臺灣博碩士論文加值系統

本研究成功設計具專一性標靶化之影像對比劑，以超順磁氧化鐵奈米粒子為核心，並利用聚乙二醇 (mPEG) 與silane作為表面修飾之材料，藉由表面修飾mPEG以提高對比劑之水溶性及生物相容性。在設計的環節中，利用silane與mPEG間之-NH2官能基作為生物探針與螢光發光團鍵結處，使超順磁氧化鐵奈米粒子兼具磁振造影與光學影像雙重功能之特性。此外，位於奈米粒子最外層mPEG亦能提供遮蔽正電荷 (-NH2 + H+  -NH3+) 之效果，進而減少對比劑與腫瘤細胞表面之負電荷產生靜電吸引力。
本研究成功合成對比劑 (MnMEIO-silane-NH2-mPEG) ，具備良好水溶性與超順磁之特性。此對比劑具有非常高的弛緩率 (r1及r2) ，分別為42.1 ± 1.7及293.5 ± 6.2 mM-1s-1，能有效地提高磁振造影之對比度。此外，不論在不同的pH值環境或室溫放置數週，其對比劑之水合粒徑呈現穩定而無聚集之現象，弛緩率 (r1及r2) 也無明顯變化，表示本研究合成之對比劑具備優越之穩定性。
體內及體外實驗結果證實，將Erbitux單株抗體鍵結在對比劑上 (MnMEIO-silane-NH2-(Erb)-mPEG) 可專一性標靶EGFR表現型腫瘤細胞。此外，本研究嘗試將MUC4單株抗體鍵結在對比劑 (MnMEIO-silane-NH2-(MUC4)-mPEG) 上，實驗結果亦證實此對比劑具備高專一性標靶mucin4表現型腫瘤細胞。因此，證實本研究所合成之對比劑 (MnMEIO-silane-NH2-mPEG) 實屬一良好平台，可鍵結不同生物探針進行不同腫瘤細胞之診斷與追蹤。本研究更進一步利用雙抗抗體 (Bispecific antibody) 作為生物探針，強化對比劑標靶之效果。實驗結果證實，對比劑MnMEIO-silane-NH2-(Bis)-mPEG可有效標靶Her2/neu及EGFR表現型腫瘤細胞，具有取代現行臨床使用之標靶抗體Herceptin之潛力。同時，目前相關研究中，尚未將雙抗抗體應用於診斷腫瘤細胞技術上，故本研究在這方面可說是一大突破。
由各項分析結果顯示，本研究成功設計具專一性標靶化之影像對比劑，除了具備高生物相容性與穩定性外，同時也兼具磁振造影與光學影像雙重功能之特性。

A new multifunctional nanoparticles (MnMEIO-silane-NH2-mPEG NPs), consisting of a manganese-doped iron oxide nanoparticle core (MnMEIO), a copolymer shell of silane and amine-functionalized poly(ethylene glycol), were successfully developed in this study for improving the solubility and biocompatibility of the contrast agent. There are two key features in MnMEIO-silane-NH2-mPEG, one is -NH2 functional group between silane and mPEG which can be used as a binding site for bio-probes and NIRF dyes result in the MR-optical dual modalities of nanoparticles. The other is the flexible PEG, which masks the non-conjugated reactive amine groups (-NH2 + H+  -NH3+) and reduces nonspecific binding of MnMEIO-silane-NH2-mPEG to cells.
The nanoparticles (MnMEIO-silane-NH2-mPEG) are provided with the properties of water solubility and superparamagnetism in this study. The relaxivities (r1 and r2) of the MnMEIO-silane-NH2-mPEG NPs measured at 20 MHz and 37.0 ± 0.1 °C were 42.1 ± 1.7 and 293.5 ± 6.2 mM-1s-1, respectively. This indicates that the nanoparticles can efficiently improve the imaging contrast. Furthermore, the DLS data indicate no significant variation in hydrodynamic size of MnMEIO-silane-NH2-mPEG NPs across a wide pH range (pH 4-10), reassuring high colloidal stability of MnMEIO-silane-NH2-mPEG NPs under physiological conditions. Finally, no significant variation in hydrodynamic size and relaxivity of MnMEIO-silane-NH2-mPEG NPs were observed over a long time period.
