開發心肌缺氧後再灌流傷害用藥與近紅外光染劑的高效率微脂體包覆方法

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姓名

余序恩(Xu-En Yu) 查詢紙本館藏

畢業系所

化學學系

論文名稱

開發心肌缺氧後再灌流傷害用藥與近紅外光染劑的高效率微脂體包覆方法

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摘要(中)

本研究開發微脂體以主動包覆方式包覆數種醫學上重要的藥物及化合物。其中被包覆物聚焦在治療心肌細胞受損(缺氧後再灌流)的藥物與近紅外光螢光染劑。
心肌缺氧後再灌流(reperfusion)對心肌的再傷害為心臟病治療一棘手問題。目前臨床上治療此傷害的方式為投放藥物治療。但由於藥物生物分布選擇性差，造成藥效降低，所以選擇性將治療再灌留藥物集中分布到受損心肌以提高藥物被利用的效果為治療的重要課題。本實驗為開發新藥物及化合物的微脂體主動包覆的方法為主。嘗試各種不同trapping agent的鹽類梯度，利用主動包覆的方法，提升大部分的藥物被包覆於微脂體內之機率及包覆效率。以供後續團隊可嘗試證實此類微脂體藥物治療心肌受損的可行性。
包覆紅外光螢光染劑則是在活體內偵測微脂體可被引信響應釋放的重要方法。目前微脂體活體內影像學僅具有只能看出微脂體的分布，而無法看出微脂體的釋放的限制。此計畫試圖開發高濃度的紅外螢光染料的主動包覆，再利用實驗室另行開發的引信響應方法，使微脂體快速將讓大部分的染劑被釋放出來，達到活體內觀測微脂體釋放的效果。

摘要(英)

My thesis work is to develop active (remote) loading methods for encapsulating (1) myocardial reperfusion injury drugs and (2) near infrared dyes (for in vivo imaging) into liposomes.
Reperfusion injury might be treated if we can spatial-selectively deliver the drug to the reperfusion area and rapidly unload the drug before irreversible damage occurs. This work is a sub-project that focuses on the development of highly efficient content encapsulation of liposome using active loading approach. We have screened and found several trapping agents / drug pairs that can offer high loading efficiency.
The second part of this work is, instead of loading myocardial infarction drugs, to encapsulate near-infrared (NIR) dyes for the detection of liposomal triggered release, in live small animal and in real time fashion. At present, dye encapsulated liposome in vivo imaging studies only allow us to see the biodistribution of liposome. To the best of our knowledge, liposome triggered-release that can be fluorescently visualized in small animal has not been reported yet. In the second project, we also tried to screen many pairs of trapping agents and NIR dyes to identify the best combination for NIR dye-encapsulated liposome in which the dye concentration is high enough for fluorescently self-quenched. In the future, hopefully we can use the fluorescent reporting, dye-encapsulated liposome to confirm the liposomal triggered release in small animal level.

關鍵字(中)

★ 微脂體
★ 藥物包覆

關鍵字(英)

論文目次

摘要 I
Abstract II
致謝 III
目錄 IV
圖目錄 VII
表目錄 X
縮寫表 XI
第一章緒論 1
1.1 前言 1
1.2 微脂體 (liposome) 2
1.3 微脂體藥物包覆方法 6
1.3.1 被動包覆 6
1.3.2 主動包覆 7
1.4 研究目的 11
第二章實驗儀器與材料 18
2.1 實驗儀器 18
2.2 實驗材料 19
第三章實驗方法 23
3.1各式微脂體製備 23
3.2微脂體定量 24
3.3藥物包覆 25
3.4自製尺寸分離液相層析法 26
3.5 Zetasizer 27
3.6冷凍生物電子顯微技術 (Cryo-EM) 28
3.7電子自旋共振儀 (electron spin resonance ; ESR) 29
第四章實驗結果與討論 (Part I) 30
4.1 不同的trapping agent 包覆藥物 30
4.1.1 IOX2 30
4.1.2 4-胺-2,2,6,6-四甲基二苯?酯 (Tempamine) 35
4.1.3 2-丁亞磺醯-4-苯-6-?吩-2-?吩並[5,4-b]?啶-3-胺 (Sw033291) 39
4.2 不同的trapping agent 包覆染劑 43
4.2.1 ICG 43
4.2.2 IR820 46
4.2.3 Cy 5.5 derivatives 48
第五章實驗結果與討論 (Part II) 57
5.1 微脂體包覆缺氧心臟再灌流傷害用藥 57
5.2 微脂體包覆近紅外光染劑 58
5.3 微脂體膜組成的決定 59
5.4 微脂體內部鹽類對包覆的影響 60
第六章總結 61
參考文獻 62
附錄 69

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指導教授

謝發坤、李賢明(Fa-Kuen Shieh Hsieng-Ming Lee)

審核日期

2017-3-6

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