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Dumbbell-Shaped Antisense Oligonucleotide Prodrugs Showed Improved Antinuclease Stability and Anticancer Efficacy

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机构: [1]School of Pharmacy, China Medical University, Shenyang 110122, China. [2]State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China. [3]Department of Clinical Research Center, Dazhou Central Hospital, Sichuan 635000, China.
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关键词: antisense oligonucleotides dumbbell-shaped prodrug stability antitumor

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Antisense oligonucleotides (ASONs) have generated widespread interest as antitumor agents. Nevertheless, the utility of natural ASONs is limited due to their rapid degradation by intracellular and extracellular nucleases. In this work, we proposed a novel prodrug-type ASON with a dumbbell conformation and a responsive disulfide switch. A degradation assay showed that the dumbbell-shaped ASON (DS-ASON) exhibited stronger stability against enzymatic degradation compared with that of the linear or single-end looped ASON. The native ASON could dissociate via breakage of the disulfide switch when in the reductive microenvironment of a tumor. In addition, an optimal DS-ASON, L2, displayed robust antitumor activity both in vitro and in vivo. This paper presents a new design of nucleic acid-based therapeutics featuring a conformational change that provides improved stability and biological efficacy.

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出版当年[2022]版:
大类 | 2 区 医学
小类 | 2 区 药学 2 区 医学:研究与实验
最新[2023]版:
大类 | 2 区 医学
小类 | 2 区 药学 3 区 医学:研究与实验
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第一作者机构: [1]School of Pharmacy, China Medical University, Shenyang 110122, China. [2]State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China.
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