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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 方俊民(Jim-Min Fang) | |
| dc.contributor.author | Tung-Yu Wu | en |
| dc.contributor.author | 吳東餘 | zh_TW |
| dc.date.accessioned | 2021-07-10T21:41:41Z | - |
| dc.date.available | 2021-07-10T21:41:41Z | - |
| dc.date.copyright | 2020-08-06 | |
| dc.date.issued | 2020 | |
| dc.date.submitted | 2020-08-04 | |
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Z.; Bonnitcha, P.; Wexselblatt, E.; Klein, A. V.; Najajreh, Y.; Gibson, D.; Hambley, T. W. Facile preparation of mono-, di- and mixed-carboxylato platinum(IV) complexes for versatile anticancer prodrug design. Chemistry 2013, 19, 1672-1676. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/76961 | - |
| dc.description.abstract | 癌症相關議題長期困擾著人類，隨著人口的增長和衰老，問題變得更加嚴重。 順鉑(cisplatin)為常用的抗癌藥物之一，其主要的細胞毒活性是通過與DNA中的鳥嘌呤螯合而產生。但是順鉑同時具有低選擇性等多種副作用，因此其使用受到限制。過去研究有展現出許多降低毒性的前驅藥方法。非共價前驅藥是一個突出的例子，藉由將順鉑包封在脂質體中以提高選擇性，減少副作用並獲得所需的生物分佈。 組合療法(combination therapy)搭配脂質體傳輸是提高抗癌藥物效率的好方法。法尼基硫柳酸(salirasib)是Ras蛋白抑制劑，也是抗癌藥的候選藥物。然而無法精確控制脂質體包封兩種藥物的比例成為法尼基硫柳酸和順鉑組合療法所面臨的挑戰。為了解決藥物開發的比例問題，本篇論文展現了順鉑的Pt（IV）前驅藥二羥基順鉑(oxoplatin)經由可生物裂解的鍵結與法尼基硫柳酸形成共軛藥物，用於脂質體封裝。使用這種共價鍵鍵結方法可確保兩種抗癌藥的比例，並在特定的癌症環境中以兩種藥物的形式釋放，從而增強細胞毒性的功效。本論文不僅表徵了二羥基順鉑-法尼基硫柳酸脂質體的性質，而且揭示可能的藥物釋放機理。預期此二羥基順鉑-法尼基硫柳酸共軛藥物的脂質體可以選擇性標靶癌細胞，並且展現協同或加成的毒殺效果。 | zh_TW |
| dc.description.abstract | Cancer has troubled humans for a long time, and becomes even more problematic with increasing population and aging. Cisplatin is one of commonly used anticancer drugs to cause cytotoxicity mainly by chelation with guanines in DNA. The use of cisplatin is limited due to the side effects of its nonselective nature. There are several approaches of prodrugs to lower systemic toxicity. One prominent example of noncovalent prodrugs is to encapsulate cisplatin in liposomes to improve selectivity, reduce side effect and gain the desired biodistribution. Combination therapy along with liposomal delivery is a good approach to improve the efficiency of anticancer drugs. Salirasib is a Ras protein inhibitor and candidate of anticancer agent. Though combination of salirasib and cisplatin can be applied in therapy, the proportion of two drugs for liposomal encapsulation cannot be precisely controlled. To solve this problem in drug development, herein, we demonstrate that oxoplatin, a Pt(IV) prodrug of cisplatin, can conjugate with salirasib via a bio-cleavable linker for liposomal encapsulation. This covalent linkage method ensures the ratio of two anticancer agents, which will be released as two free drugs in the specific cancer environment to enhance the efficacy of therapy. In this study, not only the property of oxoplatin-salirasib liposome was characterized, but also the mechanism for releasing drugs was determined. The liposomal oxoplatin-salirasib conjugate is expected to selectively target cancer cell and exert synergistic or additive cytotoxicity. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-10T21:41:41Z (GMT). No. of bitstreams: 1 U0001-0308202013352500.pdf: 4480591 bytes, checksum: ddfa07426651166a319e61c7153fb5a1 (MD5) Previous issue date: 2020 | en |
