Overcoming Multidrug Resistance by On-Demand Intracellular Release of Doxorubicin and Verapamil

Abstract

Multidrug resistance (MDR) is one of the major obstacles to the successful application of cancer chemotherapy. Herein, we developed light-responsive doxorubicin-and-verapamil-coencapsulated gold liposomes to overcome MDR. Upon ns-pulsed laser irradiation, the highly confined thermal effect increased the permeability of the phospholipid bilayer, triggering the release of doxorubicin and verapamil, leading to high concentrations in cells. Free verapamil efficiently inhibited the membrane multidrug resistance proteins (MRPs), while the high concentration of doxorubicin saturated MRPs, thus overcoming MDR. We showed that nanosecond- (ns-) pulsed laser- (532 nm, 6 ns) induced doxorubicin release from gold liposomes depended on laser fluence and pulse number. More than 58% of the doxorubicin was released with a 10-pulse irradiation (100 mJ/cm2). Furthermore, ns laser pulses also liberated doxorubicin from endocytosed gold liposomes into the cytosol in MDA-MB-231-R cancer cells. The cytotoxicity of doxorubicin coencapsulated with verapamil was significantly enhanced upon laser irradiation. This study suggested that light-triggered on-demand release of chemotherapeutic agents and MRP inhibitors could be used advantageously to overcome multidrug resistance.