葡聚醣接枝聚己內酯之兩性高分子及其奈米粒子應用於包覆藥物的研究

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研究生：	黃恩琪 En-Chi Huang
論文名稱：	葡聚醣接枝聚己內酯之兩性高分子及其奈米粒子應用於包覆藥物的研究 Nanoparticles of Amphiphilic Copolymer Dextran-grafted-poly(caprolactone) And Their Applications in Durg Delivery System
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：	2008
畢業學年度：	96
語文別：	中文
論文頁數：	65
中文關鍵詞：	奈米粒子、藥物控制釋放、紫杉醇、薑黃素、體外釋放
外文關鍵詞：	amphiphilic copolymer, nanoparticles, drug delivery system, paclitaxel, curcumin, in-vitro release
相關次數：	點閱：4 下載：0
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本研究選用生物相容性佳的Dextran作為親水性材料，接枝疏水性poly(caprolactone)，合成出兩性高分子Dex-g-PCL。此接枝狀兩性高分子在水中會自組裝形成奈米粒子，臨界聚集濃度(CAC)值約為1 ppm，且在水相溶液中形成粒徑約140 nm的奈米粒子，儲存在37℃環境可以維持至少六週的粒徑穩定。
此奈米粒子能夠包覆疏水性抗癌藥物-紫杉醇以及薑黃素。包覆紫杉醇時，依給藥比例不同，包覆效率最高可達61.9%，並且維持粒徑在140 nm；包覆薑黃素效率約為45%，粒徑略增加至240 nm，兩者皆能維持穩定粒徑達一個月以上。以透析方法作釋放實驗時，兩種藥物皆呈現兩階段釋放趨勢。
以MTT進行細胞毒殺實驗時，發現無包藥的奈米粒子在培養一至兩天內，對人類纖維母細胞HS68與子宮頸癌細胞HeLa皆沒有明顯毒性。而包覆藥物的奈米粒子對HeLa細胞進行毒殺實驗，發現以奈米粒子包覆薑黃素可以在2 ppm時殺死50%的細胞，證明藥物本身仍具有活性；就紫杉醇而言，以此奈米粒子包覆紫杉醇僅需0.0005 ppm的藥物就能殺死60%癌細胞，且能夠避免使用蓖麻油做為溶劑引發的缺點，表示此奈米粒子配方非常有潛力。

Hydrophobic segments of poly(caprolactone), PCL, were synthesized from ring-opening polymerization of ε-caprolactone and then grafted on hydrophilic dextran molecules to form amphiphilic copolymer Dextran-grafted-poly(caprolactone). The copolymers Dex-g-PCL exhibited critical aggregation concentration (CAC) at 1µg/mL in water, and self-assembled into nanoparticles of 140 nm in diameter, mainly via hydrophilic-hydrophobic interactions of polymer chains in aqueous solutions.
Water-insoluble curcumin and anticancer agent paclitaxel were incorporated into these nanoparticles with encapsulation efficiency up to 45% and 61.9%, depending on the loading ratio. The in-vitro release profiles showed biphasic patterns, while sizes remained stable in 37°C for more than 1 month. Void nanoparticles showed low cytotoxicity toward human fibroblasts HS-68 and HeLa cell line; however, paclitaxel- and curcumin-loaded nanoparticles showed IC50 value about 0.0005 and 2 ppm, respectively toward HeLa cell line. High biocompatibility of nanoparticles and effects of encapsulated anticancer agents were verified.
Composed of amphiphilic copolymer Dex-g-PCL, the nanoparticles showed great potential in the application of sustainable drug release.

摘要................................................i Abstract...........................................ii
目錄..............................................iii
圖目錄..............................................v
表目錄.............................................vi
第一章 文獻回顧.....................................1
1生醫材料簡介.....................................1
1.1合成高分子簡介.................................2
1.2天然高分子簡介.................................5
2高分子應用於藥物控制釋放系統.....................8
2.1藥物控制釋放系統簡介...........................8
2.2利用高分子包埋藥物.............................9
2.3兩性高分子共聚物與微胞.........................9
2.4癌組織標的功能(tumor targeting)...............12
2.5 In vitro藥物包覆與釋放的方式.................13
3文獻上接枝多醣類高分子與聚酯的方法..............13
4包覆藥物介紹....................................15
4.1紫杉醇(Paclitaxel)介紹........................16
4.2薑黃素(Curcumin)介紹..........................17
第二章 研究動機與目的..............................20
第三章 實驗步驟與方法..............................22
1 實驗藥品.......................................22
2 實驗相關儀器耗材...............................23
3 實驗架構.......................................25
4 實驗步驟方法...................................26
4.1合成疏水性鏈段R-PCL-COOH......................26
4.2合成接枝高分子................................26
4.3產物分析與鑑定................................28
4.4測量臨界聚集濃度..............................29
4.5製備奈米粒子..................................29
4.6包覆藥物與藥物釋放測定........................30
4.7藥物濃度測定..................................31
4.8奈米粒子外觀型態觀測..........................32
4.9細胞毒性測試..................................32
第四章 結果與討論..................................34
1合成R-PCL-COOH與結構鑑定........................34
2合成接枝狀高分子 Dex-g-PCL與結構鑑定............35
2.1 1H-NMR鑑定...................................36
2.2 FT-IR 分析結果...............................38
2.3熱分析結果....................................38
3 Dex-g-PCL在水中的臨界聚集濃度..................42
4製備奈米粒子....................................45
4.1 製備方法選擇.................................45
4.2 水相溶液與分散劑的選擇.......................46
4.3 奈米粒子包覆藥物與釋放測定...................48
4.4 奈米粒子外觀型態.............................52
4.5 奈米粒子包覆藥物的細胞毒殺性.................56
第五章 結論與未來展望..............................59
第六章 參考文獻....................................61
第七章 附錄........................................65

                                

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