Journal of Applied Polymer Science, 98, 2116-2122 (2005)
32. Dong Y. , Feng S. S. , Methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA) nanoparticles for controlled delivery of anticancer drugs, Biomaterials, 25, 2843-2849 (2004)
33. Shuai X. , Merdan T. , Schaper A. K. , Xi F. , Kissel T. , Core-cross- linked polymeric micelles as paclitaxel carriers, Bioconjugate Chem. , 15, 441-448 (2004)
34. 李怜 , 以葉酸標的之聚乙二醇-聚乳酸二團聯共聚物合成及其高分子微胞之研究 , 清大化工所碩士論文 (2006)
35. 張雅棻 , 光交聯聚乳酸-聚乙二醇-聚乳酸三團聯共聚物之水膠奈米粒子之合成及其藥物制放之應用 , 清大化工所碩士論文 (2006)
36. 黎元中 , 光交聯聚乳酸-聚乙二醇-聚乳酸三團聯共聚物之水膠奈米粒子 , 清大化工所碩士論文 (2004)
37. Zhao C. L. , Winnik M. A. , Fluorescence probe techniques used to study micelle formulation in water-soluble block copolymers, Langmuir, 6, 514-516 (1990)
38. Na K. , Lee K. H. , Lee D. H. , Bae Y. H. , Biodegradable thermo- sensitive nanoparticles from poly(L-lactide)-poly(ethylene glycol) alternating multi-block copolymer for potential anti-cancer drug carrier, European Journal of Pharmaceutical Sciences, 27, 115-122 (2006)
39. Sahoo S. K. , Panyam J. , Prabha S. , Labhasetwar V. , Residual polyvinyl alcohol associated with poly(D,L-lactide-co-glycolide) nanoparticles affects their physical properties and cellular uptake, Journal of Controlled Release , 82, 105-114 (2002)
40. Shi R. , Burt H. M. , Amphiphilic dextran-graft-poly(ε- caprolactone) films for the controlled release of paclitaxel, International Journal of Pharmaceutics, 271, 167-179 (2004)