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研究生:邱宇霆
研究生(外文):Yu-Ting Chiu
論文名稱:含維生素E接枝型高分子與團聯高分子之複合型奈米微胞於癌症治療之應用
論文名稱(外文):Mixed Micelles Based on Vitamin E-Contained Graft Polymer and Block Polymer for Application in Cancer Therapy
指導教授:駱俊良
指導教授(外文):Chun-Liang Lo
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:醫學工程研究所
學門:工程學門
學類:生醫工程學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:中文
論文頁數:80
中文關鍵詞:複合型奈米微胞藥物傳遞系統維生素E細胞凋亡
外文關鍵詞:polymeric mixed micellesdrug delivery systemvitamin Ecell apoptosis
相關次數:
  • 被引用被引用:0
  • 點閱點閱:129
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  • 下載下載:5
  • 收藏至我的研究室書目清單書目收藏:0
高分子微胞已被視為對於疏水性藥物具有前瞻性的藥物載體,高分子微胞比起其他藥物載體更能穩定地將疏水性藥物包覆於核心,且由於微胞外層屬於親水性殼層,因此可以輕易避開體內免疫系統的辨識,長時間存在於血液循環系統並且利用EPR效應有效的累積於腫瘤中。
複合型奈米微胞是由兩條以上之高分子所形成之藥物載體,此類型微胞比起單一一條高分子所組成之微胞具有更完整的殼核結構,而且每條高分子皆能發揮其自己的功能,因此使此複合型奈米微胞能夠更穩定的存在於血液循環內並且具有多功能性之應用。
α-生育酚琥珀酸酯(α-tocopheryl succinate,α-TOS)是維生素E的一種酯化衍生物。近年來研究發現,α-TOS對惡性腫瘤細胞具有高度的選擇性,且能抑制癌細胞的生長甚至促進其凋亡,因而備受矚目。
本研究透過1H-NMR以及GPC分析確認成功合成出poly(hydroxypropyl methacrylamide)-g-α-tocopheryl succinate與methoxy poly(ethylene glycol)-b-poly(D,L-lactide),並以此兩種高分子自組裝形成複合型奈米微胞,藉由DLS及TEM量測並觀察其粒徑大小與型態,此外以Doxorubicin當作抗癌藥物包覆於微胞內,進行酸鹼應答之藥物釋放行為測試,最後以L929以及HCT-116進行細胞毒性之試驗,根據本實驗之結果,此複合型奈米微胞具有良好之生物相容性、藥物控制釋放以及抑制癌細胞生長之特性,可視為一具有發展潛力之藥物載體。

Polymeric micelles are considered to be a potential drug carrier which could stabilize to encapsulate hydrophobic drugs into the core. Besides, the outer hydrophilic shell of the micelles could avoid immune system recognition, prolonging the circulating time and accumulation preferentially in tumor.
Mixed micelles are formed by more than two polymers. This type of micelles have several advantages over single component micelles, such as well core-shell structure and functions based on each copolymer in the micellar structure. Therefore, mixed micelles can be more stable in the presence of blood circulation and have multifunctions.
α-tocopheryl succinate(α-TOS) is one of vitamin E analogs. Recent studies indicated that α-TOS has highly cytotoxic selectivity to cancer cell by suppressing growth and inducing apoptosis.
In this study, the two polymers, poly(hydroxypropyl methacrylamide)-g-α-tocopheryl succinate and methoxy poly(ethylene glycol)-b-poly(D,L-lactide) were successfully synthesized and characterized by 1H-NMR and GPC. Then, the two polymers were mixed, self-assembly forming mixed micelles via dialysis. The size and core-shell morphology of mixed micelles were determined by DLS and TEM. In addition, Doxorubicin as an anti-cancer drug loaded in the micelles to test the drug release behavior under acid environment. Using L929 and HCT-116 cell line test the cytotoxicity. Based on the results of this study, this mixed micelle has good biocompatibility, well-controlled drug release and inhibition of cancer cell growth property. It can be considered as a potential drug carrier.

