以溫和水相法封裝胰島素至鋁基底金屬有機骨架材料A520於糖尿病治療之研究

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曾昭瑋(Jau-Wei Tzeng) 查詢紙本館藏

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化學學系

論文名稱

以溫和水相法封裝胰島素至鋁基底金屬有機骨架材料A520於糖尿病治療之研究
(A Mild Water-based Approach for Obtaining Encapsulation of Insulin into Aluminum -based Metal-Organic Frameworks A520 for Diabetic Treatments)

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至系統瀏覽論文 (2028-6-30以後開放)

摘要(中)

糖尿病為一種常見的慢性代謝異常疾病，根據統計全球現有五億人罹患糖尿病。即使目前有設計許多治療方法來治療第一型與第二型糖尿病，但較為嚴重的糖尿病患者只能透過直接注射胰島素來治療，所以開發口服胰島素來減輕患者因注射所帶來的痛苦與不便是必要的。有機金屬骨架材料 (MOFs) 是一種新興的奈米孔洞材料，其孔洞性質在各領域皆有很大的發展潛力，也是酵素固定化與藥物載體理想的材料之一。本篇論文成功的以較溫和的水相環境快速合成鋁基底金屬骨架有機材料A520，其材料擁有耐酸的性質，並且其中心金屬為鋁，在醫學上鋁鹽已被用作佐劑已有很長的歷史，對人體有相當好的生物相容性，而有機配體反丁烯二酸皆對於人體有很低的毒性，因此A520具有很大的潛力能夠成為口服胰島素藥物載體。本篇論文也成功的以鋁基底金屬有機骨架材料包覆胰島素，其包覆率約為5%。此外，本論文也使用模擬腸液、胃液與血液的溶液來測試材料的穩定度，其結果也驗證了材料對於胃與小腸環境之耐受性與在血液之環境能夠崩解之特性。本論文亦成功以同樣的方式合成CAT@A520，並且在大分子蛋白水解酶(proteinase K)的作用下，能夠保護過氧化氫酶並維持良好的催化活性。其證明此材料具有一定的孔洞篩選性，能夠保護酵素不被大分子蛋白酶所分解而失活，而同理可以推論其可以保護胰島素不被胃中大分子的胃蛋白酶所攻擊而分解。本研究充分顯示了A520對於成為胰島素藥物載體的可行性，期望其能夠對於口服胰島素的發展帶來突破。

摘要(英)

Diabetes is a common chronic metabolic disorder. According to statistics, there are currently 500 million people worldwide suffering from diabetes. Despite the availability of various treatment methods for type 1 and type 2 diabetes, individuals with severe diabetes can only rely on direct insulin injections for treatment. Therefore, the development of oral insulin (INS) administration to alleviate the pain and inconvenience caused by injections is necessary.Metal-organic frameworks (MOFs) are promising porous nanoscale materials with diverse applications in various fields. One area where they show great potential is in enzyme immobilization and drug delivery systems. This paper successfully achieved the rapid synthesis of aluminum-based metal-organic framework material A520 in a relatively mild water-based environment. The material exhibits acid-resistant properties, with aluminum as the central metal. Aluminum salts have a long history of use as adjuvants in medicine and are known for their good biocompatibility with the human body. Additionally, the organic ligand, fumaric acid, has low toxicity to the human body. Therefore, A520 has great potential to serve as an oral insulin drug carrier. The study achieved a 5% insulin loading capacity in the INS@A520 biocomposite. A520 exhibited remarkable stability in simulated gastric and intestinal fluids, as well as efficient dissolution in the bloodstream. This highlights its potential as an innovative carrier for oral insulin delivery, paving the way for future advancements in MOF-based drug delivery systems. Using a similar approach, we successfully obtained the CAT@A520 biocomposite by encapsulating the Catalase (CAT) enzyme within A520. In the presence of the proteinase K enzyme, this material effectively shields CAT, maintaining its catalytic activity. This showcases the material′s selective pore behavior, safeguarding enzymes from degradation by large molecule proteases and preserving their functionality. Consequently, it can be inferred that A520 may also shield insulin from gastric proteases′ attack and degradation in the stomach. This research strongly supports the viability of A520 as an insulin drug carrier, holding the potential for significant advancements in oral insulin development.

關鍵字(中)

★ 鋁基底有機金屬骨架材料
★ 胰島素
★ 蛋白固定化
★ 糖尿病治療
★ 溫和水相合成法

關鍵字(英)

論文目次

摘要 I
ABSTRACT III
目錄 V
圖目錄 VIII
表目錄 X
第 1 章緒論 1
1.1 有機金屬骨架材料（Metal Organic Frameworks） 1
1.2 鋁金屬之有機金屬骨架材料 3
1.3 鋁金屬之金屬有機骨架材料-Aluminum Fumarate (A520) 4
1.4 糖尿病 4
1.5 研究目的 5
第 2 章實驗部分 6
2.1 化學藥品 6
2.2 實驗儀器 8
2.3 實驗使用儀器 8
2.3.1 實驗鑑定儀器 9
2.4 實驗儀器之原理 10
2.4.1 X 射線粉末繞射圖譜 10
2.4.2 場發射掃描式電子顯微鏡 12
2.4.3 高效能液相層析儀 (High Performance Liquid Chromatography, HPLC) 13
2.4.4 等溫氮氣吸/脫附儀 (Nitrogen Ad/desorption Isotherms) 14
2.5 酵素與激素 17
2.5.1 過氧化氫酶 17
2.5.2 蛋白酶K 17
2.5.3 胰島素 18
2.6 實驗步驟 20
2.6.1 金屬有機骨架材料-A520之合成 20
2.6.2 金屬有機骨架材料-CAT@A520 之合成 20
2.6.3 金屬有機骨架材料-INS@A520 之合成 21
2.6.4 布拉德福蛋白質定量法 (Bradford Assay) 21
2.6.5 十二烷基硫酸鈉聚丙醯胺膠體電泳 (SDS-PAGES) 23
2.6.6 測定過氧化氫酶之活性 25
2.6.7 酵素結合免疫吸附分析法Enzyme-linked immunosorbent assay (ELISA) 27
2.6.8 高效能液相層析儀HPLC之測定 28
第 3 章結果與討論 30
3.1 A520與INS@A520之鑑定 30
3.1.1 X射線粉末繞射圖譜分析 31
3.1.2 INS@A520布拉德福蛋白質測定法 (Bradford assay) 33
3.1.3 場發射掃描電子顯微鏡 (SEM) 34
3.1.4 A520材料酸性測試 35
3.1.5 A520 PBS血液模擬崩解測試 37
3.1.6 INS@A520之BET測定 39
3.1.7 高效能液相層析儀 (HPLC) 40
3.1.8 酵素結合免疫吸附分析法(Enzyme-linked immunosorbent assay, ELISA) 41
3.2 CAT@A520之鑑定與活性測試 43
3.2.1 X射線粉末繞射圖譜分析 43
3.2.2 CAT@A520布拉德福蛋白質測定法 (Bradford Assay) 44
3.2.3 十二烷基硫酸鈉聚丙醯胺膠體電泳 45
3.2.4 場發射掃描式電子顯微鏡 (SEM) 46
3.2.5 CAT@A520之BET測定 47
3.2.6 過氧化氫酶活性測定 (FOX assay) 48
第 4 章結論與未來展望 50
參考文獻 51

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指導教授

謝發坤

審核日期

2023-8-14

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