The toxicity and antitumor activity of liposomal
vincristine preparations have been examined.
Vincristine was encapsulated inside egg
phosphatidylcholine (
EPC)/
cholesterol (55/45, mol/mol) and
distearoylphosphatidylcholine (DSPC)/
cholesterol (55/45, mol/mol) vesicles utilizing transmembrane pH gradient (inside acidic)
drug uptake processes. Trapping efficiencies approaching 100% were achieved for this procedure using
drug:
lipid ratios as high as 0.2:1 (w/w). Although both
EPC/
cholesterol and DSPC/
cholesterol liposomal systems yielded high trapping efficiencies, DSPC/
cholesterol vesicles exhibited superior
drug retention properties. This ability to retain entrapped
vincristine was related to maintenance of the transmembrane pH gradient as well as the membrane permeability properties. Thirty-day dose-response survival studies in mice indicated that
vincristine encapsulated in DSPC/
cholesterol liposomes was less toxic than free
drug. The 50% lethal dose of 1.9 mg/kg in CD-1 mice observed for free
vincristine increased to 4.8 mg/kg upon administration of the
drug in liposomal form.
Liposome encapsulation of
vincristine also enhanced the antitumor activity against murine P388 and L1210
lymphocytic leukemia models. This resulted from increased efficacy for liposomal
vincristine at doses equal to free
drug (liposomal/free
drug median survival times greater than 1.0) as well as the ability to administer increased doses of liposomal
vincristine. The combined effects of decreased toxicity and increased antitumor efficacy of liposomal
vincristine over free
drug suggest significant clinical utility of appropriate liposomal
vincristine systems.