目錄
中文摘要 i
Abstract iii
目錄 v
圖目錄 vii
表目錄 ix
第一章、 研究動機 1
第二章、 文獻回顧 3
2-1 腫瘤組織構造與藥物傳遞之關係 3
2-2 奈米藥物載體 4
2-2.1 奈米藥物載體於癌症治療之傳遞模式 8
2-2.2 奈米藥物載體之細胞吞噬機制 9
2-2.3 奈米藥物載體之藥物釋放方式 10
2-3 高分子微胞於癌症治療之應用 11
2-3.1 溫度應答型高分子微胞 11
2-3.2 酸鹼應答型高分子微胞 13
2-3.3 氧化還原應答型高分子微胞 14
2-4 維生素E之性質介紹 15
2-4.1 α-tocopheryl succinate(α-TOS)基本性質介紹 16
2-4.2 α-tocopheryl succinate(α-TOS)之抗癌機制 20
2-4.3 α-tocopheryl succinate(α-TOS)於藥物載體之應用 24
2-5 高分子材料與應用 25
2-5.1 Poly(ethylene glycol)(PEG) 25
2-5.2 Poly-lactic acid(PLA) 26
2-5.3 Poly(N-(2-hydroxypropyl) methacrylamide)(PHPMA) 27
第三章、 實驗方法 29
3-1 實驗藥品 29
3-2 儀器與裝置 31
3-3 名詞對照 32
3-4 雙團聯共聚物methoxy poly(ethylene glycol)-b-poly(D,L-lactide)之合成 33
3-5 接枝型高分子poly(hydroxypropyl methacrylamide)-g-α- tocopheryl succinate之合成 33
3-5.1 酯化反應催化劑 DPTS 之合成 33
3-5.2 線性高分子poly(hydroxypropyl methacrylamide)之合成 34
3-5.3 接枝型高分子poly(hydroxypropyl methacrylamide)-g-α- tocopheryl succinate之合成 35
3-6 高分子之性質分析 36
3-6.1 1H-NMR結構與分子量之鑑定 36
3-6.2 GPC分子量分布之鑑定 36
3-7 奈米微胞之製備 37
3-8 奈米微胞之鑑定及性質分析 37
3-8.1 奈米微胞粒徑及分布分析 37
3-8.2 奈米微胞之型態分析 37
3-8.3 奈米微胞之穩定性與酸鹼應答性分析 38
3-8.4 奈米微胞之α-TOS釋放行為探討 38
3-8.5 奈米微胞之蛋白質吸附測試 39
3-8.6 奈米微胞之藥物包覆及性質鑑定 40
3-8.7 奈米微胞之藥物釋放行為探討 41
3-8.8 奈米微胞之細胞毒性測試 42
3-8.9 奈米微胞之細胞內分布情形 44
第四章、 結果與討論 45
4-1 雙團聯共聚物 mPEG-b-PLA 之合成鑑定 45
4-2 酯化反應催化劑 DPTS 之合成鑑定 47
4-3 線性高分子 PHPMA 之合成鑑定 48
4-4 接枝型高分子 PHPMA-g-α-TOS 之合成鑑定 50
4-5 複合型奈米微胞之鑑定及性質分析 53
4-6 奈米微胞之穩定性與酸鹼應答性分析 54
4-7 奈米微胞之α-TOS釋放行為探討 56
4-8 奈米微胞之蛋白質吸附測試 57
4-9 奈米微胞之藥物包覆及性質分析 58
4-10 奈米微胞之藥物釋放行為探討 60
4-11 奈米微胞之細胞毒性測試 61
4-12 奈米微胞於細胞內之分布 68
第五章、 結論 71
參考文獻 72

圖目錄
圖2-1、藥物載體於血液循環之傳遞模式 5
圖2-2、微胞之形成原理 6
圖2-3、多功能複合型奈米微胞之不同高分子組成示意圖 8
圖2-4、被動標的與主動標的示意圖 9
圖2-5、多種不同路徑之細胞內吞作用機制 10
圖2-6、內吞作用中胞器在不同階段之pH値變化示意圖 11
圖2-7、溫度應答型之高分子結構 12
圖2-8、酸鹼應答型之高分子結構 14
圖2-9、氧化還原應答型之高分子結構 15
圖2-10、維生素E終止自由基之反應式 16
圖2-11、維生素E衍生物 17
圖2-12、α-tocopheryl succinate結構示意圖 18
圖2-13、α-tocopherol及α-tocopheryl succinate結構之主要區域 19
圖2-14、α-TOS抑制DNA之合成 21
圖2-15、α-TOS誘導細胞凋亡之外源途徑 22
圖2-16、α-TOS誘導細胞凋亡之內源途徑 24
圖2-17、TPGS-DOX conjugate結構示意圖 25
圖2-18、TPGS與lactide合成PLA-TPGS示意圖 25
圖2-19、PEG結構示意圖 26
圖2-20、PLA結構示意圖 27
圖2-21、PHPMA結構示意圖 28
圖3-1、α-TOS溶於PBS/MeOH之檢量線 39
圖3-2、Dox溶於DMSO之檢量線 41
圖3-3、Dox溶於PBS之檢量線 42
圖3-4、MTS化學結構圖 44
圖4-1、mPEG-b-PLA之1H-NMR光譜圖 46
圖4-2、mPEG-b-PLA之GPC鑑定圖 46
圖4-3、DPTS之1H-NMR光譜圖 48
圖4-4、PHPMA之1H-NMR光譜圖 49
圖4-5、PHPMA之GPC鑑定圖 50
圖4-6、PHPMA-g-α-TOS之1H-NMR光譜圖 51
圖4-7、PHPMA-g-α-TOS之GPC鑑定圖 52
圖4-8、三種不同α-TOS比例之PHPMA-g-α-TOS與mPEG-PLA35之粒徑及分布 54
圖4-9、PHPMA-g-α-TOS16與三種不同組成比之mPEG-PLA之粒徑及分布 54
圖4-10、奈米微胞於pH7.4及pH4.5環境下之粒徑變化 55
圖4-11、奈米微胞於pH7.4與pH4.5不同時間點之TEM圖 56
圖4-12、奈米微胞於pH7.4及pH4.5環境之α-TOS釋放行為 57
圖4-13、奈米微胞於BSA蛋白質溶液之粒徑變化量 58
圖4-14、奈米微胞以不同Dox濃度進行包覆之粒徑大小及分布 59
圖4-15、含藥奈米微胞於pH7.4及pH4.5環境下之藥物釋放行為 61
圖4-16、α-TOS及奈米微胞與正常細胞L929共培養之細胞毒性 63
圖4-17、α-TOS及奈米微胞與癌細胞HCT-116共培養之細胞毒性 65
圖4-18、Dox及含藥奈米微胞與癌細胞HCT-116共培養之細胞毒性 68
圖4-19、藥物及含藥奈米微胞與人類大腸癌細胞共培養0.5、1及3小時之分布情況 70


表目錄
表2-1、造成血管通透性增加之因子 4
表2-2、α-TOS對於多種細胞之毒性測試 18
表4-1、mPEG-b-PLA之組成比例 48
表4-2、PHPMA-g-α-TOS之組成比例 53
表4-3、奈米微胞以不同Dox濃度進行包覆之性質分析 61

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