In this study it was investigated whether long-circulating amphotericin B (AMB) containing liposomes could be prepared by incorporation of polyethylene glycol (1900) derivatized distearoylphosphatidylethanolamine (PEG-DSPE), and whether the incorporation of PEG-DSPE affected toxicity and biodistribution of the preparation in mice. Toxicity of two formulations of liposomes containing both PEG-DSPE and AMB (PEG-AMB-LIP, types 1 and 2) was compared with that of AMB-liposomes without PEG-DSPE (AMB-LIP) as well as that of MB-deoxycholate (AMB-DOC). The maximum tolerated dosage (MTD) of AMB-DOC, expressed in terms of death during treatment for 5 consecutive days or significant increases in the parameters used to monitor renal and hepatic functions, was 0.8 mg/kg per day. AMB-LIP were the least toxic, the MTD being 11 mg/kg per day. The formulation with AMB complexed to DSPG (PEG-AMB-LIP type 1) was as toxic as AMB-DOC. This PEG-AMB-LIP formulation was omitted from further studies on biodistribution. With AMB complexed to PEG-DSPE (PEG-AMB-LIP type 2) toxicity was substantially reduced, resulting in a MTD of 9 mg/kg per day. Biodistribution of radiolabeled PEG-AMB-LIP type 2 was compared with that of AMB-LIP. Blood residence time of PEG-AMB-LIP type 2 was prolonged as compared to AMB-LIP; For PEG-AMB-LIP type 2 at 24 h after administration 30% of the injected dosage of AMB in intact liposomes was circulating versus 6% for AMB-LIP.

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Journal of Controlled Release
Department of Medical Microbiology and Infectious Diseases