title: Targeting 15d-prostaglandin J2 to hepatic stellate cells: two options evaluated.
abstract: OBJECTIVE
  Delivery of apoptosis-inducing compounds to hepatic stellate cells (HSC) may be an effective strategy to reverse liver fibrosis. The aim of this study was therefore to examine the selective targeting of the apoptosis-inducing drug 15-deoxy-delta12,14-prostaglandin J2 (15dPGJ2) with two different HSC-carriers: human serum albumin modified with the sugar mannose-6-phosphate (M6PHSA) or albumin modified with PDGF-receptor recognizing peptides (pPBHSA).
  
  
  RESULTS
  After chemical conjugation of 15dPGJ2 to the carriers, the constructs displayed pharmacological activity and specific receptor-mediated binding to HSC in vitro. Unlike 15dPGJ2-pPBHSA, the cellular binding of 15dPGJ2-M6PHSA was reduced by a scavenger receptor antagonist. In vivo, both conjugates rapidly accumulated in fibrotic livers. Intrahepatic analysis revealed that 15dPGJ2-M6PHSA mainly accumulated in HSC, and to a lesser extent in Kupffer cells. 15dPGJ2-pPBHSA also predominantly accumulated in HSC with additional uptake in hepatocytes. Assessment of target receptors in human cirrhotic livers revealed that M6P/IGFII-receptor expression was present in fibrotic areas. PDGF-P receptor expression was abundantly expressed on human fibroblasts.
  
  
  CONCLUSIONS
  These studies show that 15dPGJ2 coupled to either M6PHSA or pPBHSA is specifically taken up by HSC and is highly effective within these cells. Both carriers differ with respect to receptor specificity, leading to differences in intrahepatic distribution. Nevertheless, both carriers can be used to deliver the apoptosis-inducing drug 15dPGJ2 to HSC in vivo.
authors.affiliation: Department of Pharmacokinetics and Drug Delivery, University Centre for Pharmacy, University of Groningen, Groningen, The Netherlands.
authors.forename: Werner I
authors.initials: WI
authors.lastname: Hagens
authors.forename: Adriana
authors.initials: A
authors.lastname: Mattos
authors.forename: Rick
authors.initials: R
authors.lastname: Greupink
authors.forename: Alie
authors.initials: A
authors.lastname: de Jager-Krikken
authors.forename: Catharina
authors.initials: C
authors.lastname: Reker-Smit
authors.forename: Annemiek
authors.initials: A
authors.lastname: van Loenen-Weemaes
authors.forename: I Annette S H
authors.initials: IA
authors.lastname: Gouw
authors.forename: Klaas
authors.initials: K
authors.lastname: Poelstra
authors.forename: Leonie
authors.initials: L
authors.lastname: Beljaars
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008297:Male; D008360:Mannosephosphates / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D015230:Prostaglandin D2 / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000737:chemistry / Q000378:metabolism; D015203:Reproducibility of Results; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism
chemical_list: C477819:15-deoxyprostaglandin J2; D051017:Apoptosis Regulatory Proteins; D008360:Mannosephosphates; D010455:Peptides; D012709:Serum Albumin; C027693:mannose-6-phosphate; D020797:Receptor, Platelet-Derived Growth Factor beta; D015230:Prostaglandin D2