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

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 (PDGFβR) 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 (IFNγ) 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 PDGFβR-specific drug delivery carrier (PPB–HSA) was developed by modifying albumin with PDGFβR-recognizing cyclic peptides. Subsequently, IFNγ was conjugated to PPB–HSA via bifunctional PEG linkers to synthesize PPB–HSA–PEG–IFNγ. In vitro, PPB–HSA–PEG–IFNγ retained complete biological activity similar to unmodified IFNγ and showed PDGFβR-specific binding to human HSC and primary culture-activated rat HSC. In TGFβ-stimulated mouse fibroblasts and human HSC, PPB–HSA–PEG–IFNγ induced significant reduction in crucial fibrotic parameters. In vivo, the conjugate rapidly accumulated into PDGFβR-expressing HSC in fibrotic livers and activated IFNγ-mediated pstat1α signaling pathway. Furthermore, in a CCl4-induced acute liver injury model in mice, treatment with HSC-targeted IFNγ strongly ameliorated hepatic fibrogenesis by inducing significant reduction (about 60%; p < 0.01) in collagen I and α-SMA expression as well as enhanced fibrolysis (increased MMP/TIMP ratio; p < 0.05) while free unmodified IFNγ was ineffective. Furthermore, in contrast to free native IFNγ, the conjugate did not induce macrophage infiltration and IL-1β expression in the liver. In conclusion, these data demonstrate the enhanced antifibrotic efficacy and reduced off-target effects of PPB–HSA–PEG–IFNγ conjugate showing the potential of cell-specific targeting of IFNγ for the treatment of liver fibrosis.