無定型碳酸鈣 (Amorphous calcium carbonate, ACC)是一種天然無毒性的生物礦物，具有pH響應性，生物相容性高，化學成分簡單，製備成本低且易於大規模生產等諸多優點，在生物醫學方面極具應用潛力，可作為藥物載體進行開發。然而，ACC在水溶液中易於溶解和結晶等不穩定因素，限制了此材料在奈米藥物載體方面的未來發展性，因此需要額外添加保護劑對其進行保護。本研究通過簡單的氣相擴散反應，在乙醇溶液中成功合成出了同時載負阿霉素 (Doxorubicin, DOX)與吲哚菁綠 (Indocyanine green, ICG)的ACC奈米藥物載體,其載負率分別為94%和98%，粒徑為46 nm。為維持其水相穩定性，實驗以聚乙烯吡咯烷酮 (Polyvinyl pyrrolidone, PVP)吸附在其表面抑制其結晶，再以植酸 (Phytic acid, IP6)形成Ca-IP6殼層，得到粒徑為78 nm的奈米複合體，并藉由XRD偵測獲知其仍維持ACC形式。進而通過鹽酸羥胺 (Hydroxylamine hydrochloride)還原四氯金酸 (Hydrogen tetrachloroaurate)，在奈米複合體表面緊密修飾上小粒徑 (15 nm)的金奈米粒子, 這些表面修飾的金奈米粒子不僅可以通過巰基修飾的聚乙二醇 (Thiol Polyethylene glycol, PEG-SH) 使其在生理環境下穩定存在，還可以通過其光熱響應特性增強近紅外光熱療。總之，一個具有pH響應特性的雙藥物控制釋放系統被成功的建立並且在腫瘤細胞治療方面得到應用。

Amorphous calcium carbonate (ACC), as a naturally nontoxic biomineral, shows great potential for biomedical applications, with intrinsic advantages of pH-dependent degradability, biocompatibility, simple chemical composition, as well as low cost and ease of large-scale production. However, the major obstacle to develop ACC nanoparticles as a pH-responsive nanomedicine is the high aqueous instability of ACC including its ease of dissolution and phase transition. Herein, an alcoholic suspension of ACC nanoparticles preloaded with doxorubicin (DOX) and indocyanine green (ICG) was obtained using a simple vapor-diffusion process. To preserve their stability while retaining their pH-responsiveness, polypyrrolidone (PVP) and phytic acid (IP6) were introduced to protect the ACC from unexpected crystallization in aqueous environment. The surface of the resulting nanoparticles was further covered with closely packed small Au nanoparticles via hydroxylamine reduction of HAuCl4. The surface coating of Au nanoparticles not only facilitated specific PEGylation through thiol linkages but also the photothermal response in the near-infrared tissue optical window. Overall, a co-drug delivery platform with pH-responsive release capability was successfully established to improve the therapeutic efficacy in tumor cells.

摘要 I
Abstract II
致謝 III
目錄 IV
圖目錄 VIII
表目錄 X
第一章 緒論 1
1.1癌症與治療 1
1.1.1癌症簡介 1
1.1.2癌症治療 1
1.1.3化學藥物治療 2
1.1.4熱療 3
1.1.5熱療與化療的聯合治療 6
1.2奈米科學與生醫應用 7
1.2.1奈米藥物載體 7
1.2.2奈米藥物載體與癌症治療 9
1.2.3奈米藥物載體的刺激響應性 10
1.3碳酸鈣 11
1.3.1碳酸鈣的概述 11
1.3.2無定形碳酸鈣的概述 14
1.3.3無定形碳酸鈣的結晶轉變 16
1.3.4碳酸鈣在生物醫學領域中的研究現狀 19
1.4研究動機與目的 21
第二章 實驗材料與方法 24
2.1 實驗藥品與儀器 24
2.1.2 實驗藥品 24
2.1.2 緩衝溶液配置 26
2.1.3 細胞培養與操作 27
2.1.4 儀器 27
2.2 無定型碳酸鈣奈米粒子的合成與藥物載負 29
2.2.1 無定型碳酸鈣奈米粒子合成 29
2.2.2無定型碳酸鈣奈米粒子的藥物載負 29
2.2.3無定型碳酸鈣奈米粒子與無定型碳酸鈣奈米藥物載體的特性鑒定 30
2.2.4無定型碳酸鈣奈米藥物載體的藥物載負率測定 30
2.3奈米藥物載體的修飾與水相穩定性 31
2.3.1奈米藥物載體的修飾 31
2.3.2奈米藥物載體的鑒定 32
2.3.3不同pH值下的藥物釋放分析 32
2.3.4藥物載體的升溫效果分析 33
2.4奈米藥物載體與目標細胞的作用 33
2.4.1細胞存活率分析 33
2.4.2螢光顯微鏡分析細胞內藥物釋放 34
第三章 實驗結果與討論 36
3.1 無定型碳酸鈣奈米粒子的合成與藥物載負 36
3.1.1 無定型碳酸鈣奈米粒子合成與鑒定 36
3.1.2無定型碳酸鈣奈米藥物載體的合成與鑒定 37
3.2奈米藥物載體的修飾與水相穩定性 38
3.2.1奈米藥物載體的修飾與轉相 38
3.2.2金奈米粒子的修飾 40
3.2.3不同pH值下的藥物釋放分析 42
3.2.4藥物載體的升溫效果分析 43
3.3奈米藥物載體與目標細胞的作用 43
3.3.1細胞存活率分析 43
3.3.2螢光顯微鏡分析細胞內藥物釋放 44
第四章 結論 46
圖表說明 47
參考文獻 64

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