請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17474完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 牟中原 | |
| dc.contributor.author | Yi-Ping Chen | en |
| dc.contributor.author | 陳奕平 | zh_TW |
| dc.date.accessioned | 2021-06-08T00:15:12Z | - |
| dc.date.copyright | 2013-08-23 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-07-31 | |
| dc.identifier.citation | Chapter 1: General Introduction
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/17474 | - |
| dc.description.abstract | 中孔洞二氧化矽奈米粒子是一個具有多功能型的奈米材料，加上具有高表面積、孔體積、高熱穩定性以及容易在表面進行特殊官能基團修飾等優點的性質，所以廣泛的被應用在催化反應、離子交換等方面，具有相當高的應用價值。近幾年的研究發現，中孔洞二氧化矽奈米粒子具有相當好的生物相容性，以及可以有效率的被生物細胞進行吞噬，被認為是極具潛力的新穎材料，因此有許多的奈米生醫相關應用的研究被大量發表。例如傳遞藥物及基因的載體、醫學造影像以及生物偵測等等。
在本論文第一部分，主要是利用蛋白質工程結合中孔洞二氧化矽奈米粒子的概念，我們是第一個在中孔洞二氧化矽奈米粒子材料上證明變性的蛋白質可以藉由chaperones進行再折疊，成為一個具有生物活性的蛋白質，應用在蛋白質或酵素治療上之新穎研究。 主論文第二部分，在提出一個以奈米粒子作為細胞訊號傳遞的調控者之創新概念，我們設計了一個結合NF-κB p65抗體與HIV 1上TAT胜肽的聰穎中孔洞二氧化矽奈米粒子，藉由抗體辨識及奈米材料的物理性質(尺寸)所造成的立體障礙，直接有效抑制癌細胞內p65的活化更進一步抑制癌細胞的增生。我們同時證明了利用奈米粒子對細胞中核蛋白來進行調控之想法的可行性。 | zh_TW |
| dc.description.abstract | Mesoporous silica nanoparticle (MSN) is one of the promising nanoparticles to serve as a multifunctional vehicle due to its high surface area, uniform pore size, easy functionalization, and biocompatibility. Therefore, it becomes highly suitable for biological applications. In additional to traditional applications of mesoporous silica such as catalysis and chromatography, biomedical applications of MSN such as enzyme immobilization, gene transfection, bioimage and drug delivery agents have recently gained much attention.
In the first part of the thesis, the strategy is to combine an engineered protein with MSN to demonstrate the denature protein refolded back into its native form which is probably regulated by chaperones in cells. Our result is the first to report that the denature superoxide dismutase (SOD) enzyme carried by MSN has refolded in the cell and exhibits cellular SOD activity. This novel study can be applied to a protein or enzyme-base therapy in the future. In the second part, we proposed nanoparticles served as nuclear translocation blocker by conjugating antibody to interact with transcriptional activator in the cellular signaling pathways. We first designed a smart functionalized MSN to conjugate nuclear factor-κB (NF-κB) anti-p65 antibody and human immunodeficiency virus 1 (HIV 1) transactivating domain which associated with non-endocytosis and nuclear pore complex (NPC) trapping. This smart MSN particle did exhibit cellular penetration and bind NF-κB p65 when activation, via size hindrance to disrupt the p65 translocation, downstream gene transcription and cell proliferation. Unlike existing research, our results demonstrated a novel idea to use nanoparticles as nuclear translocation blocker for further signal regulation. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T00:15:12Z (GMT). No. of bitstreams: 1 ntu-102-D96223202-1.pdf: 40436183 bytes, checksum: bac3d9e1996be017f7e583ab2df715a0 (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | Table of Contents