| dc.description.tableofcontents | 謝誌 I 摘要 II Abstract III Table of Contents V List of Figures IX List of Tables XI List of Schemes XII Abbreviations XIII Chapter 1. Introduction 1 1.1 Overview of cancer 1 1.2 Cause of cancer 2 1.2.1 Etiology 2 1.2.2 Pathophysiology: cancer and cell cycle 3 1.2.3 Mutation of Ras proteins 4 1.3 Chemotherapy 6 1.3.1 Cisplatin 7 1.3.2 Mechanism of cisplatin-induced cytotoxicity 8 1.3.3 Resistance of cisplatin 9 1.4 Molecularly targeted therapy 12 1.4.1 Salirasib 12 1.4.2 Mechanism of salirasib 13 1.5 Liposomal drug delivery system 15 1.5.1 Features of liposomal drug delivery system 15 1.5.2 Intracellular delivery of liposomes 18 1.5.3 Composition of liposome 20 1.5.4 Lipoplatin 21 1.6 Determination of phospholipid content 23 1.7 Determination of biological activity 23 1.8 Aim of this study 24 Chapter 2. Results and Discussion 26 2.1 Design and synthesis of oxoplatin-salirasib anticancer drug 26 2.1.1 Principle of design 26 2.1.2 Synthesis of oxoplatin-salirasib conjugate (opsal 4) 27 2.1.3 Characterization of opsal 4 30 2.1.4 Stability studies of conjugate 4 33 2.1.5 Reduction test of conjugate 4 with ascorbic acid 36 2.1.6 Enzymatic hydrolysis of conjugate 4 with carboxylesterase 38 2.1.7 Mechanism for release of two drugs by reduction of oxoplatin-salirasib conjugate 40 2.2 Preparation and characterization of opsal 4-loaded liposomes 41 2.3 Evaluation of biological activity 45 2.4 Conclusion and prospect 50 Chapter 3. Experimental Section 52 3.1 General method 52 3.2 Synthetic procedures and characterization of compounds 53 3.3 Stability studies of conjugate 4 57 3.4 Reduction test of conjugate 4 with ascorbic acid 58 3.5 Enzymatic hydrolysis of conjugate 4 with carboxylesterase 59 3.6 Preparation of 4@liposomes 59 3.7 Characterization of 4@liposomes 60 3.8 Determination of phospholipid concentration in liposome by Bartlett’s assay 61 3.9 Bioassay of cytotoxicity to cancer cells 62 3.9.1 Cell culture 62 3.9.2 In vitro cytotoxic activity 62 Chapter 4. References 64 Appendix-1 73 Appendix-2 78 Appendix-3 84 | |
| dc.language.iso | en | |
| dc.subject | 共軛抗癌藥物 | zh_TW |
| dc.subject | 順鉑 | zh_TW |
| dc.subject | 法尼基硫柳酸 | zh_TW |
| dc.subject | 脂質體傳輸 | zh_TW |
| dc.subject | 前驅藥 | zh_TW |
| dc.subject | conjugated anticancer drug | en |
| dc.subject | cisplatin | en |
| dc.subject | salirasib | en |
| dc.subject | prodrug | en |
| dc.subject | liposomal delivery | en |
| dc.title | 利用脂質體傳輸二羥基順鉑−法尼基硫柳酸共軛抗癌藥物
| zh_TW |
| dc.title | Oxoplatin−Salirasib Conjugated Anticancer Drugs for Liposomal Co-Delivery | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 108-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 吳漢忠(Han-Chung Wu),王宗興(Tsung-Shing Wang),陳振中(Chun-Chung Chan) | |
| dc.subject.keyword | 順鉑,法尼基硫柳酸,脂質體傳輸,共軛抗癌藥物,前驅藥, | zh_TW |
| dc.subject.keyword | cisplatin,salirasib,liposomal delivery,conjugated anticancer drug,prodrug, | en |
| dc.relation.page | 95 | |
| dc.identifier.doi | 10.6342/NTU202002264 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2020-08-04 | |
| dc.contributor.author-college | 理學院 | zh_TW |
| dc.contributor.author-dept | 化學研究所 | zh_TW |
| Appears in Collections: | 化學系 | |
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| U0001-0308202013352500.pdf Restricted Access | 4.38 MB | Adobe PDF |
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