Drug resistance reversal in ovarian cancer cells of paclitaxel and borneol combination therapy mediated by PEG-PAMAM nanoparticles

Liang Zou1, Di Wang1, Yichen Hu2, Chaomei Fu3, Wei Li1, Liping Dai1, Lin Yang1 and Jinming Zhang3 1School of Medicine, Chengdu University, Chengdu 610106, China 2College of Pharmacy and Biological Engineering, Chengdu University, Chengdu 610106, China 3College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China Correspondence to: Lin Yang, email: [email protected] Jinming Zhang, email: [email protected] Keywords: MDR reversal, co-delivery, P-gp inhibition, PAMAM dendrimer, borneol Received: May 04, 2017 Accepted: June 10, 2017 Published: July 31, 2017 ABSTRACT Paclitaxel (PTX) is frequently suffered from multidrug resistance (MDR), resulting in lower chemotherapeutic efficacy and even chemotherapy failure. To combine the P-glycolprotein (P-gp) inhibitor would be a useful strategy to overcome MDR. However, what is needed now is an efficient vehicle to deliver multiple drugs into tumor simultaneously. In this study, PTX and Borneol (BNL), a natural compound with P-gp inhibition effect confirmed in intestinal absorption, were co-loaded in the fabricated PEG-PAMAM nanoparticle (NPs) by a one-step nano-precipitation method with high drug loading efficiency, narrow size distribution and low hemolysis rate. Based on P-gp inhibition activity of BNL, confirmed by drug efflux test and molecular docking model, the combination of PTX and BNL could improve intracellular concentration of PTX in A2780/PTX cells. Furthermore, compared to both free PTX and PTX+BNL, PB/NPs and P/NPs plus BNL exhibited higher cellular uptake and cytotoxicity in A2780/PTX cells, as well as the decreased MMP and enhanced apoptosis rate. More importantly, although PB/NPs and P/NPs+B showed similar tumor accumulation in tumor-bearing mice, PB/NPs could significantly decrease tumor growth of A2780/PTX tumor-bearing mice, in comparison to P/NPs+B. These results indicated the advantage of PTX and BNL co-delivery NPs for MDR reversal. These findings demonstrate that the co-delivery nano-sized system comprised by PEG-PAMAM polymer with PTX and BNL co-loaded would be a promising candidate for MDR treatment.