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- Title
Targeting 15d-Prostaglandin J<sub>2</sub> to Hepatic Stellate Cells: Two Options Evaluated.
- Authors
Werner Hagens; Adriana Mattos; Rick Greupink; Alie de Jager-Krikken; Catharina Reker-Smit; AnneMiek van Loenen-Weemaes; Annette Gouw; Klaas Poelstra; Leonie Beljaars
- Abstract
AbstractPurpose??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-?12,14-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).Methods and Results??After chemical conjugation of 15dPGJ2to the carriers, the constructs displayed pharmacological activity and specific receptor-mediated binding to HSCin 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-? receptor expression was abundantly expressed on human fibroblasts.Conclusions??These studies show that 15dPGJ2coupled 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 15dPGJ2to HSCin vivo.
- Subjects
PROSTAGLANDINS; APOPTOSIS; FIBROSIS; LIVER
- Publication
Pharmaceutical Research, 2007, Vol 24, Issue 3, p566
- ISSN
0724-8741
- Publication type
Article
- DOI
10.1007/s11095-006-9175-2