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系統識別號 U0026-2008201419500700
論文名稱(中文) 以NIH3T3細胞探討不同表面修飾奈米銀微粒的細胞攝入與毒性機轉
論文名稱(英文) Cytotoxicity and cellular uptake mechanisms of different surface-modified silver nanoparticles in NIH 3T3 Cells
校院名稱 成功大學
系所名稱(中) 環境醫學研究所
系所名稱(英) Institute of Environmental and Occupational Health
學年度 102
學期 2
出版年 103
研究生(中文) 方春詠
研究生(英文) Chun-Yong Fang
學號 S76011075
學位類別 碩士
語文別 中文
論文頁數 67頁
口試委員 指導教授-王應然
召集委員-柯俊良
口試委員-蕭大智
口試委員-鄭豐裕
中文關鍵字 奈米銀  物化特性  細胞攝入  自體吞噬  2-氨基乙硫醇 
英文關鍵字 Silver nanoparticles  Physico-chemical properties  Celluar uptake  Autophagy  Cysteamine 
學科別分類
中文摘要 奈米科技的迅速發展,不僅改善人類的生活品質,同時也對我們的生活環境及健康安全產生潛在危害。現今的奈米化產品中,奈米銀已廣泛地存在我們的日常生活用品,也因此增加人體暴露奈米銀微粒的機會。然而,目前對於奈米銀微粒的毒性與危害效應機轉的了解仍然不足,因此尚有許多部份需要加以釐清。過去的研究發現,不同粒徑大小與表面修飾會產生不同的生物效應。本研究以三種最常用於奈米修飾的穩定劑(包括:檸檬酸鈉、聚乙烯吡咯烷酮、2-氨基乙硫醇)以及不同尺寸大小(約20 nm 與 80 nm)之奈米銀探討細胞攝入與毒性機轉之影響。合成的奈米銀微粒將會先分析其物化特性,再以小鼠纖維母細胞(NIH 3T3 cells)進行實驗。透過流式細胞儀分析不同表面修飾與尺寸差異的奈米銀微粒其細胞攝入程度,隨著暴露奈米銀劑量的上升其SSC (side scatter)的強度有明顯增加,尤其是粒徑較大之奈米銀;在不會造成毒性的劑量下以三種不同抑制劑(耐絲菌素、氯普麻、渥曼青黴素)阻斷奈米銀進入細胞可能的途徑,發現相同粒徑範圍之奈米銀其主要都是透過網格蛋白調控機轉以及胞飲作用來攝入,此外同時合併處理抑制劑(氯普麻、渥曼青黴素)後能更有效降低細胞攝入奈米銀的數量。在毒性方面,粒徑較小之奈米銀組別毒性較強,而在不同修飾之奈米銀其毒性由高至低分別為檸檬酸鈉、聚乙烯吡咯烷酮、2-氨基乙硫醇。在螢光顯微鏡觀察下,可以證實具螢光標記的奈米銀確實有進入小鼠纖維母細胞的溶酶體中,而小粒徑奈米微粒相較於大粒徑的組別能誘導較高的ROS生成、內質網壓力以及自體吞噬效應。透過內質網壓力抑制劑能夠有效降低自體吞噬的情況,代表自體吞噬的效應可能是透過內質網壓力所誘導。利用西方墨點法測定內質網壓力和自體吞噬的相關蛋白表現,在處理奈米銀微粒後內質網壓力指標 IRE1、自體吞噬指標LC3-II、p62的表現隨著劑量增加有明顯上升的趨勢。綜合以上結果,我們能夠釐清奈米銀微粒如何被細胞攝入及其造成的毒性機轉;起初微粒在進入細胞的過程會造成胞器內部氧化壓力上升,進一步誘發內質網壓力促使細胞產生自體吞噬效應,而且同時觀察到LC3-II以及p62蛋白大量累積,推測可能因為奈米微粒的毒性效應導致自體吞噬功能失調。此外大、小粒徑之2-氨基乙硫醇奈米銀微粒造成毒性效應並非完全相同,且奈米銀粒子的毒性效應與攝入量多寡並無絕對關係。
英文摘要 Different types of AgNPs (silver nanoparticles) have been used widely to create unique nanoscale devices possessing novel physical and chemical functional properties. The impact of silver nanoparticles on biological systems, regarding their possible effects and fate in living cells are still limited. In this study, we investigated the toxic effects and cellular uptake mechanism of silver nanoparticles (AgNPs) on NIH 3T3 cells. The results indicated the uptake of AgNPs in NIH 3T3 cells were mainly through the clathrin-mediated endocytosis and macropinocytosis and the internalized AgNPs eventually accumulated in lysosomes. In addition, our results also suggested that the smaller size of AgNPs were more toxic than larger size. Different modifications of the AgNPs represent different toxicity with the order of sodium citrate > polyvinylpyrrolidone > cysteamine. Our results implied that one of the mechanisms of AgNPs-induced autophagy could be mediated by activation of oxidative stress and ER stress signaling pathways in NIH 3T3 cells. We also found that AgNPs treatment can trigger the expression of the ER stress and autophagy markers ( IRE1, LC3-II). However, the autophagy substrate p62 was accumulated in AgNP-treated cells, which indicates that the function of autophagy may be damaged. Taken together, our results indicate that AgNPs increased ROS generation and produced misfolded protein aggregates, which lead to ER stress and autophagy dysfunction in NIH 3T3 cells.
