In the elimination of injected liposomes in vivo, it is considered that several serum components play an important role on hepatic uptake of them. This study was conducted to clarify the hepatic uptake mechanism of cetylmannoside (Man)-modified multilamellar vesicles (Man-MLV) using perfused rat liver. In the presence of serum, Man-MLV was taken up by the liver depending on the serum concentration, and it showed an approximately two-fold higher accumulation than MLV without any surface modifications (PC-MLV). These hepatic uptakes of liposomes were obviously inhibited by preheating the serum at 56 degrees C for thirty minutes or by the treatment with anti-rat C3 antiserum. Further, SDS-PAGE followed by immunoblot analysis showed the deposition of iC3b on the opsonized Man-MLV. These results obtained in the present study suggested that hepatic uptake of Man-MLV was mainly mediated by complement receptor rather than mannose receptor on Kupffer cells in vivo.

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A synergistic effect was observed between the size and the CH content on CLh. An underlying hypothesis of the synergistic effect was postulated based on the size dependent recognition of liposomes by complement system.

Complement activation is important for removing foreign substances by the mononuclear phagocyte system in vivo. The interaction between liposomes and complement components is considered to affect the clearance of liposomes from the circulation. It has been previously demonstrated in our laboratory that multilamellar vesicles (MLV) with surfaces modified by cetylmannoside (Man) were eliminated from the circulation rapidly and showed an approximately 2-fold higher hepatic accumulation compared with control MLV (PC-MLV) (Yamashita et al., Int. J. Pharmaceut., 70, 225, 1991). In this study, we investigated the effect of Man-modification on complement system activation. As far as elimination from the blood is concerned, the initial values of blood liposome concentration were decreased and liposomes were removed from the circulation rapidly in accordance with the extent of the Man content into their membranes. The Man-modification also affected the organ distribution of injected liposomes and their stability in rat serum. Except for MLV containing 50 mol% Man, it was observed that the hepatic uptake of liposomes was enhanced according to the increasing Man content, whereas splenic uptake was decreased and the splenic clearance was comparable. The stability of liposomes in rat serum decreased with increasing Man content. Liposomal instability in rat serum was significantly reduced by preheating the serum at 56 degrees C for 30 min, the treatment with anti-C3 antiserum and with EDTA but not abolished in serum treated with EGTA/MgCl2. Thus, it is considered that the activation of the complement system through the alternative pathway is facilitated as a result of increasing the Man content in the liposomes.(ABSTRACT TRUNCATED AT 250 WORDS)

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