A self-cascade terpolymer platform for amplified chemo-chemodynamic therapy with synergistic immunogenic cell death enhancement

Chemodynamic therapy, which relies on the generation of cytotoxic radicals, can be amplified by a nanoplatform that produces hydroxyl radicals while also compromising natural radical scavenging mechanisms. For this purpose, a well-defined amphiphilic terpolymer, poly(oligo(ethylene glycol) monomethyl ether methacrylate)-block-poly(N,N-dimethyl aminoethyl methacrylate-statistical-monomer bearing ferrocene graft via azobenzene linker) (POEGMA-b-P(DMAEMA-st-(M-Azo-Fc), denoted as PAzo-Fc) is prepared by a consecutive reversible addition-fragmentation chain transfer (RAFT) polymerization technique, and is further used for doxorubicin (DOX) encapsulation to afford DOX-loaded stabilized nanomicelles, DOX@PAzo-Fc with an average hydrodynamic diameter of 86.0 nm. DOX@PAzo-Fc shows a self-cascade property for amplified CDT. That is, Azo cleavage-induced glutathione (GSH) depletion alleviates reactive oxygen species (ROS) scavenging. Together with the DOX-enhanced hydrogen peroxide generation, the Fc-mediated Fenton reaction is boosted for enhanced CDT. More importantly, the resulting amplified cascade chemo-chemodynamic therapy exerts a synergistic immunogenic cell death (ICD) enhancement effect for effective cancer immunotherapy, which further resulted in a high tumor inhibition rate of 87.8% in murine tumor models. The uniqueness of this study is the construction of a minimalist nanoplatform based on M-Azo-Fc units for amplified CDT via simultaneously producing hydroxyl radicals and compromising natural radical scavenging mechanisms. Overall, this self-cascade terpolymer platform fabricated herein offers a facile yet robust approach for advanced combinatory cancer therapy with great potential for clinical translations.