Doxorubicin combined with ultrasmall Prussian blue nanoparticles to achieve effective breast cancer chemotherapy and simultaneously alleviate myocardial toxicity

Doxorubicin (DOX) is a highly effective first-line chemotherapeutic agent for various tumors. However, its clinical utility is limited by fatal dose-dependent cardiomyopathy, primarily attributed to excessive reactive oxygen species (ROS) production and mitochondrial damage. Herein, we developed ultrasmall Prussian blue nanoparticles (SPB) possessing multiple antioxidant enzyme-like activities for the prevention and treatment of doxorubicin-induced cardiomyopathy (DIC). These nanoparticles function by efficiently scavenging ROS and preserving mitochondrial integrity. In vitro studies in cardiomyocytes demonstrated that SPB effectively eliminated ROS, reversed mitochondrial membrane potential loss, enhanced mitochondrial complex I activity, promoted ATP production, attenuated mitochondrial dysfunction, and inhibited cardiomyocyte apoptosis. In a breast cancer-bearing mouse model, SPB administration protected cardiac function and reduced myocardial fibrosis without compromising the antitumor efficacy of DOX. Mechanistically, SPB upregulated antioxidant-related proteins to reduce oxidative stress by activating the Keap1-Nrf2/HO-1 signaling pathway. Acute toxicity experiments showed that SPB could be safely administered via the tail vein at a dose of 75 mg/kg, which is substantially above the effective therapeutic dose. In conclusion, these findings demonstrate that SPB confers robust cardioprotection during DOX chemotherapy and holds considerable promise for clinical translation. Graphical Ultrasmall Prussian blue nanoparticles (SPB), synthesized via a green chemistry method with excellent biocompatibility, can effectively protect the heart function of chemotherapy tumor-bearing mice by scavenging reactive oxygen species generation, activating the Keap1-Nrf2/HO-1 signal pathway and protecting mitochondrial functions, reducing the degree of myocardial fibrosis without weakening the chemotherapy efficacy of DOX. The alternative text for this image may have been generated using AI.