臺灣博碩士論文加值系統

相較於提供單一顯影功能的顯影劑，多重顯影(multimodality-imaging)的結合能提供更完整更精準的影像資訊。但是多重顯影劑的合成傳統上非常的耗費時間，且多種顯影功能很難有效的結合在同一系統內同時維持生物相容性(biocompatibility)。而奈米材料則因為其獨特的物性化性、表面修飾容易等等優勢，近年來在生醫顯影劑上蓬勃發展。聚多巴胺(polydopamine)是一種和黑色素(Melanin)化學結構相似的材料，他具有很強的金屬離子螯合能力、容易附著在各種表面等特性，在近年來被廣泛的應用。本篇使用聚多巴胺螯合三價鐵的高分子聚合物作為核磁共振(Magnetic resonance, MR)顯影劑中 T1 訊號來源，結合本身帶有 T2 、電腦斷層(Computed tomography, CT)，多光子顯影(Multiphoton imaging)等多功能顯影訊號的鐵鉑奈米粒子，利用介孔洞二氧化矽(mSiO2)殼作為間隔層(separating layer)，使 T1 訊號跟 T2 訊號不會互相干擾，同時其孔洞可讓更多聚多巴胺附著，進一步提升T1訊號的強度。首先我們合成出介孔洞二氧化矽殼包覆鐵鉑(FePt)合金奈米粒子，再利用先前提到的聚多巴胺螯合鐵的高分子聚合物包覆外層並在最外層修飾甲氧基聚乙二醇硫醇(methoxy polyethylene glycol thiol, PEG, Mw=6,000)增加分散性及生物相容性，我們可以成功合成四合一(T1, T2, CT, Optical)殼核奈米結構的多功能顯影劑FePt@mSiO2@PDA-PEG。除了帶有很好的 MRI 訊號(R1=3.502 mM-1S-1, R2=7.173 mM-1S-1)，他也具有很強的 CT 顯影能力。我們更進一步的測試其在 HeLa 細胞以及小鼠體內影像訊號的提升情形。由於人體血清內含有運鐵蛋白(transferrin)等能代謝鐵的蛋白質，其與三價鐵很強的螯合能力在之前被報導能使奈米粒子的骨架(framework)更容易被分解。在本篇我們更深入的討論不同核種(鐵鉑或氧化鐵)及包覆結構不同對崩解所產生的影響，來探討其生物降解性(biodegradability)。另外我們也研究其作為藥物載體(Drug carrier)及光熱治療(Photothermal)的可能性。因此本篇所發展之四合一多重顯影複合奈米材料可以預期其在生醫顯影劑發展上將有很高的潛力。

Multimodality-imaging strategies have been intensively developed in recent years due to the advantage of providing complementary information in preclinical research and early stage diagnosis. However, the develop of multimodality system is usually time-consuming and still remain challenging to achieve both efficiency and biocompatibility in a single nanoplatform. Polydopamine is known to preserve universal coating, metal-binding ability and multiphoton luminescence. Recently, it has been found to be a potential T1 MR contrast agent with the introduction of Fe3+. Herein, we utilized this property combined with FePt NPs, which intrinsically preserve computed tomography (CT), MRI T2-weighted effect and multiphoton contrast, and have successfully synthesized a four in one (T1, T2, CT, Optical) imaging system, FePt@mSiO2@PDA-PEG. It shows great magnetic resonance imaging efficiency (R1=3.502 mM-1S-1, R2=7.173 mM-1S-1) and strong computed tomography signal (CT) alike. In vitro and in vivo experiments have also been studied in this report. Furthermore, its biodegrading process is further explored and compared with different core/shell composition/structure (e.g. Fe3O4/nonporous SiO2). Drug releasing and photothermal therapy of FePt@mSiO2@PDA-PEG are also demonstrated to have great therapeutic potential. In summary, we have successfully designed a system with great multiple imaging efficiency and therapeutic potential, and is a promising candidate for theranostic agent.

誌謝 1
摘要 2
ABSTRACT 3
CONTENTS 4
LIST OF FIGURES 6
LIST OF TABLES 9
Chapter 1 Introduction 10
Chapter 2 Experimental Section 13
2.1 Chemicals 13
2.2 Synthesis of FePt Nanoparticles 13
2.3 Synthesis of FePt@mSiO2 Nanoparticles 13
2.4 Synthesis of FePt/Fe3O4@SiO2 Nanoparticles 14
2.5 Surface Modification of Polydopamine and mPEG-SH 14
2.6 DOX loading for Drug Delivery 15
2.7 Characterization 15
2.8 Relaxivity Measurement 16
2.9 Multiphoton Measurement 16
2.10 In Vitro MR imaging and CT imaging 17
2.11 Cell Viability 18
2.12 Cell Labeling 18
2.13 MRI in Vivo Experiment 19
2.14 CT in Vivo Experiment 19
2.15 In Vivo Multiphoton Imaging 20
2.16 Biodegradability Test 20
2.17 Confocal Fluorescence Imaging 20
2.18 Photothermal Therapy Efficiency Evaluation 21
Chapter 3 Results and discussion 22
3.1 Synthesis and characterization 22
3.2 Efficiency in MRI and CT 31
3.3 Efficiency in MRI and CT in vitro 35
3.4 Efficiency in MRI and CT in vivo 39
3.5 Multiphoton Imaging Efficiency in vivo 44
3.6 Biodegradability Test 49
3.7 Therapy Potential 57
Chapter 4 Conclusion 63
References 65

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