研究生: |
鍾艾 Ai Chung |
---|---|
論文名稱: |
通過腺嘌呤和脲嘧啶之互補性氫鍵作用力來開發超分子藥物傳載系統 Development of Supramolecular Drug Delivery System Through the Complementary Hydrogen Bonding Interaction of Adenine and Uracil |
指導教授: |
郭東昊
Dong-Hau Kuo 鄭智嘉 Chih-Chia Cheng |
口試委員: |
郭東昊
Dong-Hau Kuo 鄭智嘉 Chih-Chia Cheng 楊銘乾 Ming-Chien Yang |
學位類別: |
碩士 Master |
系所名稱: |
工程學院 - 材料科學與工程系 Department of Materials Science and Engineering |
論文出版年: | 2021 |
畢業學年度: | 109 |
語文別: | 中文 |
論文頁數: | 140 |
中文關鍵詞: | 超分子藥物傳載系統 、羅丹明6G 、腺嘌呤 、脲嘧啶 、BU-PPG |
外文關鍵詞: | supramolecular drug delivery system, R6G, adenine, uracil, BU-PPG |
相關次數: | 點閱:321 下載:0 |
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結合高螢光和穩定性的藥物傳載系統在癌症治療中仍具有很高的挑戰性。在此論文中,我們成功開發了一新型基於羅丹明的超分子藥物(A-R6G),該藥物包含多重氫鍵的腺嘌呤部分,其展現出高疏水性和獨特的物理特性,包含優異的螢光特性、特異的自組裝行為及高度細胞毒性。通過麥可加成與脲嘧啶反應的聚丙二醇二丙烯酸甲酯,創建其 A-R6G 的互補性夥伴,即含有雙官能脲嘧啶末端基的水溶性超分子微胞(BU-PPG)。由於通過腺嘌呤和脲嘧啶之間具有互補性氫鍵作用力的特性,疏水性的 A-R6G 和親水性的 BU-PPG 能夠形成複合體,進而在水溶液中形成具高度穩定包載 A-R6G 的 BU-PPG 微胞。所得包載 A-R6G 的微胞具有極高的 A-R6G 包載量(高達 84%)、出色的 A-R6G 包封性及在富含血清的培養基中的穩定性、可控的 pH /溫度響應性藥物釋放能力。有趣的是,體外細胞毒性研究證實,包載 A-R6G 的 BU-PPG 微胞對癌細胞表現出選擇性的細胞毒性,且不會傷害正常細胞,這可歸因於在癌細胞的微酸環境下,微胞中的互補性氫鍵脲嘧啶-腺嘌呤二聚體迅速解離,隨後在細胞內釋放 A-R6G,從而在癌細胞中產生高選擇性的生物毒性作用。更重要的是,螢光影像和流式細胞儀分析清楚地表明,包載 A-R6G 的 BU-PPG 微胞透過內吞途徑進入癌細胞中並有效誘導細胞凋亡,但抑制其正常細胞的內化並導致高度生物相容性。因此,新開發的互補性藥物傳遞系統是增強癌症化學療法安全性和有效性的可行策略及潛在的途徑。
The combination of both high fluorescence and stable drug delivery system for cancer therapy remains highly challenging. In this thesis, we successfully developed a novel rhodamine-based supramolecular drug (A-R6G) containing multiple hydrogen-bonded adenine moiety that exhibit high hydrophobicity and unique physical properties including excellent fluorescence features, as well as intriguing self-assembly behavior and high cytotoxicity. A complementary partner to A-R6G, water-soluble supramolecular micelles (BU-PPG) containing difunctional uracil-containing end groups, was created by Michael addition of poly(propylene glycol) diacrylate reacted with uracil. Due to the nature of the molecular recognition between the adenine and uracil moieties through complementary hydrogen bonding interactions, hydrophobic A-R6G and hydrophilic BU-PPG are able to form complexes that can form highly stable A-R6G-loaded BU-PPG micelles in aqueous solution. The resulting A-R6G-loaded micelles possess extremely ultra-high A-R6G-loading capacity (up to 84%), excellent A-R6G-encapsulation retention and stability in serum-rich medium, as well as well-controlled pH/temperature-responsive drug release ability. Interestingly, in vitro cytotoxicity studies confirmed that A-R6G-loaded BU-PPG micelles exhibit selective cytotoxicity in cancer cells, without harming normal cells, which is attributed to the rapid dissociation of the complementary hydrogen-bonded uracil-adenine dimers within the micelles at mildly acidic intracellular pH of cancer cells, followed by intracellular release of A-R6G, thus resulting in high selective cytotoxic effect in cancer cells. More importantly, fluorescence images and flow cytometric analysis clearly demonstrated that A-R6G-loaded BU-PPG micelles selectively entered cancer cells through endocytic pathways and efficiently induced apoptotic cell death, but inhibited internalization by normal cells and resulted in high biocompatibility against normal cells. Thus, this newly-developed complementary drug delivery system could be a viable strategy and potential route for enhancing the safety and efficacy of cancer chemotherapy.
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