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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 牟中原(Chung-Yuan Mou) | |
dc.contributor.author | Jou-Hsuan Liao | en |
dc.contributor.author | 廖柔瑄 | zh_TW |
dc.date.accessioned | 2021-07-11T14:36:41Z | - |
dc.date.available | 2022-08-31 | |
dc.date.copyright | 2017-08-31 | |
dc.date.issued | 2017 | |
dc.date.submitted | 2017-08-15 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77885 | - |
dc.description.abstract | 蛋白質治療已經成為現今治療蛋白質缺陷和折疊錯誤疾病的潛在方法。為了克服蛋白質在體內輸送的問題,如穩定性或細胞膜滲透性不佳、易被核內體困住或消化以及免疫系統自身反應等等,我們開發了二氧化矽中孔洞的奈米粒子(MSN) 和二氧化矽空心球 (HSN) 作為治療性載體應用於酵素治療。
在本研究的第一部分,我們期望設計一種二氧化矽中孔洞奈米粒子 (MSN),具有生物相容性、能夠在體內保持穩定,且施打後不會累積在器官內等特性。因此,我們在MSN的表面上修飾了長鏈的親水官能基PEG和PEI來增加細胞攝取,接著將具有抗氧化壓力的TAT-SOD蛋白接到MSN上,形成RMSN-Ni-TAT-SOD。我們比較於細胞施加RMSN-Ni-TAT-SOD的自然型態蛋白或變性蛋白之間的差異,並且專注在機制上的研究。我們根據結果提出一假說: 當TAT-SOD以變性蛋白形式接於MSN,會比自然態蛋白形式有較少的立體位障,因此能夠更有效的進行蛋白質輸送且增強SOD的活性。 在第二部分的研究,在治療急性淋巴性的白血病 (ALL) 上,我們利用引入矽烷 (silane) 將天門醯胺酶 (ASNase) 包裹於具PEG修飾的空心球內,我們發現HSN的球殼能幫助位於球內的ASNase對抗胰蛋白酶(trypsin) 的消化並穩定酵素的活性,和臨床上所使用的ASNase相比,可以有效延長在體內的半生期。除此之外,此方法的優點保留了良好的酵素活性,可有效的誘導細胞凋亡,是在ALL主要治療機制上的關鍵。據我們所知,這是第一個將ASNase包覆在HSN內,保持其良好酵素活性並用於來ALL治療的研究。 總而言之,利用二氧化矽奈米粒子來輸送蛋白質是具有展望性,我們試圖解決目前在發展及治療上遇到的困難,期望這項研究能將奈米蛋白質治療推向臨床前研究。 | zh_TW |
dc.description.abstract | Protein therapy had become a potential approach in treating protein deficiency and misfolding diseases. To overcome the concerns of protein delivery including poor stability, membrane impermeability, endosome trapping/digestion and immune response, we developed mesoporous silica nanoparticles (MSN) and hollow silica nanoparticles (HSN) as therapeutic carriers for enzyme therapy.
