caa a22 4500 445313501 CHVBK 20180317142638.0 cr unu---uuuuu 170323e20110801xx s 000 0 eng 10.1007/s11095-011-0430-9 doi (NATIONALLICENCE)springer-10.1007/s11095-011-0430-9 Increased Liver Uptake and Reduced Hepatic Stellate Cell Activation with a Cell-Specific Conjugate of the Rho-kinase Inhibitor Y27632 [Elektronische Daten] [Marike van Beuge, Jai Prakash, Marie Lacombe, Eduard Post, Catharina Reker-Smit, Leonie Beljaars, Klaas Poelstra] ABSTRACT: Purpose: Rho-kinase regulates activation of hepatic stellate cells (HSC) during liver fibrosis, but the ubiquitous presence of this kinase may hinder examination of its exact role and the therapeutic use of inhibitors. We therefore coupled the Rho-kinase inhibitor Y27632 to a drug carrier that binds the mannose-6-phosphate insulin-like growth factor II (M6P/IGFII)-receptor which is upregulated on activated HSC. Methods: Y27632 was coupled to mannose-6-phosphate human serum albumin (M6PHSA), and in vitro experiments were performed on primary rat HSC. Biodistribution and effect studies were performed in an acute CCl4 model in mice. Results: Y27-conjugate remained stable in serum, while drug was efficiently released in liver homogenates. Receptor-blocking studies revealed that it was specifically taken up through the M6P/IGFII-receptor on fibroblasts, and it inhibited expression of fibrotic markers in activated HSC. In vivo, liver drug levels were significantly higher after injection of Y27-conjugate as compared to Y27632, and the conjugate accumulated specifically in HSC. After acute CCl4-induced liver injury, Y27-conjugate reduced the local activation of HSC, whereas an equimolar dose of free drug did not. Conclusions: We conclude that specific targeting of a Rho-kinase inhibitor to HSC leads to enhanced accumulation of the drug in HSC, reducing early fibrogenesis in the liver. The Author(s), 2011 drug targeting nationallicence insulin-like growth factor II receptor nationallicence kinase inhibitor nationallicence liver fibrosis nationallicence Rho-kinase nationallicence α-SMA : α-smooth muscle actin nationallicence HSC : Hepatic stellate cells nationallicence M6PHSA : Mannose-6-phosphate human serum albumin nationallicence M6P/IGFII-receptor : Mannose-6-phosphate/insulin-like growth factor II receptor nationallicence ULS™ : Universal Linkage System nationallicence van Beuge Marike Department of Pharmacokinetics, Toxicology & Targeting, University of Groningen, A. Deusinglaan 1, 9713, Groningen, AV, the Netherlands aut Prakash Jai Department of Pharmacokinetics, Toxicology & Targeting, University of Groningen, A. Deusinglaan 1, 9713, Groningen, AV, the Netherlands aut Lacombe Marie Kreatech Diagnostics, Amsterdam, the Netherlands aut Post Eduard Department of Pharmacokinetics, Toxicology & Targeting, University of Groningen, A. Deusinglaan 1, 9713, Groningen, AV, the Netherlands aut Reker-Smit Catharina Department of Pharmacokinetics, Toxicology & Targeting, University of Groningen, A. Deusinglaan 1, 9713, Groningen, AV, the Netherlands aut Beljaars Leonie Department of Pharmacokinetics, Toxicology & Targeting, University of Groningen, A. Deusinglaan 1, 9713, Groningen, AV, the Netherlands aut Poelstra Klaas Department of Pharmacokinetics, Toxicology & Targeting, University of Groningen, A. Deusinglaan 1, 9713, Groningen, AV, the Netherlands aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/8(2011-08-01), 2045-2054 0724-8741 28:8<2045 2011 28 11095 https://doi.org/10.1007/s11095-011-0430-9 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-011-0430-9 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- van Beuge Marike Department of Pharmacokinetics, Toxicology & Targeting, University of Groningen, A. Deusinglaan 1, 9713, Groningen, AV, the Netherlands aut NATIONALLICENCE 700 1- Prakash Jai Department of Pharmacokinetics, Toxicology & Targeting, University of Groningen, A. Deusinglaan 1, 9713, Groningen, AV, the Netherlands aut NATIONALLICENCE 700 1- Lacombe Marie Kreatech Diagnostics, Amsterdam, the Netherlands aut NATIONALLICENCE 700 1- Post Eduard Department of Pharmacokinetics, Toxicology & Targeting, University of Groningen, A. Deusinglaan 1, 9713, Groningen, AV, the Netherlands aut NATIONALLICENCE 700 1- Reker-Smit Catharina Department of Pharmacokinetics, Toxicology & Targeting, University of Groningen, A. Deusinglaan 1, 9713, Groningen, AV, the Netherlands aut NATIONALLICENCE 700 1- Beljaars Leonie Department of Pharmacokinetics, Toxicology & Targeting, University of Groningen, A. Deusinglaan 1, 9713, Groningen, AV, the Netherlands aut NATIONALLICENCE 700 1- Poelstra Klaas Department of Pharmacokinetics, Toxicology & Targeting, University of Groningen, A. Deusinglaan 1, 9713, Groningen, AV, the Netherlands aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/8(2011-08-01), 2045-2054 0724-8741 28:8<2045 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer