title: Liposome-induced complement activation and related cardiopulmonary distress in pigs: factors promoting reactogenicity of Doxil and AmBisome.
abstract: Hypersensitivity reactions to liposomal drugs, often observed with Doxil and AmBisome, can arise from activation of the complement (C) system by phospholipid bilayers. To understand the mechanism of this adverse immune reaction called C activation-related pseudoallergy (CARPA), we analyzed the relationship among liposome features, C activation in human serum in vitro, and liposome-induced cardiovascular distress in pigs, a model for human CARPA. Among the structural variables (surface charge, presence of saturated, unsaturated, and PEGylated phospholipids, and cisplatin vs. doxorubicin inside liposomes), high negative surface charge and the presence of doxorubicin were significant contributors to reactogenicity both in vitro and in vivo. Morphological analysis suggested that the effect of doxorubicin might be indirect, via distorting the sphericity of liposomes and, if leaked, causing aggregation. The parallelism among C activation, cardiopulmonary reactions in pigs, and high rate of hypersensitivity reactions to Doxil and AmBisome in humans strengthens the utility of the applied tests in predicting the risk of CARPA.
  
  
  BACKGROUND
  The authors studied complement activation-related pseudoallergy (CARPA) in a porcine model and demonstrate that high negative surface charge and drug effects leading to distortion of liposome sphericity might be the most critical factors leading to CARPA. The applied tests might be used to predict CARPA in humans.
authors.affiliation: Nanomedicine Research and Education Center, Bay Zoltan Foundation for Applied Research, Semmelweis University, and Department of Pathophysiology, Miskolc University, Faculty of Health, and Seroscience Ltd., Budapest, Hungary. jszebeni2@gmail.com
authors.forename: János
authors.initials: J
authors.lastname: Szebeni
authors.forename: Péter
authors.initials: P
authors.lastname: Bedocs
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Rozsnyay
authors.forename: Zsóka
authors.initials: Z
authors.lastname: Weiszhár
authors.forename: Rudolf
authors.initials: R
authors.lastname: Urbanics
authors.forename: László
authors.initials: L
authors.lastname: Rosivall
authors.forename: Rivka
authors.initials: R
authors.lastname: Cohen
authors.forename: Olga
authors.initials: O
authors.lastname: Garbuzenko
authors.forename: György
authors.initials: G
authors.lastname: Báthori
authors.forename: Miklós
authors.initials: M
authors.lastname: Tóth
authors.forename: Rolf
authors.initials: R
authors.lastname: Bünger
authors.forename: Yechezkel
authors.initials: Y
authors.lastname: Barenholz
mesh_terms: D000666:Amphotericin B / Q000009:adverse effects*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D003167:Complement Activation; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000009:adverse effects* / Q000031:analogs & derivatives*; D006323:Heart Arrest / Q000209:etiology* / Q000378:metabolism; D006801:Humans; D006967:Hypersensitivity; D008081:Liposomes / Q000009:adverse effects*; D010743:Phospholipids / Q000378:metabolism; D011092:Polyethylene Glycols / Q000009:adverse effects*; D013499:Surface Properties / Q000187:drug effects; D013552:Swine
chemical_list: D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D010743:Phospholipids; C068538:liposomal amphotericin B; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D000666:Amphotericin B; D004317:Doxorubicin