title: 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: Department of Pharmaceutics, College of Pharmacy, Shandong University, 44 Wenhua Xilu, Jinan 250012, PR China.
authors: Feihu
authors: F
authors: Wang
authors: Dianrui
authors: D
authors: Zhang
authors: Qiang
authors: Q
authors: Zhang
authors: Yuxuan
authors: Y
authors: Chen
authors: Dandan
authors: D
authors: Zheng
authors: Leilei
authors: L
authors: Hao
authors: Cunxian
authors: C
authors: Duan
authors: Lejiao
authors: L
authors: Jia
authors: Guangpu
authors: G
authors: Liu
authors: Yue
authors: Y
authors: Liu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D048271:Chitosan / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005434:Flow Cytometry; D005453:Fluorescence; D005492:Folic Acid / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008823:Micelles; D008855:Microscopy, Electron, Scanning; D017239:Paclitaxel / Q000494:pharmacology*; D010316:Particle Size; D011108:Polymers / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology*; D014961:X-Ray Diffraction
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008823:Micelles; D011108:Polymers; D048271:Chitosan; D005492:Folic Acid; D014700:Verapamil; D017239:Paclitaxel