title: Role of complement activation in hypersensitivity reactions to doxil and hynic PEG liposomes: experimental and clinical studies.
abstract: Pegylated liposomal doxorubicin (Doxil) and 99mTc-HYNIC PEG liposomes (HPL) were reported earlier to cause hypersensitivity reactions (HSRs) in a substantial percentage of patients treated i.v. with these formulations. Here we report that (1) Doxil, HPL, pegylated phosphatidylethanolamine (PEG-PE)-containing empty liposomes matched with Doxil and HPL in size and lipid composition, and phosphatidylglycerol (PG)-containing negatively charged vesicles were potent C activators in human serum in vitro, whereas small neutral liposomes caused no C activation. (2) Doxil and other size-matched PEG-PE and/or PG-containing liposomes also caused massive cardiopulmonary distress with anaphylactoid shock in pigs via C activation, whereas equivalent neutral liposomes caused no hemodynamic changes. (3) A clinical study showed more frequent and greater C activation in patients displaying HSR than in non-reactive patients. These data suggest that liposome-induced HSRs in susceptible individuals may be due to C activation, which, in turn, is due to the presence of negatively charged PEG-PE in these vesicles.
authors.affiliation: Walter Reed Army Institute of Research, Silver Spring, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Szebeni
authors.forename: L
authors.initials: L
authors.lastname: Baranyi
authors.forename: S
authors.initials: S
authors.lastname: Savay
authors.forename: J
authors.initials: J
authors.lastname: Milosevits
authors.forename: R
authors.initials: R
authors.lastname: Bunger
authors.forename: P
authors.initials: P
authors.lastname: Laverman
authors.forename: J M
authors.initials: JM
authors.lastname: Metselaar
authors.forename: G
authors.initials: G
authors.lastname: Storm
authors.forename: A
authors.initials: A
authors.lastname: Chanan-Khan
authors.forename: L
authors.initials: L
authors.lastname: Liebes
authors.forename: F M
authors.initials: FM
authors.lastname: Muggia
authors.forename: R
authors.initials: R
authors.lastname: Cohen
authors.forename: Y
authors.initials: Y
authors.lastname: Barenholz
authors.forename: C R
authors.initials: CR
authors.lastname: Alving
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D003167:Complement Activation; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D050356:Lipid Metabolism; D008081:Liposomes / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism; D011092:Polyethylene Glycols / Q000378:metabolism* / Q000494:pharmacology; D013552:Swine; D013667:Technetium / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D011092:Polyethylene Glycols; D013667:Technetium; D004317:Doxorubicin