Increased Liver Uptake and Reduced Hepatic Stellate Cell Activation with a Cell-Specific Conjugate of the Rho-kinase Inhibitor Y27632
Identifieur interne : 000A55 ( Main/Exploration ); précédent : 000A54; suivant : 000A56Increased Liver Uptake and Reduced Hepatic Stellate Cell Activation with a Cell-Specific Conjugate of the Rho-kinase Inhibitor Y27632
Auteurs : Marike Marjolijn Van Beuge [Pays-Bas] ; Jai Prakash [Pays-Bas] ; Marie Lacombe [Pays-Bas] ; Eduard Post [Pays-Bas] ; Catharina Reker-Smit [Pays-Bas] ; Leonie Beljaars [Pays-Bas] ; Klaas Poelstra [Pays-Bas]Source :
- Pharmaceutical Research [ 0724-8741 ] ; 2011.
Abstract
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.
Y27632 was coupled to mannose-6-phosphate human serum albumin (M6PHSA), and
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.
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 online version of this article (doi:10.1007/s11095-011-0430-9) contains supplementary material, which is available to authorized users.
Url:
DOI: 10.1007/s11095-011-0430-9
PubMed: 21442374
PubMed Central: 3130909
Affiliations:
- Pays-Bas
- Groningue (province), Hollande-Septentrionale
- Amsterdam, Groningue (ville)
- Université de Groningue
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Le document en format XML
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Deusinglaan 1, 9713 AV Groningen, the Netherlands</nlm:aff><country xml:lang="fr" wicri:curation="lc">Pays-Bas</country><wicri:regionArea>Department of Pharmacokinetics, Toxicology & Targeting, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen</wicri:regionArea><orgName type="university">Université de Groningue</orgName><placeName><settlement type="city">Groningue (ville)</settlement><region>Groningue (province)</region></placeName></affiliation></author><author><name sortKey="Prakash, Jai" sort="Prakash, Jai" uniqKey="Prakash J" first="Jai" last="Prakash">Jai Prakash</name><affiliation wicri:level="4"><nlm:aff id="Aff1">Department of Pharmacokinetics, Toxicology & Targeting, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, the Netherlands</nlm:aff><country xml:lang="fr" wicri:curation="lc">Pays-Bas</country><wicri:regionArea>Department of Pharmacokinetics, Toxicology & Targeting, University of Groningen, A. 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Deusinglaan 1, 9713 AV Groningen, the Netherlands</nlm:aff><country xml:lang="fr" wicri:curation="lc">Pays-Bas</country><wicri:regionArea>Department of Pharmacokinetics, Toxicology & Targeting, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen</wicri:regionArea><orgName type="university">Université de Groningue</orgName><placeName><settlement type="city">Groningue (ville)</settlement><region>Groningue (province)</region></placeName></affiliation></author><author><name sortKey="Reker Smit, Catharina" sort="Reker Smit, Catharina" uniqKey="Reker Smit C" first="Catharina" last="Reker-Smit">Catharina Reker-Smit</name><affiliation wicri:level="4"><nlm:aff id="Aff1">Department of Pharmacokinetics, Toxicology & Targeting, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, the Netherlands</nlm:aff><country xml:lang="fr" wicri:curation="lc">Pays-Bas</country><wicri:regionArea>Department of Pharmacokinetics, Toxicology & Targeting, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen</wicri:regionArea><orgName type="university">Université de Groningue</orgName><placeName><settlement type="city">Groningue (ville)</settlement><region>Groningue (province)</region></placeName></affiliation></author><author><name sortKey="Beljaars, Leonie" sort="Beljaars, Leonie" uniqKey="Beljaars L" first="Leonie" last="Beljaars">Leonie Beljaars</name><affiliation wicri:level="4"><nlm:aff id="Aff1">Department of Pharmacokinetics, Toxicology & Targeting, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, the Netherlands</nlm:aff><country xml:lang="fr" wicri:curation="lc">Pays-Bas</country><wicri:regionArea>Department of Pharmacokinetics, Toxicology & Targeting, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen</wicri:regionArea><orgName type="university">Université de Groningue</orgName><placeName><settlement type="city">Groningue (ville)</settlement><region>Groningue (province)</region></placeName></affiliation></author><author><name sortKey="Poelstra, Klaas" sort="Poelstra, Klaas" uniqKey="Poelstra K" first="Klaas" last="Poelstra">Klaas Poelstra</name><affiliation wicri:level="4"><nlm:aff id="Aff1">Department of Pharmacokinetics, Toxicology & Targeting, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, the Netherlands</nlm:aff><country xml:lang="fr" wicri:curation="lc">Pays-Bas</country><wicri:regionArea>Department of Pharmacokinetics, Toxicology & Targeting, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen</wicri:regionArea><orgName type="university">Université de Groningue</orgName><placeName><settlement type="city">Groningue (ville)</settlement><region>Groningue (province)</region></placeName></affiliation></author></analytic><series><title level="j">Pharmaceutical Research</title><idno type="ISSN">0724-8741</idno><idno type="eISSN">1573-904X</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>ABSTRACT</title><sec><title>Purpose</title><p>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.