Evaluation of in vivo cardiotoxicity and efficacy of doxorubicin loading on the magnetic nanoparticles conjugated with a smart polymer containing folic acid in rat model of breast cancer

Abstract

Introduction: 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/pH sensitive magnetic nanoparticles decorated with folate (folate-poly-MNPs) as tumor-targeted drug delivery systems (DDSs) could reduce the cardiotoxicity and increase cytotoxicity properties of DOX in a rat model of breast cancer.Objective: The novel folate conjugated Thermo/pH-responsive magnetic nanoparticles (folate-poly-MNPs) have been developed as a potential nanocarrier for improving site-specific drug delivery, tumor drug accumulation, and therapeutic effects while reducing the adverse effects of conventional drug delivery systems.Method: To evaluate the anticancer efficacy of the developed tumor-targeted drug delivery system, 40 female Sprague–Dawley rats (45–48 days-old) received a subcutaneous injection of DMBA (25 mg/kg) to induce breast tumors. After 8 weeks, when the tumor volume reached 1000m3, the breast cancer models received saline as control, DOX, DOX poly MNPs, and DOX folate-poly-MNPs at a dose of 2 mg/kg/48 h for 12 days. After evaluating the cardiac hemodynamic parameters of the studied groups, qPCR tests, western blot, TUNEL staining, and ki67 IHC staining were performed on the heart and tumor tissues.Results: DOX-folate-poly-MNPs group showed a significant increase in protein expression of BAX and C-caspase-3 with concomitant downregulation of Bcl-2 expression and ki67 proliferation index in tumor tissues. The cardiac health monitoring 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 compared to free DOX.Conclusion:DOX-folate-poly-MNPs may prove to be a promising smart nanomedicine for effective DOX drug delivery by increasing drug uptake at the tumor site, reducing cardiotoxicity and improving survival in breast cancer models.