Targeting 15d-prostaglandin J(2) to hepatic stellate cells: Two options evaluated

Werner I. Hagens, Adriana Mattos Pinto, Rick Greupink, Alie de Jager-Krikken, Catharina Reker-Smit, Anne-miek van Loenen - Weemaes, Annette S. H. Gouw, Klaas Poelstra, Leonie Beljaars*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

40 Citaten (Scopus)
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Samenvatting

Purpose: 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-triangle 12,14-prostaglandin J(2) (15dPGJ(2)) 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 15dPGJ(2) to the carriers, the constructs displayed pharmacological activity and specific receptor-mediated binding to HSC in vitro. Unlike 15dPGJ(2)-pPBHSA, the cellular binding of 15dPGJ(2)-M6PHSA was reduced by a scavenger receptor antagonist. In vivo, both conjugates rapidly accumulated in fibrotic livers. Intrahepatic analysis revealed that 15dPGJ(2)-M6PHSA mainly accumulated in HSC, and to a lesser extent in Kupffer cells. 15dPGJ(2)-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-beta receptor expression was abundantly expressed on human fibroblasts.

Conclusions: These studies show that 15dPGJ(2) 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 15dPGJ(2) to HSC in vivo.

Originele taal-2English
Pagina's (van-tot)566-574
Aantal pagina's9
TijdschriftPharmaceutical Research
Volume24
Nummer van het tijdschrift3
DOI's
StatusPublished - mrt-2007

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