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Hepatic Stellate Cell Targeting Using Peptide-Modified Biologicals

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Hepatic Stellate Cells

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2669))

Abstract

Liver diseases are a leading cause of death worldwide and are rising exponentially due to increasing prevalence of metabolic disorders. Hepatic stellate cells (HSCs) are recognized as a key therapeutic target in liver diseases as these cells, upon activation during liver damage and ongoing liver inflammation, secrete excessive amounts of extracellular matrix that leads to liver tissue scarring (fibrosis) responsible for liver dysfunction (end-stage liver disease) and desmoplasia in hepatocellular carcinoma. Targeting of HSCs to reverse fibrosis progression has been realized by several experts in the field, including us. We have developed strategies to target activated HSCs by utilizing the receptors overexpressed on the surface of activated HSCs. One well-known receptor is platelet derived growth factor receptor-beta (PDGFR-β). Using PDGFR-β recognizing peptides (cyclic PPB or bicyclic PPB), we can deliver biologicals, e.g., interferon gamma (IFNγ) or IFNγ activity domain (mimetic IFNγ), to the activated HSCs that can inhibit their activation and reverse liver fibrosis. In this chapter, we provide the detailed methods and the principles involved in the synthesis of these targeted (mimetic) IFNγ constructs. These methods can be adapted for synthesizing constructs for targeted/cell-specific delivery of peptides/proteins, drugs, and imaging agents useful for various applications including diagnosis and treatment of inflammatory and fibrotic diseases and cancer.

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References

  1. Friedman SL (2008) Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 88(1):125–172. https://doi.org/10.1152/physrev.00013.2007

    Article  CAS  PubMed  Google Scholar 

  2. Yazdani S, Bansal R, Prakash J (2017) Drug targeting to myofibroblasts: implications for fibrosis and cancer. Adv Drug Deliv Rev 121:101–116. https://doi.org/10.1016/j.addr.2017.07.010

    Article  CAS  PubMed  Google Scholar 

  3. Hernandez-Gea V, Friedman SL (2011) Pathogenesis of liver fibrosis. Annu Rev Pathol 6:425–456. https://doi.org/10.1146/annurev-pathol-011110-130246

    Article  CAS  PubMed  Google Scholar 

  4. Bansal R, Nagorniewicz B, Prakash J (2016) Clinical advancements in the targeted therapies against liver fibrosis. Mediat Inflamm 2016:7629724. https://doi.org/10.1155/2016/7629724

    Article  CAS  Google Scholar 

  5. Asrani SK, Devarbhavi H, Eaton J, Kamath PS (2019) Burden of liver diseases in the world. J Hepatol 70(1):151–171. https://doi.org/10.1016/j.jhep.2018.09.014

    Article  PubMed  Google Scholar 

  6. Poelstra K, Schuppan D (2011) Targeted therapy of liver fibrosis/cirrhosis and its complications. J Hepatol 55(3):726–728. https://doi.org/10.1016/j.jhep.2011.04.008

    Article  PubMed  Google Scholar 

  7. Poelstra K, Prakash J, Beljaars L (2012) Drug targeting to the diseased liver. J Control Release 161(2):188–197. https://doi.org/10.1016/j.jconrel.2012.02.011

    Article  CAS  PubMed  Google Scholar 

  8. Borkham-Kamphorst E, Kovalenko E, van Roeyen CR, Gassler N, Bomble M, Ostendorf T et al (2008) Platelet-derived growth factor isoform expression in carbon tetrachloride-induced chronic liver injury. Lab Investig 88(10):1090–1100. https://doi.org/10.1038/labinvest.2008.71

    Article  CAS  PubMed  Google Scholar 

  9. Bansal R, Prakash J, Post E, Beljaars L, Schuppan D, Poelstra K (2011) Novel engineered targeted interferon-gamma blocks hepatic fibrogenesis in mice. Hepatology 54(2):586–596. https://doi.org/10.1002/hep.24395

