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.
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.
基金:
Beijing Natural
Science Foundation (7202146).
语种:
外文
PubmedID:
中科院(CAS)分区:
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
第一作者:
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.