中文摘要……………………………………….…………………………………….I Abstract…………………………………………………..…………………………II Table of Contents………………………………...………………………………IV List of Figures………………………………………...………………………...VIII List of Schemes……………………………..…………………………………..XIII List of Tables……………………………………………………………………XIV Chapter 1: General Introduction .1 1.1 Introduction .2 1.1.1 Brief History of Mesoporous Silica Nanoparticles (MSN) .2 1.1.2 General Introduction of Porous Materials .4 1.1.2.1 Synthesis Mechanism and Pathway of Mesopores Silica Materials. 5 1.1.3 Mesoporous Silica Nanoparticles (MSN) .7 1.1.3.1 Synthesis of MSN.. ... 8 1.1.3.2 Functionalization of MSN. 12 1.1.4 Biological Research Application of MSN 15 1.1.4.1 MSN-Based Drug Delivery System………………………... 16 1.1.4.2 Drug Delivery. 18 1.1.4.3 Protein Delivery. 20 1.1.4.4 Gene Delivery. 21 1.2 References 23 Chapter 2: A New Strategy for Intracellular Delivery of Enzyme Using Mesoporous Silica Nanoparticles: Superoxide Dismutase .30 Abstract .31 2.1 Introduction 33 2.1.1 Protein-Base Therapy 33 2.1.1.1 Nanoparticles (NPs) as a Carrier for Delivery of Protein: 33 2.1.1.2 Fusogenic Peptides (TAT) to Increase Cell Uptake and Avoid Endosome Trapping: 36 2.1.2 Mesoporous Silica Nanoparticle (MSN) on Biomedicine 37 2.1.3 Reactive Oxygen Species (ROS) and Superoxide Dismutase (SOD) 37 2.1.4 Our Strategy: A New Method for Protein Delivery by MSN. 38 2.1.4.1 TAT-SOD Fusion Protein was Conjugated to FMSN 38 2.1.4.2 The Denature SOD could be Refolded by Intracellular Chaperones. 39 2.1.5 Summary 40 2.2 Experimental Section 42 2.2.1 Synthesis of Green Fluorescent Mesoporous Silica Nanoparticles 42 2.2.2 Synthetic Scheme for NTA-Silane Linker: 42 2.2.3 Conjugation of NTA-Silane and Ni(II) with MSN (FMSN-Ni-NTA) 43 2.2.4 Immobilization of His-TAT-SOD Proteins with FMSN-Ni-NTA 44 2.2.5 Cell Lines and Reagents 44 2.2.6 Isolation of the Full-Length Human Cu,Zn-SOD 45 2.2.7 Construction of Expression Clones 45 2.2.8 Expression and Purification of Recombinant Proteins 46 2.2.9 Cell Culture 46 2.2.10 Western Blot Analysis 47 2.2.11 Immunocytochemical Staining for TAT-SOD Expression 47 2.2.12 Determination of Superoxide Dismutase Activity 48 2.2.13 Cell Viability Assay 49 2.2.14 Superoxide detection 49 2.2.15 Powder X-ray Diffraction (XRD) 50 2.2.16 Nitrogen Adsorption-Desorption Isotherms 50 2.2.17 Transmission Electron Microscopy (TEM) 50 2.2.18 Flow Cytometry Analysis 51 2.2.19 Endosome Staining of HeLa cells 51 2.3 Results and Discussion 52 2.3.1 Characterization of TAT-SOD and TAT-SOD Bioconjugate Formation with MSN Nanoparticles. .52 2.3.2 Delivery of MSN-TAT-SOD into HeLa Cells and SOD Specific Enzymes Activity Assay. .57 2.3.3 MSN-TAT-SOD Decreases LPS-Induced Apoptosis Through the Inhibition of Caspase 9 and p21 in HeLa Cells 61 2.3.4 Effect of