Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada
Philipp Uhl
Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany
Sandro Sieber
Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
Christina Kaufman
Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany; Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, INF, Heidelberg, Germany
Tomaz Einfalt
Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
Katrin Schöneweis
Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, INF, Heidelberg, Germany
Active targeting and specific drug delivery to parenchymal liver cells is a promising strategy to treat various liver disorders. Here, we modified synthetic lipid-based nanoparticles with targeting peptides derived from the hepatitis B virus large envelope protein (HBVpreS) to specifically target the sodium-taurocholate cotransporting polypeptide (NTCP; SLC10A1) on the sinusoidal membrane of hepatocytes. Physicochemical properties of targeted nanoparticles were optimized and NTCP-specific, ligand-dependent binding and internalization was confirmed in vitro. The pharmacokinetics and targeting capacity of selected lead formulations was investigated in vivo using the emerging zebrafish screening model. Liposomal nanoparticles modified with 0.25 mol% of a short myristoylated HBV derived peptide, that is Myr-HBVpreS2-31, showed an optimal balance between systemic circulation, avoidance of blood clearance, and targeting capacity. Pronounced liver enrichment, active NTCP-mediated targeting of hepatocytes and efficient cellular internalization were confirmed in mice by 111In gamma scintigraphy and fluorescence microscopy demonstrating the potential use of our hepatotropic, ligand-modified nanoparticles.
