互穿金屬有機框架之微小化及功能化並應用於癌症的光熱—放射聯合療法

余祐陞; Yu-Sheng Yu

請用此 Handle URI 來引用此文件： http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/95444

完整後設資料紀錄

DC 欄位	值	語言
dc.contributor.advisor	吳嘉文	zh_TW
dc.contributor.advisor	Kevin C.-W. Wu	en
dc.contributor.author	余祐陞	zh_TW
dc.contributor.author	Yu-Sheng Yu	en
dc.date.accessioned	2024-09-09T16:11:18Z	-
dc.date.available	2024-09-10	-
dc.date.copyright	2024-09-09	-
dc.date.issued	2024	-
dc.date.submitted	2024-08-12	-
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Intranasal monoclonal IgA antibody to respiratory syncytial virus protects rhesus monkeys against upper and lower respiratory tract infection. J. Infect. Dis. 174, 256-261. https://doi.org/10.1093/infdis/174.2.256. Ye, J., Shao, H., Hickman, D., Angel, M., Xu, K., Cai, Y., Song, H., Fouchier, R.A., Qin, A., Perez, D.R., 2010. Intranasal delivery of an IgA monoclonal antibody effective against sublethal H5N1 influenza virus infection in mice. Clin. Vaccine Immunol. 17, 1363-1370. https://doi.org/10.1128/cvi.00002-10. Yu, Y.S., AboulFotouh, K., Xu, H., Williams, G., Suman, J., Cano, C., Warnken, Z.N., Wu, K.C., Williams, R.O., 3rd, Cui, Z., 2023. Feasibility of intranasal delivery of thin-film freeze-dried, mucoadhesive vaccine powders. Int. J. Pharm. 640, 122990. https://doi.org/10.1016/j.ijpharm.2023.122990. Yu, Y.S., Xu, H., AboulFotouh, K., Williams, G., Suman, J., Sahakijpijarn, S., Cano, C., Warnken, Z.N., Wu, K.C., Williams, R.O., 3rd, Cui, Z., 2024. Intranasal delivery of thin-film freeze-dried monoclonal antibodies using a powder nasal spray system. Int. J. Pharm. 653, 123892. https://doi.org/10.1016/j.ijpharm.2024.123892. Zhang, Y., Soto, M., Ghosh, D., Williams, R.O., 2021. Manufacturing stable bacteriophage powders by including buffer system in formulations and using Thin Film Freeze-drying technology. Pharm. Res. 38, 1793-1804. https://doi.org/10.1007/s11095-021-03111-y.	-
dc.identifier.uri	http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/95444	-
dc.description.abstract	近年來，孔洞材料用於生醫領域的潛力逐漸受到重視，本論文探討了兩類新興孔洞材料的開發、合成、鑑定，並且將它們應用於癌症治療、骨折治療，以及鼻腔藥物輸送。其中，在本論文第一、二章節中探討了鋯基/鉿基金屬有機框架Zr/Hf-PEB的製備，並且透過配位調控的策略，在不破壞結晶性的情況下，將這兩種互穿結構之金屬有機框架之粒徑縮小至約200奈米，適合用於生醫領域。接著，利用了Hf-PEB配位體上三鍵的特性，將鈀金屬奈米顆粒嵌入到Hf-PEB的孔洞之中。考量到鉿元素具有高原子序，可以做為癌症放射治療的增敏劑，並且鈀金屬奈米顆粒可以吸收近紅外光的特性，可作為光熱治療的增敏劑，因此，包覆了鈀金屬奈米顆粒的鉿基金屬有機框架Pd@Hf-PEB可以被應用在癌症的光熱-放射聯合療法中。而本論文的第三章節探討了鐵基金屬有機框架 MIL-100(Fe) 材料的合成以及修飾，並將其作為鎂離子的載體，應用於骨頭的修復。由於鎂離子的直徑小於MIL-100(Fe) 孔洞的窗口大小，因此在鎂離子被載入MIL-100(Fe) 的孔洞之中後，需要進行表面修飾，使得鎂離子能夠停留於孔洞之中，對此，本研究提出了兩個策略：1. 將聚丙烯酸的鈉鹽修飾到搭載鎂離子之MIL-100(Fe) 之表面。 2. 將聚丙烯酸透過EDC/NHS反應修飾到搭載鎂離子之NH2-MIL-100(Fe) 表面，據我們所知，NH2-MIL-100(Fe) 是由我們團隊最先發表之材料，是帶有NH2官能基版本的MIL-100(Fe) 金屬有機框架，先前我們已展示其在修飾後，可以被應用在蛋白質的純化。在這個研究中，元素分析的結果表明第一種聚丙烯酸修飾方式更能夠提升鎂離子的搭載量，並且，將其與MG-63骨肉瘤細胞株共培養時，可以在初期提升細胞鹼性磷酸酶的活性，顯示搭載鎂離子的MIL-100(Fe) 具有加速骨細胞分化的特性。而本論文的第四章節則是關於鼻腔乾粉疫苗劑型的開發，透過薄膜冷凍技術以及凍乾製程，液體疫苗可以被轉化為具高度孔洞性，適合透過鼻腔輸送的乾粉劑型，在研究中，我們合成了含有微脂體佐劑的模式疫苗，並且發現添加羧甲基纖維素可以提升疫苗粉末對黏膜的黏附性，當使用鼻噴劑系統將疫苗粉末輸送到鼻腔模型時，粉末可以抵達鼻甲以及鼻咽區域，顯示此疫苗粉末搭配鼻噴劑系統的有效性。在第五章節中，薄膜冷凍技術以及凍乾製程被用來將中和SARS-CoV-2的單株抗體轉化為乾粉劑型。此劑型不僅具有高度孔洞性，且其中的單株抗體並不會在冷凍乾燥的過程中大量團聚，適合被輸送至鼻腔之中，以及用於預防或治療上呼吸道的病毒感染。同樣的，當使用鼻噴劑系統將疫苗粉末輸送到鼻腔模型時，此單株抗體粉末劑型可以抵達鼻甲以及鼻咽區域。總的來說，這些章節皆探討了新穎孔洞材料的開發，以及於生醫領域的應用潛力，並且範圍涵蓋了癌症治療、骨治療，疫苗的輸送，以及病毒的預防及治療。	zh_TW
