ENHANCING EFFECT OF CHOLESTEROL ON THE ELIMINATION OF LIPOSOMES FROM CIRCULATION IS MEDIATED BY COMPLEMENT ACTIVATION

The effects of cholesterol (Chol) content on the biodistribution of li posomes as well as the interaction of liposomes with plasma proteins, primarily complement (C) components, were examined in this study. The elimination of liposomes from blood circulation was enhanced by increa sing the Chol content in liposomes. Furthermore, included Chol augment ed the rate of liposome degradation as measured by the urinary excreti on of H-3-inulin encapsulated in liposomes. We have also examined the effect of liposomal Chol on organ clearance (CL) and renal CL (CLrel). The values of organ CL and CLrel reflect the affinity of liposomes fo r the organ and the degree of liposome degradation in the blood, respe ctively, Hepatic CL and CLrel, but not splenic CL, increased with the rise of Chol content in liposomes. The amount of liposome degradation in vitro, which reflects the extent of C activation, was correlated wi th degradation observed in vivo (CLrel). However, the amount of plasma proteins bound to the liposomes was inversely proportional to the ext ent of in vitro liposome degradation. We have investigated the role of C activating factor (CAF) (Funato et al., 1994, Plasma factor trigger ing alternative complement pathway activation by liposomes, Pharm. Res ., 11, 372-376) on Chol-dependent-C activation. Our results showed tha t binding of CAF to the liposomes is directly proportional to the amou nt of Chol present in the liposome. Thus, C activation by Chol in lipo somes may proceed via a mechanism involving CAF. Taken together, these results suggest that increasing the Chol content of liposomes enhance s the binding of CAF to the liposomes, which in turn, mediates Chol de pendent-C activation, resulting in the augmentation of both degradatio n in blood and hepatic uptake of the liposomes. (C) 1997 Elsevier Scie nce B.V.