Facile design of amphiphilic multi-functional copolyprodrug for pH/GSH dual-responsive tumor chemotherapy and self-enhanced ferroptosis

Abstract

Ferroptosis has been widely recognized as a promising anticancer therapy. However, its anticancer efficiency is still restricted by the low level of reactive oxygen species (ROS) in tumor cells. Here, an amphiphilic multi-functional copolyprodrug (P(DSH-DOX-Fc)-PEG) was synthesized via facile polycondensation for synergistic tumor chemotherapy and self-enhanced ferroptosis. By incorporating both active ingredients, doxorubicin (DOX, 65.5%) and ferrocene (Fc, 14.0%), as structural units in the polyprodrug main chain via bioreducible disulfide bond, acid-sensitive hydrazone and imine bonds alternatively, pH/GSH dual-triggered complete drug release was achieved within 56 h in the simulated tumor intracellular microenvironment, while maintaining low premature leakage (7.2%). Moreover, the Fc-induced ferroptosis could be double-enhanced by the up-regulation of H₂O₂ level by DOX and depletion of GSH concentration by disulfide bond, resulting in a synergistic effect with combination index (CI) of 0.68.