Selective targeting of pentoxifylline to hepatic stellate cells using a novel platinum-based linker technology.

The present invention relates to a cell-targeting complex comprising a targeting moiety and a deliverable compound, wherein said targeting moiety and said deliverable compound are joined by means of a (transition) metal ion complex having at least a first reactive moiety for forming a coordination bond with a reactive site of said targeting moiety and having at least a second reactive moiety for forming a coordination bond with a reactive site of said deliverable compound, and wherein said deliverable compound is a therapeutic compound.

Method of conjugating therapeutic compounds to cell targeting moieties via metal complexes

The renin-angiotensin system (RAS) plays a fundamental role in liver fibrogenesis and hence the use of losartan is proposed as an attractive antifibrotic strategy. However, the use of RAS blockers can worsen the development of systemic hypotension associated with liver fibrosis. To avoid the systemic interactions of losartan and improve its liver accumulation, we have developed losartan-M6PHSA, a drug targeting preparation that selectively accumulates in hepatic stellate cells (HSC), the main fibrogenic cell type in liver fibrosis. We investigated the liver accumulation of losartan-M6PHSA and its antifibrotic effects in the carbon tetrachloride (CCL4) model of rat liver fibrosis. After 9 weeks of CCL4 inhalation, rats were treated with four daily doses of losartan-M6PHSA (8mg/kg, containing 0.3 mg losartan/kg), free losartan (0.3mg/kg) or M6PHSA carrier alone (8mg/kg). Expression of M6P/IGF II target receptors and accumulation of losartanM6PHSA in the fibrotic liver were confirmed immunohistochemically. We determined losartan levels in the liver by HPLC, demonstrating a liver accumulation of 13.2 ±6.4% vs. 5.4±0.2% of the cumulative dose for losartan-MPHSA and free losartan, respectively, at 10 minutes after the last dose. Hepatic collagen deposition, as assessed by morphometric analysis of Sirius red staining, was markedly lower in rats treated with losartan-M6PHSA whereas treatment with losartan alone had no effect (p<0.05) Accumulation of α-smooth muscle actin-positive cells was reduced in rats treated with M6PHSA-losartan or losartan (p<0.05), but not after treatment with M6PHSA carrier. Finally, losartan-M6PHSA and losartan reduced procollagen α1(II) gene expression by 80% and 70%, respectively. We conclude that losartan acts as a potent antifibrogenic drug in the CCL4 model of liver fibrosis, and that targeting of losartan to HSC strongly potentiates its effects.

A potential strategy to treat liver fibrosis

Liver fibrosis is the 9th leading cause of death in the world. This chronic disease cannot be treated successfully with conventional antifibrotic and anti-inflammatory drugs currently on the market, because they either lack efficacy or cause too many side-effects. Targeting of antifibrotic agents to hepatic stellate cells is considered a promising strategy to increase their therapeutic potential. This thesis will present a novel strategy to synthesize drug targeting conjugates aimed at hepatic stellate cells. The core of our invention is a novel platinum based a linker system, the so-called Universal Linkage System (ULS), that allows us to couple a broad range of drugs. Three different drugs have been employed in the present thesis. Pentoxifylline is an anti-inflammatory drug that has been suggested as a potential antifibrotic drug once delivered specifically to hepatic stellate cells (1). Losartan is an angiotensin II receptor antagonist that is widely used for the treatment of hypertension and renal disease. Its beneficial effects on the renin-angiotensin system can be applied to improve the liver function during fibrosis (2). The third drug we have employed is a PDGF-R tyrosine kinase inhibitor (PTKI), a gleevec-like compound. Due to the role of platelet derived growth factor (PDGF-B) as the most potent mitogen to the HSC during liver fibrosis (3), PTKI is regarded as a potential new drug to stop the fibrogenic process. The aim of the present thesis is therefore to study the therapeutical approach of targeting antifibrotic drugs specifically to the hepatic stellate cells to improve the liver injury. Three different drug targeting conjugates are discussed in detailed, as well as the screening of its efficacy in vitro and in vivo.

/pdf/a-potential-strategy-to-treat-liver-fibrosis-drug-targeting-2zctzf3mk1.pdf

A potential strategy to treat liver fibrosis: Drug targeting to hepatic stellate cells applying a novel linker technology

Understanding the mechanisms regulating liver fibrosis (including the use of imaging techniques in its study and diagnosis)

Short-term treatment with losartan targeted to activated stellate cells reduces advanced liver fibrogenesis : A new strategy to treat liver fibrosis

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Short-term treatment with losartan targeted to activated stellate cells reduces advanced liver fibrogenesis : A new strategy to treat liver fibrosis