In vitro and in vivo complement activation and related anaphylactic effects associated with polyethylenimine and polyethylenimine-graft-poly(ethylene glycol) block copolymers

Olivia M. Merkel, Rudolf Urbanics, Peter Bedocs, Zoltán Rozsnyay, L. Rosivall, Miklós Toth, Thomas Kissel, J. Szebeni

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

Complement activation by polymeric gene and drug delivery systems has been overlooked in the past. As more reports appear in the literature concerning immunogenicity of polymers and their impact on gene expression patterns, it is important to address possible immune side effects of polymers, namely complement activation. Therefore, in this study the activity of low and high molecular weight poly(ethylene imine) and two PEGylated derivatives to induce complement activation were investigated in human serum. These in vitro results revealed that PEI 25 kDa caused significant and concentration dependent complement activation, whereas none of the other polymers induced such effects at their IC50 concentrations determined by MTT-assays. To verify these in vitro results, additionally, studies were carried out in a swine model after intravenous administration, showing complement activation-related pseudoallergy (CARPA), reflected in symptoms of transient cardiopulmonary distress. Injections of PEI 25 kDa or PEI(25k)-PEG(2k)10 at a dose of 0.05 and 0.1 mg/kg caused strong reactivity, while PEI 5 kDa and with PEI(25k)-PEG(20k)1 were also reactogenic at 0.1 mg/kg. It was found that PEI 25 kDa caused both self- and cross-tolerance, whereas the PEG-PEIs were neither self- nor cross-reactively tachyphylactic. As a result of this study, it was shown that PEGylation of polycations with PEG of 20 kDa or higher molecular weight may be favorable. However, potential safety concerns in the development of PEI-based polymeric carriers for drugs and nucleic acids and their translation from bench to bedside need to be taken into consideration for human application.

Original languageEnglish
Pages (from-to)4936-4942
Number of pages7
JournalBiomaterials
Volume32
Issue number21
DOIs
Publication statusPublished - Jul 2011

Fingerprint

Polyethyleneimine
Polyetherimides
Ethylene Glycol
Complement Activation
Grafts
Polyethylene glycols
Block copolymers
Chemical activation
Transplants
Polymers
Molecular Weight
Gene Transfer Techniques
Drug Carriers
Molecular weight
Drug Delivery Systems
Intravenous Administration
Nucleic Acids
Inhibitory Concentration 50
Swine
In Vitro Techniques

Keywords

  • Cardiopulmonary distress
  • CARPA
  • Complement activation
  • PEGylation
  • PEI
  • Swine model

ASJC Scopus subject areas

  • Biomaterials
  • Bioengineering
  • Ceramics and Composites
  • Mechanics of Materials
  • Biophysics

Cite this

In vitro and in vivo complement activation and related anaphylactic effects associated with polyethylenimine and polyethylenimine-graft-poly(ethylene glycol) block copolymers. / Merkel, Olivia M.; Urbanics, Rudolf; Bedocs, Peter; Rozsnyay, Zoltán; Rosivall, L.; Toth, Miklós; Kissel, Thomas; Szebeni, J.

In: Biomaterials, Vol. 32, No. 21, 07.2011, p. 4936-4942.

Research output: Contribution to journalArticle

Merkel, Olivia M. ; Urbanics, Rudolf ; Bedocs, Peter ; Rozsnyay, Zoltán ; Rosivall, L. ; Toth, Miklós ; Kissel, Thomas ; Szebeni, J. / In vitro and in vivo complement activation and related anaphylactic effects associated with polyethylenimine and polyethylenimine-graft-poly(ethylene glycol) block copolymers. In: Biomaterials. 2011 ; Vol. 32, No. 21. pp. 4936-4942.
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