The in vitro and in vivo results experimentally demonstrated that the anti-EGFR antibody conjugated nanoparticles (MnMEIO-silane-NH2-(Erb)-mPEG NPs) could significantly reduce nonspecific binding and increase the imaging specificity to EGFR-overexpressing tumors. Besides, the anti-mucin4 antibody (MUC4) were used to forming the nanoparticles (MnMEIO-silane-NH2-(MUC4)-mPEG NPs) for diagnosis of mucin4-expressing pancreatic tumors. Besed on the results, MnMEIO-silane-NH2-mPEG NPs is a well-established platform to combine different targeting moieties for diagnostic and therapeutic use of various tumors. Furthermore, a multifunctional nanoparticles (MnMEIO-silane-NH2-(Bis)-mPEG NPs) which covalently conjugated anti-Her2/neu and anti-EGFR receptors bispecific antibody (Bis) were also developed for recognizing the tumors expressing both Her2/neu and/or EGFR. For Her2/neu-overexpressing tumors, MnMEIO-silane-NH2-(Bis)-mPEG can be a potential targeting agent for Herceptin replacement. For the current tumor diagnosis associated studies, this study which applied bispecific antibosies as a targeting moiety is the first approach in tumoral diagnosis area. These experimental results demonstrated that nanoparticles conjugated with various monoclonal antibody could specifically and effectively target to tumors.
As a results, a MR-optical dual modality contrast agent system with high biocompatibility and stability is performed for the design and development of the next-generation nanoscale diagnostic and therapeutic modalities.

致謝 I
中文摘要 III
Abstract V
目錄 VII
圖目錄 XII
表目錄 XV
Scheme XVI
一、前言 1
1. 磁振造影對比劑的演進 1
2. 磁振造影對比劑之種類與原理 1
3. 氧化鐵奈米粒子之合成方法 3
4. 氧化鐵奈米粒子表面之修飾 5
5. 超順磁氧化鐵奈米粒子多功能性之發展 6
(1) 生物探針 (Biological probe) 之應用 6
(2) 光學影像探針 (Optical imaging probe) 之應用 9
6. 氧化鐵奈米粒子非專一性鍵結之探討 11
二、研究動機與目的 14
三、實驗儀器與試藥 15
1. 儀器 (Instrumentation) 15
(1) 穿透式電子顯微鏡 (Transmission Electron Microscope, TEM) 15
(2) X光能譜散佈分析儀 (Energy Dispersive Spectrometer, EDS) 15
(3) 超導量子干涉磁量儀 (Superconducting Quantum Interference Device Magnetometor, SQUID) 15
(4) 磁振造影光譜儀 (Nuclear Magnetic Resonance Spectrometer, NMR) 15
(5) 傅立葉轉換紅外光譜儀 (Fourier Transform Infrared Spectrometry, FT-IR) 15
(6) 高效能液相層析系統 (High-Performance Liquid Chromatography, HPLC) 16
(7) 動態光散射儀 (Dynamic Light Scattering, DLS) 16
(8) 張弛測量器 (Relaxometer) 16
(9) 超微量全波長分光光譜儀 (NanoDrop spectrophotometer) 16
(10) 流式細胞儀 (Flow cytometer) 16
(11) 共軛焦螢光顯微鏡 (Confocal fluorescence microscope) 17
(12) 磁振造影儀 (Magnetic Resonance Imaging, MRI) 17
(13) 非侵入式活體光學影像系統 (Caliper IVIS spectrum system) 17
(14) 感應藕合電漿質譜儀 (Inductively Coupled Plasma Mass Spectrometry, ICP-MS) 17
2. 實驗藥品 (Reagents) 17
(1) Abcam 17
(2) Agar Scientific 18
(3) Aldrich 18
(4) Alfa Aesar 19
(5) AnaSpec 19
(6) Bayer Schering Pharma AG 19
(7) BD Bioscience 19
(8) Fluka 19
(9) GE Healthcare Life Sciences 19
(10) Malliockrodt 20
(11) Merck 20
(12) NovaBiochem 20
(13) Pierce 20
(14) RDH 20
(15) Roche 20
(16) Spectrum 20
