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Redox/ATP switchable theranostic nanoparticles for real-time fluorescence monitoring of doxorubicin delivery†
Journal of Materials Chemistry B ( IF 7 ) Pub Date : 2018-03-22 00:00:00 , DOI: 10.1039/c7tb03325g
Yi Lin 1, 2, 3, 4 , Yidi Yang 1, 2, 3, 4 , Jianqin Yan 1, 2, 3, 4 , Jun Chen 1, 2, 3, 4 , Jun Cao 1, 2, 3, 4 , Yuji Pu 1, 2, 3, 4 , Li Li 1, 2, 3, 4 , Bin He 1, 2, 3, 4
Affiliation  

In this study, redox/ATP switchable theranostic nanoparticles (TNs) with precise specificity and controllable mobility were developed for the real-time monitoring of the release of an anticancer drug. A fluorescent probe (FAM) and a quencher (BHQ-1) were covalently conjugated to one end of an adenosine-5′-triphosphate (ATP) aptamer and its complementary DNA (cDNA), respectively. Then, doxorubicin (DOX) was intercalated within the DNA duplex to form a stable physical conjugate (FBA@DOX). Poly(ethylene glycol)-block-poly (aspartic acid-graft-cystamine) (PAS), a glutathione-sensitive cationic polymer, was synthesized and complexed with the FBA@DOX, endowing it with excellent stability in physiological solutions. Fluorescence recovery/quenching, DNase degradation, in vitro drug release, cellular uptake, and intracellular trafficking results revealed that the TNs remained in the “OFF” state, with a minimal FAM fluorescent signal and negligible DOX premature release, in low-glutathione and/or low-ATP environments. In contrast, the TNs turned “ON” and rapidly released FBA@DOX in glutathione-rich environments after internalization in cancer cells. The intracellular ATP triggered the conformational changes in FBA@DOX, thereby enabling the controlled release of DOX and simultaneous recovery of the fluorescence for monitoring the DOX release. In a cytotoxicity and apoptosis study, the redox/ATP switchable TNs demonstrated strong anticancer effects, attributable to their selective release of the drug. Overall, our findings may offer a promising strategy for developing a new generation of “smart” theranostic platforms.

中文翻译:

氧化还原/ ATP可转换的治疗性纳米颗粒,用于实时荧光监测阿霉素的运输

在这项研究中,具有精确的特异性和可控制的迁移性的氧化还原/ ATP可转换的治疗性纳米颗粒(TNs)被开发用于实时监测抗癌药物的释放。将荧光探针(FAM)和淬灭剂(BHQ-1)分别共价偶联至5'-三磷酸腺苷(ATP)适体及其互补DNA(cDNA)的一端。然后,将阿霉素(DOX)插入DNA双链体中以形成稳定的物理偶联物(FBA @ DOX)。聚(乙二醇) -嵌段-聚(天冬氨酸-接枝-cystamine)(PAS),谷胱甘肽敏感性阳离子聚合物,合成并与FBA @ DOX复合,在生理溶液中良好的稳定性赋予它。荧光恢复/猝灭,DNase降解,体外药物释放,细胞吸收和细胞内运输结果表明,在低谷胱甘肽和/或低ATP环境中,TNs保持“ OFF”状态,具有最小的FAM荧光信号和可忽略的DOX过早释放。相反,在癌细胞内化后,TNs在富含谷胱甘肽的环境中变成“ ON”并迅速释放FBA @ DOX。细胞内ATP触发了FBA @ DOX的构象变化,从而实现了DOX的受控释放并同时回收了荧光以监测DOX的释放。在细胞毒性和凋亡研究中,氧化还原/ ATP可转换的TNs表现出强大的抗癌作用,这归因于它们的选择性释放。总体而言,我们的发现可能为开发新一代“智能”治疗论平台提供有希望的战略。
更新日期:2018-03-22
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