臺灣博碩士論文加值系統

高分子混合型奈米微胞由兩種以上高分子所組成，具有疏水性核心和親水性外殼，內部攜載疏水性藥物，可應用於改善疏水性藥物治療效率。
此研究開發一高分子混合型奈米微胞系統，攜載抗癌藥物之高分子混合型奈米微胞來達到毒殺癌細胞的效果。該高分子混合型奈米微胞由高分子poly-γ-benzyl-l-glutamate (PBLG)與雙親性高分子d-α-tocopherol polyethylene glycol 1000 succinate (TPGS)所組成；PBLG構成高分子混合型奈米微胞疏水性內核，TPGS則貫穿高分子混合型奈米微胞殼層結構，TPGS的親水端PEG能構成外殼層，而另一邊疏水端則延伸進內部，與PBLG形成疏水性內核。
本研究利用動態光散射儀測量之高分子混合型奈米微胞粒徑大小約為150 nm並且具有單一分散性，藉穿透式電子顯微鏡可觀察其具有微胞之核-殼型態；本研究利用粒徑大小變化來探討高分子混合型奈米微胞的穩定性與酸鹼應答性同時優化製備條件；結果顯示在中性環境pH 7.4下，24小時後粒徑沒有改變，具有安定性；在酸性環境pH 4.0下，粒徑改變，顯示該高分子混合型奈米微胞具有酸鹼應答性。而藥物釋放曲線可發現在中性環境下，高分子混合型奈米微胞僅有少量藥物被釋出；酸性環境下則於短時間內大量釋出藥物；藉由共軛焦顯微鏡在酸性胞器(如：溶酶體pH 4.0)中也可發現抗癌藥物大量從高分子混合型奈米微胞釋出的情形。
本研究已成功製備出具有酸鹼應答性之高分子混合型奈米微胞，該微胞在中性生理環境下(pH 7.4)能夠維持高穩定性，未來在抗癌治療上極具開發之潛能。

Polymeric mixed micelles were composed of two or more polymers. Polymeric mixed micelles have the structure of the hydrophobic core and the hydrophilic shell, the hydrophobic core exhibited a loading capacity of hydrophobic drugs. The loading capacity of polymeric mixed micelles could improve the therapy efficiency of hydrophobic drugs.
In this study, we developed a polymeric mixed micellar system loading anticancer drug to have toxicity against the cancer cell. The polymeric mixed micelles included poly-γ-benzyl-l-glutamate (PBLG) and amphiphilic d-α-tocopherol polyethylene glycol 1000 succinate (TPGS). PBLG in the system enabled to form the hydrophobic core； TPGS in the system could insert through the core and the shell. The hydrophilic polyethylene glycol (PEG) part of TPGS formed the shell, whereas the hydrophobic part of TPGS inserted into the core to form the hydrophobic core with PBLG.
In the study, we used dynamic laser scattering (DLS) to measure the particle sizes of the polymeric mixed micelles. The results of particle sizes showed approximately 150 nm in monodispersity. The core-shell structure of polymeric mixed micelles was observed by transmission electron microscopy (TEM). The stability and pH-sensitivity of the polymeric mixed micelles were determined and optimized using particle size measurement. The results of stability tests showed the polymeric mixed micelles exhibited stable particle sizes at pH 7.4 after 24 hours incubation at 37°C； at pH 4.0 condition, the particle size changed owing to the pH responsiveness. Drug releasing profile showed that at neutral environment, only little drug would be released from polymeric mixed micelles, while at acidic condition, polymeric mixed micelles would release a lot of drug within short period. We also observed a huge amount of anticancer drug releasing in acidic organelles (such as lyosomes) by confocal laser scanning microscopy (CLSM).
In this study, pH sensitive polymeric mixed micelles were successfully prepared, which could maintain the high stability in neutral environment. The polymeric mixed micellar system was potential for further anticancer application.

致謝辭 Ⅰ
縮寫表 Ⅱ
中文摘要 Ⅲ
英文摘要 Ⅳ
目次 Ⅴ
圖目次 Ⅶ
表目次 Ⅹ
第一章 緒論
1.1 實驗背景 1
1.2 實驗目的 2
第二章 文獻探討
2.1 癌症
2.1.1 癌症造成原因及治療方式 4
2.1.2 化學藥物療法 5
2.2 高分子奈米微胞應用於癌症治療 21
2.2.2 奈米藥物載體的簡介 22
2.3 酸鹼應答性高分子奈米微胞
2.3.1 腫瘤環境之酸鹼值 28
2.3.2 酸鹼應答性高分子奈米微胞的設計機制 29
2.4 載體材料之介紹
2.4.1 D-α-tocopherol polyethylene glycol
1000 succinate (TPGS) 34
2.4.2 Poly-γ-benzyl-l-glutamate (PBLG) 45
第三章 實驗部分
3.1 實驗藥品 52
3.2 實驗儀器 53
3.3 實驗方法
3.3.1 高分子混合型奈米微胞載體的製備與特性 54
3.3.2 高分子混合型奈米微胞藥物包覆與釋放 56
3.3.3 高分子混合型奈米微胞進入細胞與釋放 58
3.3.4 統計分析 63
3.4 結果與討論
3.4.1 高分子混合型奈米微胞載體的製備與特性 64
3.4.2 高分子混合型奈米微胞藥物包覆與釋放 72
3.4.3 高分子混合型奈米微胞進入細胞與釋放 74
第四章 結論 78
參考書目 80

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