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研究生:黎元中
研究生(外文):Yung-Chung Li
論文名稱: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
論文名稱(外文):The study of photocrosslinked poly(D,L-lactic acid-ethylene glycol-D,L-lactic acid) diacrylate nanogel
指導教授:朱一民朱一民引用關係
指導教授(外文):I-Ming Chu
學位類別:碩士
校院名稱:國立清華大學
系所名稱:化學工程學系
學門:工程學門
學類:化學工程學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:60
中文關鍵詞:光交聯聚乳酸聚乙二醇奈米水膠
外文關鍵詞:photocrosslinkedpoly(lactic acid)poly(ethylene glycol)nanogel
相關次數:
  • 被引用被引用:2
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近十年來,利用光交聯(photocrosslinking)的方式去製備水膠,一直被認為是一個簡單又比較不會殘留毒性單體的方法。此外,又因為水膠的澎潤性質、高通透性與高生物相容性,使得水膠在組織工程方面有相當多的應用,例如:組織表面貼附型材料[6]、藥物控制釋放系統[7]、軟骨再生所需的鷹架(scaffold)材料[8]與牙科,整形外科所需的材料[9]等等。此外,透過生醫與奈米技術的結合,做為藥物制放系統的載體粒子微小化,接觸表面積增加而大幅提高療效,同時也因減少使用劑量及隔絕與正常細胞之接觸而降低其副作用[54]。
本研究內容是先製備出具有生物可分解性、高生物相容性的及親疏水性的PDLLA41-PEG4K-PDLLA41 diacrylate之後,使其在micelle的排列方式下進行光交聯反應。透過高強度UV燈的照射,micelle核心部分的PLA鏈段會進行free radical photocrosslinking,而彼此交聯成網狀結構,進而從micelle的排列方式變成nanogel,具有較一般micelle高的穩定性。本研究除探討nanogel的粒徑大小、膨潤性質、熱性質及穩定性之外,更嘗試使用此材料去包覆Camptothecin(CPT),以提供包覆藥物性質跟藥物釋放等資訊。
本研究製備出的nanogels除了具備有生物可分解性、高生物相容性更具備有高穩定性,而且透過改變交聯劑EGDMA的添加量(3 wt% ~ 50 wt%)或是UV燈照射的時間,便能簡單地控制水膠粒子的大小在150∼250 nm之間,上述特點在作為藥物制放系統上是一大優勢。在包覆CPT的應用上,各組成的nanogel均有約80%的包覆效率(entrapped CPT/loaded CPT),而且nanogel在包覆藥物前後粒徑大小並無明顯變化。至於CPT的釋放實驗方面,初步結果顯示,在20天的釋藥實驗過程中,不同組成的nanogel均能夠穩定、緩慢地釋放出CPT(在第20天時,各組釋放比率為:A=0.08,B=0.05,C=0.03,D=0.018,E=0.008),而且各個組成的nanogel在包覆CPT之後,不論是保存在4℃或室溫下仍具有相當高的穩定性。再者,隨著EGDMA添加量的增加(3 wt% ��50 wt%),交聯密度隨之提升,nanogel球體內部網狀結構排列更為緻密,CPT釋出的速率也更加緩慢,此現象在控制釋藥速率方面是一項很重要的依據,更是劑型最適化的參考。本研究所開發出之nanogel包覆CPT的劑型很有可能成為一個穩定、緩慢釋放的劑型,當然這都要視未來進一步的實驗確認。
目錄

