開發可由葡萄醣醛酸苷酶調控式之金奈米近紅外光造影劑

Chia Nan University of Pharmacy & Science Institutional Repository > 藥理學院 > 藥學系(所) > 科技部計畫 > Item 310902800/32733

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標題:	開發可由葡萄醣醛酸苷酶調控式之金奈米近紅外光造影劑 Developmet of Off/On Beta-Glucuronidase Activated Near-Infrared Gold Naraparticles Probes
作者:	呂玉玲鄭添祿
貢獻者:	嘉南藥理大學藥學系(含碩士班)
關鍵字:	β-葡萄醣酸苷酶glucuronidas 近紅光造影劑 β-glucuronidase near infrared (NIR) probe
日期:	2017
上傳時間:	2020-11-16 15:05:04 (UTC+8)
摘要:	β-葡萄醣酸苷酶glucuronidas (βG)為重要的腫瘤標記，近年來有許多以βG為基礎之前驅抗癌藥物被開發；此外研究也指出，腸道βG活性會促進已解毒物質在腸道的再活化而引起病變，並導致大腸癌生成。因此，建構一個可調控式(off/on)的βG近紅光造影劑來偵測活體內βG活性將有助於以βG為基礎的臨床應用，包含βG前驅藥物與預防大腸癌藥物-βG抑制劑的開發。先前我們已成功建構了βG的近紅外光捕捉型造影劑NIR-TrapG，此造影劑經βG活化後可與附近蛋白結合，可用來偵測腫瘤βG活性並搭配前驅藥物治療。然而，NIR-TrapG活化前後都會持續散發螢光訊號，造成其他區域有高背景值而影響造影結果。為了解決這個問題，我們將開發新一代可由G調控之金奈米(AuNPs)近紅外光造影劑Glu-NIRoff-AuNPs，利用金奈米淬熄近紅光訊號，只有在βG水解後才會恢復近紅外光訊號，將可降低在其他區域的背景值而增加造影的敏感度及準確性。目前我們已經完成一系列Glu-NIRoff-的合成，成功連接葡萄醣醛酸glucuronide與近紅外光分子IR-775，並連接上SH-linker以提供金奈米粒子修飾用。基於上述成果，本計畫將進行：(1)建立βG可調控式(off/on)金奈米近紅外光造影劑Glu-NIRoff-AuNPs；(2) 用造影劑Glu-NIRoff-AuNPs偵測活體內原位大腸癌βG活性高低並搭配化療藥物CPT-11發展個人化治療；(3)以造影劑Glu-NIRoff-AuNPs檢測活體內腸道βG活性以開發腸道βG抑制劑，進一步預防大腸癌。我們相信本創新造影劑Glu-NIRoff-AuNPs的成功，可克服過去βG造影劑高背景的問題，用於即時有效偵測活體內腫瘤及腸道βG活性，將可加速以βG為標的之個人化癌症治療與預防藥物的開發。 β-glucuronidase (βG) is an important tumor maker, which is used as a prodrug-converting enzyme for selective chemotherapy therapy, thus various G-prodrugs have been developed. Moreover, studies also indicated that intestinal G activity reactivates the detoxified chemicals and releases toxic chemicals thus causing toxicity and intestinal injury, leading to tumorigenesis. Therefore, developing an off/on glucuronide near infrared (NIR) probe for real-time imaging of G activity can accelerate G-based drugs development for clinical application, including G-prodrugs for cancer treatment and G inhibitor for prevention of colon cancer. Previously, we have developed a NIR glucuronide probe (NIR-TrapG) which was used to detect tumor G activity and access the therapeutic efficacy of glucuronide prodrugs. However, sustained releasement of NIR signal increases background signal that interferes the imaging results. To overcome this problem, our strategy is to generate an off/on G-activated NIR gold naraparticles (Au-NPs) probes, Glu-NIRoff-AuNPs. This probe contains Au-NPs that quench NIR signal. The NIR signal is released only after hydrolysis by G, thus decreasing the background signal and increasing the sensitivity and accuracy for real-time imaging. We have successfully conjugated glucuronide with IR775, and further synthesized with a SH-linker for the Au-NPs to conjugate. Based on these results, the aim of this study is to: (1) Generate an off/on glucuronide NIR probe, Glu-NIRoff-AuNPs, (2) Assess tumor G activity by Glu-NIRoff-AuNPs probe in orthotropic colon cancer models for developing personalized chemotherapy treatment of CPT-11, and (3) Image intestinal G activity by Glu-NIRoff-AuNPs probe for developing intestinal G inhibitor for chemoprevention of colon cancer. We believe upon completion, this new probe will used to real-time monitor tumor or the intestinal G activity, accelerating G-based personalized cancer treatment and prevention.
關聯:	計畫編號：MOST106-2320-B041-001 計畫年度：106 執行起迄：2017-08~2018-07
显示于类别:	[藥學系(所)] 科技部計畫

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