A Novel Cu(II) Loaded Polypeptide SO2 Prodrug Nanoformulation Combining Chemodynamic and Gas Anticancer Therapies

Abstract Sulfur dioxide (SO 2 )‐based gas therapy and chemodynamic therapyare both reactive oxygen species (ROS)‐mediated anticancer strategies, but there are few reports of their combined application. To this end, a novel graft‐type copolymeric SO 2 prodrug, PLG‐ g ‐mPEG‐DNs, is designed and synthesized in this work. The amphiphilic polypeptides can self‐assemble into nanoparticles (NPs) and encapsulated Cu(II) ions by metal‐carboxyl coordination. In vitro release results showed that the obtained NPs‐Cu can respond to the acidic pH and high glutathione levels typical of a tumor microenvironment to release Cu(II) and SO 2 simultaneously. Both a Cu(II)‐triggered Fenton‐like reaction and the SO 2 gas would promote ROS production and upregulate the oxidative stress in tumor cells, leading to an enhanced killing effect towards 4T1 cancer cells compared to either Cu(II) or the NPs alone. Furthermore, the in vitro hemolysis of NPs‐Cu is less than 1.0% at a high concentration of 8 mg/mL, indicating good blood compatibility and the potential for in vivo tumor inhibition application.