In our previous study, we have developed mesoporous silica nanoparticles (MSN) as enzyme delivery approach to successfully deliver superoxide dismutase (SOD) and glutathione peroxidase (GPx) into cells. The results demonstrated these denatured antioxidant enzymes conjugated on the MSN surface could be delivered and refolded with specific enzyme activity to protect cells attacked by ROS. The approach not only overcomes the challenges of protein delivery, including poor stability, membrane impermeability, endosome trapping/digestion and immune response, but provides the following advantages: (1) one-step protein conjugation and purification, (2) easy mass production and (3) multiple enzymes delivery to regulate cascade reactions. In the first part of this study, we aim to design an ideal MSN for use in vivo, achieving the characteristics of biocompatible, stability, and free of organ accumulation after administration. Hence, PEGylated MSN with polyethyleneimine (PEI) to increase cell uptake was synthesized, followed by the TAT-SOD conjugation to form RMSN-Ni-TAT-SOD. We compared the difference between the native and denatured form of RMSN-Ni-TAT-SOD after cell delivery, focusing on the mechanism study in details. From our results, we proposed that denatured form of TAT-SOD had less steric hindrance than native form when conjugated onto MSN, promoting efficiently delivery and result in enhanced SOD activity. In the second part, we report a novel approach to generate L-asparaginase (ASNase) encapsulated HSN by introducing silane strategy for the treatment of acute lymphoblastic leukemia (ALL). We investigated the shell of HSN was able to help internal ASNase against trypsin digestion and stabilize enzyme activity that would efficiently improve the problem of short half-life in vivo compared to free ASNase used in clinical now. In addition, the advantages of the approach retained good enzymatic activity which played a critical role in inducing cell apoptosis, a mainly therapeutic mechanism to ALL. To our best knowledge, this is the first work reporting the HSN encapsulated ASNase with good enzyme activity could be applied in treating ALL. Taken together, using silica nanoparticles to deliver protein is a promising approach. We expect this study would push the nano based protein therapy into preclinical, as well as attempt to address the current developmental and therapeutic challenges. | en |
dc.description.provenance | Made available in DSpace on 2021-07-11T14:36:41Z (GMT). No. of bitstreams: 1 ntu-106-R04223201-1.pdf: 5054494 bytes, checksum: b4ffc10f99b33122486901cb4da122f7 (MD5) Previous issue date: 2017 | en |
dc.description.tableofcontents | 謝辭 I
摘要 I Abstract II Table of Contents i List of Figures vii List of Tables xii List of Abbreviations xiii Chapter 1 Introduction 1 1.1 Introduction of Silica Based Nanomaterials 1 1.2 Protein/Enzyme Therapy of Cancer 2 1.3 Bio-Applications of Mesoporous Silica Nanoparticles (MSN) 5 1.3.1 General Introduction 5 1.3.2 MSN as an Enzyme Delivery System 7 1.4 Bio-Application of Hollow Silica Nanospheres (HSN) 9 1.4.1 Different Materials of L-Asparaginase Immobilization/Carriers 9 1.4.2 HSN as an Enzyme Delivery System 11 1.4.3 The FDA-Approved Drugs of Acute Lymphoblastic Leukemia 12 1.4.3.1 General Introduction 12 1.4.3.2 The Advantages and Disadvantages of Clinically Used Drugs 14 1.5 Motivations and Objectives 17 Chapter 2 Experimental Section 20 2.1 Materials and Method 20 2.1.1 Chemicals and Reagents 20 2.1.2 Characterization of Mesoporous Silica Nanoparticles 21 2.2 Synthetic Procedure 23 2.2.1 Mesoporous Silica Nanoparticles (MSN)-Mediated Denatured Protein Delivery: Focus on the Mechanism