Overcoming multidrug resistance by intracellular drug release and inhibiting p-glycoprotein efflux in breast cancer

Abstract

Doxorubicin (DOX) is limited to use in clinical practice because of poor targeting, serious side effects and multidrug resistance (MDR). Vitamin E and its derivatives are currently considered as hydrophobic material that can reverse tumor MDR by suppressing the action of p-glycoprotein (p-gp). Therefore, reduction-sensitive amphiphilic heparosan polysaccharide-cystamine-vitamin E succinate (KSV) copolymers were designed to reverse breast cancer MDR cells. The spherical micelles (DOX/KSV) micelles which had suitable particle size presented redox-sensitive release character. Simultaneously, DOX-loaded reduction insensitive heparosan-adipic dihydrazide-vitamin E succinate (KV) micellar system was designed as a control. DOX/KSV and DOX/KV micelles had the higher capability to overcome tumor MDR than that free DOX. However, DOX/KSV had the highest amount of cellular uptake which might be caused by the synergistic intracellular drug release and inhibition of p-gp expression. The mechanism experiments revealed that DOX/KSV could be fast disassembled to release DOX after internalization into tumor cells. Moreover, DOX/KSV produced more ROS than free DOX and DOX/KV resulting in enhanced anticancer effect. In vivo tumor-bearing mice study suggested that DOX/KSV micelles could efficiently enhance antitumor effect by overcoming tumor MDR and reduce toxicity of DOX. The DOX/KSV micelles could synergistically increase the therapeutic effect of chemotherapeutic drug on tumor MDR cells.