A glutathione-responsive sulfur dioxide polymer prodrug as a nanocarrier for combating drug-resistance in cancer chemotherapy.

Multidrug resistance (MDR) in cancer remains a significant challenge for curing cancer by chemotherapy. In this work, a kind of glutathione (GSH)-responsive polymer prodrug of SO was designed and synthesized, which presented synergistic effect with doxorubicin (DOX) for combating MCF-7 ADR human breast cancer cell. Firstly, a small molecular prodrug of SO, N-(3-azidopropyl)-2,4-dinitrobenzenesulfonamide (AP-DNs), was chemically conjugated onto the side chain of methoxy poly (ethylene glycol)-block-poly (γ-propargyl-l-glutamate) (mPEG-PPLG) block copolymer to generate an amphiphilic polymer prodrug of SO, mPEG-PLG (DNs). The obtained mPEG-PLG (DNs) prodrug could self-assemble into micelles in aqueous media and release SO rapidly in response to thiol compounds. Then, DOX was loaded into mPEG-PLG (DNs) nanoparticles with ultrahigh drug-loading efficiency (97.3%). In vitro drug release tests indicated that the DOX-loaded nanoparticles could simultaneously release SO and DOX by GSH triggering. Moreover, the effective cellular uptake of the DOX-loaded nanoparticles and subsequent intracellular release of SO and DOX were verified by confocal laser scanning microscopy (CLSM) and flow cytometry (FCM) analyses. The released SO could promote the reactive oxygen species (ROS) level in tumor cells, which thereby resulted in oxidative damages of cancer cells, together with restoration of MCF-7 ADR cells sensitivity to DOX. As a result, the released DOX and SO showed synergistic therapeutic effect against MCF-7 ADR cells. In vivo antitumor evaluation further indicated that, compared with free DOX, the DOX-loaded nanoparticles exhibited better antitumor effect in a MCF-7 ADR-xenografted nude mice model while had lower system toxicity. Overall, we demonstrated, for the first time, that a SO polymer prodrug, acting as a stimuli-responsive nanocarrier to codeliver DOX, can efficiently inhibit the proliferation of MDR tumor cells, which may offer a new weapon for combating MDR in cancer therapy.