dc.description.abstract	In recent years, the potential of porous materials as biomedical materials has gained attention. This dissertation explores the development, synthesis, and characterization of two kinds of porous materials (i.e., metal-organic frameworks and thin-film freeze-dried powders), and their applications in cancer therapy, bone healing, and intranasal drug delivery. In Chapter 1 and Chapter 2, the synthesis of interpenetrated Zr or Hf-based metal-organic frameworks (MOFs) (Zr-PEB or Hf-PEB) was studied. Since methods that could produce nanoscale Zr-PEB or Hf-PEB have not been reported, coordination modulation strategy was tuned to reduce their sizes to about 200 nm for the first time, making them suitable for biomedical applications. The ethynyl group on the linker of Hf-PEB has been utilized to incorporate Pd nanoparticles into the pores. Considering that Hf, as a high-Z element, can sensitize X-ray during radiotherapy, and Pd nanoparticles can sensitize near-infrared (NIR) during photothermal therapy, the Pd-loaded Hf-PEB (Pd@Hf-PEB) can be applied in the combined photothermal-radiation therapy of cancer. In Chapter 3, the synthesis and surface modification of the iron-based MOF MIL-100(Fe) was studied, and Mg ions were loaded to the pores of MIL-100(Fe) for bone healing. Since the diameter of Mg ions is smaller than the window size of MIL-100(Fe), a surface modification is required to improve the loading of Mg ions. Two strategies were utilized in this study: 1. Grafting the surface of Mg-loaded MIL-100(Fe) with the sodium salt of poly(acrylic acid). 2. Functionalizing the surface of Mg-loaded NH2-MIL-100(Fe) with poly(acrylic acid) via EDC/NHS reaction. Where NH2-MIL-100(Fe) is MIL-100(Fe) with a NH2 substitution group on the linker. To the best of our knowledge, NH2-MIL-100(Fe) was reported by our group for the first time, and previously we have demonstrated that NH2-MIL-100(Fe) after surface modification can be utilized in the purification of proteins. The results show that the material produced using the first strategy (i.e., Mg@MIL-100(Fe)-PAA) had a higher Mg loading. When osteosarcoma cells MG-63 were treated with Mg@MIL-100(Fe)-PAA, the alkaline phosphatase (ALP) activity increased in the first few days, indicating that Mg@MIL-100(Fe)-PAA can potentially promote osteoblast differentiation and accelerate bone healing. In Chapter 4, the development of a nasal powder vaccine formulation was study. By utilizing the thin-film freezing (TFF) technology and