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研究生:許宣翎
研究生(外文):Xuan-Ling Hsu
論文名稱:PLGA奈米球結合玻尿酸水膠作為長效複合藥物劑型於濕性老年性黃斑部病變治療上之應用
論文名稱(外文):Application of Nanosphere-Hydrogel Composite Ocular Drug Delivery System for the Treatment of Wet Age-Related Macular Degeneration
指導教授:黃義侑黃義侑引用關係
指導教授(外文):Yi-You Huang
口試委員:黃意真許馨云
口試委員(外文):Yi-Cheng HuangHsin-Yun Hsu
口試日期:2020-07-20
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:醫學工程學研究所
學門:工程學門
學類:綜合工程學類
論文種類:學術論文
論文出版年:2020
畢業學年度:108
語文別:中文
論文頁數:74
中文關鍵詞:老年性黃斑部病變聚乳酸甘醇酸奈米球粒玻尿酸水膠可注射式藥物傳輸系統控制釋放
外文關鍵詞:Age-related macular degenerationPoly lactic-co-glycolic acidNanosphereHyaluronic acid hydrogelInjectable drug delivery systemControlled release
DOI:10.6342/NTU202002367
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濕性老年性黃斑部病變是由於脈絡膜層的血管往上新生到視網膜層,破壞了視網膜上的感光細胞導致視力受損的疾病。目前現行主要治療方式是透過玻璃體內注射抗血管新生因子的蛋白質藥物,藉此抑制脈絡膜血管生長,以達到治療目的,然而由於蛋白質藥物在玻璃體內的半衰期極短,導致患者必須每個月接受一次玻璃體內注射,才足以維持有效的藥物治療濃度,不僅會造成眼內發炎或視網膜剝離等副作用,對患者的心理與經濟上也帶來一大負擔。本研究透過結合PLGA奈米球粒與化學交聯型玻尿酸水膠,製作出包覆模型藥物牛血清白蛋白的可注射式複合型藥物傳輸系統,探討其在體外控制釋放藥物的能力。研究結果顯示,化學交聯型玻尿酸水膠可以在pH 7.4的生理環境下自發反應成膠並同時包覆含有BSA之PLGA奈米球粒,形成可注射式的複合型藥物傳輸系統,且此傳輸系統在37°C的環境下放置6週後仍保有六成以上的重量。體外試驗中,透過MTT試驗與Live/Dead染色證明此複合型藥物傳輸系統對於人類視網膜色素上皮細胞並沒有表現出明顯之細胞毒性,也不會對細胞型態有所影響,顯示材料擁有良好的生物相容性。最後,透過結合兩種藥物傳輸系統的方式,本研究可以將BSA之釋放時間從原本的一個禮拜延長到一個月以上,且所釋放出的藥物濃度依舊維持在有治療意義的濃度之上,顯示出此複合型藥物傳輸系統在濕性老年性黃斑部病變治療上,可以改善注射頻率並表現出一個更好的藥物釋放曲線的能力。
Wet age-related macular degeneration is mainly caused by the development of choroidal neovascularization, which penetrates the fibrous barrier between choroid and retina and damages the photoreceptor cells. The current treatment for wet AMD is monthly intravitreal injection of anti-vascular endothelium growth factor protein drugs. The monthly intravitreal injection increases the risks of adverse effects including endophthalmitis and retinal detachment; moreover, the psychological and economic burdens further reduce patient compliance. In the current study, we combine PLGA nanospheres with chemically crosslinked hyaluronic acid hydrogel to create an injectable composite drug delivery system encapsulating model drug bovine serum albumin and evaluate its capability of extending BSA release in vitro. The results suggest that the modified HA polymer can gel at phycological condition and encapsulate the drug-laden PLGA nanosphere upon injection. The in situ forming injectable composite DDS can maintain more than 60% of its wet weight at 37°C for more than six weeks. According to in vitro studies, the composite DDS have no cytotoxicity on human retinal pigmented epithelium cells (ARPE-19). Finally, the composite DDS can maintain BSA at the therapeutically relevant concentration for more than one month which is much longer than encapsulating BSA in chemically crosslinked HA hydrogel only. These outcomes show that the injectable composite drug delivery system can be a potential replacement for the treatment of wet AMD.
