Self-supply of hydrogen peroxide by a bimetal-based nanocatalytic platform to enhance chemodynamic therapy for tumor treatment

Abstract The tumor microenvironment (TME) is characterized by low pH, hypoxia, and overexpression of glutathione (GSH). Owing to the complexity of tumor pathogenesis and the heterogeneity of the TME, achieving satisfactory efficacy with a single treatment method is difficult, which significantly impedes tumor treatment. In this study, composite nanoparticles of calcium-copper/alginate-hyaluronic acid (HA) (CaO 2 -CuO 2 @SA/HA NC) with pH and GSH responsiveness were prepared for the first time through a one-step synthesis using HA as a targeting ligand. Nanoparticles loaded with H 2 O 2 can enhance the chemodynamic therapy effects. Simultaneously, Cu 2+ can generate oxygen in the TME and alleviate hypoxia in tumor tissue. Cu 2+ and H 2 O 2 undergo the Fenton reaction to produce cytotoxic hydroxyl radicals and Ca 2+ ions, which enhance the localization and clearance of nanoparticles in tumor cells. Additionally, HA and sodium alginate (SA) were utilized to improve the targeting and biocompatibility of the nanoparticles. Fourier transform infrared, x-ray diffraction, dynamic light scattering, SEM, transmission electron microscope, and other analytical methods were used to investigate their physical and chemical properties. The results indicate that the CaO 2 -CuO 2 @SA/HA NC prepared using a one-step method had a particle size of 220 nm, a narrow particle size distribution, and a uniform morphology. The hydrogen peroxide self-supplied nanodrug delivery system exhibited excellent pH-responsive release performance and glutathione-responsive •OH release ability while also reducing the level of reactive oxide species quenching. In vitro cell experiments, no obvious side effects on normal tissues were observed; however, the inhibition rate of malignant tumors HepG2 and DU145 exceeded 50%. The preparation of CaO 2 -CuO 2 @SA/HA NC nanoparticles, which can achieve both chemokinetic therapy and ion interference therapy, has demonstrated significant potential for clinical applications in cancer therapy.