Arming drug carriers to disable the Hepatic Stellate Cell: the targeted delivery of apoptosis-inducing drugs to the fibrotic liver

Chronic liver damage of various origins (e.g. viral hepatitis; chronic intoxication by alcohol, chemicals or drugs; Wilson’s disease) can eventually lead to liver cirrhosis, the end stage of liver fibrosis. This process is characterized by the accumulation of excessive amounts of scar tissue within the liver. The hepatic stellate cell (HSC) plays a crucial role during this fibrotic process. After liver damage, this cell-type becomes activated and starts to proliferate, during which it transforms from a resting vitamin A-storing cell into an activated myofibroblast-like cell. This activated HSC produces excessive amounts of extracellular matrix compounds and inhibitors of matrix degradation, thereby strongly affecting the liver architecture and hepatic organ function. Up till now, no pharmaceutical intervention is available to treat this fibrotic disease, leaving liver transplantation as the only option left. Animal model studies revealed however that this fibrotic process is reversible. Livers can undergo regression of fibrosis after withdrawal of the damaging stimulus, even in an advanced stage of cirrhosis. This regression was found to be accompanied by the disappearance of activated HSC via apoptosis. This important observation suggests that inducing or accelerating HSC apoptosis during fibrogenesis might attenuate or reverse the fibrogenic process. However, the therapeutic application of these apoptosis-inducing drugs might be troublesome because these drugs do not accumulate at the target cell in the diseased liver and therefore may cause side effects elsewhere in the body. A drug-targeting approach in which the chosen drug is specifically delivered in the HSC may therefore be highly relevant for apoptosis-inducing drugs. Such an approach would lead to increased accumulation of the drug at the desired site, but it may also reduce the adverse effects after systemic administration of the targeted drug. The aim of this research project was therefore to examine the possibility of HSC-specific induction of apoptosis. A drug targeting construct, capable of selective delivery of apoptosis-inducing drugs to the HSC during liver fibrosis was developed. The HSC-selective drug carrier mannose-6-phosphate-modified human serum albumin (M6PHSA) was used in these studies. This carrier was designed to specifically bind to insulin-like growth factor-II/mannose-6-phosphate (IGF-II/M6P) receptors, which are upregulated on the cell surface of activated HSC. As apoptosisinducing drugs, we applied gliotoxin and 15-deoxy-Δ12,14-prostaglandin J2. Both drugs were chosen because of their potent ability to induce apoptosis in HSC, yet their pharmacokinetic and pharmacodynamic profiles makes a targeting approach essential