title: Enhanced effectivity of an ALK5-inhibitor after cell-specific delivery to hepatic stellate cells in mice with liver injury.
abstract: Transforming growth factor-β (TGF-β) is a major pro-fibrotic cytokine, causing the overproduction of extracellular matrix molecules in many fibrotic diseases. Inhibition of its type-I receptor (ALK5) has been shown to effectively inhibit fibrosis in animal models. However, apart from its pro-fibrotic effects, TGF-β also has a regulatory role in the immune system and influences tumorigenesis, which limits the use of inhibitors. We therefore explored the cell-specific delivery of an ALK5-inhibitor to hepatic stellate cells, a key cell in the development of liver fibrosis. We synthesized a conjugate of the ALK5-inhibitor LY-364947 coupled to mannose-6-phosphate human serum albumin (M6PHSA), which binds to the insulin-like growth factor II receptor on activated HSC. The effectivity of the conjugate was evaluated in primary HSC and in an acute liver injury model in mice. In vitro, the free drug and the conjugate significantly inhibited fibrotic markers in HSC. In hepatocytes, TGF-β-dependent signaling was inhibited by free drug, but not by the conjugate, thus showing its cell-specificity. In vivo, the conjugate localized in desmin-positive cells in the liver and not in hepatocytes or immune cells. In the acute liver injury model in mice, the conjugate reduced fibrogenic markers and collagen deposition more effectively than free drug. We conclude that we can specifically deliver an ALK5-inhibitor to HSC using the M6PHSA carrier and that this targeted drug reduces fibrogenic parameters in vivo, without affecting other cell-types.
authors: Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands. m.m.van.beuge@rug.nl
authors: Marike Marjolijn
authors: MM
authors: van Beuge
authors: Jai
authors: J
authors: Prakash
authors: Marie
authors: M
authors: Lacombe
authors: Eduard
authors: E
authors: Post
authors: Catharina
authors: C
authors: Reker-Smit
authors: Leonie
authors: L
authors: Beljaars
authors: Klaas
authors: K
authors: Poelstra
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D011804:Quinolines
chemical_list: D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles; D011758:Pyrroles; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C506615:HTS 466284; D011804:Quinolines; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse; C000625843:Tgfbr1 protein, rat