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Optimization-by-design of hepatotropic lipid nanoparticles targeting the sodium-taurocholate cotransporting polypeptide

Dominik Witzigmann, Philipp Uhl, Sandro Sieber, Christina Kaufman, Tomaz Einfalt, Katrin Schöneweis, Philip Grossen, Jonas Buck, Yi Ni, Susanne H. Schenk, Janine Hussner, Henriette E. Meyer zu Schwabedissen, Gabriela Québatte, Walter Mier, Stephan Urban, Jörg Huwyler

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 th... Full description

Main Author: Witzigmann, Dominik
Contributors: Uhl, Philipp | Author
Kaufman, Christina | Author
Schöneweis, Katrin | Author
Ni, Yi | Author
Mier, Walter | Author
Urban, Stephan | Author
Published: 23 July 2019
Contained in: eLife Cambridge : eLife Sciences Publications, 2012 8(2019) Artikel-Nummer e42276, 28 Seiten
Journal Title: eLife
Fulltext access:
Availability is being checked...
Links: Volltext (doi.org)
Additional Link (elifesciences.org)
ISSN: 2050-084X
Keywords: Myrcludex B
NTCP
hepatitis B virus
hepatocyte targeting
liposomes
nanocarriers
DOI: 10.7554/eLife.42276
Regional Holdings: TIB – German National Library of Science and Technology
Physikalisch-Technische Bundesanstalt
Language: English
Notes: Gesehen am 06.11.2019
Physical Description: 28
ID (e.g. DOI, URN): 10.7554/eLife.42276
PPN (Catalogue-ID): 1681161028
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520 |a 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. 
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