PUBLICATION
Optimization-by-design of hepatotropic lipid nanoparticles targeting the sodium-taurocholate cotransporting polypeptide
- Authors
- Witzigmann, D., Uhl, P., Sieber, S., Kaufman, C., Einfalt, T., Schöneweis, K., Grossen, P., Buck, J., Ni, Y., Schenk, S.H., Hussner, J., Meyer Zu Schwabedissen, H.E., Québatte, G., Mier, W., Urban, S., Huwyler, J.
- ID
- ZDB-PUB-190724-35
- Date
- 2019
- Source
- eLIFE 8: (Journal)
- Registered Authors
- Keywords
- biochemistry, chemical biology, infectious disease, microbiology, mouse, rat, zebrafish
- MeSH Terms
-
- Animals
- Drug Carriers/administration & dosage*
- Drug Delivery Systems/methods*
- Hepatitis B Surface Antigens/administration & dosage
- Liposomes/administration & dosage*
- Liver/diagnostic imaging
- Organic Anion Transporters, Sodium-Dependent/administration & dosage
- Organic Anion Transporters, Sodium-Dependent/pharmacokinetics*
- Radionuclide Imaging
- Symporters/administration & dosage
- Symporters/pharmacokinetics*
- Zebrafish
- PubMed
- 31333191 Full text @ Elife
Citation
Witzigmann, D., Uhl, P., Sieber, S., Kaufman, C., Einfalt, T., Schöneweis, K., Grossen, P., Buck, J., Ni, Y., Schenk, S.H., Hussner, J., Meyer Zu Schwabedissen, H.E., Québatte, G., Mier, W., Urban, S., Huwyler, J. (2019) Optimization-by-design of hepatotropic lipid nanoparticles targeting the sodium-taurocholate cotransporting polypeptide. eLIFE. 8:.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping