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Liposomal Encapsulation of Topotecan Enhances Anticancer Efficacy in Murine and Human Xenograft Models¹

Inex Pharmaceuticals Corporation, Burnaby, British Columbia, V5J 5J8 Canada [T. D. M.]; Department of Advanced Therapeutics, British Columbia Cancer Agency [P. T., E. C., D. M., M. B.], Vancouver, British Columbia, V5Z 4E3 Canada; and Northern Lipids Inc., Jack Bell Research Centre, Vancouver, British Columbia, V6H 3Z6 Canada [T. R.]

Topotecan was encapsulated in sphingomyelin/cholesterol liposomes using an ionophore-generated proton gradient. After i.v. injection, liposomal topotecan was eliminated from the plasma much more slowly than free drug, resulting in a 400-fold increase in plasma area under the curve. Further, high-performance 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 improved pharmacokinetics observed with liposomal topotecan correlated with increased efficacy in both murine and human tumor models. In the L1210 ascitic 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% long-term survival (>60 days) was achieved. In contrast, long-term survivors were rarely seen after treatment with free topotecan. Further, in a human breast carcinoma model (MDA 435/LCC6), liposomal topotecan provided greatly improved increase in life span relative to the free drug. These results suggest that liposomal encapsulation can significantly enhance the therapeutic activity of topotecan.

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