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.
Keywords: antisense oligonucleotides; antitumor; dumbbell-shaped; prodrug; stability.