Receptor-mediated delivery of drugs to hepatocytes

Standard pharmacologic approaches to liver diseases have been frustrated by inadequate delivery of active agents into liver cells as well as nonspecific toxicity towards other organs. Drug targeting to hepatocytes via the binding of a drug-ligand or macromolecule-ligand complex to a cell surface receptor with subsequent endocytosis and release within the cell may improve the drug's therapeutic ratio. Several receptor molecules specific for liver parenchymal cells exist and could serve such a drug-delivery function. One such receptor, the asialoglycoprotein (ASGP)-receptor has been studied in hepatocytes as well as in a well-differentiated hepatoma cell line, HepG2. This cell line resembles mature hepatocytes in many metabolic, synthetic, and structural features. In this model system, ligand bound to receptor is internalized via coated pits and enters an acidic compartment where ligand-receptor dissociation occurs followed by receptor recycling to plasma membrane and eventual transfer of ligand to lysosome for degradation. Other intracellular routes not resulting in degradation of ligand have also been elucidated in hepatocytes and the HepG2 cell line. This has been demonstrated for the ASGP receptor, the transferrin receptor and the polymeric Ig-IgA receptor. It is apparent that macromolecular pharmacologic agents complexed to ligands for any of these receptors (such as monoclonal antibodies, enzymes, or nucleic acids) must dissociate from the ligand and permeate the endosomal membrane to reach their intracellular sites of action. Recent studies of viral pathogenesis and intracellular protein targeting have revealed key features of protein domain structure that are necessary for membrane permeation. Further understanding of the mechanisms responsible for these pathways of intracellular sorting will enable drug-carrier design that will fully exploit the potential of hepatocyte receptor-mediated endocytosis for drug delivery.