Nanomedicine: Nanotechnology, Biology and Medicine
Volume 8, Issue 2 , Pages 176-184, February 2012

Liposome-induced complement activation and related cardiopulmonary distress in pigs: factors promoting reactogenicity of Doxil and AmBisome

  • János Szebeni, MD, PhD, DSc

      Affiliations

    • 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
    • Corresponding Author InformationCorresponding author: Nanomedicine Research and Education Center, Semmelweis University, Budapest, 1089 Nagyvárad tér 4, Hungary.
    • Equal contributors.
    • ,
  • Péter Bedőcs, MD

      Affiliations

    • Semmelweis University, Budapest, Hungary, and Department of Anatomy, Physiology and Cell Biology, Uniformed Services University of Health Sciences, Bethesda, Maryland, USA
    • Equal contributors.
    • ,
  • Zoltán Rozsnyay, MSc, PhD

      Affiliations

    • Seroscience Ltd., Budapest, Hungary
    • ,
  • Zsóka Weiszhár, MSc

      Affiliations

    • Seroscience Ltd., Budapest, Hungary
    • ,
  • Rudolf Urbanics, MD, PhD

      Affiliations

    • Seroscience Ltd., Budapest, Hungary
    • ,
  • László Rosivall, MD, PhD, DSc

      Affiliations

    • Department of Pathophysiology, Faculty of Medicine, Semmelweis University, Hungarian Academy of Sciences-Semmelweis University, Nephrology Research Group, Budapest, Hungary
    • ,
  • Rivka Cohen, PhD

      Affiliations

    • Laboratory of Membrane and Liposome Research, Hebrew University-Hadassah Medical School, Jerusalem, Israel
    • ,
  • Olga Garbuzenko, PhD

      Affiliations

    • Laboratory of Membrane and Liposome Research, Hebrew University-Hadassah Medical School, Jerusalem, Israel
    • ,
  • György Báthori, MD, PhD

      Affiliations

    • Nanomedicine Research and Education Center, Bay Zoltan Foundation for Applied Research, and Semmelweis University, Budapest, Hungary
    • ,
  • Miklós Tóth, MD, PhD, DSc

      Affiliations

    • Department of Health Science and Sport Medicine, Faculty of Physical Education and Sport Science, Semmelweis Medical University, Budapest, Hungary
    • ,
  • Rolf Bünger, MD, PhD

      Affiliations

    • Department of Anatomy, Physiology and Cell Biology, Uniformed Services University of Health Sciences, Bethesda, Maryland, USA
    • ,
  • Yechezkel Barenholz, PhD

      Affiliations

    • Laboratory of Membrane and Liposome Research, Hebrew University-Hadassah Medical School, Jerusalem, Israel

Received 22 September 2010; accepted 4 June 2011. published online 27 June 2011.

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.

Graphical Abstract 

Blood pressure changes in pigs following bolus administration of AmBisome.

Key words: Nanomedicines, Cancer chemotherapy, Drug targeting, Immune toxicity, Infusion reactions

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 Financial support from the following organizations is gratefully acknowledged: The Barenholz Fund; Nanomedi and Carpa777 grants from the National Office of Research and Technology of Hungary; FP7 grant “Anticarb", USUHS RO70LO; TÁMOP-4.2.1/B-09/1/KMR for Semmelweis University and TAMOP-4.2.1.B-10/2/KONV-2010-0001 for Miskolc University, with support by the European Union, co-financed by the European Social Fund.

PII: S1549-9634(11)00256-5

doi:10.1016/j.nano.2011.06.003

Nanomedicine: Nanotechnology, Biology and Medicine
Volume 8, Issue 2 , Pages 176-184, February 2012

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