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 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-per...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2000-07, Vol.60 (13), p.3389-3393
Main Authors: TARDI, P, CHOICE, E, MASIN, D, REDELMEIER, T, BALLY, M, MADDEN, T. D
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - therapeutic use
Biological and medical sciences
Breast Neoplasms - drug therapy
Chemotherapy
Drug Carriers
Female
Humans
Leukemia L1210 - drug therapy
Leukemia L1210 - pathology
Liposomes
Liver Neoplasms - drug therapy
Liver Neoplasms - secondary
Medical sciences
Mice
Mice, Inbred BALB C
Mice, Inbred Strains
Mice, SCID
Pharmacology. Drug treatments
Survival Rate
Topotecan - administration & dosage
Topotecan - pharmacokinetics
Topotecan - therapeutic use
Transplantation, Heterologous
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Summary: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.
ISSN:0008-5472
1538-7445