金錯合物在癌症治療的應用上，展現良好的腫瘤抑制效果。本研究藉由加入腺嘌呤 (Adenine, A)和金離子 (Au3+)自組裝，同時摻雜三磷酸腺苷 (ATP)及硫醇-聚乙二醇 (HSPEG)，合成水和粒徑約89 ± 17 nm 的配位奈米金粒子。摻雜ATP後未影響Au:A的配位情形，其含量~8%且ATP多在奈米粒子表面，提供奈米粒子表面負電排斥力獲得良好的分散性。摻雜HSPEG後，增加鹽類穩定性及降低水和粒徑。HSPEG-(Au:A/ATP)奈米粒子具有穀胱甘肽 (Glutathione, GSH)應答性，在高濃度GSH環境下，奈米粒子會被破壞並釋出內部金離子。使用配位奈米金粒子對Tramp-C1細胞株進行細胞毒性測試，得到24小時IC50~48 μM ，優於金離子 (IC50~51 μM)，且有促使細胞凋亡的情形發生。藉由添加GSH 抑制劑，亦可提升HSPEG-(Au:A/ATP)的作用能力，證實開發奈米藥物與細胞內GSH濃度具一定關聯性。最後，藉由配位聚合物能容納客體 (guest molecules)的特性包覆光敏劑Protoporphyrin IX (PpIX)，藉由奈米粒子與細胞內GSH作用，促進PpIX的光照效果以降低6小時之IC50~55 μM。此配位金奈米粒子可經由觸發應答性釋放內部金離子，與細胞內GSH作用特性及包覆藥物特性於生醫領域應用上展現良好的前瞻性，在未來，期望使用配位金奈米粒子克服順鉑 (Cisplatin)之抗藥性問題。

Stable Au (III) and Au (I) complexes, including cyclometallated gold complex, are promising candidates for anticancer drugs that exhibit potent in vitro and in vivo antitumor activities against human carcinoma xenografts tumors. Herein, a supramolecular synthesis route was presented for hierarchical self-assembly of coordinated adenine-Au (III) complexes into colloidal nanoparticles. During the polymerization process, the addition of adenosine triphosphate (ATP) and thiolated poly(ethylene glycol) was found to greatly improve the particle size control as well as the colloidal stability to against demetallation in physiological conditions. ATP taken up about 8% of coordinated Au-nanoparticles and mostly on the surface . However, the as-prepared colloidal Au-nanoparticles could be easily decomposed in high glutathione (GSH) levels, leading to a fast release inside living tumor cells. When incubated with cancer cells, the coordinated Au-nanoparticles displayed a significant in vitro antitumor effect with low IC50 value (~48 uM). Apoptosis analysis also confirmed that the nanoparticulate formulation promoted a higher cell dead rate of cancer cells than Au ions with the same dose. The relation of intracellular GSH concentration to Au-nanoparticles was found by pretreatment of GSH inhibitor. Photosensitizer were furthermore incorporated into the supramolecular assemblies and an increased Au-based therapeutic efficacy for prostate cancers treatment was successfully achieved . Overall, these nanoparticulate Au-bearing complexes represent an attractive alternative to overcome the failure of cisplatin resistance in traditional chemotherapy.

摘要 1
Abstract 2
致謝 3
總目錄 4
圖目錄 6
表目錄 7
第一章:緒論 8
1.1 癌症及臨床藥物治療 8
1.1.1金屬錯合物簡介及分類 8
1.1.2 鉑錯合物介紹與作用機制 10
1.1.3 金錯合物介紹與作用機制 12
1.2 奈米藥物 16
1.2.1奈米藥物載體 16
1.2.2 有機奈米藥物 17
1.2.3 無機配位奈米藥物 18
1.3 研究動機與目的 21
第二章:實驗材料與方法 23
2.1 實驗藥品與儀器 23
2.1.1 實驗藥品 23
2.1.2 緩衝溶液配製 24
2.1.3 細胞培養與操作 25
2.1.4 儀器 25
2.2 奈米藥物的合成 26
2.2.1 腺嘌呤衍生物摻雜腺嘌呤/金配位奈米粒子的合成 26
2.2.2 硫醇-聚乙二醇摻雜(腺嘌呤-三磷酸腺苷)/金配位奈米粒子的合成 26
2.2.3 包覆染劑之硫醇-聚乙二醇-(腺嘌呤-三磷酸腺苷)/金配位奈米粒子的合成 27
2.2.4 奈米藥物之穀胱甘肽 (Glutathione, GSH)應答性 27
2.3 奈米藥物對細胞Tramp-C1的作用 27
2.3.1細胞存活率分析 27
2.3.2 流式細胞儀分析細胞凋亡情形 28
第三章:結果與討論 29
3.1 奈米藥物的合成與鑑定 29
3.1.1 不同腺嘌呤衍生物摻雜對腺嘌呤/金配位奈米粒子影響探討 29
3.1.2 硫醇-聚乙二醇參雜(腺嘌呤-三磷酸腺苷)/金配位奈米粒子探討 30
3.1.3 高解析X光電子能譜儀 (HRXPS)鑑定奈米藥物 31
3.1.4 傅立葉轉換紅外光譜儀鑑定奈米藥物 32
3.1.5 X光吸收光譜儀 (XAS)鑑定奈米藥物 33
3.1.6 小角度X光散射儀 (SAXS)鑑定奈米藥物 33
3.1.7 X光射線繞射儀 (XRD) 33
3.2 奈米藥物之穀胱甘肽 (Glutathione, GSH)應答性 33
3.3 奈米藥物對細胞Tramp-C1的作用 35
3.3.1奈米藥物在Tramp-C1細胞內的釋放 35
3.3.2 細胞測試分析 35
3.3.3細胞毒性機制探討 36
3.3.4 包覆光敏劑PpIX對奈米藥物之影響 37
圖表說明 39
參考文獻 57

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