Heptocyte Specific Drug Targeting

Hepatic disorders affect millions of people around the globe and incidence rates are further increasing. While survival rates have improved for most diseases during recent decades, liver diseases still represent a considerable public health burden. Current therapies for diseases of hepatocytes are limited and in most cases only treat symptoms. Therefore, improved therapeutic technologies are urgently needed. Targeted nanomedicines for the delivery of small molecules or nucleic acids have the potential to overcome the lack of satisfactory and alternative treatment options. Our research is focused on the development of novel nanomedicines for targeted drug delivery to liver parenchymal cells. These technologies offer the possibility to specifically target drugs to hepatocytes, thus giving access to a defined cell type within the liver.

As a proof-of-concept, we have designed asialofetuin-conjugated liposomal drug carriers, which are directed towards the asialoglycoprotein receptor (ASGPR). This receptor is abundantly and almost exclusively expressed on hepatocytes. ASGPR is a C type lectin (“galactose receptor”), which removes glycoproteins from the circulation from which sialic acid has been removed to expose terminal galactose or N-Acetylgalactosamine (GalNac) residues. After binding to its ligand, the receptor is internalized by receptor-mediated endocytosis. We have analyzed ASGPR expression in more than ten different liver-derived cell lines. Expression of the ASGPR was as well tested in human tissue samples (i.e. a tissue microarray of more than 350 human biopsies from patients suffering from various liver diseases) to evaluate the applicability of our approach in the clinic (collaboration with Prof. Dr. Luigi Terracciano, Molecular Pathology, University Hospital Basel).