    Article  CAS  PubMed  Google Scholar 

  10. Bansal R, Prakash J, De Ruiter M, Poelstra K (2014) Targeted recombinant fusion proteins of IFNgamma and mimetic IFNgamma with PDGFbetaR bicyclic peptide inhibits liver fibrogenesis in vivo. PLoS One 9(2):e89878. https://doi.org/10.1371/journal.pone.0089878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bansal R, Prakash J, De Ruiter M, Poelstra K (2014) Interferon gamma peptidomimetic targeted to hepatic stellate cells ameliorates acute and chronic liver fibrosis in vivo. J Control Release 179:18–24. https://doi.org/10.1016/j.jconrel.2014.01.022

    Article  CAS  PubMed  Google Scholar 

  12. Bansal R, Prakash J, de Ruijter M, Beljaars L, Poelstra K (2011) Peptide-modified albumin carrier explored as a novel strategy for a cell-specific delivery of interferon gamma to treat liver fibrosis. Mol Pharm 8(5):1899–1909. https://doi.org/10.1021/mp200263q

    Article  CAS  PubMed  Google Scholar 

  13. Bansal R, Tomar T, Ostman A, Poelstra K, Prakash J (2012) Selective targeting of interferon gamma to stromal fibroblasts and pericytes as a novel therapeutic approach to inhibit angiogenesis and tumor growth. Mol Cancer Ther 11(11):2419–2428. https://doi.org/10.1158/1535-7163.MCT-11-0758

    Article  CAS  PubMed  Google Scholar 

  14. Jia Z, Gong Y, Pi Y, Liu X, Gao L, Kang L et al (2018) pPB peptide-mediated siRNA-loaded stable nucleic acid lipid nanoparticles on targeting therapy of hepatic fibrosis. Mol Pharm 15(1):53–62. https://doi.org/10.1021/acs.molpharmaceut.7b00709

    Article  CAS  PubMed  Google Scholar 

  15. Li F, Li QH, Wang JY, Zhan CY, Xie C, Lu WY (2012) Effects of interferon-gamma liposomes targeted to platelet-derived growth factor receptor-beta on hepatic fibrosis in rats. J Control Release 159(2):261–270. https://doi.org/10.1016/j.jconrel.2011.12.023

    Article  CAS  PubMed  Google Scholar 

  16. Li Q, Yan Z, Li F, Lu W, Wang J, Guo C (2012) The improving effects on hepatic fibrosis of interferon-gamma liposomes targeted to hepatic stellate cells. Nanotechnology 23(26):265101. https://doi.org/10.1088/0957-4484/23/26/265101

    Article  CAS  PubMed  Google Scholar 

  17. Li Q, Yu Q, Ju J, You T, Yan Z, Nan X et al (2017) Long-circulating liposomal delivery system targeting at PDGFR-beta enhances the therapeutic effect of IFN-alpha on hepatic fibrosis. Curr Pharm Des 23(20):3034–3046. https://doi.org/10.2174/1381612822666161208144953

    Article  CAS  PubMed  Google Scholar 

  18. Li Q, Ding Y, Guo X, Luo S, Zhuang H, Zhou J et al (2019) Chemically modified liposomes carrying TRAIL target activated hepatic stellate cells and ameliorate hepatic fibrosis in vitro and in vivo. J Cell Mol Med 23(3):1951–1962. https://doi.org/10.1111/jcmm.14097

    Article  CAS  PubMed  Google Scholar 

  19. Poosti F, Bansal R, Yazdani S, Prakash J, Beljaars L, van den Born J et al (2016) Interferon gamma peptidomimetic targeted to interstitial myofibroblasts attenuates renal fibrosis after unilateral ureteral obstruction in mice. Oncotarget 7(34):54240–54252. https://doi.org/10.18632/oncotarget.11095

    Article  PubMed  PubMed Central  Google Scholar 

  20. van Dijk F, Olinga P, Poelstra K, Beljaars L (2015) Targeted therapies in liver fibrosis: combining the best parts of platelet-derived growth factor BB and interferon gamma. Front Med (Lausanne) 2:72. https://doi.org/10.3389/fmed.2015.00072

