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Effect of Cholesterol Content on Antitumor Activity and Toxicity of Liposome-encapsulated 1-ß-D-Arabinofuranosylcytosine in Vivo¹

Comprehensive Cancer Center for the State of Florida and Department of Oncology, University of Miami School of Medicine, Miami, Florida 33101 [R. G., A. K., C. G. Z.]; Arthur D. Little, Inc., Cambridge, Massachusetts 02140 [I. W.]; and Drug Concentration Laboratory, University of Massachusetts Medical Center, Worcester, Massachusetts 01605 [L. J. L.]

1-ß-D-Arabinofuranosylcytosine (ara-C) was encapsulated in anionic multilamellar liposomes prepared with different lecithin: cholesterol (L:C) ratios. The chemotherapeutic activity of encapsulated ara-C was compared with comparable doses of ara-C in 0.85% saline solution (single- and multiple-dose schedules) in mice bearing L1210 (i.p.) leukemia. Maximum survival was obtained in animals given injections of ara-C (40 mg/kg) encapsulated in liposomes with a L:C ratio of 1:1. The effect of L:C ratio on survival was not pronounced in multiple-dose schedules. Multiple doses (every 4.5 hr for 3 separate injections) of 40 mg/kg with L:C ratios of 1:1 and 1:0.5 were toxic, resulting in 83 and 50% mortality, respectively, of mice by Day 7. This study shows that drug efflux and in vivo antitumor activity and toxicity of encapsulated ara-C is influenced by the cholesterol content of the liposomal lipid bilayer.

¹ Supported by USPHS Grants CA-23688 and NOI-CM-53765 from National Cancer Institute. Preliminary report of this work was presented at the 70th Annual Meeting of the American Association for Cancer Research, New Orleans, 1979 (3).

² Submitted to the Massachusetts College of Pharmacy, Boston, Mass., in partial fulfillment for the Ph.D. degree (May 1977).

³ To whom requests for reprints may be addressed, at Cancer Center, R71, University of Miami School of Medicine, P. O. Box 016960, Miami, Fla. 33101.

Received 5/11/79. Accepted 11/14/79.