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研究生:蘇穎真
研究生(外文):Ying-Zhen Su
論文名稱:以胜肽分子修飾超順磁性氧化鐵作為腦腫瘤之奈米診斷與治療試劑
論文名稱(外文):Peptide decorated Iron oxide as a nanotheranostic agent targeting to brain tumors
指導教授:王麗芳王麗芳引用關係
指導教授(外文):Li-Feng Wang
學位類別:碩士
校院名稱:高雄醫學大學
系所名稱:醫藥暨應用化學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:中文
論文頁數:92
中文關鍵詞:氧化鐵腦癌
外文關鍵詞:iron oxidebrain tumor
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本研究利用高分子聚合物與水溶性氧化鐵反應,再接枝上胜肽分子,得到一多功能之磁性奈米粒子。經過高分子聚合物之修飾可以增加此磁性奈米粒子在血液中的循環及抵抗細胞的多重抗藥性;接上胜肽分子使此磁性奈米粒子可穿透血腦障壁(blood-brain barrier, BBB),進而標靶到人類腦部腫瘤組織。以FT-IR觀測此磁性奈米粒子之酯鍵吸收。使用DLS及TEM觀察修飾後之磁性奈米粒子之粒徑大小及型態。對此磁性奈米粒子作毒性測試,得到優良之細胞存活率。以流式細胞儀、CLSM觀察在U87細胞中的表現。利用動物實驗觀察磁性奈米粒子在裸鼠大腦的顯影情形,由實驗結果得知,此磁性奈米粒子具標靶性可作為標靶、診斷及治療之磁性顯影試劑,可做為生醫上的應用。

In this study, we used polymer modified water-dispersible superparamagnetic iron oxide nanoparticles to prevent the recognition from the reticuloendothelial system (RES). We further conjugated a blood-brain-barrier penetrating peptide, to the surface of Polymer-PAAIO. Particle diameters and distributions were measured using dynamic light scattering (DLS) and transmission electron microscope (TEM). From FT-IR measurements, we confirmed the successful synthesis of Polymer-PAAIO and Peptide-Polymer-PAAIO by observing the characteristic peak of ester bonds. The cellular viability in U87 cells treated with Peptide-Polymer-PAAIO was > 90%, indicating it was a non toxicmaterial. The cellular internalization of Polymer-PAAIO and Peptide-Polymer-PAAIO in U87 cells were acquired using a flow cytometer and visualized using a confocal laser scanning microscope (CLSM). Taken together of results, we concluded that the Peptide-Polymer-PAAIO with the BBB penetrating peptide would target tumors of the brain. Because the Peptide-Polymer-PAAIO contained the superparamagnetic Fe3O4, the micellar polymer, and the BBB targeting peptide, it is potential to be used as a diagnostic imaging agent as well as a chemotherapeutic agent specifically for brain diseases.

目錄
第一章 前言 1
1-1前言 1
1-2研究動機與目的 2
第二章 文獻回顧 3
2-1腦癌 3
2-1.1腦癌簡介[2] 3
2-1.2血腦障壁(Blood brain barrier,BBB)[3-6] 3
2-2奈米診斷治療試劑(Nanotheranostics) 8
2-2.1 奈米診斷治療試劑[7-11] 8
2-3超順磁奈米氧化鐵 10
2-3.1超順磁氧化鐵之磁學特性[12-20] 10
2-3.2 超順磁氧化鐵之製備與表面修飾 12
2-3.3超順磁氧化鐵之應用 15
2-4 表面修飾材料 19
2-4.1 表面修飾材料之結構特性 19
2-4.2癌細胞之多重抗藥性(Multidrug resistance, MDR)[27-30] 20
2-4.3 Peptide[31-37] 23
第三章 材料與實驗方法 25
3-1 實驗試劑 25
3-2 實驗儀器 28
3-3 材料製備與方法分析 31
3-3.1 琥珀酸酐接枝高分子聚合物[27] 31
3-3.2 合成IR820-6-Aminohexanoic acid (IR820-COOH)及IR820-1,6-Diaminohexane (IR820-NH2) 32
3-3.3 水溶性四氧化三鐵之製備 33
3-3.4 X-光粉末繞射儀 34
3-4 磁性奈米粒子 35
3-4.1磁性奈米粒子製備 35
3-4.2具標靶性之磁性奈米粒子製備 36
3-4.3具螢光基團磁性奈米粒子製備 38
3-4.4具螢光基團磁性奈米粒子製備 38
3-4.5 傅立葉轉換紅外線光譜儀 (FT-IR) 39
3-4.6基質輔助雷射離子質譜儀 (MALDI-MS) 39
3-4.7 雷射奈米粒徑暨界面電位測量儀 (DLS) 39
3-4.8 元素分析儀(EA) 40
3-4.9 穿透式電子顯微鏡 (TEM) 40
3-4.10 感應耦合電漿放光光譜儀 (ICP-OES) 40
3-4.11 超導量子干涉儀 (SQUID) 41
3-4.12 磁振造影偵測 (MRI) 41
3-5 體外實驗 (In vitro) 42
3-5.1細胞培養 (Cell culture) 42
3-5.2 磁性奈米粒子之毒性測試 42
3-5.3細胞吞噬測試 43
3-5.4細胞吞噬途徑測試 44
3-5.5 細胞內鐵含量之定性 45
3-5.6 細胞内鐵含量之定量 46
3-5.7 共軛聚焦顯微鏡觀察磁性奈米粒子在細胞內之傳遞 47
3-5.8 體外磁振造影偵測 (MRI) 48
3-5.8體外血腦障壁模型實驗 49
3-6 動物實驗 (In vivo) 50
3-6.1腦腫瘤誘發[38] 50
3-6.2 腦內顯影 50
第四章 結果與討論 51
4-1 材料分析與鑑定 51
4-1.1 Succinic anhydrade-Polymer之1H NMR鑑定 51
4-1.2 氧化鐵晶形測試 53
4-1.3 IR820-COOH/IR820-NH2分子量鑑定測試 54
4-2.1 IR820-COOH/IR820-NH2紅外線分析 56
4-2 磁性奈米粒子特性分析 57
4-2.1 紅外線分析 57
4-2.2 粒徑大小與表面電位分析 59
4-2.3 磁性奈米粒子型態觀察 60
4-2.4 磁性奈米粒子鐵含量分析 62
4-2.5 磁性奈米粒子元素分析 62
4-2.6 超導量子干涉儀測試超順磁性 64
4-2.7 磁振造影偵測 66
4-3 體外實驗(In vitro) 68
4-3.1 磁性奈米粒子毒性測試 68
4-3.2 細胞吞噬測試 69
4-3.3 細胞內氧化鐵之定性與定量 71
4-3.4 細胞吞噬途徑測試 74
4-3.5 共軛聚焦顯微鏡觀察磁性奈米粒子在細胞內之傳遞 77
4-3.6 體外磁振造影偵測 79
4-3.7 體外血腦障壁模型實驗 80
4-4 動物實驗(In vivo) 82
4-4.1 裸鼠腦內顯影觀察 82
第五章 結論 84
第六章 參考文獻 88



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