    Article  PubMed  Google Scholar 

  21. Beljaars L, Weert B, Geerts A, Meijer DK, Poelstra K (2003) The preferential homing of a platelet derived growth factor receptor-recognizing macromolecule to fibroblast-like cells in fibrotic tissue. Biochem Pharmacol 66(7):1307–1317. https://doi.org/10.1016/s0006-2952(03)00445-3

    Article  CAS  PubMed  Google Scholar 

  22. Rogers MA, Campana MB, Long R, Fantauzzo KA (2022) PDGFR dimer-specific activation, trafficking and downstream signaling dynamics. J Cell Sci 135(17). https://doi.org/10.1242/jcs.259686

  23. Poosti F, Bansal R, Yazdani S, Prakash J, Post E, Klok P et al (2015) Selective delivery of IFN-gamma to renal interstitial myofibroblasts: a novel strategy for the treatment of renal fibrosis. FASEB J 29(3):1029–1042. https://doi.org/10.1096/fj.14-258459

    Article  CAS  PubMed  Google Scholar 

  24. Turaga RC, Yin L, Yang JJ, Lee H, Ivanov I, Yan C et al (2016) Rational design of a protein that binds integrin alphavbeta3 outside the ligand binding site. Nat Commun 7:11675. https://doi.org/10.1038/ncomms11675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Turaga RC, Satyanarayana G, Sharma M, Yang JJ, Wang S, Liu C et al (2021) Targeting integrin alphavbeta3 by a rationally designed protein for chronic liver disease treatment. Commun Biol 4(1):1087. https://doi.org/10.1038/s42003-021-02611-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Schnittert J, Bansal R, Storm G, Prakash J (2018) Integrins in wound healing, fibrosis and tumor stroma: high potential targets for therapeutics and drug delivery. Adv Drug Deliv Rev 129:37–53. https://doi.org/10.1016/j.addr.2018.01.020

    Article  CAS  PubMed  Google Scholar 

  27. Patsenker E, Stickel F (2011) Role of integrins in fibrosing liver diseases. Am J Physiol Gastrointest Liver Physiol 301(3):G425–G434. https://doi.org/10.1152/ajpgi.00050.2011

    Article  CAS  PubMed  Google Scholar 

  28. Patsenker E, Popov Y, Stickel F, Schneider V, Ledermann M, Sagesser H et al (2009) Pharmacological inhibition of integrin alphavbeta3 aggravates experimental liver fibrosis and suppresses hepatic angiogenesis. Hepatology 50(5):1501–1511. https://doi.org/10.1002/hep.23144

    Article  CAS  PubMed  Google Scholar 

  29. Henderson NC, Arnold TD, Katamura Y, Giacomini MM, Rodriguez JD, McCarty JH et al (2013) Targeting of alphav integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med 19(12):1617–1624. https://doi.org/10.1038/nm.3282

    Article  CAS  PubMed  Google Scholar 

  30. Bansal R, Nakagawa S, Yazdani S, van Baarlen J, Venkatesh A, Koh AP et al (2017) Integrin alpha 11 in the regulation of the myofibroblast phenotype: implications for fibrotic diseases. Exp Mol Med 49(11):e396. https://doi.org/10.1038/emm.2017.213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. van Beuge MM, Prakash J, Lacombe M, Post E, Reker-Smit C, Beljaars L et al (2013) Enhanced effectivity of an ALK5-inhibitor after cell-specific delivery to hepatic stellate cells in mice with liver injury. PLoS One 8(2):e56442. https://doi.org/10.1371/journal.pone.0056442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. van Beuge MM, Prakash J, Lacombe M, Post E, Reker-Smit C, Beljaars L et al (2011) Increased liver uptake and reduced hepatic stellate cell activation with a cell-specific conjugate of the rho-kinase inhibitor Y27632. Pharm Res 28(8):2045–2054. https://doi.org/10.1007/s11095-011-0430-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. van Beuge MM, Prakash J, Lacombe M, Gosens R, Post E, Reker-Smit C et al (2011) Reduction of fibrogenesis by selective delivery of a Rho kinase inhibitor to hepatic stellate cells in mice. J Pharmacol Exp Ther 337(3):628–635. https://doi.org/10.1124/jpet.111.179143

