betadex and 1-2-distearoylphosphatidylethanolamine

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.

Topics: Analysis of Variance; Animals; Antineoplastic Agents, Phytogenic; beta-Cyclodextrins; Cell Line, Tumor; Chemistry, Pharmaceutical; Delayed-Action Preparations; Drug Carriers; Drug Compounding; Drug Stability; Female; Injections, Intravenous; Kinetics; Liposomes; Male; Maximum Tolerated Dose; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Models, Chemical; Phosphatidylethanolamines; Polyethylene Glycols; Prostatic Neoplasms; Solubility; Technology, Pharmaceutical; Tumor Burden; Vincristine