Dual drug delivery system of PLGA nanoparticles to reverse drug resistance by altering BAX/Bcl-2

Abstract

Arise of multidrug resistance in cancer cells is a major obstacle for effective cancer chemotherapy. Multi-drug resistant (MDR) may be treated using combinations of encapsulated cytotoxic drugs and chemosensitizers. Dual drug delivery can control the drug-releasing pattern and improve the accumulation of chemotherapeutic agents at targeting sites. MDR reversal agent such as verapamil simultaneously with a traditional anticancer drug to cancer cells for enhanced chemotherapy efficacy have been limited due to the lack of efficient co-delivery methods.To optimize the effectiveness of this combinational, this study presents a system constructed of poly-lactid-co-glycolide (PLGA) carries SN38 and verapamil. SN38 is the active metabolite of irinotecan, a chemotherapeutic agent which acts as an inhibitor of topoisomerase 1 and verapamil which is a MDR1 reversal agent. Biological evaluation designed for determining cytotoxicity and cellular uptake evaluation on MDA-MB-231 breast cancer cells. Nanoparticles fabrication were optimized by small central composite design and characterized.Nanoparticles showed cytotoxic effects on MDA-MB-231 cells. Increasing of BAX expression and decreasing of Bcl-2 levels verified our hypothesis based on using verapamil to increase apoptosis following P-gp inhibition. PLGA nanoparticles also showed a selective distribution in animal body.