In situ oxidative polymerization of platinum(iv) prodrugs in pore-confined spaces of CaCO(3) nanoparticles for cancer chemoimmunotherapy

Drug resistance and metastases are the leading causes of death in clinics. To overcome this limitation, there is an urgent need for new therapeutic agents and drug formulations that are able to therapeutically intervene by non-traditional mechanisms. Herein, the physical adsorption and oxidative polymerization of Pt(iv) prodrugs in pore-confined spaces of CaCO(3) nanoparticles is presented, and the nanomaterial surface was coated with DSPE-PEG(2000)-Biotin to improve aqueous solubility and tumor targeting. While the nanoparticle scaffold remained stable in an aqueous solution, it quickly degraded into Ca(2+) in the presence of acid and into cisplatin in the presence of GSH. The nanoparticles were found to interact in cisplatin-resistant non-small lung cancer cells by a multimodal mechanism of action involving mitochondrial Ca(2+) overload, dual depletion of GSH, nuclear DNA platination, and amplification of ROS and lipid peroxide generation, resulting in triggering cell death by a combination of apoptosis, ferroptosis and immunogenic cell death in vitro and in vivo. This study could present a novel strategy for the treatment of drug-resistant and metastatic tumors and therefore overcome the limitations of currently used therapeutic agents in the clinics.