1. Biochemistry and Chemical Biology
  2. Microbiology and Infectious Disease
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Optimization-by-design of hepatotropic lipid nanoparticles targeting the sodium-taurocholate cotransporting polypeptide

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Cite this article as: eLife 2019;8:e42276 doi: 10.7554/eLife.42276

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

  1. Dominik Witzigmann

    Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
    For correspondence
    dominik.witzigmann@unibas.ch
    Competing interests
    The authors declare that no competing interests exist.
  2. Philipp Uhl

    Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Sandro Sieber

    Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  4. Christina Kaufman

    Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Tomaz Einfalt

    Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  6. Katrin Schöneweis

    Department of Infectious Diseases, University Hospital Heidelberg, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Philip Grossen

    Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3416-5570
  8. Jonas Buck

    Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  9. Yi Ni

    Department of Infectious Diseases, University Hospital Heidelberg, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Susanne H Schenk

    Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  11. Janine Hussner

    Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  12. Henriette E Meyer zu Schwabedissen

    Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0458-4579
  13. Gabriela Québatte

    Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  14. Walter Mier

    Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  15. Stephan Urban

    Department of Infectious Diseases, University Hospital Heidelberg, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  16. Jörg Huwyler

    Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
    For correspondence
    joerg.huwyler@unibas.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1748-5676

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

  1. Bavesh D Kana, University of the Witwatersrand, South Africa

Publication history

  1. Received: September 24, 2018
  2. Accepted: July 17, 2019
  3. Accepted Manuscript published: July 23, 2019 (version 1)
  4. 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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