Tumor-Targeted Drug Delivery as a Successful Approach for Reducing Doxorubicin–Induced Cardiotoxicity

Doxorubicin (DOX) is an effective chemotherapy drug used to treat many malignancies, including breast cancer. However, its clinical application is severely limited by cardiotoxicity. This study investigated if using thermo/pHsensitive magnetic nanoparticles decorated with folate (folate-poly-MNPs) as tumor-targeted drug delivery systems (DDSs) could reduce the cardiotoxicity and inflammatory properties of DOX in a rat model of breast cancer. In this study, forty rats were intravenously administered the control, DOX, DOX-poly-MNPs, and DOXfolate-poly-MNPs every 48 hours for 12 days. The cardiac health monitoring following breast cancer therapy confirmed that the novel smart DDS improved ECG pattern, left ventricular function, blood pressure parameters, and heart weight index. Moreover, it could decrease myocardial cell death by decreasing the protein levels of BAX, c-PARP1, and c-caspase-3, with concomitant downregulation of the BAX/Bcl-2 ratio, compared to the commercial DOX. In addition, the DOXfolate-poly-MNPs treatment significantly reduced NLRP3 inflammasome activation in cardiomyocytes, which was mediated by caspase-1 inhibition, and suppressed upregulation of IL-1β and IL18 protein expression to prevent myocardial damage. In this regard, the developed folatepolyMNPs could be represented as a new potential drug delivery system for breast cancer chemotherapy due to the combination of passive and active targeting aimed at preventing nonspecific body distribution, inhibiting NLRP3 inflammasome activation, and consequently reducing DOX cardiotoxicity as its main adverse effect.