</p></sec><sec><title>Methods</title><p>Y27632 was coupled to mannose-6-phosphate human serum albumin (M6PHSA), and <italic>in vitro</italic> experiments were performed on primary rat HSC. Biodistribution and effect studies were performed in an acute CCl<sub>4</sub> model in mice.</p></sec><sec><title>Results</title><p>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. <italic>In vivo</italic>, liver drug levels were significantly higher after injection of Y27-conjugate as compared to Y27632, and the conjugate accumulated specifically in HSC. After acute CCl<sub>4</sub>-induced liver injury, Y27-conjugate reduced the local activation of HSC, whereas an equimolar dose of free drug did not.</p></sec><sec><title>Conclusions</title><p>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.</p></sec><sec><title>Electronic Supplementary Material</title><p>The online version of this article (doi:10.1007/s11095-011-0430-9) contains supplementary material, which is available to authorized users.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Schuppan, D" uniqKey="Schuppan D">D Schuppan</name></author><author><name sortKey="Afdhal, N" uniqKey="Afdhal N">N Afdhal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Thompson, A" uniqKey="Thompson A">A Thompson</name></author><author><name sortKey="Patel, K" uniqKey="Patel K">K 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Somlyo</name></author><author><name sortKey="Hautmann, M" uniqKey="Hautmann M">M Hautmann</name></author><author><name sortKey="Somlyo, Ap" uniqKey="Somlyo A">AP Somlyo</name></author><author><name sortKey="Owens, Gk" uniqKey="Owens G">GK Owens</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ikeda, H" uniqKey="Ikeda H">H Ikeda</name></author><author><name sortKey="Nagashima, K" uniqKey="Nagashima K">K Nagashima</name></author><author><name sortKey="Yanase, M" uniqKey="Yanase M">M Yanase</name></author><author><name sortKey="Tomiya, T" uniqKey="Tomiya T">T Tomiya</name></author><author><name sortKey="Arai, M" uniqKey="Arai M">M Arai</name></author><author><name sortKey="Inoue, Y" uniqKey="Inoue Y">Y Inoue</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Olson, Mf" uniqKey="Olson M">MF Olson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gonzalo, T" uniqKey="Gonzalo T">T Gonzalo</name></author><author><name sortKey="Talman, Eg" uniqKey="Talman E">EG Talman</name></author><author><name sortKey="Ven, A" uniqKey="Ven A">A Ven</name></author><author><name sortKey="Temming, K" uniqKey="Temming K">K Temming</name></author><author><name sortKey="Greupink, R" uniqKey="Greupink R">R Greupink</name></author><author><name sortKey="Beljaars, L" uniqKey="Beljaars L">L Beljaars</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Moreno, M" uniqKey="Moreno M">M Moreno</name></author><author><name sortKey="Gonzalo, T" uniqKey="Gonzalo T">T Gonzalo</name></author><author><name sortKey="Kok, Rj" uniqKey="Kok R">RJ Kok</name></author><author><name sortKey="Sancho Bru, P" uniqKey="Sancho Bru P">P Sancho-Bru</name></author><author><name sortKey="Beuge, M" uniqKey="Beuge M">M Beuge</name></author><author><name sortKey="Swart, J" uniqKey="Swart J">J Swart</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Pays-Bas</li></country><region><li>Groningue (province)</li><li>Hollande-Septentrionale</li></region><settlement><li>Amsterdam</li><li>Groningue (ville)</li></settlement><orgName><li>Université de Groningue</li></orgName></list><tree><country name="Pays-Bas"><region name="Groningue (province)"><name sortKey="Van Beuge, Marike Marjolijn" sort="Van Beuge, Marike Marjolijn" uniqKey="Van Beuge M" first="Marike Marjolijn" last="Van Beuge">Marike Marjolijn Van Beuge</name></region><name sortKey="Beljaars, Leonie" sort="Beljaars, Leonie" uniqKey="Beljaars L" first="Leonie" last="Beljaars">Leonie Beljaars</name><name sortKey="Lacombe, Marie" sort="Lacombe, Marie" uniqKey="Lacombe M" first="Marie" last="Lacombe">Marie Lacombe</name><name sortKey="Poelstra, Klaas" sort="Poelstra, Klaas" uniqKey="Poelstra K" first="Klaas" last="Poelstra">Klaas Poelstra</name><name sortKey="Post, Eduard" sort="Post, Eduard" uniqKey="Post E" first="Eduard" last="Post">Eduard Post</name><name sortKey="Prakash, Jai" sort="Prakash, Jai" uniqKey="Prakash J" first="Jai" last="Prakash">Jai Prakash</name><name sortKey="Reker Smit, Catharina" sort="Reker Smit, Catharina" uniqKey="Reker Smit C" first="Catharina" last="Reker-Smit">Catharina Reker-Smit</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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