Novel Folate−phenylfuran P‐gp Inhibitor Conjugates for Overcoming Multidrug Resistance in MCF‐7/ADR Cell

P‐glycoprotein (P‐gp) functions as a critical membrane transporter that drives tumor resistance by mediating drug efflux, ultimately contributing to multidrug resistance (MDR). Recently potent inhibitors have shown significant potential in countering chemotherapeutic resistance, particularly in breast cancer. However, P‐gp's presence in essential organs complicates clinical applications, underscoring the importance of developing tumor‐specific targeting strategies. Given the high‐level expression of folate receptors (FR) on the surface of breast cancer cells, this study conjugated a previously developed P‐gp inhibitor with folic acid, with the goal of harnessing FR‐mediated targeting for enhanced tumor cell specificity. In vitro evaluations revealed that the resultant conjugate maintained substantial resistance reversal efficacy against the MCF‐7/ADR breast cancer‐resistant cell line, comparable to the standalone inhibitor. The conjugate emerged as a highly potent and safe P‐gp inhibitor in xenograft mouse, likely attributable to its enhanced tumor‐targeting specificity, exhibiting superior in vivo efficacy when administered in combination with doxorubicin, relative to the original P‐gp inhibitor.