    Article  CAS  PubMed  Google Scholar 

  34. Moreno M, Gonzalo T, Kok RJ, Sancho-Bru P, van Beuge M, Swart J et al (2010) Reduction of advanced liver fibrosis by short-term targeted delivery of an angiotensin receptor blocker to hepatic stellate cells in rats. Hepatology 51(3):942–952. https://doi.org/10.1002/hep.23419

    Article  CAS  PubMed  Google Scholar 

  35. Klein S, Van Beuge MM, Granzow M, Beljaars L, Schierwagen R, Kilic S et al (2012) HSC-specific inhibition of rho-kinase reduces portal pressure in cirrhotic rats without major systemic effects. J Hepatol 57(6):1220–1227. https://doi.org/10.1016/j.jhep.2012.07.033

    Article  CAS  PubMed  Google Scholar 

  36. Lee J, Byun J, Shim G, Oh YK (2022) Fibroblast activation protein activated antifibrotic peptide delivery attenuates fibrosis in mouse models of liver fibrosis. Nat Commun 13(1):1516. https://doi.org/10.1038/s41467-022-29186-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sato Y, Murase K, Kato J, Kobune M, Sato T, Kawano Y et al (2008) Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone. Nat Biotechnol 26(4):431–442. https://doi.org/10.1038/nbt1396

    Article  CAS  PubMed  Google Scholar 

  38. Huang L, Xie J, Bi Q, Li Z, Liu S, Shen Q et al (2017) Highly selective targeting of hepatic stellate cells for liver fibrosis treatment using a d-enantiomeric peptide ligand of Fn14 identified by mirror-image mRNA display. Mol Pharm 14(5):1742–1753. https://doi.org/10.1021/acs.molpharmaceut.6b01174

    Article  CAS  PubMed  Google Scholar 

  39. Kurniawan DW, Booijink R, Pater L, Wols I, Vrynas A, Storm G et al (2020) Fibroblast growth factor 2 conjugated superparamagnetic iron oxide nanoparticles (FGF2-SPIONs) ameliorate hepatic stellate cells activation in vitro and acute liver injury in vivo. J Control Release 328:640–652. https://doi.org/10.1016/j.jconrel.2020.09.041

    Article  CAS  PubMed  Google Scholar 

  40. Nagorniewicz B, Mardhian DF, Booijink R, Storm G, Prakash J, Bansal R (2019) Engineered Relaxin as theranostic nanomedicine to diagnose and ameliorate liver cirrhosis. Nanomedicine 17:106–118. https://doi.org/10.1016/j.nano.2018.12.008

    Article  CAS  PubMed  Google Scholar 

  41. Ramachandran P, Dobie R, Wilson-Kanamori JR, Dora EF, Henderson BEP, Luu NT et al (2019) Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 575(7783):512–518. https://doi.org/10.1038/s41586-019-1631-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Translational Liver Research, Department of Medical Cell BioPhysics, Technical Medical Centre, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands

    Ruchi Bansal

  2. Department of Nanomedicine and Drug Targeting, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands

    Klaas Poelstra

Authors
  1. Ruchi Bansal
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  2. Klaas Poelstra
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Corresponding authors

Correspondence to Ruchi Bansal or Klaas Poelstra .

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Editors and Affiliations

  1. Institut für Molekulare Pathobiochemie, Experimentelle Gentherapie und Klinische Chemie (IFMPEGKC), Universitätsklinikum Aachen AöR, Aachen, Germany

    Ralf Weiskirchen

  2. Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Scott L. Friedman

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Bansal, R., Poelstra, K. (2023). Hepatic Stellate Cell Targeting Using Peptide-Modified Biologicals. In: Weiskirchen, R., Friedman, S.L. (eds) Hepatic Stellate Cells. Methods in Molecular Biology, vol 2669. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-3207-9_17

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  • DOI: https://doi.org/10.1007/978-1-0716-3207-9_17

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-3206-2

  • Online ISBN: 978-1-0716-3207-9

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