title: Studies on the targeted delivery of the antifibrogenic compound mycophenolic acid to the hepatic stellate cell.
abstract: OBJECTIVE
  Hepatic stellate cell (HSC) activation and proliferation are key events in the pathology of liver fibrosis. Inhibiting these parameters, therefore, is a relevant option to treat liver fibrosis pharmacologically. The immunosuppressive drug mycophenolic acid (MPA) has been shown to inhibit proliferation and activation of various types of fibroblasts. In an effort to circumvent the immunosuppression and at the same time enhance this antifibrotic effect, we coupled MPA to the HSC-selective drug carrier mannose-6-phosphate modified human serum albumin and evaluated this conjugate for its specificity and antifibrotic activity.
  
  
  RESULTS
  We found that MPA inhibited proliferation of HSC in vitro. The drug coupled to the drug carrier bound specifically to HSC and reduced HSC proliferation in vitro. In vivo studies demonstrated that our conjugate accumulated selectively in the liver with significant uptake in HSC apart from Kupffer and endothelial cells, whereas primary and secondary lymphoid tissues were avoided. Treatment of bile duct-ligated rats with this conjugate reduced hepatic inflammation and hepatic alpha-beta-Crystallin mRNA expression, a marker for HSC activation.
  
  
  CONCLUSIONS
  This study shows that targeted delivery of MPA to HSC results in a decrease in HSC activation, making it the first drug that is successfully delivered to this cell type.
authors.affiliation: Groningen University Institute for Drug Exploration (GUIDE), Department of Pharmacokinetics and Drug Delivery, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. a.h.greupink@farm.rug.nl
authors.forename: Rick
authors.initials: R
authors.lastname: Greupink
authors.forename: Hester I
authors.initials: HI
authors.lastname: Bakker
authors.forename: Catharina
authors.initials: C
authors.lastname: Reker-Smit
authors.forename: Anne-miek
authors.initials: AM
authors.lastname: van Loenen-Weemaes
authors.forename: Robbert-Jan
authors.initials: RJ
authors.lastname: Kok
authors.forename: Dirk K F
authors.initials: DK
authors.lastname: Meijer
authors.forename: Leonie
authors.initials: L
authors.lastname: Beljaars
authors.forename: Klaas
authors.initials: K
authors.lastname: Poelstra
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects*; D003094:Collagen / Q000378:metabolism; D003459:Crystallins / Q000235:genetics / Q000378:metabolism; D003893:Desmin / Q000378:metabolism; D004337:Drug Carriers; D005355:Fibrosis / Q000188:drug therapy / Q000473:pathology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008360:Mannosephosphates / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D009173:Mycophenolic Acid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D000903:Antibiotics, Antineoplastic; D003459:Crystallins; D003893:Desmin; D004337:Drug Carriers; D005904:Glial Fibrillary Acidic Protein; D008360:Mannosephosphates; D020033:Protein Isoforms; D017382:Reactive Oxygen Species; C027693:mannose-6-phosphate; D003094:Collagen; D009173:Mycophenolic Acid