Overcoming ABCG2-mediated multidrug resistance by a mineralized hyaluronan-drug nanocomplex

Multidrug resistance (MDR), caused by the overexpression of ATP-binding cassette (ABC) transporters on the cell membrane, is a major obstacle in the chemotherapy of cancers. Among various transporters, ATP-binding cassette subfamily G member 2 (ABCG2) has garnered increasing attention as it has been proven to play a critical role in various cancer cells and even in many cancer stem cells. In this study, we developed a novel multicomponent nanocomplex by using a simple hyaluronan-based biomimetic mineralization reaction to simultaneously encapsulate a tyrosine kinase inhibitor (afatinib) as a non-traditional ABCG2 inhibitor and an anticancer drug (doxorubicin) as an apoptosis inducer. The resulting nanocomplex can achieve a highly synergistic effect to overcome ABCG2-mediated MDR by synchronously enhancing drug uptake and inhibiting drug efflux. It follows that a spatial-temporal synchronization of multiple components via a targeted biomimetic pathway would hold great promise for chemotherapy of ABCG2-mediated resistant cancers.