摘要 I
目錄 III
圖目錄 VI
表目錄 IX

第一章 文獻回顧 1
1.1 生物可分解性高分子簡介 1
1.1.1 生物可分解性分解高分子性質 2
1.1.2 生物可分解性高分子種類 2
1.2 生物可分解性團聯共聚物 6
1.2.1 分類 6
1.2.2 合成方法 8
1.2.3 團聯共聚物的降解 9
1.3 光交聯水膠 9
1.3.1 何謂水膠 9
1.3.2 關於光交聯 10
1.3.3 製備光交聯水膠的方法 11
1.3.4 光交聯材料 12
1.3.5 光交聯水膠的應用 14
1.4 藥物載體奈米化 16
1.5 藥物控制釋放系統的必要性 16
1.6 Camptothecin的性質與應用 17
第二章 研究動機與目的 19
第三章 實驗部分 21
3.1 實驗藥品 21
3.2 實驗儀器與裝置 21
3.3 實驗方法 23
3.3.1 藥品的純化 23
3.3.2 PDLLA-PEG-PDLLA三團聯共聚物的合成 23
3.3.3 PDLLA-PEG-PDLLA diacrylate的製備 24
3.3.4 PDLLA-PEG-PDLLA diacrylate的CMC之量測 25
3.3.5 PDLLA-PEG-PDLLA diacrylate水膠奈米粒子的製備 25
3.3.6 奈米水膠粒子包覆Camptothecin ( CPT ) 26
第四章 結果與討論 28
4.1 4.1.1 PDLLA-PEG-PDLLA結構鑑定 28
4.1.2 PDLLA-PEG-PDLLA diacrylate結構鑑定 30
4.1.3 GPC分析結果 32
4.1.4 PDLLA-PEG-PDLLA熔點測定 33
4.2 PDLLA-PEG-PDLLA diacrylate的CMC 34
4.3 UV光交聯的鑑定及熱性質分析 35
4.4 水膠奈米粒子的粒徑、澎潤性質及穩定性
測量 38
4.4.1 nanogels的粒徑大小及膨潤性質 38
4.4.2 nanogels的穩定性探討 40
4.5 nanogels的形態(morphology) 42
4.6 nanogels包覆Camptothecin(CPT)之實驗 42
4.6.1 CPT螢光強度衰退測試 42
4.6.2 nanogels組成與包覆效率的關係 43
4.6.3 nanogel包覆CPT後的熔點測試 44
4.6.4 CPT釋放實驗及nanogel包覆CPT劑型的穩定性測
試 45
第五章 結論與未來展望 50
參考文獻 52
附錄A Camptothecin檢量線及計算公式 59
附錄B 螢光染劑1-pyrenehexanoic acid的結構 59
附錄C EGDMA及DMPA的結構 60

圖目錄

圖1-1 不同型態的lactide 3
圖1-2 PLA水解途徑 4
圖1-3 熔融縮合聚合聚酸酐反應示意圖 5
圖1-4 常見的脂肪族(SA)與芳香族(CPP)聚酸酐單體 5
圖1-5 團聯共聚物的類型 7
圖1-6 光起始劑產生自由基的機制簡圖 11
圖1-7 PEG跟PETA進行光交聯的示意圖 12
圖1-8 常見dextran衍生物的結構 13
圖1-9 dex-HEMA水膠的聚合跟降解 14
圖1-10 傳統製劑與控釋藥物製劑血中藥物濃度變化之比較 17
圖1-11 CPT之兩種形式及其存在條件 18
圖1-12 兩種CPT衍生物irinotecan及topotecan的結構 18
圖3-1 PDLLA-PEG-PDLLA三團聯共聚物合成反應示意圖 23

圖3-2 PDLLA-PEG-PDLLA acrylation示意圖 24
圖3-3 光交聯反應示意圖 25
圖4-1 PDLLA-PEG-PDLLA開環聚合反應機制圖 28
圖4-2 PDLLA-PEG-PDLLA的1H-NMR圖 29
圖4-3 PDLLA-PEG-PDLLA diacrylate的1H-NMR圖 30
圖4-4 PEG與PDLLA-PEG-PDLLA的FT-IR光譜圖 31
圖4-5 PDLLA-PEG-PDLLA與PDLLA-PEG-PDLLA diacrylate的FT-IR
光譜圖 32

