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Vol. 281, Issue 1, 566-573, 1997

Influence of Drug Release Characteristics on the Therapeutic Activity of Liposomal Mitoxantrone1

Howard J. Lim, Dana Masin, Thomas D. Madden and Marcel B. Bally

Division of Medical Oncology, British Columbia Cancer Agency (H.J.L., D.M., M.B.B.), and Department of Pharmacology and Therapeutics, University of British Columbia (T.D.M.),Vancouver, British Columbia, Canada

The influence of liposome drug release on the therapeutic activity of encapsulated mitoxantrone was investigated. Liposomes prepared from 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)/cholesterol (Chol) (55:45, molar ratio) or 1,2 dimyristoyl-sn-glycero-3-phosphocholine (DMPC)/Chol (55:45, molar ratio) were loaded with mitoxantrone using the transmembrane pH gradient loading procedure. In vivo studies demonstrated that DMPC/Chol liposomes released drug faster (1.7 µg drug/µg lipid/hr) than did DSPC/Chol liposomes (<0.025 µg drug/µg lipid/hr). In BDF1 mice, the acute toxicities of DMPC/Chol and DSPC/Chol liposomal mitoxantrone were similar, with a maximum tolerated dose of approximately 30 mg drug/kg, in comparison with the maximum tolerated dose of free drug, which was approximately 10 mg/kg. Efficacy studies were conducted in BDF1 mice inoculated i.v. with murine P388 cells or L1210 tumor cells. These cells seed in the liver and spleen of animals after i.v. inoculation, and a single dose of DMPC/Chol liposomal mitoxantrone of 10 mg drug/kg resulted in 100% of the treated animals surviving for >60 days. In contrast, no long-term survivors were obtained in any other treatment group, even when drug doses were escalated to the maximum tolerated dose. Pharmacodynamic studies with DMPC/Chol liposomal mitoxantrone and DSPC/Chol liposomal mitoxantrone illustrate the importance of achieving a balance between drug release characteristics and drug delivery to the site of tumor progression.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


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