Interferon gamma peptidomimetic targeted to hepatic stellate cells ameliorates acute and chronic liver fibrosis in vivo.
Hepatic stellate cells play a crucial role in the pathogenesis of hepatic fibrosis. Thus, pharmacological inhibition of pro-fibrotic activities of these cells might lead to an effective therapy for this disease. Among the potent anti-fibrotics, interferon gamma (IFNγ), a proinflammatory cytokine, is highly efficacious but it failed in clinical trials due to the poor efficacy and multiple adverse effects attributed to the ubiquitous IFNγ receptor (IFNγR) expression. To resolve these drawbacks, we chemically synthesized a chimeric molecule containing (a) IFNγ signaling peptide (IFNγ peptidomimetic, mimγ) that retains the agonistic activities of IFNγ but lacks an extracellular receptor recognition sequence for IFNγR; coupled via heterobifunctional PEG linker to (b) bicyclic platelet derived growth factor beta receptor (PDGFβR)-binding peptide (BiPPB) to induce internalization into the stellate cells that express PDGFβR. The synthesized targeted IFNγ peptidomimetic (mimγ-BiPPB) was extensively investigated for its anti-fibrotic and adverse effects in acute and chronic CCl4-induced liver fibrosis models in mice. Treatment with mimγ-BiPPB, after the onset of disease, markedly inhibited both early and established hepatic fibrosis as reflected by a reduced intrahepatic α-SMA, desmin and collagen-I mRNA expression and protein levels. While untargeted mimγ and BiPPB had no effect, and native IFNγ only induced a moderate reduction. Additionally, no off-target effects, e.g. systemic inflammation, were found with mimγ-BiPPB, which were substantially observed in mice treated with native IFNγ. The present study highlights the beneficial effects of a novel BiPPB mediated cell-specific targeting of IFNγ peptidomimetic to the disease-inducing cells and therefore represents a highly potential therapeutic approach to treat fibrotic diseases.
Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, The Netherlands; Department of Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands. Electronic address: R.Bansal@utwente.nl.
Ruchi
R
Bansal
Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, The Netherlands; Department of Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
Jai
J
Prakash
Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, The Netherlands.
Marieke
M
De Ruiter
Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, The Netherlands.
Klaas
K
Poelstra
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000208:Acute Disease; D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D003893:Desmin / Q000235:genetics / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000199:Actins; D024042:Collagen Type I; D003893:Desmin; D007371:Interferon-gamma; D057786:Peptidomimetics; D012333:RNA, Messenger; D020797:Receptor, Platelet-Derived Growth Factor beta; C498862:Acta2 protein, rat
Fibrosis; IFNγ peptidomimetic; PDGFβR-recognizing bicyclic peptide; Stellate cells; Targeted delivery