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.
|Kwalificatie||Doctor of Philosophy|
|Gedrukte ISBN's||9036727200, 9036727545|
|Status||Published - 2006|