為改善癌症治療中化學療法缺乏專一性之問題，且同時提高化療藥物在人體之療效，本研究設計具不同親水鏈段、相同疏水鏈段之兩親性高分子mPEG44-DTPM與mPEG113-DTPM，並探討其自組裝結構差異與藥物輸送效果的影響。此高分子系統以馬來醯亞胺作為刺激響應節點，其2號位與3號位之碳硫鍵具有與硫醇類分子進行硫醇置換的能力，並藉由親/疏水作用力於水相自組裝形成內層為疏水核心之奈米載體，用於將阿黴素 (doxorubicin, DOX) 靶向輸送至癌細胞，藉由癌細胞內之高穀胱甘肽的環境，以硫醇置換方式釋放所攜帶之藥物。結果顯示mPEG44-DTPM由於疏水鏈段佔比較大，自組裝形成微胞後之穩定度優於mPEF113-DTPM，然而將阿黴素包覆於其中後，皆能穩定微胞結構。最後，分別模擬穀胱甘肽在癌細胞 (10 mM) 與生理環境 (10 μM) 的濃度作為藥物釋放實驗之條件，結果可得兩高分子微胞在濃度為10 mM穀胱甘肽環境中的藥物釋放量皆高於濃度為10 μM 之穀胱甘肽環境的釋放量，顯示此高分子系統於穀胱甘肽響應下皆能成功釋放負載於其中的藥物，以達到提升選擇性與療效之目的。

The study aims to improve the lack of specificity for chemotherapy in cancer treatments and the curative effect of antineoplastic drugs in human body. With amphiphilic polymers mPEG44-DTPM and mPEG113-DTPM as drug carriers, the differences in their self-assembled structures and the efficiency of drug delivery are put into discussion. In this drug delivery system, maleimide served as the stimulative node, where thioether bonds in the resulting dithiomaleimide conjugate could be substituted by excess thiols for being used as a GSH-responsive moiety. Drug carriers targeting the delivery of doxorubicin (DOX) into the cancer cell would release the encapsulated drug due to the high concentration of GSH (10 mM) in the cell. According to the experiment, mPEG44-DTPM is more stable than mPEG113-DTPM as drug carrier in the physiological environment. Both DOX-encapsulated polymers achieved nearly 50% of drug loading efficiency. The in vitro releasing profile of DOX-encapsulated mPEG44-DTPM and mPEG113-DTPM were respectively 6.2 μg and 7.3 μg at 10 mM GSH and 3.6 μg and 4.5 μg at 10 μM GSH.

摘要 I
Abstract II
謝誌 III
目錄 V
圖目錄 IX
表目錄 XII
式目錄 XIII
第一章 文獻回顧 1
1-1 癌症 (Cancer) 1
1-2 癌症治療 (Cancer Treatments) 4
1-2-1 手術治療與放射治療 4
1-2-2 化學治療 5
1-2-3 標靶藥物治療 6
1-3 奈米載體應用於癌症治療 8
1-3-1 增強通透與滯留效應 (Enhanced Permeability and Retention Effect, EPR effect) 9
1-3-2 腫瘤微環境 (Tumor Microenvironment, TME) 10
1-3-3 核內體逃脫 (Endosomal Escape) 12
1-4 刺激響應型高分子奈米載體 (Stimuli-Responsive Polymeric Nanocarrier) 14
1-4-1 線性－樹枝狀共聚物 (linear-dendritic block copolymers, LDBCs) 15
1-4-2 氧化還原響應型高分子奈米載體 (Reduction-Responsive Polymeric Nanocarrier) 19
1-4-3 酸鹼響應型高分子奈米載體 (pH-Responsive Polymeric Nanocarrier) 20
1-4-4 其他響應型高分子奈米載體 (Other Responsive Polymeric Nanocarrier) 21
1-5 2,3-二溴馬來醯亞胺 (2,3-Dibromomaleimide, DBM) 24
1-5-1 可逆反應之高度選擇性 25
1-5-2 功能性修飾之螢光現象 26
1-5-3 高分子修飾 27
1-6 研究動機 29
第二章 藥品儀器與實驗步驟 31
2-1 藥品 31
2-2 儀器 32
2-3 mPEGn-DTPM 之合成步驟與鑑定 36
2-3-1 聚乙二醇單甲醚對甲苯磺酸酯 (mPEG113-OTs) 之合成 36
2-3-2 聚乙二醇單甲醚-疊氮化物 (mPEG113-N3) 之合成 37
2-3-3 聚乙二醇單甲醚對甲苯磺酸酯 (mPEG44-OTs) 之合成 39
2-3-4 聚乙二醇單甲醚-疊氮化物 (mPEG44-N3) 之合成 40
2-3-5 N-propargyl-2,3-dibromomaleimide (DBM) 之合成 42
2-3-6 N-propargyl-2,3-dithiophenolmaleimide (DTPM) 之合成 43
2-3-7 2,3-Dithiophenolmaleimide-functional mPEG113之合成 45
2-3-8 2,3-Dithiophenolmaleimide-functional mPEG44 之合成 47
2-4 mPEGn-DTPM之材料特性及刺激響應分析 49
2-4-1 以穀胱甘肽進行高分子硫醇置換 49
2-4-2 高分子奈米微胞製程 49
2-4-3 高分子奈米粒徑分析 49
2-4-4 高分子奈米微胞之穀胱甘肽響應分析 50
2-5 高分子奈米微胞之阿黴素包覆及釋放 51
2-5-1 製備包覆阿黴素之高分子奈米微胞與分析 51
2-5-2 高分子微胞負載阿黴素前後之螢光強度 52
2-5-3 製作阿黴素於二甲基甲醯胺之檢量線 52
2-5-4 製作阿黴素於磷酸鹽緩衝液之檢量線 53
2-5-5 包覆阿黴素之高分子奈米微胞在穀胱甘肽響應下之釋放 54
第三章 結果與討論 56
3-1 mPEGn-DTPM與mPEGn-G2之合成 56
3-2 高分子mPEGn-DTPM之材料特性與刺激響應分析 62
3-2-1 以穀胱甘肽 (GSH) 進行高分子硫醇置換 62
3-2-2 . 高分子奈米微胞粒徑大小與穩定性測試 63
3-2-3 高分子奈米微胞之穀胱甘肽響應分析 67
3-3 雙性高分子形成奈米微胞包覆抗癌藥物阿黴素 70
3-3-1 包覆阿黴素之高分子奈米微胞製備以及負載效率之計算 70
3-3-2 包覆阿黴素之高分子微胞前後粒徑大小與螢光強度變化 72
3-3-3 包覆阿黴素之高分子於不同穀胱甘肽濃度條件下之釋放情形 74
3-4 合成mPEGn-G2 之瓶頸與解決辦法 77
3-4-1 以鍵擊反應合成化合物 c 77
3-4-2 以N-Boc-3-氨基丙基溴保護2,3-二溴馬來醯亞胺之氮端 79
3-4-3 以無銅催化之鍵擊反應解決mPEGn-G2之合成問題 80
3-5 結論 82
第四章 參考文獻 83

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