IDENTIFICATION OF VESICLE PROPERTIES THAT ENHANCE THE ANTITUMOR-ACTIVITY OF LIPOSOMAL VINCRISTINE AGAINST MURINE L1210 LEUKEMIA

The influence of vesicle lipid composition, size and drug-to-lipid rat io on the antitumour activity of liposomal vincristine was assessed in the murine L1210 ascitic leukemia model. A pH gradient-dependent entr apment procedure was used to encapsulate vincristine and allowed such vesicle properties to be independently varied. Free vincristine delive red i. v. at the maximum tolerated dose (2.0 mg/kg) resulted in a 27.8 % increase in the life span (ILS) of mice inoculated i. p. with L1210 cells. Encapsulation of the drug in egg phosphatidylcholine/cholestero l vesicles did not significantly increase the antitumour efficacy of v incristine (ILS, 38.9%). In contrast, administration of vincristine en trapped in vesicles composed of distearoylphosphatidylcholine (DSPC)/c holesterol resulted in ILS values as high as 133%. This enhanced antit umour activity of the DSPC/cholesterol formulations was sensitive to t he size of the liposomes; increasing the vesicle size from 100 nm to 1 mum decreased the ILS from 133.3% to 55.6% at a drug dose of 2.0 mg/k g. Decreasing the drug-to-lipid ratio from 0.1:1 to 0.05:1 (w/w) had n egligible effects on the activity of liposomal vincristine; however, a further decrease in the drug-to-lipid ratio to 0.01:1 (w/w) decreased the antitumour potency at all drug doses studied. Pharmacology studie s indicated that the antitumour activities of free and various liposom al forms of vincristine correlated well with the residence time of the drug in the circulation. These studies indicate that efforts to enhan ce the therapeutic activity of vincristine through liposome encapsulat ion must address not only the circulation lifetime of the vesicle syst ems but also the capacity of the liposomes to retain entrapped drug in vivo.