Synergistic effect of folate-mediated targeting and verapamil-mediated P-gp inhibition with paclitaxel -polymer micelles to overcome multi-drug resistance.

Abstract

Multidrug resistance (MDR) in tumor cells is a significant obstacle for successful cancer chemotherapy. Overexpression of drug efflux transporters such as P-glycoprotein (P-gp) is a key factor contributing to the development of tumor drug resistance. Verapamil (VRP), a P-gp inhibitor, has been reported to be able to reverse completely the resistance caused by P-gp. For optimal synergy, the drug and inhibitor combination may need to be temporally colocalized in the tumor cells. Herein, we investigated the effectiveness of simultaneous and targeted delivery of anticancer drug, paclitaxel (PTX), along with VRP, using DOMC-FA micelles to overcome tumor drug resistance. The floate-functionalized dual agent loaded micelles resulted in the similar cytotoxicity to PTX-loaded micelles/free VRP combination and co-administration of two single-agent loaded micelles, which was higher than that of PTX-loaded micelles. Enhanced therapeutic efficacy of dual agent micelles could be ascribe to increased accumulation of PTX in drug-resistant tumor cells. We suggest that the synergistic effect of folate receptor-mediated internalization and VRP-mediated overcoming MDR could be beneficial in treatment of MDR solid tumors by targeting delivery of micellar PTX into tumor cells. As a result, the difunctional micelle systems is a very promising approach to overcome tumor drug resistance.

• Authors: Feihu Wang, Dianrui Zhang, Qiang Zhang, Yuxuan Chen, Dandan Zheng, Leilei Hao, Cunxian Duan, Lejiao Jia, Guangpu Liu, Yue Liu
• Journal: Biomaterials (Biomaterials) Vol. 32 Issue 35 Pg. 9444-56 (Dec 2011) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 21903258 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Micelles
• Polymers
• Chitosan
• Folic Acid
• Verapamil
• Paclitaxel

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, metabolism)
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Nucleus (drug effects, metabolism)
• Chitosan (chemistry)
• Drug Delivery Systems (methods)
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Flow Cytometry
• Fluorescence
• Folic Acid (pharmacology)
• Humans
• Inhibitory Concentration 50
• Micelles
• Microscopy, Electron, Scanning
• Paclitaxel (pharmacology)
• Particle Size
• Polymers (pharmacology)
• Verapamil (pharmacology)
• X-Ray Diffraction