圖4-6 PDLLA-PEG-PDLLA diacrylate的DSC圖 33
圖4-7 添加不同共聚單體對PEG-DA水膠EV及EWC的影響 34
圖4-8 PDLLA41-PEG4K-PDLLA41 diacrylate的CMC值 35
圖4-9 光交聯前後A組的C=C官能基吸收峰的變化 36
圖4-10 交聯劑添加量對交聯後的團聯共聚物熔點的影響 37
圖4-11 micelles及nanogels的粒徑大小跟交聯劑濃度的關係 38
圖4-12 nanogels的膨潤比例( in H2O / in microemulsion) 39
圖4-13 UV燈照射時間對nanogel粒徑大小的影響 40
圖4-14 nanogels儲存在4℃下的穩定性 41
圖4-15 nanogels儲存在室溫下的穩定性 41
圖4-16 nanogel E(EGDMA:50 wt%;DMPA:3 wt%)的AFM圖 42
圖4-17 CPT的飽和水溶液在不同照射時間下的螢光強度變化 43
圖4-18 以nanogel A~E組包覆CPT的效率 44
圖4-19 nanogel B(EGDMA:6 wt%;DMPA:3 wt%)及nanogel B包
覆CPT(0.08mg CPT/10mg nanogel)後的DSC圖 44
圖4-20 以nanogel A∼E包覆CPT,藥物在37℃下的釋放比率與時
間之關係圖 45
圖4-21 nanogel A~E組在CPT釋放實驗過程中粒徑的變化 46
圖4-22 以micelle A~E組包覆CPT,藥物在37℃下的釋放比率與時
間之關係圖 47
圖4-23 以PEG-DA hydrogel包覆BSA,BSA在藥物在37℃下的釋放
比率與時間之關係圖 48
圖4-24 nanogel A~E組包覆CPT之劑型保存在4℃下的粒徑變化 49
圖4-25 nanogel A~E組包覆CPT之劑型保存在室溫下的粒徑變化 49
表目錄

表1-1 添加不同共聚單體對PEG-DA水膠EV及EWC的影響 13
表1-2 光交聯水膠應用上的優缺點 15
表4-1 合成高分子的特性分析結果 33
表4-2 進行光交聯時光起始劑及交聯劑相對於單體的比例 36
參考文獻

1. Chandra R., Rustgi R., “Biodegrable polymers”, Prog. Polym. Sci., 1998, 23, 1273-1335.
2. Li S., Vert M., “Biodegradable polymers: polyesters”, Global Chinese Symposium on Biomaterials and Controlled Release, 1999, 332-355.
3. Kumar N., Ravilkumar M. N. V., Domb A. J., “Biodegradable block polymers”, Adv. Drug. Deliver. Rev., 2001, 53, 23-44.
4. 范國榮, “PLLA-PEOz-PLLA三團聯共聚物降解行為的探討”, 清大化工所碩士論文, 2003, part I, 23-29.
5. Shah S. S., Zhu K. J., Pitt C. G., “Poly(D,L-lactic acid)-poly(ethylene glycol) block copolymers. The influence of polyethylene glycol on the degradation of poly(lactic acid)”, J. Biomat. Sci-Polym. E., 1994, 421-431.
6. Hill-West J. L., Chowdhury S. M. et al., “Efficacy of a resorbable hydrogel barrier, oxidized regenerated cellulose, and hyaluronic acid in the prevention of ovarian adhesions in a rabbit model”, Fertil. Steril., 1994, 62, 630-634.
7. Chowdhury S. M., Hubbell J. A., “Adhesion prevention with ancord release via a tissue-adherent hydrogel”, J. Surg. Res., 1996, 61, 58-64
8. Elisseeff J., McIntosh W. et al., “Photoencapsulation of chondrocytes in poly(ethylene oxide)-based semi-interpenetrating networks”, J. Biomed. Mater. Res., 2000, 51, 164-171.
9. Venhoven B. A. M., Gee A. J., Davidson C. L., Biomaterials, 1996, 17, 2313-2318.
10. Nguyen K. T., West J. L., “Photopolymerization hydrogels for tissue engineering applications”, Biomaterials, 2002, 23, 4307-4314.

11. Scranton A. B., Bowman C. N. et al., “Photopolymerization fundamentals and applications”, New Orleans: ACS Publishers, 1996.
12. Decker C., “UV-curing chemistry: past, present, and future”, J. Coat. Technol., 1987, 59, 97-106.
13. Fisher J. P., Dean D., Engel P. S., Mikos A. G., “Photoinitiated polymerization of biomaterials”, Annu. Rev. Mater. Res., 2000, 31, 171-181.
14. Byrant S. J., Nuttelman C. R. et al., “Cytocompatibility of UV and visible kight photoinitiating systems on cultured NIH/3T3 fibroblasts in vitro”, J. Biomater. Sci. Polym. Ed., 2000, 11, 439-457.
15. West J. L., Hubbell J. A., “Separation of the arterial wall from blood contact using hydrogel barriers reduces intimal thickening after balloon injuries in the rat:the roles of medial and luminal factors in arterial healing”, Proc. Natl. Acad. Sci. USA, 1996, 93, 13188-13193.
16. Mellott M. B., Searcy K., Pishko M. V., Biomaterial, 2002, 22, 929-941.
17. Hubbell J. A., “Hydrogel systems for barriers and local drug delivery in the control of wound healing”, Journal of controlled release, 1996, 39, 305-313.
18. West J. L., Hubbell J. A., “Photopolymerized hydrogel materials for drug delivery applications”, Reactive polymers, 1995, 25, 139-147.
19. Groot C. J., Luyn M. J. A., Dijk-Wolthuis W. N. E., Cade’e J. A., Plantinga J. A., Otter W., Hennink W. E., “In vitro biocompatibility of biodegradable dextran-based hydrogels tested with human fibroblasts”, Biomaterials, 2001, 22, 1197-1203.



