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研究生： 蔡朝淵
Tsai, Chiau-Yuang
論文名稱： 奈米金在奈米生物技術與奈米醫學上的應用
Applications of nanogold in nanobiotechnology and nanomedicine
指導教授： 吳昭良
Wu, Chao-Liang
學位類別： 博士
Doctor
系所名稱： 醫學院 - 基礎醫學研究所
Institute of Basic Medical Sciences
論文出版年： 2007
畢業學年度： 95
語文別： 中文
論文頁數： 71
中文關鍵詞： 奈米粒子 、抗血管新生 、血管內皮細胞生長因子 、Au:EGFP 奈米結合物 、奈米金 、膠原蛋白誘發類風濕性關節炎 、奈米生物技術 、奈米醫學
外文關鍵詞： nanobiotechnology, nanogold, nanoparticle, collagen-induced arthritis, nanomedicine, Au:EGFP nanoconjugates, antiangiogenesis, vascular endothelial growth factor
相關次數： 點閱：141  下載：7 
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    • 我們的研究著重於奈米金粒子在奈米生物技術與奈米醫學領域上的應用。近年來，修飾硫基的單股核苷酸已被廣泛的應用在官能性金奈米架構的組合上。然而，製作一個結合直線狀、官能性雙股DNA之奈米金複合體的研究則尚未被報導出來。因此，我們使用生物酵素的策略來合成帶有硫基的雙股DNA片段，大小約為1.7 kb，並製作出新穎的奈米金-DNA晶體。根據瓊脂膠電泳與原子力顯微鏡的分析結果，我們得到一個金奈米可連結一、二或三條EGFP DNA片段的Au:EGFP奈米結合物，不僅如此，這樣的金奈米晶體上的EGFP DNA片段亦可透過限制酶的作用與在哺乳類細胞中表現活性蛋白，進而證明DNA在與金奈米共價結合後仍能保有原本之生物活性。這樣生物性製備奈米金複合體的策略在未來可應用在分子影像、奈米醫學以及奈米偵測技術上。另外，血管新生在類風濕性關節炎的病理進程中是扮演著重要的角色而奈米金具有抑制血管內皮細胞生長因子活性的功能。因此，我們也將探討奈米金在大鼠類風濕性關節炎模式中是否具有改善其臨床症狀的功能。血管內皮細胞生長因子大量地存在於病人的血清、關節液與發炎的滑液膜中。所以，奈米金可與病人關節液中的血管內皮細胞生長因子結合，進而抑制類風濕性關節炎病人的關節液所誘發之人類臍靜脈內皮細胞的增生與移動能力。我們的結果是首次證明在大鼠的膠原蛋白誘發類風濕性關節炎模式中，關節施打奈米金具有改善此疾病臨床上進程的效果。奈米金可產生抗血管新生能力，接著抑制巨噬細胞的浸潤與發炎作用，進而達到抗關節炎的效果。這些結果證明了奈米金對於類風濕性關節炎可作為新穎治療物質的原理與證據。

    In our works, we focus on the applications of nanogold (gold nanoparticles, Au NPs) in nanobiotechnology and nanomedicine. Recently, thiolated oligonucleotides were used to assemble Au NPs into ordered functional nanostructures. However, approaches for fabricating Au:DNA conjugates by using a linear, functional, double-stranded (ds) DNA fragment that directly binds to Au NP surface have not been reported. Thus, we used a ligase-dependant strategy to synthesize a 1.7-kb, thiolated dsDNA fragment and generated novel nanocrystals by coupling it to 13-nm Au NPs. The conjugates contained Au:EGFP with EGFP:Au molar ratios of 1:1, 2:1, and 3:1, as determined by their electrophoretic mobility and AFM imaging. The Au:EGFP nanoconjugates could be digested by restriction endonuclease and expressed as functional proteins in mammalian cells, indicating the biological activities of Au NP-conjugated DNA fragments were still retained. This biological strategy for fabrication of Au:DNA conjugates may be applied to molecular imaging, nanomedicine and nanobiosensor technology. Angiogenesis plays a part in the pathogenesis of rheumatoid arthritis (RA) and nanogold inhibits the activity of an angiogenic factor, vascular endothelial growth factor (VEGF). We therefore investigated whether intraarticular delivery of nanogold ameliorated collagen-induced arthritis (CIA) in rats. The levels of VEGF are elevated in the serum, synovial fluid (SF), and inflamed synovium of RA patients. Nanogold bound to VEGF in RA SF, resulting in inhibiting RA SF-induced endothelial cell proliferation and migration. Our results are the first to demonstrate that intraarticular administration of nanogold ameliorates the clinical course of CIA in rats. Nanogold exerted antiangiogenic activities and subsequently reduced macrophage infiltration and inflammation, which resulted in attenuation of arthritis. These results demonstrate proof of principle for the use of nanogold as a novel therapeutic agent for the treatment of RA.

