由於腫瘤快速生長，伴隨著血管分布不全而導致缺氧的情況，而氧氣的缺乏不僅影響放射線及化療的療效，同時亦使癌細胞的行為改變。許多研究團隊致力於改善腫瘤區缺氧環境，以改善缺氧帶來的副作用。然而，目前大多數研究都是輸送二氧化錳材料來與腫瘤環境中的雙氧水反應產生氧氣，而採用貴重金屬奈米粒子的應用相對稀少。另外，早在上個世紀，就有一派學者提出透過阻斷癌細胞獲取養分來抑制腫瘤生長，並有許多相關的研究證實其效果1,2。因此，在本研究中我們將開發一種兼具催化及光熱特性的複合水膠系統，使其不僅可實現飢餓及光熱合併療法，並同時可以改善腫瘤缺氧環境，進而提升抑制腫瘤成長的效果。
首先，我們將鉑金屬還原於中空金奈米粒子（Hollow gold nanoparticle, HGN）上，以UV-Vis光譜、TEM及EDS mapping影像，觀察不同合成條件的結果，證明合成出含有鉑成分的金屬奈米粒子（HGN@Pt）。進一步透過摻混奈米粒子、葡萄糖氧化酶（Glucose oxidase, GOx）與絲素蛋白水溶液（Silk Fibroin solution, SFs），形成可注射的複合水膠（SFs/HGN@Pt+GOx），並測試複合水膠中HGN@Pt的產氧能力及GOx對於催化葡萄糖的分解能力測試；再來，驗證HGN@Pt的光熱能力能誘導複合水膠能即時成膠。在細胞實驗部分，以小鼠乳癌細胞株4T1進行複合水膠的細胞毒性測試，及以多種試劑驗證其對於雙氧水分解、氧氣程度變化、葡萄糖消耗等效果的影響。最終，我們建立Balb/c小鼠原位乳癌模型，將複合水膠原位注射於小鼠腫瘤後，立即以近紅外光照射，藉由複合水膠的光熱轉換能力提高腫瘤區的溫度，達到即時成膠的效果。腫瘤區的複合水膠能固定住內部的奈米粒子，達到多次的光熱治療，抑制腫瘤生長；而包覆在內的葡萄糖氧化酶，能夠快速消耗腫瘤區的葡萄糖，達到飢餓療法的效果。更重要的是，在消耗葡萄糖的過程中，雖然伴隨著氧氣的損耗及雙氧水的產生，而我們設計的奈米粒子則可有效將產生的雙氧水分解成氧氣，進而使得飢餓療法能不斷進行，提升其抑制腫瘤效果。

Hypoxia, the lack of oxygen, is a phenomenon usually happened as the tumor growth rapidly. Hypoxia would not only decrease the efficacy of radiotherapy and chemotherapy, but also change the behavior of cancer cells. Many research teams put efforts to ameliorate the level of hypoxia, in order to reduce the side effects caused by it. However, most of them use MnO2 nanoparticles to generate oxygen via decomposition of H2O2 in the tumor microenvironment, only few of them use noble metal nanoparticles as catalase. Additionally, some scientist hypothesis that we can starve cancer cell to die by blocking the way which cancer cell obtain nutrition like glucose, called “starving therapy”. So far, many researches approve that this is a potential way for cancer treatment.
Herein, we aim to develop a novel cancer treatment by combining photothermal and starving therapy for breast cancer treatment. First, we synthesized HGNs and sequentially reduced various amounts of platinum on them to form HGN@Pt. UV-Vis spectra, TEM images, and EDS mapping results of the nanostructures confirmed that the platinum was successfully deposited on to HGNs. Then, we mixed HGN@Pt, glucose oxidase (GOx), silk fibroin solution together to form an injectable hydrogel solution, (SFs/HGN@Pt+GOx), and evaluated the O2 generation ability of HGN@Pt and glucose oxidation ability of GOx in the multifunctional silk fibroin hydrogels. We also validated the light-induced gelation performance of composite hydrogel. At 50 oC, the hydrogel underwent sol-gel transition within 5 min because of the NIR laser-heating; yet at 37 oC it still kept the original solution state within 30 min. Moreover, the cytotoxicity of the composite hydrogel upon 4T1 breast cancer cells was evaluated. We also measured the amelioration ability of hypoxia by immunofluorescence staining. Finally, an orthotopic female Balb/c mice model was used to confirm the in vivo efficacy. The SFs/HGN@Pt+GOx solution was orthotopically injected into the mice bearing with 4T1 breast cancer tumor and followed by laser irradiation. The light-induced heat from HGN@Pt would trigger in situ gel formation. The preliminary data showed that the designedr composite hydrogel would be a potential way for breast cancer treatment.

摘要………………………………………………………………………………….........................1
Abstract…………………………………………………………………………….......................2
縮寫表…………………………………………………………………………….........................4
圖目錄…………………………………………………………………………….........................7
第一章、 緒論..………………………………………………………...............……….…....12
1.1 研究動機…………………….……………………...……….....................……….12
1.2 論文架構…………………….…………………………………........................……13
第二章、 文獻回顧………….……………………………………………………...................14
2.1 缺氧………….………………………………………………………..........................14
2.1.1 腫瘤缺氧與影響………….………………………………...................…….14
2.1.2 臨床上恢復氧氣含量方法………………………….………..................16
2.1.3 實驗研究上恢復氧氣含量方法………………………..............………..17
2.2 飢餓療法……………………………………………………………..........................20
2.2.1 原理…………………………………………………………….........................20
2.2.2 日常生活中的飢餓療法………………………………………...................21
2.2.3 葡萄糖氧化酶……………………………………………....................……..24
2.3 金屬奈米粒子………………………………………………….......................…….30
2.3.1 金屬催化劑…………………………………….….....................…………….30
2.3.2 奈米粒子…………………………………….…………......................……….30
2.3.3 鉑…………………………………….………………………….........................30
2.3.4 鉑奈米粒子…………………………………….………………......................31
2.4 光熱療法……………………………………………………………..........................32
2.5 絲素蛋白水膠簡介…………………………………………………........................35
第三章、 開發結合催化及光熱能力之複合水膠系統以應用於乳癌合併治療策略………37
3.1 研究目的…………………………………………………………............................37
3.2 研究材料與方法……………………………………………………........................38
3.3 研究結果與討論……………………………………………………........................47
3.3.1 HGN@Pt奈米粒子.....................................….47
3.3.2 HGN@Pt奈米粒子的光熱能力測試..........................52
3.3.3 HGN@Pt奈米粒子的產氧能力測試..........................55
3.3.4 葡萄糖氧化酶的催化能力測試……………………………….................62
3.3.5 細胞實驗……………………………………...……………….......................66
3.3.6 動物實驗…………………………………………...………….......................76
第四章、 總結……………………………………………………………………........................…81
第五章、 未來展望……………………………………………………………......................……82
參考文獻……………………………………………………………………………..........................83

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