title: Development of pegylated liposomal vincristine using novel sulfobutyl ether cyclodextrin gradient: is improved drug retention sufficient to surpass DSPE-PEG-induced drug leakage?
abstract: The purpose of this study is to develop novel stable PEGylated liposome vincristine formulations with optimal antitumor efficacy. Vincristine could interact with negatively charged distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG), leading to rapid drug release from vesicles. To improve drug retention, vincristine was loaded into vesicles using sulfobutyl ether cyclodextrin (sbe-CD) as trapping agent. Despite that, vincristine could not form a precipitate with sbe-CD; the aggregation status of vincristine/sbe-CD inside vesicles must be complicated because drug retention was considerably improved in vivo. Theoretical consideration revealed that the release constant K equals to pA(m)k(1)k(2)/([H(+)](i)[sbe(-)](i)V(i) ), which can be used to expound why increasing drug/lipid ratio induced decreased vincristine circulation half-life. The stabilization effect afforded by sbe-CD was sufficient to surpass DSPE-PEG-induced drug leakage, so PEGylated liposomal vincristine formulations with prolonged circulation half-life (t(1/2): from 43.6 to 70.0 h) could be achieved, of which the formulation pLV-c-2.9-3 exhibited optimal antitumor effects and reduced toxicity. The strategy might be used to load other vinca alkaloids into PEGylated liposomes and improve their retention inside vesicles.
authors.affiliation: School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, Hebei, PR China.
authors.forename: Jingxia
authors.initials: J
authors.lastname: Cui
authors.forename: ChunLei
authors.initials: C
authors.lastname: Li
authors.forename: Caixia
authors.initials: C
authors.lastname: Wang
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Li
authors.forename: Lan
authors.initials: L
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Xian
authors.initials: X
authors.lastname: Xiu
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Li
authors.forename: Na
authors.initials: N
authors.lastname: Wei
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004339:Drug Compounding; D004355:Drug Stability; D005260:Female; D007275:Injections, Intravenous; D007700:Kinetics; D008081:Liposomes; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008956:Models, Chemical; D010714:Phosphatidylethanolamines / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D047368:Tumor Burden / Q000187:drug effects; D014750:Vincristine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D008081:Liposomes; D010714:Phosphatidylethanolamines; D047392:beta-Cyclodextrins; C038089:1,2-distearoylphosphatidylethanolamine; C093196:SBE4-beta-cyclodextrin; D011092:Polyethylene Glycols; D014750:Vincristine