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

Abstract

Liver fibrosis is characterized by excessive proliferation and activation of hepatic stellate cells (HSC), a process in which platelet-derived growth factor (PDGF) plays an important role. Inhibition of liver fibrosis via specific delivery of a PDGF kinase inhibitor to HSC might therefore be an attractive strategy. The HSC-selective carrier mannose-6-phosphate modified human serum albumin (M6PHSA) was equipped with a tyrosine kinase inhibitor, 4-chloro-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (PAP19) (an imatinib derivative), by means of the platinum-based universal linkage system (ULS). The antifibrotic activity of PAP19-M6PHSA was evaluated in culture-activated rat HSC and precision-cut liver slices from fibrotic rats. After 24-h incubation, both free inhibitor PAP19 and PAP19-M6PHSA showed potent activity, as determined by quantitative reverse transcription-polymerase chain reaction analysis of ␣-smooth muscle actin (␣SMA) and procollagen 1a1. Next, we examined the organ distribution and antifibrotic activity of PAP19-M6PHSA in bile duct-ligated (BDL) rats. Male Wistar rats at day 10 after BDL were administered a single dose of PAP19-M6PHSA and sacrificed at 2 h, 1 day, or 2 days afterward. The accumulation of PAP19-M6PHSA in the liver was quantified by high-performance liquid chromatography analysis (30% of the injected dose at 2 h) and detected in the liver by staining of the carrier. Liver drug levels were sustained at 24 and 48 h after the single dose. Furthermore, PAP19-M6PHSA reduced collagen deposition (Sirius red staining) and ␣SMA staining of activated HSC at these time points in comparison with saline-treated rats. We therefore conclude that delivery of a PDGF-kinase inhibitor to HSC is a promising technology to attenuate liver fibrogenesis.

Evolving therapies for liver fibrosis

“…Finally, the use of ligands specific to receptors on activated myofibroblasts can target drugs or siRNA, thus increasing efficacy and minimizing detrimental off-target effects. Examples supporting this approach in vivo include delivery of IFN via a cyclic PDGFRβ-binding peptide, of a PDGFRβ-specific kinase inhibitor via mannose-6-phosphate (which addresses the IGF-II receptor), and of Hsp47 (which is involved in collagen processing) via vitamin Acoupled liposomes (45)(46)(47)(48). Although these therapies would largely need to be given parenterally, such application can be justified in situations in which treatment is likely to be highly effective, e.g., for reversing advanced fibrosis.…”

Targeting of a platinum-bound sunitinib analog to renal proximal tubular cells

“…Upon intravenous administration, the majority of the targeted drug persisted in the designated cells in the ULS-bound form. 25,28 In the current study, we therefore designed a sunitinib analog which retained its activity in the ULS-bound form, and thus could display its activity as a platinum conjugate upon delivery in the proximal tubular cells of the kidneys.…”

Specific delivery of kinase inhibitors in nonmalignant and malignant diseases

“…After a single treatment, the conjugate was very effective in reducing HSC activation and collagen deposition in rat livers. Liver drug levels were high and were sustained at least until 48 h after injection of a single dose [37] while showing a slow release of the drug from the carrier, which is particularly relevant for the treatment of chronic diseases. In contrast to this, free drug was accumulated in very low amounts in these livers and the drug was rapidly cleared, leading to low efficacy of this PDGFRb-inhibitor.…”