A pH-Responsive Polycarbonate Nanoplatform for Synergistic Chemodynamic/Chemotherapy via Cinnamaldehyde Prodrug-Enhanced Fe³⁺-Mediated Fenton-Like Reaction

Chemodynamic therapy (CDT) is an innovative cancer treatment strategy that leverages Fenton or Fenton-like reactions to convert hydrogen peroxide (H₂O₂) in the tumor microenvironment (TME) into highly cytotoxic hydroxyl radicals (•OH). However, the therapeutic efficacy of CDT against tumor cells is limited by two primary constraints: 1) insufficient H₂O₂ levels in the TME, which restricts •OH generation; and 2) elevated concentrations of reduced glutathione (GSH) in the TME, which neutralizes excess reactive oxygen species (ROS). To address these challenges, this study developed a nanoplatform based on mixed micelles composed of two distinct polycarbonate materials. One polycarbonate is conjugated with cinnamaldehyde (CA) via side chains to form a polymeric prodrug, enabling pH-responsive release of CA. The other polycarbonate chelates Fe³⁺ through side-chain carboxyl groups to initiate Fenton-like reactions. In the acidic TME, the mixed micelles release CA, which elevates intracellular H₂O₂ levels, thereby overcoming the limitation of inadequate H₂O₂ supply in tumor cells. Simultaneously, the Fe³⁺ complex within the micelles depletes GSH, reducing it to Fe²⁺, which triggers Fenton-like reactions that amplify ROS production, thus enhancing CDT efficacy. Additionally, pH-triggered disassembly of the micelles in the acidic TME releases encapsulated doxorubicin (DOX), which induces tumor cell apoptosis by damaging DNA, further augmenting antitumor therapeutic outcomes. The nanocarrier developed in this study integrates a synergistic strategy of “H₂O₂ elevation and Fenton-like reaction” with chemotherapy, significantly improving tumor cell eradication and demonstrating substantial potential for cancer treatment.