Liposomal encapsulation of topotecan enhances anticancer efficacy in murine and human xenograft models

Topotecan was encapsulated in sphingomyelin/cholesterol liposomes using an ionophore-generated proton gradient. After i.v. injection, liposomal topote can was eliminated from the plasma much more slowly than free drug, resulti ng in a 400-fold increase in plasma area under the curve. Further, high-per formance liquid chromatography analysis of plasma samples demonstrated that topotecan was protected from hydrolysis within the liposomal carrier with >80% of the drug remaining as the active, lactone species up to 24 h, The i mproved pharmacokinetics observed with liposomal topotecan correlated with increased efficacy in both murine and human tumor models. In the L1210 asci tic tumor model, optimal doses of liposomal topotecan resulted in a 60-day survival rate of 60-80%, whereas in a L1210 liver metastasis model, 100% lo ng-term survival(>60 days) was achieved. In contrast, long-term survivors w ere rarely seen after treatment with free topotecan. Further, in a human br east carcinoma model (MDA 435/CC6), liposomal topotecan provided greatly im proved increase in life span relative to the free drug. These results sugge st that liposomal encapsulation can significantly enhance the therapeutic a ctivity of topotecan.