Study 23 2.2.1.1 Synthesis of Red Fluorescent RMSN 23 2.2.1.2 Synthesis of RMSN-Ni 23 2.2.1.3 Synthesis of Native Form and Denatured Form of RMSN-Ni-TAT-SOD 24 2.2.1.4 Plasmid Construction 25 2.2.1.5 Expression and Purification of Recombinant Proteins 25 2.2.1.6 Determination Activity of Superoxide Dismutase (SOD) 25 2.2.1.7 Cell Culture 26 2.2.1.8 Western Blotting Analysis 26 2.2.1.9 Flow Cytometry Analysis 27 2.2.1.10 Circular Dichroism (CD) Measurements 27 2.2.1.11 Cellular Uptake Mechanism 28 2.2.1.12 In-Vivo Bio-Distribution 28 2.2.2 L-Asparaginase (ASNase) in Hollow Silica Nanospheres (HSN) for Protein Therapy 29 2.2.2.1 Synthesis of RITC-PEG-MPTMS-Asparaginase (PEGs-ASNase) 29 2.2.2.2 Encapsulation of PEGs-ASNase in the Hollow Silica Nanospheres (PEGs-ASNase@PEG-HSN and PEGs-ASNase@TA-PEG-HSN) 29 2.2.2.3 Loading Yield and Encapsulation Efficiency of ASNase 30 2.2.2.4 Cell Culture 31 2.2.2.5 ASNase Activity Assay 31 2.2.2.6 Trypsin Tolerance of ASNase 32 2.2.2.7 Cell Viability of Free ASNase, PEGs-ASNase@PEG-HSN, PEGs-ASNase@TA-PEG-HSN, PEG-HSN and TA-PEG-HSN 33 2.2.2.8 Flow Cytometry Analysis 33 2.2.2.9 Alteration in Nuclear Morphology of MOLT-4 Leukemic Cells 34 2.2.2.10 Cell Cycle Analysis of MOLT-4 Cells 34 2.2.2.11 In-Vivo Circulation 35 2.2.2.12 In-Vivo Bio-Distribution 35 Chapter 3 Mesoporous Silica Nanoparticles (MSN)-Mediated Denatured Protein Delivery: Focus on the Mechanism Study 36 3.1 Characterization of RMSN, RMSN-Ni, RMSN-Ni-TAT-SOD 36 3.2 Characterization of TAT-SOD 38 3.3 In-Vitro Study 40 3.3.1 Cellular Uptake Efficiency 40 3.3.2 SOD Overexpression after Cell Delivery 41 3.3.3 The Enzymatic Activity of SOD 42 3.3.4 The Secondary Structure of RMSN-Ni-TAT-SOD 43 3.3.5 Pathway of RMSN-Ni-TAT-SOD in Cells. 44 3.4 In-Vivo Bio-Distribution 46 Chapter 4 L-Asparaginase (ASNase) in Hollow Silica Nanospheres (HSN) for Protein Therapy 48 4.1 Bioapplication of Hollow Silica Nanospheres (HSN) 48 4.2 Encapsulation Efficiency Improvement 48 4.2.1 Silane Strategy 49 4.2.2 Time-Separated Addition of Silica Source and Surface Modification 51 4.2.2.1 Enzymatic Activity of ASNase 51 4.2.2.2 Variety of Morphologies with Different Synthetic Processes 53 4.3 Characterization of PEGs-ASNase@PEG-HSN (C15) & PEGs-ASNase@TA-PEG-HSN (C17) 54 4.4 The Amount of ASNase Added and the Results of Encapsulation Efficiency and Loading Yield 57 4.5 In-Vitro Study 58 4.5.1 The Enzymatic Activity of Trypsin Tolerance 58 4.5.2 Cell Viability 59 4.5.2.1 Acute Leukemic Cells (Circulation Tumor) 59 4.5.2.2 4T1 Cells (Solid Tumor) 62 4.5.3 Cellular Uptake Efficiency 64 4.5.3.1 Acute Leukemic Cells (Circulation Tumor) 64 4.5.3.2 4T1 Cells (Solid Tumor) 65 4.5.4 ASNase-Induced Apoptosis 67 4.5.5 Cell Cycle 68 4.6 In-Vivo Study 70 4.6.1 Circulation 70 4.6.2 Bio-Distribution 71 Chapter 5 Conclusion 74 Reference 77 Supporting Information A S1 Protein Corona A | |
dc.language.iso | en | |
dc.title | 發展功能性的二氧化矽奈米粒子應用於酵素治療 | zh_TW |
dc.title | Developing Functional Silica Nanoparticles for Enzyme Therapy | en |
dc.type | Thesis | |
dc.date.schoolyear | 105-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 戴桓青(Hwan-Ching Tai),陳培菱(Pei-Lin Chen) | |
dc.subject.keyword | 中孔洞二氧化矽奈米粒子,空心球,蛋白治療,抗氧化酵素,化療藥物,門冬醯胺?,急性淋巴性白血病, | zh_TW |
dc.subject.keyword | mesoporous silica nanoparticles,hollow silica nanospheres,protein therapy,antioxidant enzymes,chemotherapy drugs,L-Asparaginase,acute lymphoblastic leukemia (ALL), | en |
dc.relation.page | 88 | |
dc.identifier.doi | 10.6342/NTU201703369 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2017-08-16 | |
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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