Abstract
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 vivostudies 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.
Footnotes
-
Send reprint requests to: Marcel B. Bally, Department of Medical Oncology, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 4E6.
-
↵1 This work was supported by grants from the Medical Research Council of Canada (M.B.B.) and the National Cancer Institute of Canada (T.D.M., M.B.B.)
- Abbreviations:
- AUC
- area under the curve
- CDE
- cholesteryl hexadecyl ether
- Chol
- cholesterol
- DMPC
- 1,2-dimyristoyl-sn-glycero-3-phosphocholine
- DSPC
- 1,2-distearoyl-sn-glycero-3-phosphocholine
- HEPES
- N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid
- ILS
- increase in lifespan
- MTD
- maximum tolerated dose
- Received June 24, 1996.
- Accepted December 30, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|