Doxorubicin- and Cisplatin-Based Nanotherapeutic as a Tumor Microenvironment-Biodegradable Nanoplatform for Combined Multidrug Chemotherapy/Chemodynamic/Mild Photothermal Cancer Treatment

The combination of chemotherapy with chemodynamic therapy (CDT) presents a potential strategy for cancer treatment. However, the insufficient exogenous catalytic ions, low endogenous hydrogen peroxide (H2O2) level, and overexpressed glutathione (GSH) in the tumor microenvironment challenge the efficacy of CDT. In addition, chemotherapy is constrained by the poor tumor accumulation ability, drug resistance, and severe system toxicity. To address these challenges, herein, we fabricated a pH-, reduction-, and NIR light-sensitive nanodrug delivery system, PDDC NPs, based on doxorubicin (DOX) and cisplatin for the combined chemotherapy, CDT, and mild photothermal therapy (PTT) against cancer. The “all-in-one” nanodrug, PDDC NPs, was constructed by the Cu2+-driven coordination of free DOX•HCl and tandem prodrug D-Pt-D, which was formed by the conjugation of cisplatin and norcantharidin, while polydopamine (PDA) was developed for the subsequent coating. In tumor cells, the elevated GSH reduces the platinum(IV) prodrug and Cu2+ in PDDC nanoparticles to active platinum(II) and Cu+, thereby inducing drug release, GSH depletion, and nanoparticle disassembly. The released DOX and platinum(II) in tumor cells can induce the production of reactive oxygen species, including •OH and H2O2, thereby amplifying the CDT efficacy induced by the Fenton-like reaction of Cu+. Additionally, the PDDC NPs possess photothermal conversion ability due to the PDA coating. This work provides a comprehensive strategy integrating “GSH depletion, H2O2 production, and Fenton-like reaction” with multidrug chemotherapy and mild PTT for cancer treatment.