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研究生:吳國廷
研究生(外文):Kou-Ting Wu
論文名稱:鐵-金奈米合金之合成與生醫應用研究鐵-金奈米合金之合成與生醫應用研究
論文名稱(外文):Study of Iron-Gold Alloy nanoparticle for Biomedical Application
指導教授:鍾仁傑鍾仁傑引用關係
指導教授(外文):Ren-Jei Chung
口試委員:吳錫芩嚴大任侯邵毅
口試委員(外文):Hsi-Chin WuTa-Jen YenShao-Yi Hou
口試日期:2012-01-16
學位類別:碩士
校院名稱:國立臺北科技大學
系所名稱:工程科技研究所
學門:工程學門
學類:材料工程學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:76
中文關鍵詞:鐵-金合金奈米粒子磁性奈米材料熱治療藥物制放
外文關鍵詞:Iron-gold alloymagnetic materialdrug deliveryhyperthermia
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本研究旨在發展鐵-金合金奈米粒子(NFA),此材料具超順磁性可應用在生醫相關領域,例如藥物制放或作癌症熱治療。以熱裂解法合成出來的NFA在二次水中有很好的分散性,由成份分析得知其鐵與金的莫耳比約為2:1,平均粒徑約為3.932 nm,在20 KOe的磁場下飽合磁化量為 3.5 emu/g,且在室溫下為超順磁性。由細胞毒性測試可以得知500 μg/mL對老鼠纖維母細胞(L929)及人類肝癌細胞(Hep-G2)沒有明顯毒性。葉酸拮抗劑(MTX)為一抗癌藥物,並可用以標定癌症細胞,為了在NFA表面接枝MTX,先在NFA表面修飾2-氨基乙烷硫醇(SH),再利用SH上的胺基與MTX上的羧基形成醯胺鍵,成功完成在NFA上接枝MTX,並可以透過傅立葉轉換紅外線光譜儀檢測加以驗證。為了證明NFA-MTX能有效標定癌症細胞,透過ICP測量Hep-G2對NFA-MTX的食入量,發現NFA-MTX的食入量為0.789 pg/cell,約為L929對NFA-MTX的1.5倍,由此推論出在NFA-MTX對Hep-G2有標靶性。NFA在高週波(頻率:700~1100KHz)下產生熱能,經過計算每一顆NFA可以產生2.03×10-16焦耳的熱能。經施加高週波(頻率:700~1100KHz,反應時間20分鐘),Hep-G2在NFA濃度為200μg/mL的條件下,其細胞存活率大約下降了45%,代表此材料可以應用於作癌症治療;研究中發現高週波處理產生的熱能可打斷NFA與MTX間的鍵結,經不同的高週波操作時間,可發現MTX的釋放量隨時間變長而增加,代表可以透過高週波之控制達到藥物制放的目的。

The aim of this study is to develop Iron-Gold Alloyed nanoparticles (NFAs), which are superparamagnetic and of great potential to be applied in the biomedical fields, including hyperthermia treatment for cancer and drug controlling release. The NFAs were prepared through a pyrolysis method and well dispersed in distilled water. The ratio of iron to gold was 2 : 1 through analyzing. The mean diameter was 3.932 nm. The saturated magnetization was 3.5 emu/g under 20 KOe magnetic field. The material was superparamagnetic at room temperature. The result of in vitro tests showed that under a dose of 500μg/mL were not cytotoxic to L929 cell and Hep-G2 cell. Methotrexate (MTX) is an anti-cancer medicine and able to target the cancer cells. MTX was further conjugated on to NFA through a series of chemical modifications, including 2-aminoethanethiol grafting, and then the amine bonded with the carboxyl group on MTX to form an amide bond. Immobilization of MTX on the NFA was confirmed using FTIR. The uptake of Hep-G2 cells was 0.789 pg/cell for NFA-MTX, which was 1.5 times of the L929 cells. The results indicated the targeting efficiency of NFA-MTX to cancer cells. After calculation, per NFA would generate a 2.03×10-16 J heat under a high frequency magnetic field (700 to 1100)KHz. After treating with 200μg/mL NFA-MTX and then being applied a (700 to 1100) KHz high frequency magnetic field treatment for 20 minutes, the residual viability of Hep-G2 cells dramatically decreased 45%. Besides, we also discovered that the releasing of MTX from NFA-MTX was dependent with the applied time of high frequency magnetic field. The generated heat was able to break the amide bonds between NFA and MTX. The release of MTX could be successfully controlled. Using NFA-MTX, a hyperthermia treatment and drug controlling release will be achieved under high frequency alternating magnetic field.






