Spermidine and folic acid dual-functionalized PLGA nanoparticles for co-delivery of doxorubicin and tariquidar to overcome multidrug resistance in breast cancer

Multidrug resistance (MDR) remains a major challenge in breast cancer treatment, mainly due to the overexpression of efflux transporters such as P-glycoprotein (P-gp), which reduces intracellular drug accumulation. In this study, spermidine–folic acid dual-functionalized PLGA nanoparticles were developed to co-deliver doxorubicin and the P-gp inhibitor tariquidar as a strategy to overcome MDR in breast cancer cells. The nanoparticles were physicochemically characterized and evaluated in doxorubicin-resistant EMT6/AR1 breast cancer cells. Drug release studies showed a sustained release behavior under physiological and mildly acidic conditions. Cytotoxicity and fluorescence microscopy studies demonstrated that the dual-functionalized, co-loaded nanoparticles produced the strongest reduction in cell viability and showed increased intracellular doxorubicin accumulation compared to free drug solutions and non-modified nanoparticle formulations. The improved activity is attributed to a combination of folate receptor–mediated uptake, spermidine-related cellular interactions, surface charge modulation, and inhibition of P-gp–mediated drug efflux by tariquidar. Overall, the developed dual-functionalized nanoparticle system offers a promising approach to improve intracellular drug delivery and overcome multidrug resistance in breast cancer therapy.