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Effect of Lipid Vesicle (Liposome) Encapsulation of Methotrexate on Its Chemotherapeutic Efficacy in Solid Rodent Tumors¹

Departments of Experimental Therapeutics, Grace Cancer Drug Center [M. J. K., F. R., R. J. M.] and Experimental Pathology, Cancer Cell Center [D. P.], Roswell Park Memorial Institute, New York State Department of Health, Buffalo, New York 14263

The possibility of the use of unilamellar phospholipid vesicles (liposomes) as carriers of methotrexate (MTX) was explored to overcome the resistance of solid tumors to the drug. Unilamellar vesicles were prepared by sonic dispersion of phosphatidylcholine:cholesterol:stearylamine (4:3:1) in an aqueous solution containing MTX. In MTX-resistant, cortisol-sensitive P1798 mouse lymphosarcoma cells in suspension, the uptake of [³H]MTX at a concentration of 10^-6 M was 54% greater when the drug was encapsulated in lipid vesicles than that observed with the free drug. Daily i.p. injections of vesicle-entrapped MTX (1.0 mg/kg) into mice bearing established P1798 tumors for 4 consecutive days, a regimen that was ineffective with free MTX, resulted in an 80% reduction in tumor mass; this effect was greater than that achieved by 5 times the dosage of free drug. MTX-sensitive Murphy-Sturm rat lymphosarcoma cells in suspension showed a 2.6-fold increase in MTX uptake when the drug was encapsulated in lipid vesicles as compared to the free MTX at a concentration of 10^-6 M. Treatment of rats bearing the rat Murphy-Sturm lymphosarcoma tumor with MTX (0.5 mg/kg), following the regimen used previously, caused a 82% reduction in tumor mass when MTX was encapsulated in lipid vesicles compared to a 52% reduction in tumor mass achieved by administration of free drug.

These results indicate that encapsulation of MTX in lipid vesicles enhances its association with tumor cells in vitro and improves the response of solid rodent tumors to treatment with MTX.

¹ This study was supported by Grants CA-13038 and CA-18527 from the National Cancer Institute.

² To whom requests for reprints should be addressed.

Received 1/30/78. Accepted 5/31/78.

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