一氧化氮是氣體自由基，同時是參與諸多生理反應的氣體傳訊分子。一氧 化氮供體已經發展超過 150 年，然而半衰期短(-s ~ -hrs)、一氧化氮攜載量不足、 缺乏良好一氧化氮輸送系統，將限制一氧化氮供體在臨床上的進展，因此非常需 要有一氧化氮高攜載量、長期釋放一氧化氮的平台。
本研究中，我們以 RRE-MPTMS 為一氧化氮供體修飾在金屬奈米粒子的 表面，以 UV-VIS 光譜、TEM 和 EDS mapping 影像，觀察調整不同合成條件之 結果，證明合成出攜載一氧化氮供體的金屬奈米粒子(NO-HGN)。透過摻混奈米 粒子與絲素蛋白水溶液形成可注射的複合水膠 (SFS/NO-HGN)，接著驗證 NO- HGN 的光熱能力能賦予複合水膠具有一樣的的熱能力，誘導複合水膠即時成膠。 最後測試複合水膠在 PBS 中的之一氧化氮緩釋能力，能持續釋放到 ~50 天。以 小鼠乳癌細胞株 4T1 進行細胞毒性測試，可以看到合併一氧化氮結合光熱的組 別對細胞毒殺效果最顯著。建立 balb/c 小鼠原位乳癌模型，將奈米複合水膠原 位注射於小鼠腫瘤，接著以近紅外光照射，藉由奈米複合水膠的光熱轉換能力提 高腫瘤區的溫度，使奈米複合水膠即時成膠。固定於腫瘤區的複合水膠能執行多 次光熱治療，抑制腫瘤生長;輔以一氧化氮在腫瘤區長期釋放，增加細胞凋亡之 傾向。

Nitric oxide, a free radical with short half-life, is a gasotransmitter known for its diverse physiological functions throughout living organisms. Several NO donors have been developed for over 150 years. Unfortunately, limited NO payloads, too rapid NO release (-s ~ -hrs), and the lack of targeted NO delivery have hindered the clinical utility of NO donor compounds. High-payload, long-term NO-releasing platforms to improve its pharmacological potential are in need.
Herein, we attempt to develop a novel injectable hydrogel system for breast cancer combination therapy by hybridizing NO-functionalized hollow gold nanoparticles (NO- HGN) into SF solution. First, we synthesized HGNs (photothermal reagent) and modified them with a novel NO donor, dinitrosyl iron complex (DNIC) through the silane condensation reaction. Silane-premodified DNIC undergoes silanization and forms DNIC/SiOx molecular layers on the surface of HGN. UV-VIS spectra, TEM image, and EDS mapping of NO-HGN demonstrated the NO-donors were successfully loaded on to the nanoparticles. We also validated the light-induced gelation performance and NO sustained release profiles of composite silk fibroin hydrogel (SFG/ NO-HGN). At 50 ̊C, the gel formed in-situ within 5 min due to the light-heating induced sol-gel transition; yet at 37 ̊C (mimic physiological environment) still kept the original solution state within 30 min. Our SFG/NO-HGN system exhibits strong NIR- absorbance and thus displays excellent photothermal ability, originated from the extinctive surface plasmon resonance of the nanoparticles. With the outstanding durability and thermal stability, the composite hydrogel maintained similar temperature changes (> 25 ̊C) throughout 10-cycle irradiation. Following, we found that the NO- releasing profile of the composite hydrogel was temperature-dependent. More importantly, the sustained release duration of NO was drastically reached over 50 days,
2
especially compared to a very short lifetime for free Iron-Sulfur Cluster Nitrosyls (~1h). Moreover, the cytotoxicity of the composite hydrogel upon 4T1 breast cancer cells was evaluated. Finally, an orthotopic female BABL/c mice model was used to evaluate the in vivo efficacy. The SFS/NO-HGN solution was intratumorally injected into the mice bearing with 4T1 breast cancer and followed by laser irradiation. The light-induced heat from the SFS/NO-HGN would increase the local temperature and induced in situ formation of SFG/NO-HGN. Our preliminary data shows that we could conduct multiple treatments with the composite hydrogel.

目錄
摘要 ............................................................................................................................... 1
Abstract ......................................................................................................................... 2
縮寫表 ........................................................................................................................... 4
圖目錄 ........................................................................................................................... 8
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 一氧化氮 (Nitric Oxide, NO) .......................................................................... 14
2.1.1 一氧化氮與調控機制 ................................................................................ 14
2.1.2 一氧化氮與癌症 ........................................................................................ 16
2.2 一氧化氮供體 (Nitric Oxide Donor, NO Donor) .......................................... 19
2.2.1 有機硝酸鹽Organic Nitrates (R-ONO2) ............................................... 19
2.2.2 N-diazeniumdiolate (NONOate) ............................................................ 21
2.2.3 亞硝基硫醇Nitrosothiols (RSNOs) ......................................................... 21
2.2.4 雙亞硝基鐵錯合物Dinitrosyl Iron Thiol Complexs (DNICs) .............. 22
2.3 不同的一氧化氮載體/輸送系統與其釋放機制 .............................................. 24
2.3.1 微脂體 ......................................................................................................... 25
2.3.2 二氧化矽奈米粒子 (Silica Nanoparticle) ................................................ 26
2.3.3 金屬奈米粒子 (Metal Nanoparticle) ....................................................... 28
2.4 一氧化氮載體/高分子複合物 (polymer Hybrid) ......................................... 31
2.5 絲素蛋白水膠之簡介 ........................................................................................ 33
第三章、以奈米複合水膠系統作為一氧化氮緩釋載體並結合光熱療法應用於乳
癌新穎治療策略 ......................................................................................................... 36
3.1 研究目的 ........................................................................................................... 36
3.2 研究材料與方法 ................................................................................................ 37
3.3 研究結果與討論 ............................................................................................... 45
7
3.3.1 NO-HGN 奈米粒子 .................................................................................... 45
3.3.2 NO-HGN 奈米粒子的光熱性質 ............................................................. 49
3.3.3 NO-HGN 誘導複合水膠成膠及複合水膠之特性分析 ......................... 51
3.3.4 複合水膠之一氧化氮緩慢釋放能力 ...................................................... 53
3.3.5 細胞之光熱治療 ...................................................................................... 57
3.3.6 動物實驗 .................................................................................................. 58
第四章、總結 ............................................................................................................. 64
參考文獻 ..................................................................................................................... 65

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