Synergistic combination chemotherapy using carrier-free celastrol and doxorubicin nanocrystals for overcoming drug resistance.

ABSTRACT

A key challenge of chemotherapy in clinical treatments is multidrug resistance (MDR), which mainly arises from drug efflux-induced tumor cell survival. Thus, it is necessary to provide biocompatible chemotherapeutics to improve drug accumulation in MDR cells. Herein, two clinical small molecular drugs, celastrol (CST) and doxorubicin (DOX), were self-assembled into carrier-free and biocompatible nanoparticles (CST/DOX NPs) via a simple and green precipitation method for synergistic combination chemotherapy to overcome DOX resistance. These spherical CST/DOX NPs can improve the water-solubility of CST, reduce the dosage of DOX, and therefore significantly enhance cellular drug accumulation by activating heat shock factor 1 (HSF-1) and inhibiting NF-κB to depress P-gp expression, which results in apoptosis and autophagy of DOX resistant cells through the ROS/JNK signaling pathway. Finally, synergistic combination chemotherapy was attained in both MCF-7/MDR cells and 3D multicellular tumor spheroids. Thus, CST/DOX NPs provide an alternative for overcoming drug resistance in future clinical applications.