Publication

Peptide-Modified Albumin Carrier Explored as a Novel Strategy for a Cell-Specific Delivery of Interferon Gamma To Treat Liver Fibrosis

Barisal, R., Prakash, J., de Ruijter, M., Beljaars, L. & Poelstra, K., 2011, In : Molecular pharmaceutics. 8, 5, p. 1899-1909 11 p.

Research output: Contribution to journalArticleAcademicpeer-review

Excessive accumulation of the extracellular matrix proteins primarily produced by activated hepatic stellate cells (HSC) leads to liver fibrosis. To date, no successful therapeutic intervention is available for the treatment of this disease. Platelet derived growth factor beta receptor (PDGF beta R) is highly upregulated on disease-inducing activated HSC and thus can be used for delivery of antifibrotic drugs to increase therapeutic efficacy with reduced adverse effects. Interferon gamma (IFN gamma) has been recognized as a potent antifibrotic cytokine; however, poor pharmacokinetics and side effects due to frequent administration have limited its clinical use. For HSC-specific delivery, a PDGF beta R-specific drug delivery carrier (PPB-HSA) was developed by modifying albumin with PDGF beta R-recognizing cyclic peptides. Subsequently, IFN gamma was conjugated to PPB-HSA via bifunctional PEG linkers to synthesize PPB-HSA-PEG-IFN gamma. In vitro, PPB-HSA-PEG-IFN gamma retained complete biological activity similar to unmodified IFN gamma and showed PDGF beta R-specific binding to human HSC and primary culture-activated rat HSC. In TGF beta-stimulated mouse fibroblasts and human HSC, PPB-HSA-PEG-IFN gamma induced significant reduction in crucial fibrotic parameters. In vivo, the conjugate rapidly accumulated into PDGF beta R-expressing HSC in fibrotic livers and activated IFN gamma-mediated pstat1 alpha signaling pathway. Furthermore, in a CCl(4)-induced acute liver injury model in mice, treatment with HSC-targeted IFN gamma strongly ameliorated hepatic fibrogenesis by inducing significant reduction (about 60%; p <0.01) in collagen I and alpha-SMA expression as well as enhanced fibrolysis (increased MMP/TIMP ratio; p <0.05) while free unmodified IFN gamma was ineffective. Furthermore, in contrast to free native IFN gamma, the conjugate did not induce macrophage infiltration and IL-1 beta expression in the liver. In conclusion, these data demonstrate the enhanced antifibrotic efficacy and reduced off-target effects of PPB-HSA-PEG-IFN gamma conjugate showing the potential of cell-specific targeting of IFN gamma for the treatment of liver fibrosis.

Original languageEnglish
Pages (from-to)1899-1909
Number of pages11
JournalMolecular pharmaceutics
Volume8
Issue number5
Publication statusPublished - 2011

    Keywords

  • platelet derived growth factor beta receptor, cyclic peptide, stellate cells targeting, interferon-gamma, liver fibrosis, HEPATIC STELLATE CELLS, GROWTH-FACTOR RECEPTOR, IFN-GAMMA, ALBINTERFERON ALPHA-2B, RANDOMIZED-TRIAL, ACTIVATION, EXPRESSION, INJURY, CIRRHOSIS, INFERIOR

ID: 5409318