Supramolecular self-assemblies of H6/doxorubicin reverse P-gp-mediated multidrug resistance in breast cancer.

Tumor multidrug resistance (MDR) remains a major cause of chemotherapy failure. Inhibiting the P-glycoprotein (P-gp)-mediated excessive efflux of chemotherapeutic drugs represent an effective strategy to overcome MDR. Conventional P-gp inhibitors are limited in clinical use due to systemic toxicity and risks of normal tissue dysfunction. In this study, we constructed a self-assembled system based on H6, the α-hederagenin derivative with potent MDR reversal activity, and the chemotherapeutic agent doxorubicin (DOX). Guided by the CREKA peptide, this system specifically targets fibronectin in tumor tissues, thereby enhancing drug accumulation at the lesion site. The combination therapy of H6 and DOX exhibited a combination index (CI) of 0.16 (CI < 1), indicating strong synergistic effects. Both in vitro and in vivo experiments demonstrated that H6 interferes with ATP production and effectively inhibits P-gp efflux function. In a breast cancer MDR model, this strategy achieved a tumor inhibition rate of 81.7%, offering a promising approach to combat tumor MDR.