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Stealth Liposomes: An Improved Sustained Release System for 1-ß-D-Arabinofuranosylcytosine¹

Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada, T6G 2H7

Newly developed liposomes with prolonged circulation half-lives and dose-independent pharmacokinetics (Stealth® liposomes) have been tested for their efficacy as a slow release system for the rapidly degraded, schedule-dependent, antineoplastic drug 1-ß-D-arabinofuranosylcytosine (ara-C) in the treatment of murine L1210/C2 leukemia. Mice were given injections of either 10⁵ cells or 10⁶ cells by either the i.v. or the i.p. routes. Leukemia-bearing mice were treated with either i.v. or i.p. injections of free drug, i.v. or i.p. injections of liposome-entrapped drug, or 24-h i.v. infusions of free drug. Long-circulating liposomes contained, as the stealth component, either monosialoganglioside or polyethylene glycol-distearoylphosphatidylethanolamine. Liposomes lacking the stealth components (non-stealth liposomes) were also injected for comparison. At lower dose ranges, stealth liposomes were superior to non-stealth liposomes in prolonging mean survival times of the mice, and all liposome preparations were superior to injections of the free drug. Drug entrapped in stealth liposomes, when administered at or near the maximum tolerated dose of 100 mg/kg ara-C were considerably superior to 24-h free drug infusions given at the same total drug dose. Therapeutic effect was related to the half-life of leakage of ara-C from the liposome formulations, as well as to circulation half-life, with maximum therapeutic effect achieved with long circulation half-lives and more rapid leakage rates. The therapeutic efficacy of non-stealth liposomes increased with increasing liposome (and drug) dose as a result of saturation of liposome uptake by the mononuclear phagocyte system, which resulted in longer circulation half-lives for these liposomes at higher doses (Michaelis-Menten pharmacokinetics). Liposome entrapment can protect rapidly degraded drugs from breakdown in vivo, with release of the drugs in a therapeutically active form over periods of up to several days. The dose-independent pharmacokinetics and reduced mononuclear phagocyte system uptake of stealth liposomes gives them distinct advantages over non-stealth liposomes.

¹ This work was supported by a grant from the Medical Research Council of Canada (MA-9127) and by Liposome Technology, Inc., Menlo Park, CA, who provided the PEG-DSPE and HSPC for the experiments. T. M. was supported by a graduate studentship, and Y. C. C. by a summer studentship, from the Alberta Heritage Foundation for Medical Research.

² To whom requests for reprints should be addressed.

Received 7/31/91. Accepted 2/19/92.

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