摘要 i
Abstract iii
誌謝 v
目錄 vi
表目錄 xi
圖目錄 xii
第一章 前言……………. 1
1-1 研究動機 1
1-2 研究目的 2
第二章 文獻回顧與理論分析 3
2-1 研究背景 3
2-2 奈米粒子簡介 4
2-2-1 奈米的定義 4
2-2-2 奈米材料的分類 4
2-2-3 奈米的特性 6
2-2-4 奈米粒子之應用 7
2-3 磁性奈米顆粒理論與文獻探討 8
2-3-1 磁性奈米粒子簡介 8
2-3-2 磁性材料的分類 9
2-3-3 磁滯曲線 10
2-3-4 磁區 11
2-3-5 外加磁場或溫度對鐵磁性、順磁性材料的影響 12
2-3-6 超順磁性 13
2-4 磁性奈米粒子在生醫領域應用 14
2-4-1 藥物制放 15
2-4-2 高溫治療 15
2-4-3 顯像技術 16
2-5 金奈米粒子介紹及生醫應用 17
2-5-1 金奈米粒子介紹 17
2-5-2 雙光子影像造影 18
2-5-3 光熱療法 18
2-6 熱裂解理論 19
2-6-1 熱裂解法 19
2-6-2 控制奈米粒子大小 19
2-6-3 反應時間與反應物濃度 19
2-6-4 反應溫度 19
2-6-5 保護劑的種類 20
2-7 類葉酸結構抗癌藥物(Methorexate) 20
2-8 FePt奈米合金粒子應用於生醫領域 21
2-8-1 有生物功能性FePt奈米合金粒子 21
2-8-2 有生物功能性FePt奈米合金粒子應用於顯影技術 22
2-9 NFA文獻回顧 23
2-10 利用高週波控制藥物釋放文獻回顧 24
第三章 材料與方法 25
3-1 NFA材料 25
3-1-1 藥品 25
3-1-2 製備裝置 26
3-2 實驗步驟 27
3-2-1 熱裂解法製NFA 27
3-2-2 純化樣品 27
3-2-3 NFA材料分析流程圖 28
3-3 NFA表面修飾 29
3-3-1 藥品 29
3-3-2 NFA表面修飾2-氨基乙烷硫醇 29
3-3-3 NFA表面修飾2-氨基乙烷硫醇再接枝MTX 29
3-3-4 NFA表面修飾之實驗流程圖 30
3-4 設備簡介 31
3-4-1 X光繞射分析儀(X-ray diffraction,XRD) 31
3-4-2 X射線螢光光譜儀(X-ray Fluorescence Spectrometer,XRF) 32
3-4-3 分析電子能譜儀(Electron Spectroscopy for chemical Analysis System,ESCA) 33
3-4-4 穿透式電子顯微鏡(Transmission electron microscopy,TEM) 34
3-4-5 超導量子干涉磁量儀(Superconducting Quantum Interference Device,SQUID) 35
3-4-6 動態光粒徑分析儀(Dynamic Light Scattering,DLS) 36
3-4-7 傅立葉轉換紅外線光譜儀(Fourier transform infrared spectrometer,FTIR) ……………………………………………………………………………37
3-4-8 感應偶合電漿原子發射光譜儀(Inductively Coupled Plasma-Atomic Emission Spectroscopy,ICP-AES) 38
3-4-9 高週波電感應加熱器(High Frequency- Induc tion Heating machine,HF-IHM) 39
第四章 結果與討論 40
4-1 NFA結構特性研究 40
4-1-1 X光繞射分析(XRD) 40
4-1-2 X射線螢光光譜儀分析(XRF) 41
4-1-3 化學分析電子光譜儀分析(ESCA) 43
4-1-4 穿透式電子顯微鏡分析(TEM) 47
4-1-5 NFA在交流磁場加熱測試 51
4-1-6 NFA的在施加高週波下的熱療性質 52
4-2 NFA磁性研究 53
4-2-1 磁化率(M)對外加磁場(H)之曲線(M-H curve) 53
4-2-2 磁化量(M)對溫度(T)之曲線(M-T curve) 54
4-2-3 NFA飽合磁化量討論 55
4-3 紅外光光譜儀分析NFA表面修飾 56
4-3-1 NFA表面修飾2-氨基乙烷硫醇 56
4-3-2 NFA表面修飾2-氨基乙烷硫醇再接枝MTX 56
4-3-3 針對不同修飾作表面電位分析 58
4-4 生物相容性測試(in vitro tests) 59
4-4-1 NFA生物相容性測試(in vitro tests) 59
4-4-2 NFA-MTX生物相容性測試(in vitro tests) 61
4-4-3 NFA-MTX的細胞食入測試 63
4-5 利用高週波的交流磁場來打斷硫-金鍵 65
4-6 利用高週波的交流磁場作藥物制放 66
4-7 交流磁場下MTX的釋放量 67
4-8 交流磁場下NFA-MTX對Hep-G2的影響 68
第五章 結論…………. 71
參考資料 72


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