Antibody dependent, complement mediated liver uptake of liposomes containing GM1.
OBJECTIVE
We have previously reported that GM1 exhibits an opposite effect on regulating liposome circulation time in mice and rats (Liu et al. Pharm. Res. Vol. 12:508-512 (1995)). Inclusion of GM1 into liposomes significantly prolongs liposome circulation time in mice, while it dramatically decrease the blood half life and increases liver uptake of liposomes in rats. The purpose of this study was to elucidate the mechanism that underlies this phenomenon.


METHODS
Single-pass liver perfusion in vitro and complement mediated liposome lysis assay was used.


RESULTS
Serum appeared to play an important role in determining the liver uptake of GM1 liposomes. Specifically, rat serum enhanced the uptake of GM1-containing liposomes by the perfused liver. Such activity was also found in human and bovine serum, but not in mouse serum. Taking human serum as an example, we demonstrated that such serum activity can be blocked by EDTA and EGTA/Mg2+. Antibodies against human IgM and the third component of complement system (C3) also inhibited serum activity.


CONCLUSIONS
The presence of naturally occurring anti-GM1 antibodies in rats, through the activation of the classic pathway of complement system, is likely the cause of rapid blood clearance of GM1-liposomes. The third component of complement is likely to serve as the opsonin that is directly involved in mediating liposome clearance.
Liu
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Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pennsylvania 15261, USA.
Song
Y K
YK
Liu
F
F
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D002417:Cattle; D002614:Chelating Agents / Q000494:pharmacology; D003176:Complement C3 / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology*; D004492:Edetic Acid / Q000494:pharmacology; D005677:G(M1) Ganglioside / Q000276:immunology* / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology; D008081:Liposomes / Q000737:chemistry / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D010477:Perfusion; D051381:Rats
D000906:Antibodies; D002614:Chelating Agents; D003176:Complement C3; D007075:Immunoglobulin M; D008081:Liposomes; D005677:G(M1) Ganglioside; D003165:Complement System Proteins; D004492:Edetic Acid