Metal Ion and TAT Peptide on the Delivery of MSN-TAT-SOD. 65 2.4 Conclusion 72 2.5 References 73 2.6 Appendix 83 Chapter 3: Nanoparticles as Nuclear Translocation Blocker: Nuclear Factor-κB (NF-κB) 85 Abstract 86 3.1 Introduction 88 3.1.1 Nuclear Translocation 88 3.1.2 NF-κB: A Good Target for Cancer Therapy 89 3.1.3 NF-κB Inactivation: Strategy for Cancer Therapy 90 3.1.4 Antibody Targeting as a Cancer Therapy 90 3.1.5 Nanoparticles and Tumors. 91 3.1.6 Conjugation Antibody to Nanoparticles. 92 3.1.7 Antibody-Conjugated Nanoparticles for Biomedical Applications. 93 3.1.8 Our Strategy: To Build Nanoparticles as p65 Nuclear Translocation Blockers through Antibody Targeting Associated with Non-Endocytosis and NPC Trapping 95 3.1.9 Summary .97 3.2 Experimental Section 98 3.2.1 Synthesis of Green Fluorescent Mesoporous Silica Nanoparticles (MSN) .98 3.2.2 Preparation of Amine-Functionalized MSN (MSN-APTMS) 98 3.2.3 Conjugation of PEGlLinker with MSN-APTMS (MSN-PEG2k, MSN-PEG3.4k) 99 3.2.4 Immobilization of p65 Antibody on MSN-PEG 3.4k 100 3.2.5 Synthesis of TAT Conjugated MSN-PEG 3.4k-Ab 100 3.2.6 Transmission Electron Microscopy (TEM) 100 3.2.7 Cell Culture 101 3.2.8 Western Blotting Analysis 101 3.2.9 Cytotoxicity of MSN-PEG2k, MSN-PEG3.4k and in Vitro Pull-Down Assay of MSN-PEG3.4k-Ab-TAT 102 3.2.10 Cell Viability Assay .102 3.2.11 Immunocytochemical Staining for p65 Expression 103 3.2.12 3D-Confocal Microscopy 103 3.3 Results and Discussion 105 3.3.1 Surface Functionalization and Chemical Characterization of MSN. 105 3.3.2 Cytotoxicity of MSN-PEG2k, MSN-PEG3.4k and in Vitro Pull-Down Assay of MSN-PEG3.4k-Ab-TAT. 109 3.3.3 MSN-PEG3.4k-Ab-TAT Blocks NF-κB p65 Nuclear Translocation. 110 3.3.4 MSN-PEG3.4k-Ab-TAT Blocks NF-κB p65 Translocation in a Dose Dependent Manner. 116 3.3.5 MSN-PEG3.4k-Ab(1:24)-TAT Inhibits the NF-κB p65 Downstream Protein Expression and the Proliferation in HeLa and HNSCC Cells……..……119 3.3.6 MSN-PEG3.4k-Ab(1:24)-TAT Highly Move toward Nucleus is may due to TAT Peptides Interacting with Importins and Enhancing the Blocking Nuclear Translocation………………………………………….. ………123 3.4. Conclusion 126 3.5. References 127 Chapter 4: Conclusin and Perspective 134 Abbreviations 138 | |
| dc.language.iso | en | |
| dc.title | 中孔洞二氧化矽奈米粒子於生物醫學上之應用：酵素輸送及標靶治療 | zh_TW |
| dc.title | Biomedical Application of Mesoporous Silica Nanoparticles：Enzymes Delivery and Target Therapy | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 詹維康,陳建志,陳逸聰,陳 平 | |
| dc.subject.keyword | 中孔洞二氧化矽奈米粒子,超氧化物歧化酵素,立體障礙,癌細胞增生, | zh_TW |
| dc.subject.keyword | Mesoporous silica nanoparticle,superoxide dismutase,hindrance,cancer proliferation, | en |
| dc.relation.page | 141 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2013-07-31 | |
| dc.contributor.author-college | 理學院 | zh_TW |
| dc.contributor.author-dept | 化學研究所 | zh_TW |
| 顯示於系所單位： | 化學系 | |
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