PEGylation of interleukin-10 improves the pharmacokinetic profile and enhances the antifibrotic effectivity in CCl4-induced fibrogenesis in mice

Adriana Mattos Pinto, Alie de Jager-Krikken, Marianne de Haan, Leonie Beljaars, Klaas Poelstra*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

12 Citations (Scopus)

Abstract

Liver fibrosis represents a scar formation process as a response to chronic injury and a major cause of death worldwide. To date, no drug is available for this condition. Interleukin-10 (IL-10) has potent anti-inflammatory and antifibrotic properties but its short half-life in the circulation hampers its clinical use. Our aim was therefore to modify IL-10 with polyethylene glycol (PEG) to prolong its circulation time and enhance its effectivity. IL-10 was modified with 5 or 20 kDa PEG. The biological activity was preserved after PEGylation as assessed by inhibition of TNF-alpha production by macrophages. In vivo, during CCl4-induced fibrogenesis in mice, both 5PEG-IL-10 and 20PEG-IL-10 showed a longer circulation time compared to IL-10, which was associated with a significant increased liver accumulation. Immunohistochemical analysis of fibrotic livers of mice receiving treatment with IL-10 or its PEGylated forms, revealed a decrease in markers reflecting HSC and KC activation induced by 5PEG-IL10. Transcription levels of IL-6 were decreased upon treatment with IL-10 and both PEGylated forms, whereas IL-1 beta levels were only down-regulated by 5PEGIL-10 and 20PEGIL-10. We conclude that PEGylation of IL-10 is a good strategy to attenuate liver fibrosis and that 5PEGIL-10 is the most effective conjugate. (C) 2012 Elsevier B. V. All rights reserved.

Original languageEnglish
Pages (from-to)84-91
Number of pages8
JournalJournal of Controlled Release
Volume162
Issue number1
DOIs
Publication statusPublished - 20-Aug-2012

Keywords

  • Interleukin-10
  • PEGylation
  • Pharmacokinetic profile
  • Liver fibrosis
  • Macrophage
  • HEPATIC STELLATE CELLS
  • RECOMBINANT HUMAN INTERLEUKIN-10
  • LIVER FIBROSIS
  • BIOLOGICAL-ACTIVITY
  • EXPRESSION
  • MACROPHAGES
  • RAT
  • RECEPTOR
  • IL-10
  • INFLAMMATION

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