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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Vydáno v:	eLife Ročník 8
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	England eLife Science Publications, Ltd 23.07.2019 eLife Sciences Publications Ltd eLife Sciences Publications, Ltd
Témata:	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
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2050-084X 2050-084X
DOI:	10.7554/eLife.42276