Toxicity and Antitumor Activity of Liposome-Entrapped Retinoid Rol3-7410

Abstract

We compared the toxicity of free and liposome-entrapped retinoid, Rol3-7410 in C₂DF₁ mice. Mice received 7 daily i.p. injections of liposome-entrapped Rol3-7410 at doses of 5, 10, 100, 500, or 1000 (μg/kg bw/day. For comparison, two groups of mice were used as controls, one group received Rol3-7410 in corn oil and a second group received liposome-entrapped Rol3-7410 that had been solubilized with detergent. The liposomes were then tested for chemotherapeutic activity against human myelocytic leukemia (HL-60/MRI) implanted in athymic NCr-nu mice. The doses used in the chemotherapy experiment (20, 50, and 100 μg/kg bw/day) were selected based on the results of the toxicity experiment in CD2F₁ mice.

CD2_F mice were marginally protected from toxicity after receiving retinoid in liposomes relative to controls. There were 2/5 survivors in the 1000 μg/kg bw/day Rol3-7410-liposome group after 7 daily i.p. doses compared to 0/5 for both the corn oil and solubilized liposome groups, and 4/5 survivors in the 500 μg/kg bw/day Rol3-7410-liposome group after 7 daily i.p. doses compared to 2/5 for both the corn oil and solubilized liposome groups. We observed no dramatic differences in toxicity among the treatment groups over the range of doses administered.

There were 2/6 long-term tumor-free survivors in athymic mice receiving liposome-entrapped retinoid, at 50 μg/kg bw/day for 7 days, compared with 0/6 and 0/9 survivors in groups receiving empty liposomes or no treatment. The median day of death (calculated using day 90 as the day of death for the surviving animals) for this group was 59 days compared with 32 days for mice receiving empty liposomes. We observed slight or no increase in life-span for mice receiving treatments with retinoid administered in corn oil or in detergent solubilized liposomes. Compared to an equivalent dose of Rol3-7410 in corn oil, the liposome preparations provided moderate protection from Rol3-7410 toxicity in athymic mice. These results suggest that liposomes may enhance the therapeutic effectiveness of retinoids against human leukemia.