lyophilization, liquid vaccines can be converted into porous dry powder vaccines suitable for intranasal delivery. Therefore, a model vaccine containing liposomal adjuvant and ovalbumin as antigen was synthesized. It was found that the addition of sodium carboxymethyl cellulose (CMC) can enhance the powder's mucoadhesion property. When the vaccine powder was delivered to the nasal replica casts using a nasal spray system from Aptar, it reached the turbinates and nasopharyngeal regions, demonstrating the efficacy. In Chapter 5, again, TFF technology and lyophilization were used to convert a monoclonal antibody (mAb) neutralizing SARS-CoV-2 into dry powder formulations without causing significant aggregation of the mAb. Similarly, when delivered to nasal replica casts using Aptar’s nasal spray system, the mAb powder could reach the turbinate region and nasopharynx, indicating that the powder is suitable for intranasal delivery to prevent or treat upper respiratory infections Overall, this dissertation focusses on the development of novel (porous) materials and their potential biomedical applications, including cancer therapy, bone healing, intranasal vaccine, and viral infection prevention and treatment.	en
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dc.description.tableofcontents	致謝 i 中文摘要 ii ABSTRACT iv TABLE OF CONTENTS vi LIST OF FIGURES xii LIST OF TABLES xxi Chapter 1. Downsizing and Soft X-ray Tomography for Cellular Uptake of Interpenetrated Metal-Organic Frameworks 1 Abstract 1 1.1. Introduction 2 1.2. Materials and Methods 8 1.2.1. Materials 8 1.2.2. Synthesis of H2PEB Linker 8 1.2.3. Synthesis of Zr-PEB and Hf-PEB Powders 9 1.2.4. Synthesis of Zr-PEB and Hf-PEB Nanoparticles 10 1.2.5. Scanning Electron Microscopy 11 1.2.6. X-ray Diffraction (XRD) 11 1.2.7. Fourier Transform Infrared Spectroscopy (FT-IR) 11 1.2.8. Photoluminescence Spectroscopy (PL) 12 1.2.9. Zeta Potential 12 1.2.10. Specific Surface Area 12 1.2.11. Viability Assay 13 1.2.12. Observing the Cellular Uptake of Hf-PEB/TFA Using Confocal Microscopy 13 1.2.13. Observing the Cellular Uptake of Hf-PEB/TFA Using SXT 14 1.3. Results and Discussion 16 1.3.1. Synthesis of Zr-PEB and Hf-PEB Powders 16 1.3.2. Synthesis of Zr-PEB and Hf-PEB Nanoparticles 20 1.3.3. Biocompatibility of Zr-PEB/TFA and Hf-PEB/TFA 23 1.3.4. Observing the Cellular Uptake of Hf-PEB/TFA using Confocal Microscopy 24 1.3.5. Observing the Cellular Uptake of Hf-PEB/TFA using SXT 26 1.4. Conclusions 29 1.5. References 30 Chapter 2. Dual-Sensitization of X-ray and Near-Infrared Based on Pd-Loaded Metal-Organic Framework for Radiation-Photothermal Combined Cancer Therapy 39 Abstract 39 2.1. Introduction 40 2.2. Materials and Methods 45 2.2.1. Materials 45 2.2.2. Cell Lines 45 2.2.3. General Characterization Methods 46 2.2.4. Synthesis of 1,4-Bis(2-[4-carboxyphenyl]ethynyl)benzene (H2PEB) Linker. 