設計合成可被葡萄醣醛酸?活化之近紅外光探針應用於癌症診斷與治療

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標題:	設計合成可被葡萄醣醛酸?活化之近紅外光探針應用於癌症診斷與治療 Design and Synthesis β-Glucuronidase Based (off/on) Near-Infrared Probes for Anticancer Diagnosis and Therapy 本研究旨在設計與合成可藉由β-葡萄醣醛酸?(β-glucuronidase, βG)調控(off/on) 之近紅外光探針Glu-NIRoff-Quencher。其設計策略係將葡萄醣醛酸基通過一可自分解(self-immolative) 的芐基苯環中間棒，連接近紅外光發光基團和淬熄劑基團，使兩者之間有足夠近的距離，透過如π-相互作用、凡得瓦接觸…等形成分子內複合物，因為靜態和動態交互作用實現螢光猝熄。此探針，可被βG專一性水解，然後經由1, 6-脫去反應(1, 6-elimination reaction)釋放出螢光團或猝熄團，二者距離變大而交互作用消失，螢光恢復。可調控螢光探針Glu-NIRoff-Quencher具有背景低，專一性激活和非侵入性深層組織成像的優點，可以即時觀察某些腫瘤和腸道中βG的活性，將是加速癌症預防與治療的重要工具。通過相同的策略，我們也設計了Glu-NIRoff-Drug，是可藉βG調控的治療型探針。我們將喜樹鹼類化學治療藥物做為猝熄分子將近紅外光淬熄，因為是前驅藥，毒性較原形藥弱，經βG活化後毒性和螢光才恢復，達到同時殺死腫瘤細胞和顯影。Glu-NIRoff-Drug結合診斷和治療的功能，可以選擇性地靶向癌細胞，提供細胞毒性藥物，又同時在腫瘤組織中產生易於監測的成像信號，這有助於減少副作用和實時監測藥效的潛力，從而促進癌症個性化醫療的發展。 This study aims to design and synthesize a βG-based (off/on) near-infrared (NIR) probe, Glu-NIRoff-Quencher. In which glucuronic acid is connected via a self-immolative aromatic linker to NIR fluorophore and quencher. The control of intramolecular complex formation between fluorophore and quencher like π-interactions, van der Waals contact, etc., results in fluorescence quenching via both static and dynamic quenching. Upon hydrolyzed by βG specificity to liberate fluorophore or quencher through a 1, 6-elimination reaction, then restore the fluorescence. Fluorescence switchable Glu-NIRoff-Quencher probe has the advantages of low background, specific activation, and noninvasive deep-tissue imaging. It is a valuable tool for instantly visualizing βG activity in some tumors and intestinal to accelerate the development of personalized cancer treatment and prevention. By use of the same strategy, we design Glu-NIRoff-Drug as a βG-specific fluorescent theragnostic prodrug containing glucuronic acid, a chemotherapeutic drug, and NIR fluorophore along with an aromatic self-immolative linker. Chemotherapeutic drug plays the role of quenching and be released to kill tumor cells after activation. Therefore, Glu-NIRoff-Drug can target cancer cells selectively, offer a cytotoxic drug and produce readily monitored imaging signals in tumor tissues. It is foreseeable that combining specialized diagnosis and therapy would be the potential to enhanced anticancer efficacy, correct diagnosis and real-time monitoring for advancing the fields of personalized medicine.
作者:	林偉琪
貢獻者:	藥學系呂玉玲
關鍵字:	葡萄醣醛酸? 近紅外光探針 β-glucuronidase near-infrared probe
日期:	2020
上傳時間:	2022-10-21 10:32:41 (UTC+8)
關聯:	學年度：108， 80頁
顯示於類別:	[藥學系(所)] 博碩士論文

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