title: Activation of the human complement system by cholesterol-rich and PEGylated liposomes-modulation of cholesterol-rich liposome-mediated complement activation by elevated serum LDL and HDL levels.
abstract: Intravenously infused liposomes may induce cardiopulmonary distress in some human subjects, which is a manifestation of "complement activation-related pseudoallergy." We have now examined liposome-mediated complement activation in human sera with elevated lipoprotein (LDL and HDL) levels, since abnormal or racial differences in serum lipid profiles seem to modulate the extent of complement activation and associated adverse responses. In accordance with our earlier observations, cholesterol-rich (45 mol% cholesterol) liposomes activated human complement, as reflected by a significant rise in serum level of S-protein-bound form of the terminal complex (SC5b-9). However, liposome-induced rise of SC5b-9 was significantly suppressed when serum HDL cholesterol levels increased by 30%. Increase of serum LDL to levels similar to that observed in heterozygous familial hypercholesterolemia also suppressed liposome-mediated SC5b-9 generation considerably. While intravenous injection of cholesterol-rich liposomes into pigs was associated with an immediate circulatory collapse, the drop in systemic arterial pressure following injection of liposomes preincubated with human lipoproteins was slow and extended. Therefore, surface-associated lipoprotein particles (or apolipoproteins) seem to lessen liposome-induced adverse haemodynamic changes, possibly as a consequence of suppressed complement activation in vivo. PEGylated liposomes were also capable of activating the human complement system, and the presence of surface projected methoxypoly(ethylene glycol) chains did not interfere with generation of C3 opsonic fragments. We also show that poly(ethylene glycol) is not responsible for PEGylated liposome-mediated complement activation. The net anionic charge on the phosphate moiety of the phospholipid-mPEG conjugate seemed to play a critical role in activation of both the classical and alternative pathways of the complement system.
authors.affiliation: Molecular Targeting and Polymer Toxicology, School of Pharmacy, University of Brighton, Brighton, UK. s.m.moghimi@brighton.ac.uk
authors.forename: S
authors.initials: S
authors.lastname: Moein Moghimi
authors.forename: Islam
authors.initials: I
authors.lastname: Hamad
authors.forename: Rolf
authors.initials: R
authors.lastname: Bünger
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Andresen
authors.forename: Kent
authors.initials: K
authors.lastname: Jørgensen
authors.forename: A Christy
authors.initials: AC
authors.lastname: Hunter
authors.forename: Lajos
authors.initials: L
authors.lastname: Baranji
authors.forename: Laszlo
authors.initials: L
authors.lastname: Rosivall
authors.forename: Janos
authors.initials: J
authors.lastname: Szebeni
mesh_terms: D000818:Animals; D002784:Cholesterol; D008076:Cholesterol, HDL / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood*; D003167:Complement Activation; D006801:Humans; D008081:Liposomes; D011092:Polyethylene Glycols; D013552:Swine
chemical_list: D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D008081:Liposomes; D011092:Polyethylene Glycols; D002784:Cholesterol