論文目次 目錄
第一章、序論 1
第二章、文獻回顧 2
第一節、奈米銀的應用及潛在毒性 2
第二節、奈米微粒物化特性與毒性效應 2
第三節、奈米銀表面修飾的效應 3
第四節、奈米銀in vitro及in vivo毒性比較 5
第五節、奈米微粒之細胞攝入 6
第六節、奈米微粒之細胞攝入機轉 6
第七節、奈米微粒攝入細胞後之宿命 7
第八節、奈米銀微粒重要生物毒性指標 8
第三章、研究目的 13
第四章、研究材料與方法 14
第一節、研究材料 14
第二節、研究方法與實驗步驟 19
一、奈米銀合成 19
二、物化特性分析 21
三、細胞培養(Cell culture) 22
四、細胞解凍 23
五、細胞冷凍 23
六、細胞存活率(Cell viability)23
七、奈米銀攝入量分析 23
八、奈米銀微粒攝入途徑分析 24
九、細胞內之奈米銀微粒分布 24
十、以穿透式電子顯微鏡觀察暴露奈米銀微粒後之細胞情況 24
十一、氧化壓力(Oxidative stress)分析 25
十二、內質網壓力(ER stress)分析 25
十三、溶酶體活性(Lysosomal activity)分析 25
十四、自體吞噬(Autophagy)分析 26
十五、奈米銀微粒造成毒性之途徑探討 26
十六、免疫螢光染色 26
十七、西方墨點法(Western blot)分析 26
第五章、研究架構 29
第六章、研究結果 30
第一節、奈米微粒物化特性分析結果 30
第二節、硝酸銀、檸檬酸鈉、聚乙烯吡咯烷酮、2-氨基乙硫醇對於
NIH 3T3細胞之毒性結果 32
第三節、以流式細胞儀(flow cytometry)分析比較大、小粒徑之奈米
銀微粒攝入量 33
第四節、以螢光標記奈米銀微粒並進行溶酶體染色探討奈米銀攝入後之宿
命 33
第五節、以穿透式電子顯微鏡觀察暴露奈米銀微粒後之細胞情況 33
第六節、以流式細胞儀(flow cytometry)探討各種表面修飾之大粒徑
奈米銀微粒攝入機轉 34
第七節、暴露LAS及SAS奈米銀微粒後進行ROS的偵測 35
第八節、暴露LAS及SAS奈米銀微粒後以ER-tracker進行內質網壓力的
偵測 35
第九節、暴露LAS及SAS奈米銀微粒後以Lysosensor進行溶酶體活性的
偵測 35
第十節、探討暴露LAS及SAS奈米銀微粒後誘發細胞自體吞噬效應 35
第十一節、透過內質網壓力抑制劑探討細胞誘發內質網壓力而造成自體吞噬
效應 36
第十二節、探討暴露LAS及SAS奈米銀微粒後誘發細胞內質網壓力與自體
吞噬之相關蛋白表現 36
第十三節、透過合併處理Bafilomycin A1探討暴露LAS及SAS奈米銀微
粒後自體吞噬之相關蛋白表現 37
第七章、討論 38
第八章、結論及建議 43
第九章、參考文獻 44
圖表 52
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