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

Mattos Pinto, A., de Jager-Krikken, A., de Haan, M., Beljaars, L. & Poelstra, K., 20-Aug-2012, In : Journal of Controlled Release. 162, 1, p. 84-91 8 p.

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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
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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