(17) TEDIA 21
四、實驗方法 22
1. silane-NH2-mPEG之合成 22
(1) Methoxy poly(ethylene glycol) acrylate (mPEG-Ac) 之合成 23
(2) 3-Aminopropyltriethoxysilane acrylate (APTES-Ac) 之合成 23
(3) N，N-APTES-NBoc-ethylenediamine-mPEG (silane-NBoc-EA-mPEG) 之合成 24
(4) Silane-ethylamine-methoxy poly(ethylene glycol) (silane-NH2-mPEG) 之合成 24
2. 近紅外光螢光發光團CyTE777之合成 27
3. 對比劑之合成 27
(1) MnMEIO-silane-NH2-mPEG NPs之合成 28
(2) MnMEIO-silane-NH2 NPs 之合成 28
(3) MnMEIO-silane-NH2-mPEG及MnMEIO-silane-NH2 NPs鍵結螢光染劑及抗體之合成 29
4. 超順磁氧化鐵奈米粒子及聚合物分子純度鑑定分析 29
5. X光能譜散佈分析儀 (EDS) 之鑑定 30
6. 超導量子干涉磁量儀 (SQUID) 之磁性分析 30
7. 動態光散射儀 (Dynamic Light Scattering, DLS) 之粒徑與表面電位 (Zeta potential) 測定 30
8. 抗體鍵結螢光染劑之合成 31
9. 單株抗體與對比劑鍵結效率 (Conjugation efficiency) 之測定 31
10. 對比劑於試管內之磁振造影 (T2-weighted MR images) 31
11. 西方墨點法 (Western blotting) 分析 32
12. 腫瘤細胞株與動物模式 32
13. 流式細胞儀 (Flow cytometer) 測定 33
14. 共軛焦螢光顯微鏡 (Confocal fluorescence microscope) 測定 34
15. 穿透式電子顯微鏡 (TEM) 測定 34
16. 體外 (In vitro) 磁振造影分析 35
17. 體內 (In vivo) 磁振造影分析 35
18. 體內 (In vivo) 活體光學影像 (Optical imaging) 分析 36
19. 對比劑在生物體內分佈之研究 (Biodistribution study) 36
20. 組織切片與免疫染色 (Immunohistochemistry stain) 36
五、結果與討論 38
1. 摻雜錳之超順磁氧化鐵奈米粒子 (MnMEIO) 物化性探討 38
(1) 穿透式電子顯微鏡 (TEM) 之鑑定 38
(2) X光能譜散佈分析儀 (EDS) 之鑑定 39
(3) 超導量子干涉磁量儀 (SQUID) 之磁性探討 40
(4) MnMEIO-silane-NH2-mPEG及MnMEIO-silane-NH2-(Erb)-mPEG NPs之物化性探討 41
(5) 對比劑穩定性之探討 43
2. 超順磁氧化鐵奈米粒子表面電位與腫瘤專一性標靶之探討 45
(1) 流式細胞儀 (Flow cytometer) 之探討 48
(2) 共軛焦螢光顯微鏡 (Confocal fluorescence microscope) 之探討 51
(3) 穿透式電子顯微鏡 (TEM) 之探討 52
(4) 體外 (In vitro) 磁振造影實驗之探討 54
(5) 體內 (In vivo) 磁振造影實驗之探討 55
(6) 體內 (In vivo) 光學影像實驗之探討 57
(7) 鍵結不同單株抗體之對比劑專一性標靶探討 60
(8) 組織切片與免疫染色 (Immunohistochemistry stain) 探討 62
3. 超順磁氧化鐵奈米粒子應用於胰臟癌早期診斷之研究 63
(1) MnMEIO-silane-NH2-mPEG及MnMEIO-silane-NH2-(MUC4)-mPEG NPs之物化性探討 65
(2) 對比劑於試管內之磁振造影 (T2-weighted MR images) 66
(3) 胰臟癌腫瘤細胞之黏蛋白表現量之探討 68
(4) 體外 (In vitro) 磁振造影之探討 69
(5) 流式細胞儀 (Flow cytometer) 之探討 71
(6) 共軛焦螢光顯微鏡 (Confocal fluorescence microscope) 與細胞普魯士藍 (Prussian blue) 之探討 72
(7) 體內 (In vivo) 光學影像及生物體內分佈之探討 (Biodistribution study) 75
(8) 體內 (In vivo) 磁振造影實驗之探討 77
4. 超順磁氧化鐵奈米粒子鍵結雙抗抗體之研究 82
(1) 雙抗抗體之製備 84
(2) MnMEIO-silane-NH2-mPEG、MnMEIO-silane-NH2-(Bis)-mPEG、MnMEIO-silane-NH2-(Her)-mPEG、MnMEIO-silane-NH2-(Erb)-mPEG及MnMEIO-silane-NH2-(Erb+Her)-mPEG NPs之物化性探討 86
(3) 細胞毒性分析 (MTT assay) 87
(4) 腫瘤細胞之Her2/neu與EGFR受體蛋白表現量之探討 88
(5) 對比劑對Her2/neu及EGFR表現型腫瘤專一性標靶之探討 89
(6) 細胞普魯士藍 (Prussian blue) 之探討 93
(7) 體外 (In vitro) 光學影像之探討 95
(8) 體外 (In vitro) 磁振造影之探討 96
(9) 共軛焦螢光顯微鏡 (Confocal fluorescence microscope) 之探討 98
(10) 藥物動力學之探討 (Pharmacokinetic study) 100
(11) 體內 (In vivo) 光學影像及對比劑在生物體內分佈之探討 (Biodistribution study) 102
(12) 體內 (In vivo) 磁振造影之探討 104
(13) 組織切片與免疫染色 (Immunohistochemistry stain) 之探討 105
六、結論 106
1. 對比劑MnMEIO-silane-NH2-mPEG能有效減少非專一性鍵結 106
2. 對比劑MnMEIO-silane-NH2-mPEG鍵結MUC4抗體具備高專一性標靶mucin4表現型腫瘤細胞 106
3. 對比劑MnMEIO-silane-NH2-mPEG鍵結雙抗抗體 (Bis) 可強化標靶多樣性腫瘤細胞 107
七、參考文獻 108
八、Publication 114

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