Optimization-by-design of hepatotropic lipid nanoparticles targeting the sodium-taurocholate cotransporting polypeptide
- University of Basel, Switzerland
- University Hospital Heidelberg, Germany
- Cited 1
- Views 1,392
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Abstract
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, i.e. 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.
Article and author information
Author details
Henriette E Meyer zu Schwabedissen
Funding
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (174975)
- Dominik Witzigmann
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (173057)
- Jonas Buck
- Jörg Huwyler
Deutsche Forschungsgemeinschaft (209091148)
- Stephan Urban
Deutsches Zentrum für Infektionsforschung (5.704)
- Stephan Urban
Deutsches Zentrum für Infektionsforschung (5.807)
- Stephan Urban
Freiwillige Akademische Gesellschaft (FAG Basel)
- Dominik Witzigmann
- Sandro Sieber
- Jörg Huwyler
Stiftung zur Förderung des pharmazeutischen Nachwuchses in Basel
- Sandro Sieber
Novartis University Basel Excellence SCholarship for Life Sciences
- Dominik Witzigmann
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal experimentation: Zebrafish embryo (Danio rerio) studies were performed in strict accordance with Swiss animal welfare regulations. Mouse and rat experiments were carried out in accordance with German legislation on animal welfare. All of the animals were handled according to approved institutional animal care and use protocol of the University of Basel and University of Heidelberg.
Reviewing Editor
- Bavesh D Kana, University of the Witwatersrand, South Africa
Publication history
- Received: September 24, 2018
- Accepted: July 17, 2019
- Accepted Manuscript published: July 23, 2019 (version 1)
- Version of Record published: August 5, 2019 (version 2)
Copyright
© 2019, Witzigmann et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Further reading
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- Biochemistry and Chemical Biology
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- Biochemistry and Chemical Biology
- Structural Biology and Molecular Biophysics
