title: FG020326-loaded nanoparticle with PEG and PDLLA improved pharmacodynamics of reversing multidrug resistance in vitro and in vivo.
abstract: OBJECTIVE
  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-loaded nanoparticle formed with diblock copolymers of poly (ethylene glycol)-block-poly (D,L-lactic acid) (PEG:PDLLA, PEDLLA) that can solubilize FG020326. This work was intended to evaluate the pharmacodynamics of PEDLLA-FG020326 on reversing MDR in vitro and in vivo.
  
  
  METHODS
  Cytotoxicity was determined by tetrazolium assay. The intracellular accumulation and efflux of doxorubicin (Dox) were detected by fluorescence spectrophotometry. The function of P-glycoprotein was examined by Rhodamine 123 (Rh123) accumulation detected by flow cytometry. The KBv200 cell xenograft model was established to investigate the effect of PEDLLA-FG020326 on reversing MDR in vivo.
  
  
  RESULTS
  PEDLLA-FG020326 and FG020326 exhibited 56.4- and 35.9-fold activity in reversing KBv200 cells to vincristine (VCR) resistance, respectively and 14.98- and 7.64-fold to Dox resistance, respectively. PEDLLA-FG020326 was much stronger than FG020326, resulting in the increase of Dox and Rh123 accumulation and the decrease of intracellular Dox extrusion in KBv200 cells. Importantly, PEDLLA-FG020326 exhibited more powerful activity than FG020326 in enhancing the effect of VCR against KBv200 cell xenografts in nude mice, but did not appear more toxic.
  
  
  CONCLUSIONS
  The pharmacodynamics of FG020326 was improved by incorporating it into a micellar nanoparticle formed with PEG-block-PDLLA copolymers.
authors.affiliation: State Key Laboratory of Oncology in Southern China Cancer Center, Sun Yat-Sen University, Guangzhou 510060, China.
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Deng
authors.forename: Xiao-Qiang
authors.initials: XQ
authors.lastname: Yang
authors.forename: Yong-Ju
authors.initials: YJ
authors.lastname: Liang
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Chen
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Yan
authors.forename: Xin-Tao
authors.initials: XT
authors.lastname: Shuai
authors.forename: Li-Wu
authors.initials: LW
authors.lastname: Fu
mesh_terms: D000179:Acrylates / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D004317:Doxorubicin / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D019344:Lactic Acid / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014750:Vincristine / Q000493:pharmacokinetics
chemical_list: D000179:Acrylates; D004337:Drug Carriers; D007093:Imidazoles; C531580:methyl 3-(4-(4,5-bis(4-(isopropyl(methyl)amino)phenyl)-1H-imidazol-2-yl)phenyl)acrylate; D019344:Lactic Acid; D011092:Polyethylene Glycols; D014750:Vincristine; D004317:Doxorubicin