Animal models of complement-mediated hypersensitivity reactions to liposomes and other lipid-based nanoparticles

J. Szebeni, Carl R. Alving, L. Rosivall, Rolf Bünger, Lajos Baranyi, Péter Bedöcs, Miklós Tóth, Yezheckel Barenholz

Research output: Contribution to journalArticle

122 Citations (Scopus)

Abstract

Intravenous injection of some liposomal drugs, diagnostic agents, micelles and other lipid-based nanoparticles can cause acute hypersensitivity reactions (HSRs) in a high percentage (up to 45%) of patients, with hemodynamic, respiratory and cutaneous manifestations. The phenomenon can be explained with activation of the complement (C) system on the surface of lipid particles, leading to anaphylatoxin (C5a and C3a) liberation and subsequent release reactions of mast cells, basophils and possibly other inflammatory cells in blood. These reactions can be reproduced and studied in pigs, dogs and rats, animal models which differ from each other in sensitivity and spectrum of symptoms. In the most sensitive pig model, a few miligrams of liposome (phospholipid) can cause anaphylactoid shock, characterized by pulmonary hypertension, systemic hypotension, decreased cardiac output and major cardiac arrhythmias. Pigs also display cutaneous symptoms, such as flushing and rash. The sensitivity of dogs to hemodynamic changes is close to that of pigs, but unlike pigs, dogs also react to micellar lipids (such as Cremophor EL) and their response includes pronounced blood cell and vegetative neural changes (e.g., leukopenia followed by leukocytosis, thrombocytopenia, fluid excretions). Rats are relatively insensitive inasmuch as hypotension, their most prominent response to liposomes, is induced only by one or two orders of magnitude higher phospholipid doses (based on body weight) compared to the reactogenic dose in pigs and dogs. It is suggested that the porcine and dog models are applicable for measuring and predicting the (pseudo)allergic activity of particulate "nanodrugs".

Original languageEnglish
Pages (from-to)107-117
Number of pages11
JournalJournal of Liposome Research
Volume17
Issue number2
DOIs
Publication statusPublished - Apr 2007

Fingerprint

Liposomes
Nanoparticles
Hypersensitivity
Swine
Animal Models
Lipids
Dogs
Hypotension
Blood Cells
Phospholipids
Hemodynamics
Anaphylatoxins
Skin Manifestations
Basophils
Complement Activation
Leukocytosis
Leukopenia
Micelles
Exanthema
Pulmonary Hypertension

Keywords

  • Adverse drug reactions
  • Animal models
  • Complement
  • Hypersensitivity
  • Liposomes
  • Nanomedicines

ASJC Scopus subject areas

  • Pharmacology

Cite this

Animal models of complement-mediated hypersensitivity reactions to liposomes and other lipid-based nanoparticles. / Szebeni, J.; Alving, Carl R.; Rosivall, L.; Bünger, Rolf; Baranyi, Lajos; Bedöcs, Péter; Tóth, Miklós; Barenholz, Yezheckel.

In: Journal of Liposome Research, Vol. 17, No. 2, 04.2007, p. 107-117.

Research output: Contribution to journalArticle

Szebeni, J. ; Alving, Carl R. ; Rosivall, L. ; Bünger, Rolf ; Baranyi, Lajos ; Bedöcs, Péter ; Tóth, Miklós ; Barenholz, Yezheckel. / Animal models of complement-mediated hypersensitivity reactions to liposomes and other lipid-based nanoparticles. In: Journal of Liposome Research. 2007 ; Vol. 17, No. 2. pp. 107-117.
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