Liposome-induced complement activation and related cardiopulmonary distress in pigs

Factors promoting reactogenicity of Doxil and AmBisome

J. Szebeni, Péter Bedocs, Zoltán Rozsnyay, Zsóka Weiszhár, Rudolf Urbanics, L. Rosivall, Rivka Cohen, Olga Garbuzenko, G. Báthori, Miklós Tóth, Rolf Bünger, Yechezkel Barenholz

Research output: Contribution to journalArticle

114 Citations (Scopus)

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. From the Clinical Editor: 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.

Original languageEnglish
Pages (from-to)176-184
Number of pages9
JournalNanomedicine: Nanotechnology, Biology, and Medicine
Volume8
Issue number2
DOIs
Publication statusPublished - Feb 2012

Fingerprint

Liposomes
Complement Activation
Swine
Chemical activation
Doxorubicin
Surface charge
Phospholipids
Hypersensitivity
Pharmaceutical Preparations
Cisplatin
Antigen-antibody reactions
liposomal doxorubicin
liposomal amphotericin B
Serum
Agglomeration
In Vitro Techniques

Keywords

  • Cancer chemotherapy
  • Drug targeting
  • Immune toxicity
  • Infusion reactions
  • Nanomedicines

ASJC Scopus subject areas

  • Molecular Medicine
  • Bioengineering
  • Biomedical Engineering
  • Materials Science(all)
  • Medicine (miscellaneous)
  • Pharmaceutical Science

Cite this

Liposome-induced complement activation and related cardiopulmonary distress in pigs : Factors promoting reactogenicity of Doxil and AmBisome. / Szebeni, J.; Bedocs, Péter; Rozsnyay, Zoltán; Weiszhár, Zsóka; Urbanics, Rudolf; Rosivall, L.; Cohen, Rivka; Garbuzenko, Olga; Báthori, G.; Tóth, Miklós; Bünger, Rolf; Barenholz, Yechezkel.

In: Nanomedicine: Nanotechnology, Biology, and Medicine, Vol. 8, No. 2, 02.2012, p. 176-184.

Research output: Contribution to journalArticle

Szebeni, J. ; Bedocs, Péter ; Rozsnyay, Zoltán ; Weiszhár, Zsóka ; Urbanics, Rudolf ; Rosivall, L. ; Cohen, Rivka ; Garbuzenko, Olga ; Báthori, G. ; Tóth, Miklós ; Bünger, Rolf ; Barenholz, Yechezkel. / Liposome-induced complement activation and related cardiopulmonary distress in pigs : Factors promoting reactogenicity of Doxil and AmBisome. In: Nanomedicine: Nanotechnology, Biology, and Medicine. 2012 ; Vol. 8, No. 2. pp. 176-184.
@article{40ff1c50ab2241a1b98bfcd258c01342,
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. From the Clinical Editor: 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.",
keywords = "Cancer chemotherapy, Drug targeting, Immune toxicity, Infusion reactions, Nanomedicines",
author = "J. Szebeni and P{\'e}ter Bedocs and Zolt{\'a}n Rozsnyay and Zs{\'o}ka Weiszh{\'a}r and Rudolf Urbanics and L. Rosivall and Rivka Cohen and Olga Garbuzenko and G. B{\'a}thori and Mikl{\'o}s T{\'o}th and Rolf B{\"u}nger and Yechezkel Barenholz",
year = "2012",
month = "2",
doi = "10.1016/j.nano.2011.06.003",
language = "English",
volume = "8",
pages = "176--184",
journal = "Nanomedicine: Nanotechnology, Biology, and Medicine",
issn = "1549-9634",
publisher = "Elsevier Inc.",
number = "2",

}

TY - JOUR

T1 - Liposome-induced complement activation and related cardiopulmonary distress in pigs

T2 - Factors promoting reactogenicity of Doxil and AmBisome

AU - Szebeni, J.

AU - Bedocs, Péter

AU - Rozsnyay, Zoltán

AU - Weiszhár, Zsóka

AU - Urbanics, Rudolf

AU - Rosivall, L.

AU - Cohen, Rivka

AU - Garbuzenko, Olga

AU - Báthori, G.

AU - Tóth, Miklós

AU - Bünger, Rolf

AU - Barenholz, Yechezkel

PY - 2012/2

Y1 - 2012/2

N2 - 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. From the Clinical Editor: 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.

AB - 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. From the Clinical Editor: 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.

KW - Cancer chemotherapy

KW - Drug targeting

KW - Immune toxicity

KW - Infusion reactions

KW - Nanomedicines

UR - http://www.scopus.com/inward/record.url?scp=84855840953&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84855840953&partnerID=8YFLogxK

U2 - 10.1016/j.nano.2011.06.003

DO - 10.1016/j.nano.2011.06.003

M3 - Article

VL - 8

SP - 176

EP - 184

JO - Nanomedicine: Nanotechnology, Biology, and Medicine

JF - Nanomedicine: Nanotechnology, Biology, and Medicine

SN - 1549-9634

IS - 2

ER -