PEGylation improves pharmacokinetic profile, liver uptake and efficacy of Interferon gamma in liver fibrosis

Bansal, R., Post, E., Proost, J. H., de Jager-Krikken, A., Poelstra, K. & Prakash, J., 25-Sep-2011, In : Journal of Controlled Release. 154, 3, p. 233-240 8 p.

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Interferon gamma (IFN gamma) is a potent cytokine that displays a variety of anti-viral, anti-proliferative, immunomodulatory, apoptotic and anti-fibrotic functions. However, its clinical use is limited to the treatment of few diseases due to the rapid clearance from the body. PEGylated IFN-alpha formulations are shown to be beneficial in viral hepatitis, but PEGylation of IFN gamma to enhance its therapeutic effects in liver fibrosis is not yet explored. Liver fibrosis is characterized by the extensive accumulation of an abnormal extracellular matrix and is the major cause of liver-related morbidity and mortality worldwide. To date, there is no pharmacotherapy available for this disease. We modified IFN gamma with different-sized linear PEG molecules (5, 10 and 20 kDa) and assessed the biological activity in vitro and in vivo. All PEGylated IFN gamma constructs were biologically active and activated IFN gamma signaling in vitro as determined with a nitric oxide release assay and a pGAS-Luc reporter plasmid assay, respectively. Similar to IFN gamma, all PEGylated IFN gamma induced a significant reduction of fibrotic parameters in mouse NIH3T3 fibroblasts as shown with immunohistochemical staining and quantitative PCR analyses. In vivo, the pharmacokinetic profile of radiolabeled (125)I-IFN gamma-PEG conjugates revealed a decreased renal clearance and an increased plasma half-life with an increase of PEG size. Moreover, the liver accumulation of PEGylated IFN gamma constructs was significantly higher than the unmodified IFN gamma, which was also confirmed by increased MHC-II expression in the livers. Furthermore, in a CCI(4)-induced acute liver injury model in mice. PEGylated constructs reduced the early fibrotic parameters more drastically than unmodified IFN gamma. Of note, these effects were stronger with higher PEG-sized IFN gamma constructs. These data nicely correlated with the pharmacokinetic data. In conclusion, PEGylation significantly improved the pharmacokinetics, liver uptake and anti-fibrotic effects of IFN gamma. This study opens new opportunities to exploit the therapeutic applications of PEGylated IFN gamma for the treatment of liver fibrosis and other diseases. (C) 2011 Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)233-240
Number of pages8
JournalJournal of Controlled Release
Issue number3
Publication statusPublished - 25-Sep-2011



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