47 2.2.5. Synthesis of Hf-PEB. 49 2.2.6. Incorporation of Pd NPs in Hf-PEB 50 2.2.7. PEGylation of Hf-PEB and Pd@Hf-PEB 50 2.2.8. In Vitro Photothermal Activity 52 2.2.9. Cytotoxicity Assay 52 2.2.10. Detection of ROS 53 2.2.11. Observing the Cellular Uptake of Pd@Hf-PEB-PEG 54 2.2.12. Comet Assay 55 2.2.13. Colony Formation Assay 57 2.3. Results and Discussion 60 2.3.1. Synthesis and Characterization of H2PEB Linker 60 2.3.2. Synthesis and Characterization of Hf-PEB Particles 63 2.3.3. Incorporation of Pd NPs in Hf-PEB 65 2.3.4. Photothermal Activity of Pd@Hf-PEB-PEG 70 2.3.5. The Generation of ROS 71 2.3.6. Cytotoxicity Assay 72 2.3.7. The Cellular Uptake of Pd@Hf-PEB-PEG 73 2.3.8. Colony Formation Assay 75 2.3.9. DNA Strand Breaks 76 2.4. Conclusions 78 2.5. References 79 Chapter 3. Poly(acrylic acid)-Grafted Metal-Organic Framework Carrying Mg Ions for Bone Repair 89 Abstract 89 3.1. Introduction 90 3.2. Materials and Methods 95 3.2.1. Materials 95 3.2.2. General Characterization Methods 95 3.2.3. Synthesis of MIL-100(Fe) 96 3.2.4. Synthesis of NH2-MIL-100(Fe) 96 3.2.5. Synthesis of the Mg@MIL-100(Fe)-PAA 97 3.2.6. Synthesis of Mg@NH2-MIL-100(Fe)-PAA 97 3.2.7. Loading Efficiency of the Mg Ions 98 3.2.8. Release Profile of the Mg Ions 98 3.2.9. Biocompatibility of the Materials 98 3.2.10. Alkaline Phosphatase Assay 99 3.2.11. Statistical analysis 100 3.3. Results and Discussion 101 3.3.1. Synthesis and Characterization of MIL-100(Fe) 101 3.3.2. Synthesis and Characterization of NH2-MIL-100(Fe) 103 3.3.3. Encapsulation of the Mg Ions in MIL-100(Fe) or NH2-MIL-100(Fe) 105 3.3.4. The Release Profile of the Mg Ions from the Mg@MIL-100(Fe)-PAA 110 3.4.5. The Biocompatibility of the Mg@MIL-100(Fe)-PAA 111 3.4.6. The ALP Assay of the Mg@MIL-100(Fe)-PAA 112 3.5. Conclusions 114 3.6. References 115 Chapter 4. Feasibility of Intranasal Delivery of Thin-Film Freeze-Dried, Mucoadhesive Vaccine Powders 125 Abstract 125 4.1. Introduction 127 4.2. Materials and Methods 130 4.2.1. Materials 130 4.2.2. Preparation of the AdjLMQ/OVA Model Vaccine 130 4.2.3. Preparation of AdjLMQ/OVA Model Vaccines with CMC 131 4.2.4. Thin-Film Freeze-Drying of the AdjLMQ/OVA Model Vaccines 131 4.2.5. Determination of Particle Size and Zeta Potential 132 4.2.6. Evaluation of the Integrity of the OVA and the Liposomes 132 4.2.7. In vitro Mucoadhesion Test 133 4.2.8. Characterization of the TFF Vaccine Powders 133 4.2.9. Plume Geometry, Spray Pattern, and the Particle Size Distribution of the Aerosolized Powder 135 4.2.10. Deposition Pattern of the TFF Vaccine Powder 136 4.2.11. Statistical Analysis 139 4.3. Results and Discussion 140 4.3.1. Preparation and Thin-Film Freeze-Drying of the AdjLMQ/OVA Model Vaccine 140 4.3.2. Preparing AdjLMQ/OVA Vaccine Formulations with CMC 140 4.3.3. In vitro Mucoadhesion Test 141 4.3.4. The Integrity of the OVA Before and After the