Characterization, toxicity and therapeutic efficacy of adrïamycin encapsulated in liposomes

Abstract

The inherent toxicities of drug-free liposomes were compared. Positively charged liposomes were more toxic in vitro (chick heart cells) and in vivo (5-fold reduction in LD50 in mice) than neutral or negatively charged liposomes. Based on these findings, adriamycin was encapsulated in negatively charged liposomes (PG:PC:Chol-1:4:5), sequentially extruded through polycarbonate membranes (to 0.2 μm pore size) and purified by exhaustive dialysis. This preparation had a mean vesicle diameter of 0.24 μm and was stable in serum (24 hr drug retention of 85%). As compared with free drug, liposome-encapsulated adriamycin was less toxic in vitro to chick heart cells. In mice, adriamycin displayed short- (4-14 day) and long- (45-70 day) term toxicity. Encapsulating adriamycin increased both short- (20-50 mg/kg) and long- (10-15 mg/kg to 25-30 mg/kg) term LD50 levels. As compared with free drug, administering encapsulated adriamycin in vivo reduced the incidence of cardiac histopathologic lesions at 20 and 40 mg/kg. Compared in vitro, plasma levels of liposome-encapsulated adriamycin were 2 3-fold higher than free drug up to 24 hr post drug administration. Cardiac uptake of adriamycin was reduced 2-fold (conc. × time value for 48 hr) following encapsulated drug administration. Encapsulating adriamycin in liposomes did not alter its therapeutic effect against L1210 leukemic cells in vivo. © 1982.