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

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...

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Published in:eLife Vol. 8
Main Authors: Witzigmann, Dominik, Uhl, Philipp, Sieber, Sandro, Kaufman, Christina, Einfalt, Tomaz, Schöneweis, Katrin, Grossen, Philip, Buck, Jonas, Ni, Yi, Schenk, Susanne H, Hussner, Janine, Meyer zu Schwabedissen, Henriette E, Québatte, Gabriela, Mier, Walter, Urban, Stephan, Huwyler, Jörg
Format: Journal Article
Language:English
Published: England eLife Science Publications, Ltd 23.07.2019
eLife Sciences Publications Ltd
eLife Sciences Publications, Ltd
Subjects:
Animals
Biochemistry and Chemical Biology
Drug Carriers - administration & dosage
Drug delivery
Drug delivery systems
Drug Delivery Systems - methods
Drug dosages
Fluorescence
Fluorescence microscopy
Hepatitis
Hepatitis B
Hepatitis B Surface Antigens - administration & dosage
Hepatitis B virus
hepatocyte targeting
Hepatocytes
Internalization
Ligands
Lipids
liposomes
Liposomes - administration & dosage
Liver
Liver - diagnostic imaging
Liver diseases
Microbiology and Infectious Disease
Microscopy
Myrcludex B
nanocarriers
Nanoparticles
NTCP
Optimization
Organic Anion Transporters, Sodium-Dependent - administration & dosage
Organic Anion Transporters, Sodium-Dependent - pharmacokinetics
Peptides
Pharmaceutical sciences
Pharmacokinetics
Physicochemical properties
Polypeptides
Production processes
Proteins
Radionuclide Imaging
Scintigraphy
Sodium
Statistical analysis
Symporters - administration & dosage
Symporters - pharmacokinetics
Technology application
Variance analysis
Veins & arteries
Viral envelope proteins
Zebrafish
United States
Heidelberg Germany
Basel Switzerland
Switzerland
Germany
hepatocyte targeting
rat
liposomes
hepatitis B virus
nanocarriers
microbiology
mouse
chemical biology
Myrcludex B
infectious disease
NTCP
biochemistry
zebrafish
ISSN:2050-084X, 2050-084X
Online Access:Get full text
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Summary: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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ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.42276