AdjLMQ/OVA Vaccine Formulations were Subjected to Thin-Film Freeze-Drying 143 4.3.5. Characterization of the TFF AdjLMQ/OVA Vaccine Powders with 0 or 1.9% w/w CMC 144 4.3.6. Spraytec Analysis of the Thin-Film Freeze-Dried AdjLMQ/OVA Vaccine Powders Sprayed with a UDSP Nasal Device 147 4.3.7. The Plume Geometry and Spray Pattern of the Thin-Film Freeze-Dried AdjLMQ/OVA Vaccine Powders Sprayed with the UDSP Nasal Device 150 4.3.8. The Integrity of the OVA and the AdjLMQ After the AdjLMQ/OVA Vaccine Powders were Sprayed Using the UDSP Nasal Device 151 4.3.9. Deposition Patterns of the TFF AdjLMQ/OVA/CMC1.9% Vaccine Powder in Nasal Replica Casts 152 4.4. Conclusions 163 4.5. References 164 Chapter 5. Intranasal Delivery of Thin-Film Freeze-Dried Monoclonal Antibodies Using a Powder Nasal Spray System 171 Abstract 171 5.1. Introduction 173 5.2. Materials and Methods 176 5.2.1. Materials 176 5.2.2. Preparation of AUG-3387 Dry Powders 176 5.2.3. Size Exclusion Chromatography (SEC) Analysis 177 5.2.4. Micro-Flow Imaging (MFI) Analysis 177 5.2.5. Measurement of the Residual Moisture Content 179 5.2.6. Measurement of the Specific Surface Area 179 5.2.7. X-ray Diffraction (XRD) 179 5.2.8. Plume Geometry and Spray Pattern 180 5.2.9. Scanning Electron Microscopy 180 5.2.10. Measurement of the Particle Size Distribution 181 5.2.11. Measurement of the Particle Size Distribution (“Dry” Method) 181 5.2.12. Intranasal Deposition Patterns of the TFF mAb Powder 182 5.2.13. Statistical Analyses 183 5.3. Results and discussion 184 5.3.1. Preparationd Characterization of TFF mAb Powders 184 5.3.2. Deposition Patterns of TFF AUG-3387C Powder in Nasal Replica Casts 195 5.4. Conclusions 198 5.5. References 199	-
dc.language.iso	en	-
dc.subject	孔洞材料	zh_TW
dc.subject	放射治療	zh_TW
dc.subject	增敏劑	zh_TW
dc.subject	金屬有機框架	zh_TW
dc.subject	鼻腔藥物輸送	zh_TW
dc.subject	Porous materials	en
dc.subject	Intranasal drug delivery	en
dc.subject	Radiotherapy	en
dc.subject	Sensitizers	en
dc.subject	Metal-organic frameworks	en
dc.title	互穿金屬有機框架之微小化及功能化並應用於癌症的光熱—放射聯合療法	zh_TW
dc.title	Downsizing and Functionalization of Interpenetrated Metal–Organic Frameworks for Combined Photothermal and Radiation Cancer Therapy	en
dc.type	Thesis	-
dc.date.schoolyear	112-2	-
dc.description.degree	博士	-
dc.contributor.oralexamcommittee	胡哲銘;游佳欣;陳慧文;萬德輝	zh_TW
dc.contributor.oralexamcommittee	Che-Ming Jack Hu;Jiashing Yu;Hui-Wen Chen;Dehui Wan	en
dc.subject.keyword	孔洞材料,金屬有機框架,增敏劑,放射治療,鼻腔藥物輸送,	zh_TW
dc.subject.keyword	Porous materials,Metal-organic frameworks,Sensitizers,Radiotherapy,Intranasal drug delivery,	en
dc.relation.page	205	-
dc.identifier.doi	10.6342/NTU202403823	-
dc.rights.note	同意授權(限校園內公開)	-
dc.date.accepted	2024-08-13	-
dc.contributor.author-college	工學院	-
dc.contributor.author-dept	化學工程學系	-
dc.date.embargo-lift	2026-08-07	-
顯示於系所單位：	化學工程學系

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