本研究中，我們開發一新穎蠶絲蛋白混摻中空金奈米粒子與艾黴素之可注射式複合水膠系統，討論其在近紅外光照射下之成膠行為、光熱效應及藥物緩釋效果，並以原位乳癌小鼠模型驗證其應用於原位光熱治療暨化學治療的可行性。目前，對於乳癌已有許多的療程，例如手術切除、化學療法或是放射線治療，但是仍然有許多問題需要克服，像是手術切除後美觀上的問題或是無法在不傷害到正常細胞的情況下殺死癌細胞。因此，我們成功開發出一個多功能可注射型的複合水膠系統，利用天然的絲素蛋白形成水膠載體，再將具有光熱現象的中空金奈米粒子與化療藥物艾黴素均勻混摻其中，希望結合光熱治療與化學藥物療法以達到抑制腫瘤的目的。首先，我們探討水膠在不同條件下的成膠行為，發現可以藉由提升水膠的溫度增進其成膠程度，並有效縮短成膠所需時間；接著研究複合水膠的光熱特性，確認可以利用近紅外光雷射誘導複合水膠產生高溫進而達到快速成膠的目的，同時藉由提升複合水膠的溫度，對於艾黴素的藥物釋放產生輔助效果。此外，也觀察到艾黴素的藥物釋放會受到環境的酸鹼值影響，在偏酸的環境下，藥物釋放量會顯著提升，此結果表示當此複合水膠系統應用在腫瘤治療上時，可利用腫瘤微環境偏酸性的特性，促進幫助藥物的釋放；然後我們利用生化分析與電子顯微影像評估複合水膠系統對於抑制乳癌細胞株生長的效果，可以看到複合水膠系統在輔以近紅外光雷射時，不僅可以藉由熱誘導癌細胞死亡外，還能成為一個連續的藥物釋放系統；最後，我們建構具有乳癌原位模型的小鼠，把複合水膠混合液直接注射在腫瘤位置，再以近紅外光雷射照射腫瘤區，可以觀察到水膠迅速於腫瘤處固化。而由於中空金奈米粒子與化療藥物已包埋在水膠中，我們觀察到奈米粒子與藥物的滯留時間接顯著延長，透過進行多次光熱治療及藥物的長期釋放，最終成功達到副作用較小的腫瘤抑制效果。因此，此多功能複合水膠系統的開發對於癌症的治療具有相當大的潛力。

The thesis describes a fabrication of an injectable light-induced hollow gold nanoparticles (HGNs) /doxorubicin (DOX) embedded silk fibroin (SF) hydrogel system, and systematic evaluations of therapy efficiency of combined photothermal-chemotherapy for breast cancer in situ. Many therapies, including surgery, chemotherapy and radiotherapy, are used to treat cancer, but most of them do not accomplish the desired purposes. For example, it is still a challenge to resolve the aesthetic problem of the patient after surgery or to efficiently kill cancer cells without hurting normal tissues. Herein, we successfully developed an injectable, multifunctional hydrogel system, by embedding HGNs and DOX into a biodegradable natural polymer, SF. We anticipated that combination of photothermal and chemotherapy can achieve the purpose of therapy of breast cancer. First, we explored the degree of sol-gel transition at different temperatures, and found that the light-induced heat would significantly accelerate the formation of SF hydrogel within a few minutes, by using a near-infrared (NIR) laser. Moreover, we also found that DOX could be released successively from the hydrogel because of the acidic environment, degradation of SF hydrogel, and heat-enhanced diffusion. Then, the photothermal and chemo cytotoxicity of multifunctional hydrogel system upon 4T1 breast cancer cells was evaluated. We observed that hydrogel system could inhibit the growth of tumor cells via the gradual release of DOX and the photothermal effect. Finally, the mixed SF solution was orthotopically injected into the mice bearing with 4T1 breast cancer and followed by laser irradiation. The light-induced heat from the HGNs would increase the local temperature and induced in situ formation of SF hydrogel through sol-gel transition. In this case, most of HGNs and DOX could be trapped well within the tumor region and thus the retention time of both agents would be significantly prolonged. Tumor-bearing mice could undergo multiple treatments and DOX would be successively released to directly, thoroughly kill the tumor cells with minor side effects for normal tissue. Thus, the development of multifunctional hydrogel systems is extremely valuable, especially for combination cancer therapy.

致謝 I
摘要 II
Abstract III
縮寫表 V
目錄 VII
圖目錄 IX
第一章 、緒論 1
1.1 研究動機 1
1.2 論文架構 2
第二章 、文獻回顧 3
2.1 癌症 3
2.1.1 乳癌 3
2.1.2 臨床上的乳癌治療方法 5
2.2 光熱治療 6
2.2.1 原理 6
2.2.2 不同的光熱粒子 9
2.2.3 金奈米粒子 12
2.2.4 靜脈注射 14
2.2.5 原位注射 16
2.3 化療藥物治療 17
2.3.1 艾黴素 17
2.3.2 腫瘤靶向奈米藥物遞送系統 19
2.3.3 水膠傳遞系統 20
2.4 絲素蛋白 22
2.4.1 絲素蛋白之簡介 22
2.4.2 絲素蛋白水膠的應用 24
第三章 、絲素蛋白水膠系統之開發及其應用於乳癌之光熱暨化學原位治療 26
3.1 研究目的 26
3.2 研究材料與方法 27
3.3 研究結果與討論 36
3.3.1 絲素蛋白水膠系統特性 36
3.3.2 中空金奈米粒子光熱性質 40
3.3.3 中空金光熱特性誘導複合水膠成膠行為之探討 42
3.3.4 複合水膠系統之降解與藥物釋放調控 44
3.3.5 細胞之光熱治療 47
3.3.6 動物實驗 52
第四章 、總結 62
參考文獻 63
著作清單 73

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