20. Franssen L., Roders V. P., Hennink W. E., “Degradable dextran hydrogels:controlled release of a model protein from cylinders and microspheres”, Journal of controlled release, 1999, 60, 211-221.
21. Lee J., Macosko C. W., Urry D. W., “Swelling behavior of crosslinked elastomeric polypentapeptide-based hydrogels”, Macromolecules, 2001,34, 4114-4123.
22. Sawhney A. S., Pathak C. P. et al., “Optimization of photopolymerized bioerodible hydrogel properties for adhesion prevention”, J. Biomed. Mater. Res., 1994, 28, 831-8.
23. Lu S., Ramirez W. F. et al., “Photopolymerized, multilaminated matrix devices with optimized nonuniform initial concentration profiles to control drug release”, J. Pharm. Sci., 2000, 89, 45-51.
24. Mann B. K., Gobin A. S. et al., “Smooth muscle cell growth in photopolymerized hydrogels with cell adhesive and proteolytically degradable domains: synthetic ECM analogs for tissue engineering”, Biomaterials, 2001, 22, 3045-51.
25. Hennink W. E., Van Nostrum C. F., “Novel crosslinking methods to design hydrogels”, Adv. Drug. Del. Rev., 2002, 54, 13-36.
26. Hoffman A. S., “Hydrogel for biomedical applications”, Advanced Drug Delivery Reviews, 2002, 43, 3-12.
27. Andini S., Ferrara L., Maglio G., Palumbo R., Makromol Chem Rapid Commun, 1988, 9, 119.
28. Bruin P., Veenstra G. J., Nijenehuis A. J., Pennings A. J., J Makromol Chem Rapid Commun, 1988, 9, 584.
29. Du Y. J., Lemstra P. J., Nijenhuis A. J., Hubb A. M., Bastiaansen C., “ABA type copolymers of lactide with poly(ethylene glycol). Kinetic, Mechanistic, and Model Studies”, Macromolecules, 1995, 28, 2124-2132.

30. Kim I. S., Jeong Y., Kim S. H., “Self-assembled hydrogel nanoparticles composed of dextran and poly(ethylene glycol) macromer”, International journal of pharmaceutics, 2000, 205, 109-116.
31. Chasin M., Langer R., “Biodegradable polymers as drug delivery systems”, Marcel Dekker, Inc., New York, 1990.
32. Hollinger J. O., “Biomedical applications of synthetic biodegradable polymers”, CRC Press, Inc., Boca Raton, 1995.
33. Holland S. J., Tighe B. J., Gould P. L., “Polymers for biodegradable medical devices, I. The potential of polyesters as controlled macromolecular release systems”, J. Control. Rel., 1996, 4, 155.
34. Anderson J. M., Shive M. S., ”Biodegradable and biocompatibility of PLA and PLGA microspheres”, Adv. Drug. Del. Rev.,1997, 28, 5-24.
35. Athanasiou K. A., Agrawal C. E., Barber F. A., Burkhart S. S., “Orthopaedic applications for PLA-PGA biodegradable polymer”, J. Arthrosc. Relat. Surg., 1998, 14(7), 726-737.
36. Kimura H., Tabata Y., Ogura Y., Moridera T., Honda Y., Ikada Y., “In vitro phagocytosis of polylactide microspheres by retinal pigment epithelial cells and intracellular drug release”, Current Eye Research, 1994, 13, 353-360.
37. Hollinger J. O., Battistone G. C., “Biodegradable bone repair materials”, Clinical. Ortho. Relat. Res., 1986, 207, 290-305.
38. Sodergard A., Stolt M., “Properties of lactic acid based polymers and their correlation with compostition”, Prog. Polym. Sci., 2002, 27, 1123-1163.
39. Wall M. E., Wani M. C., Cook C. E., “The isolation and structure of camptothecin, a novel alkaloid leukemia and tumor inhibitor from Camptothecin acuminates”, J. Am. Chem. Soc., 1996, 88, 3888-3890.

