title: Inhibition of liposome-induced complement activation by incorporated poly(ethylene glycol)-lipids.
abstract: Complement activation causes opsonization of foreign particles leading to particle elimination from the blood. Complement-mediated opsonization of charged and large liposomes presents a fundamental problem in their use to deliver therapeutic agents in vivo. To prolong the circulation half-lives of such liposomes, complement activation must be curtailed. The aim of this study was to assess the ability of poly(ethylene glycol)-lipids (PEG-lipids) to inhibit the in vitro activation of the classical pathway of complement in human serum by anionic liposomes. Incorporation of cholesterol-PEG600 (CH-PEG600), cholesterol-PEG1000 (CH-PEG1000), or phosphatidylethanolamine-PEG2000 (PE-PEG2000) resulted in dose-dependent inhibition of C1q binding and complement activation. The dose of PEG-lipid at which complement activation was blocked was inversely related to the PEG chain length. Complement activation was strongly inhibited when 15 mole% of CH-PEG600, 10 mole% CH-PEG1000, or 5 mole% PE-PEG2000 was incorporated into 100-nm anionic liposomes. PEG-lipid incorporation into larger liposomes (240 nm) was also successful in blocking C1q binding and complement activation. Radiolabeled cholesterol-PEG approximately 1400 was prepared and used to determine both the percentage of CH-PEG incorporated into the liposomes and the percentage maintained in the liposomes in the presence of 50% human serum at 37 degrees C for up to 24 h.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: A J
authors.initials: AJ
authors.lastname: Bradley
authors.forename: D V
authors.initials: DV
authors.lastname: Devine
authors.forename: S M
authors.initials: SM
authors.lastname: Ansell
authors.forename: J
authors.initials: J
authors.lastname: Janzen
authors.forename: D E
authors.initials: DE
authors.lastname: Brooks
mesh_terms: D002784:Cholesterol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D015922:Complement C1q / Q000037:antagonists & inhibitors / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000378:metabolism / Q000494:pharmacology; D003171:Complement Pathway, Classical / Q000187:drug effects*; D004337:Drug Carriers; D006801:Humans; D008081:Liposomes / Q000378:metabolism / Q000494:pharmacology*; D008970:Molecular Weight; D010316:Particle Size; D010714:Phosphatidylethanolamines / Q000378:metabolism / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects
chemical_list: D003169:Complement Inactivator Proteins; D004337:Drug Carriers; D008081:Liposomes; D010714:Phosphatidylethanolamines; C095164:poly(oxyethylene) cholesteryl ether; C067972:dioleoyl-N-(monomethoxypolyethylene glycol succinyl)phosphatidylethanolamine; D011092:Polyethylene Glycols; D015922:Complement C1q; D002784:Cholesterol