摘要 I
Abstract II
目錄 IV
圖目錄 VII
表目錄 IX
第一章 序論 1
1.1 老年性黃斑部病變 1
1.1.1 發病機制 2
1.1.2 治療方式 5
1.1.2.1 雷射治療 5
1.1.2.2 抗血管內皮生長因子之蛋白質藥物治療 6
1.1.2.2.1 貝伐單抗(Bevacizumab) 7
1.1.2.2.2 蛋白質藥物治療風險 8
1.2 長效型藥物傳輸系統在AMD治療上的應用 9
1.2.1 高分子奈米球粒(Polymeric Nanosphere) 9
1.2.2 可注射式水膠(Injectable Hydrogel) 11
1.2.3 複合型藥物釋放系統(Composite Drug Delivery System) 13
1.3 聚乳酸-甘醇酸 14
1.4 玻尿酸 15
1.5 牛血清白蛋白 16
第二章 研究概述 17
2.1研究動機與目的 17
2.2研究方法概述 18
2.3實驗流程圖 19
2.4複合型藥物傳輸系統示意圖 19
第三章 實驗材料與方法 20
3.1實驗藥品 20
3.2實驗儀器 21
3.3材料製備 22
3.3.1 搭載牛血清白蛋白之PLGA奈米球 22
3.3.2 雙乙烯碸改質之玻尿酸(HA-VS) 23
3.3.3 二硫蘇糖醇改質之玻尿酸(HA-SH) 24
3.3.4 搭載蛋白質藥物之複合型藥物釋放系統 25
3.4材料分析 26
3.4.1 PLGA奈米球之蛋白質包覆率/蛋白質搭載率測定 26
3.4.2 PLGA奈米球之水合粒徑分析(Dynamic Light Scattering, DLS) 27
3.4.3 全反射式紅外線傅立葉光譜儀分析(ATR-FTIR) 27
3.4.4 掃描式電子顯微鏡分析(Scanning Electron Microscope, SEM) 27
3.4.5 核磁共振光譜儀分析(Nuclear Magnetic Resonance, NMR) 27
3.4.6 水膠/複合型藥物傳輸系統之膨潤以及降解曲線測定 28
3.4.7 化學交聯玻尿酸水膠之可注射性 30
3.4.8 水膠/複合型藥物傳輸系統成膠時間測定 30
3.5體外試驗 31
3.5.1 體外生物相容性測試 31
3.5.2 細胞影像觀察 32
3.5.3 水膠/複合型藥物傳輸系統於體外控制釋放牛血清白蛋白 33
3.6統計分析 34
第四章 結果與討論 35
4.1含牛血清白蛋白之聚乳酸-甘醇酸奈米球粒合成參數設定 35
4.2含牛血清白蛋白之聚乳酸-甘醇酸奈米粒子特性分析 38
4.3改質後玻尿酸高分子之化學結構分析 40
4.4化學交聯玻尿酸水膠之膨潤/降解趨勢 42
4.5複合型藥物傳輸系統之膨潤/降解趨勢 44
4.6化學交聯玻尿酸水膠之可注射性 46
4.7化學交聯玻尿酸水膠/複合型藥物傳輸系統之成膠時間 47
4.8複合型藥物傳輸系統對ARPE-19之細胞毒性 49
4.9複合型藥物傳輸系統對ARPE-19細胞型態之影響 51
4.10化學交聯玻尿酸水膠於體外控制釋放牛血清白蛋白之能力 57
4.11複合型藥物傳輸系統於體外控制釋放牛血清白蛋白之能力 60
第五章 結論 65
參考文獻 68
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