GSH responsive nanomedicines self-assembled from small molecule prodrug alleviate the toxicity of cardiac glycosides as potent cancer drugs.

Cardiac glycosides (CGs) have been used to treat cancer for hundreds of years. However, the narrow therapeutic window and system toxicity have hindered their wide clinical applications. Herein, the small molecule prodrug strategy and nanotechnology were integrated into one drug delivery system with enhanced therapeutic effect. Using periplocymarin (PPM) as a target agent, we designed a novel redox-responsive prodrug conjugated with linoleic acid (PPM-ss-LA), which was capable of self-assembling independent of exogenous excipients. This prodrug could co-assemble with DSPE_2k to form PEGylated prodrug nanoparticles (PPM-ss-LA/DSPE_2k-NPs) with enhanced colloidal stability and blood circulation. Compared with free PPM, PPM-ss-LA/DSPE_2k-NPs retained high anti-proliferative activity and showed increased cell uptake and therapeutic efficacy. Furthermore, the PPM-ss-LA/DSPE_2k-NPs acquired a greatly enhancement of 50% lethal dose (LD₅₀) in mice and reduced system toxicity compared with the free drug. Overall, the on-demand release of nanoprodrug delivery system could improve the therapeutic window and anticancer efficacy of CGs.