Role of complement activation in hypersensitivity reactions to doxil and hynic PEG liposomes: experimental and clinical studies.
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.
Szebeni
J
J
Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Baranyi
L
L
Savay
S
S
Milosevits
J
J
Bunger
R
R
Laverman
P
P
Metselaar
J M
JM
Storm
G
G
Chanan-Khan
A
A
Liebes
L
L
Muggia
F M
FM
Cohen
R
R
Barenholz
Y
Y
Alving
C R
CR
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
D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D011092:Polyethylene Glycols; D013667:Technetium; D004317:Doxorubicin