FG020326-loaded nanoparticle with PEG and PDLLA improved pharmacodynamics of reversing multidrug resistance in vitro and in vivo

Aim:FG020326,a novel imidazole derivative,is a potent multidrug-resistance(MDR) modulator in vitro and in vivo.However,FG020326 is insoluble.PEDLLA-FG020326 is a FG020326-1oaded nanoparticle formed with diblock copolymers ofpoly (ethylene glycol)-block-poly (D,L-lactic acid) (PEG:PDLLA,PEDLLA) thatcan solubilize FG020326.This work was intended to evaluate the pharmacody-namics of PEDLLA-FG020326 on reversing MDR in vitro and in vivo.Methods:Cytotoxicity was determined by tetrazolium assay.The intracellular accumulationand efflux of doxorubicin (Dox) were detected by fluorescence spectrophotometry.The function of P-glycoprotein was examined by Rhodamine 123 (Rh123) accumu-lation detected by flow cytometry.The KBv200 cell xenograft model was estab-lished to investigate the effect of PEDLLA-FG020326 on reversing MDR in vivo.Results:PEDLLA-FG020326 and FG020326 exhibited 56.4-and 35.9-fold activityin reversing KBv200 cells to vincristine (VCR) resistance,respectively and 14.98-and 7.64-fold to Dox resistance,respectively.PEDLLA-FG020326 was much stron-ger than FG020326,resulting in the increase of Dox and Rh 123 accumulation andthe decrease of intracellular Dox extrusion in KBv200 cells.Importantly,PEDLLA-FG020326 exhibited more powerful activity than FG020326 in enhancing the effectof VCR against KBv200 cell xenografts in nude mice,but did not appear more toxic.Conclusion:The pharmacodynamics of FG020326 was improved by incorporatingit into a micellar nanoparticle formed with PEG-block-PDLLA copolymers.