    考試合格證明............................................I 中文摘要................................................II 英文摘要................................................III 誌謝....................................................V 總目錄..................................................VI 圖目錄..................................................X 縮寫索引................................................XII 緒論....................................................1 一、奈米科技（nanotechnology）與其衍生之研究領域......................................................1 奈米科技是什麼？........................................1 從生物界看奈米..........................................2 奈米生物技術（nanobiotechnology）.......................3 奈米醫學（nanomedicine）................................3 二、奈米金的製備、特性與應用............................4 奈米金（nanogold）的歷史................................4 奈米金的製備............................................5 奈米金的基本特性........................................6 奈米金的應用：..........................................7 （一）奈米金與DNA的結合.................................7 （二）奈米金與蛋白質的結合..............................8 三、類風濕性關節炎（rheumatoid arthritis，簡稱RA）......9 RA的特徵................................................9 RA是如何造成關節的破壞？................................9 RA的致病機轉............................................10 四、研究動機與實驗設計..................................11 材料與方法..............................................14 一、材料................................................14 （一）質體..............................................14 （二）酵素..............................................14 （三）DNA回收套組（kit..................................14 （四）寡聚核苷酸........................................14 （五）細胞株............................................15 （六）動物..............................................15 二、方法................................................16 （一）硫化雙股DNA片段（S-EGFP）的合成...................16 （二）13-nm奈米金的製備.................................16 （三）金奈米結合S-EGFP片段（Au:EGFP conjugates）的製備..17 （四）原子力顯微鏡（atomic force microscopy，簡稱AFM）影像分析....................................................17 （五）利用限制內切酶處理結合奈米金的EGFP DNA片段........18 （六）細胞培養和傳送基因................................18 （七）人類關節液檢體....................................18 （八）polyethylene glycol（PEG）-奈米金的製備...........19 （九）奈米金結合VEGF165和VEGF121的測定..................19 （十）細胞增生分析......................................20 （十一）細胞爬行遷移分析................................20 （十二）誘導CIA的老鼠模式和奈米金的傳送.................21 （十三）臨床上和X光照相技術的評估.......................21 （十四）組織切片和免疫組織染色..........................22 （十五）酵素連結免疫吸附分析法（ELISA）.................22 （十六）統計分析........................................22 結果....................................................23 一、13-nm奈米金結合直線狀官能性雙股DNA的研究............23 （一）製備硫基化的(S)-EGFP DNA片段與Au:EGFP結合物的策略.23 （二）Au:EGFP接合物形成的證據...........................24 （三）Au:EGFP在原子力顯微鏡下所呈現的型態...............25 （四）連結奈米金的S-EGFP片段的生物活性..................26 二、13-nm奈米金結合血管新生因子，包括VEGF121和VEGF165，與 其在大鼠CIA模式中是否具有預防或治療疾病的研究...........27 （一）奈米金與PEG-奈米金的特徵..........................27 （二）人類RA SF中的VEGF含量測定.........................28 （三）13-nm奈米金對於VEGF的結合能力與抑制VEGF活性的能力.28 （四）13-nm奈米金可與RA SF中的VEGF相結合與抑制RA SF所誘發 的內皮細胞增生與移動能力................................29 （五）在大鼠CIA模式中，奈米金具有減少其臨床上的、X光照相上的（radiographic）與組織學上的（histologic）特徵........30 （六）奈米金在CIA大鼠的滑液膜中具降低血管新生的功能.....32 （七）奈米金在CIA大鼠的滑液膜中具降低巨噬細胞浸潤與誘發發炎反應細胞激素的功能......................................32 （八）奈米金對於CIA大鼠的治療效果.......................33 討論....................................................34 利於連接反應的設計......................................34 AFM影像所造成的奈米粒子粒徑誤差.........................34 在奈米金上的DNA生物活性.................................34 13-nm奈米金可同時結合VEGF121和VEGF165...................35 奈米金可能無法完全抑制RA SF所誘發的內皮細胞增生與爬行的能力......................................................36 奈米金在大鼠CIA模式中的療效.............................36 奈米金可抑制血管新生與發炎反應之間的自我放大效應 （autoamplification loop）..............................37 奈米金與傳統金鹽的比較：體內分布與可能的副作用..........38 奈米金結合其他治療方式的組合性治療（combination therapy）策略可能性................................................39 結論....................................................40 參考文獻................................................41 作者簡歷................................................70

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