INFLUENCE OF DRUG-RELEASE CHARACTERISTICS ON THE THERAPEUTIC ACTIVITYOF LIPOSOMAL MITOXANTRONE

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 tr ansmembrane pH gradient loading procedure, In vivo studies demonstrate d that DMPC/Chol liposomes released drug faster (1.7 mu g drug/mu g li pid/hr) than did DSPC/Chol liposomes (<0.025 mu g drug/mu g lipid/hr). In BDF1 mice, the acute toxicities of DMPC/Chol and DSPC/Chol liposom al mitoxantrone were similar, with a maximum tolerated dose of approxi mately 30 mg drug/kg, in comparison with the maximum tolerated dose of free drug, which was approximately 10 mg/kg. Efficacy studies were co nducted in BDF1 mice inoculated i.v. with murine P388 cells or L1210 t umor cells, These cells seed in the liver and spleen of animals after i.v. inoculation, and a single dose of DMPC/Chol liposomal mitoxantron e of 10 mg drug/kg resulted in 100% of the treated animals surviving f or >60 days. In contrast, no long-term survivors were obtained in any other treatment group, even when drug doses were escalated to the maxi mum tolerated dose. Pharmacodynamic studies with DMPC/Chol liposomal m itoxantrone and DSPC/Chol liposomal mitoxantrone illustrate the import ance of achieving a balance between drug release characteristics and d rug delivery to the site of tumor progression.