40. Gottlieb J. A., Guarino A. M., Call J. B., “Preliminary pharmacologic and clinical evaluation of camptothecin sodium”, Cancer Chemother. Rep., 1970, 54, 461-470.
41. Hertzberg R. P., Caranfa M. J., Holden K. G., Jajas D. R., Gallagher G., Mattern M. R., Mong S. M., Bartus J. O., Johnson R. K., Kingsbury W. D., “Modificaton of the hydroxy lactone ring of camptothecin: inhibition of mammalian topoisomerase I and biological activity”. J. Med. Chem., 1989, 32, 715-720.
42. Miyasaka T., Sawada S., Nokata K., Sugino E., Mutai M., “Camptothecin derivates and process for preparing same”, United State Patent, patent number 4604463.
43. Berges D. A., Taggart J. J., “Water soluble camptothecin analogs”, United State Patent, patent number 5663177.
44. 沙彥文, “抗癌藥物camptothecin與脂質於單分子層及微脂粒中分子交互作用情形之研究”, 清大化工所碩士論文, 2003, 1-3.
45. Nakamura K., Endo R., Takeda M., J. Polym. Sci., Polym. Phys. Ed., 1976, 14, 135 and 1287.
46. Zhao C. L., Winnik M. A., “Fluorescence Probe Technique Used To Study Micelle Formation in Water-Soluble Block Copolymers”, Langmuir 1990, 6, 514-516.
47. Candau F., Leong Y. S., Fitch R. M., Makromol. Chem., Macromol. Symp., 1990, 35/36, 105-119.
48. Candau F., Leong Y. S., Fitch R. M., Makromol. Chem., Macromol. Symp., 1990, 31, 27-40.
49. Medizabel E., Lopez S. F., Alvarez J., Eur. Polym. J., 1998, 34, 411-420.
50. Morgan J. D., Lusvardi K. M., Kaler E. W., Macromolecules, 1997, 30, 1897-1905.

51. McAllister K., Sazani P., Adam M., Cho M. J., Rubinstein M., Samulski R. J., DeSimone J. M., “Polymeric nanogels produced via inverse microemulsion polymerization as potential gene and antisense delivery agents”, J. Am. Chem. Soc., 2002, 124, 15201.
52. Verrecchia T., Spenhauer G., Bazile D. V., Murry B. A., Archimbaud Y., Veillard M., “Non-stealth(poly(lactic acid/albumin)) and stealth (poly(lactic acid-polyehtylene glycol)) nanoparticles as injectable drug carriers”, Journal of Controlled Release, 1995, 36, 49-61.
53. Soppimath K. S., Aminabhavi T. M., Kulkarni A. R., Rudzinski W. E., “Biodegradable polymeric nanoparticles as drug delivery devices”, Journal of Controlled Release, 2001, 70, 1-20.
54. Petrak K. Pharmaceutical particulate carriers. In: Rolland A, editor. Therapeutic application. New York: Marcel Dekker Inc, 1993, 275-297.
55. Grislain L., Couvreur P., Lenaerts V., Roland M., Deprezdecampeneere D., Speiser P., “Pharmacokinetics and distribution of a biodegradable drug-carrier”, Int. J. Pharm., 1983, 15, 335-45.
56. Yong H., Xiqun J., Yin D., Haixiong G., Yuyan Y., Changzheng Y., “Synthesis and characterization of chitosan-poly(acrylic acid) nanoparticles”, Biomaterials, 2002, 23, 3193.
57. 郭芝瑩, “聚癸二酸酐-聚丙二醇共聚物合成及在生醫材料上之應用”, 清大化工所碩士論文, 2003, 7.
58. Wani M. C., Ronmol / Lan P. E., Lindley L. T., Wall M. E., “Synthesis and biological activity of camptothecin analogues”, J. Med. Chem., 1980, 23, 554-560.
59. http://www.tast.or.th/news9/
60. http://www.chemnet.com.tw/magazine/200306/index7.htm

61. Kruszewski S., Burke T. G., “Properties of camptothecin analogues- promising topoisomerase I inhibitors determined by fluorescence spectroscopy methods”, J. Med. Phys. & Eng., 2002, 8(3), 183-192.
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