Designing pegylated dextran sheathed doxorubicin loaded iron nanoparticles against premenopausal breast cancer

Premenopausal women, often iron-deficient, face a heightened risk of breast cancer. Magnetic nanoparticles (MNPs) show promise for cancer therapy but are limited by challenges in pharmacokinetics, biocompatibility, and magnetic property stability, leading to reduced efficacy and resistance. To overcome these hurdles, a double-shelled magnetic nanoparticle (DOX-RA-MNP) system was developed for pH-sensitive delivery of Retinoic acid and Doxorubicin using an immunomodulatory polymeric approach. Optimized by using a QbD framework, the formulation demonstrated ideal size, polydispersity index, zeta potential, and enhanced doxorubicin loading. The formulation depicted sustained drug release with enhanced release at tumor pH. In vitro studies on MDA-MB-231 cells revealed improved cytotoxicity, cellular uptake, G2 phase cell cycle arrest, mitochondrial membrane depolarization, and PgP protein inhibition. In in vivo, the system showed significant tumor regression, favorable pharmacokinetics, biodistribution, and safety, with lower hemolysis and improved survival rates. The biochemical studies provide insights about the role of ferroptosis increasing reactive oxygen species (ROS) level and immunomodulatory effects. Further, the lower hemolysis and enhanced survival of animals confirmed safety of the developed formulation. These findings suggest the DOX-RA-MNP system effectively targets and localizes drugs, reducing toxicity and offering a potent strategy for breast cancer treatment.