Glutathione boosting the cytotoxicity of a magnetic platinum(IV) nano-prodrug in tumor cells

Abstract

Superparamagnetic iron oxide nanoparticles (SPIONs) are potential vehicles for targeted drug delivery and viable contrast agents for magnetic resonance imaging (MRI). A Pt-IV prodrug (HSPt) derived from functionalization of cisplatin with hydroxyl and succinate is conjugated with a poly(ethylene glycol) (PEG)-modified SPION for cancer therapy and monitoring of therapeutic responses. The relaxivity of HSPt-PEG-SPIONs is larger than that of commercial contrast agent Feridex, and a tumor-selective negative contrast is observed in MRI in a magnetic field. HSPt-PEG-SPIONs can be dissociated and reduced into PtII species by glutathione (GSH). Instead of forming DNA-Pt crosslinks, the reduced product induces direct DNA single- or double-strand breaks, which is uncommon for Pt drugs. The cytotoxicity of HSPt-PEG-SPIONs is positively correlated with the GSH level of tumor cells, which is opposite to the scenario of current Pt drugs. HSPt-PEG-SPIONs are as cytotoxic as cisplatin against cancer cells but are almost nontoxic towards normal cells. Since the mechanism of action of the nanocomposite is different from the established paradigm for Pt drugs, it may become a special theranostic agent for cancer treatment.