Design, characterization and biological evaluation of a new chimeric 4A2–5-antisense prodrug combined with chemotherapy

Abstract

Issues surrounding rapid degradation and limited therapeutic efficacy still exist in the development of native antisense oligonucleotides (ASONs). In this paper, a novel strategy of chimeric 4A_2–5-ASON prodrug combined with chemotherapy for oncotherapy was proposed. The self-assembled hairpin-end prodrug structure provided a DOX loading site, while enhancing stability against nuclease degradation. The disulfide led responsive drug release, and excellent therapeutic effects were achieved by the combined action of RNase H and RNase L recruitment, along with chemotherapy drug Doxorubicin (DOX), both in vitro and in vivo. This work provides evidence for the development of designing nucleic acid drugs with combined mechanisms.