title: Enhanced activity of doxorubicin in drug resistant A549 tumor cells by encapsulation of P-glycoprotein inhibitor in PLGA-based nanovectors.
abstract: Effective chemotherapy remains an important issue in the treatment of drug resistant cancer. The aim of the present study was to establish novel polymeric nanoparticles composed of the antitumor drug, doxorubicin (DOX), and an inhibitor of the drug efflux pump-associated protein, P-glycoprotein (P-gp), in order to overcome drug resistance in tumor cells. Poly(D,L-lactide-co-glycolide) (PLGA), DOX-loaded PLGA (PLGA-DOX), P-gp inhibitor (cyclosporin A; CsA)-coated PLGA (PLGA-CsA) and DOX and CsA co-loaded PLGA (PLGA-DOX-CsA) nanoparticles were prepared using solvent evaporation. The size distribution, ζ potential and electron microscopy observations of the nanoparticles were characterized. Accumulation and efflux assays were performed using confocal and fluorescence-activated cell sorting (FACS), and the pump activity of P-gp was detected through FACS. The uptake of the nanoparticles and the viability of Taxol-resistant A549 cells treated with various nanoparticles were analyzed via FACSin vitro.Furthermore, the tumor growth and survival rates of A549-Taxol-bearing mice were monitoredin vivo. Prepared particles were nanosized and the efflux rates of PLGA-DOX and PLGA-DOX-CsA were significantly decreased compared with the free DOX. Drug efflux pump activity was effectively inhibited by the PLGA-CsA and PLGA-DOX-CsA groups compared with the PLGA, PLGA-DOX and free DOX groups. Cell viability results demonstrated that PLGA-DOX and PLGA-DOX-CsA induced the increased death of A549-Taxol cells.In vivotumor models demonstrated that PLGA-DOX and PLGA-DOX-CsA markedly inhibited the tumor growth and improved the survival rate of A549-Taxol-bearing mice. Antitumor drug and drug efflux pump inhibitor co-loaded nanoparticles offer advantages to overcome the drug resistance of tumors and highlight new therapeutic strategies to control drug resistant tumors.
authors.affiliation: Department of Critical Care Medicine, Wuhan City Hospital No. 3 and Tongren Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Gynaecology & Obstetrics, Tianyou Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei 430064, P.R. China.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: Medical College, Wuhan University of Science and Technology, Wuhan, Hubei 430065, P.R. China.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Critical Care Medicine, Wuhan City Hospital No. 3 and Tongren Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Dong
authors.affiliation: Department of Critical Care Medicine, Wuhan City Hospital No. 3 and Tongren Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
authors.forename: Huangbing
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Radiology, Wuhan Center and Second Hospital, Wuhan, Hubei 430014, P.R. China.
authors.forename: Shutong
authors.initials: S
authors.lastname: Zhang
keywords: P-glycoprotein; drug resistance; efflux pump; poly(D,L-lactide-co-glycolide) nanoparticles