Targeting 15d-Prostaglandin J2 to Hepatic Stellate Cells: Two Options Evaluated

Abstract

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-D12,14-prostaglandin J 2 (15dPGJ 2 ) with two different HSCcarriers: 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-b 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.

Local Inhibition of Liver Fibrosis by Specific Delivery of a Platelet-Derived Growth Factor Kinase Inhibitor to Hepatic Stellate Cells

“…To allow for a more complete accumulation of the conjugate within the liver, we sacrificed the animals at a rather late time point (2 h) compared with other studies from our group in which staining was performed 10 to 20 min after administration (Gonzalo et al, 2006;Greupink et al, 2006b;Hagens et al, 2007). Most probably, this prolonged period allowed for the uptake and degradation of the carrier by target cells, whereas the majority of the compound was bound extracellularly or in the endosomes at the 10-to 20-min time point.…”

Evaluation of a 99mTc-Labeled AnnexinA5 Variant for Non-invasive SPECT Imaging of Cell Death in Liver, Spleen and Prostate

“…In this respect, annexin-imaging could provide an interesting biomarker when evaluating new treatments for primary or secondary liver cancer. Yet, the approach may also aid in the evaluation of antifibrotic drugs that aim to induce apoptosis in the populations of liver fibroblasts responsible for the excessive production of collagens that characterize this disease (9,20). Finally, imaging of the PS-Cys-AnxA5 interaction may be applied to study the undesired induction of cell death by drugs in the liver and spleen in more detail.…”

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“…A further modification was made to the peptide by substituting cysteine with lysine (C*GRGDSPK*) in order to replace the less stable cyclizing disulfide (-S-) bond with a more stable peptide bond (-NH-CO-) in the latter, without adversely influencing targeting efficacy 46,47 Receptors for platelet-derived growth factors (PDGFs), which mediate many of the HSC responses to cytokines, are generally upregulated during liver injury. Expression of the PDGF receptor type, in particular, is acquired at high levels during the myofibroblastic transformation of HSC 48 . The scavenger receptors (ScRs) present on HSCs act as an alternative endocytotic uptake route for nanoparticle therapeutics, particularly for the HSA-based therapeutic systems due to their polyanionic nature 49,50 .…”