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ACS Nano. 2018 Mar 27;12(3):2138-2150. doi: 10.1021/acsnano.7b06995. Epub 2018 Jan 18.

Directing Nanoparticle Biodistribution through Evasion and Exploitation of Stab2-Dependent Nanoparticle Uptake.

Author information

1
Department of Supramolecular and Biomaterials Chemistry , Leiden Institute of Chemistry (LIC), Leiden University , P.O. Box 9502, 2300 RA Leiden , The Netherlands.
2
Hubrecht-Institute-KNAW and University Medical Centre and Centre for Biomedical Genetics , Uppsalalaan 8 , 3584 CT Utrecht , The Netherlands.
3
Division of Pharmaceutical Technology, Department of Pharmaceutical Science , University of Basel , Klingelbergstrasse 50 , Basel CH-4056 , Switzerland.
4
Department of Molecular Cell Biology , Institute Biology Leiden (IBL), Leiden University , P.O. Box 9502, 2300 RA Leiden , The Netherlands.

Abstract

Up to 99% of systemically administered nanoparticles are cleared through the liver. Within the liver, most nanoparticles are thought to be sequestered by macrophages (Kupffer cells), although significant nanoparticle interactions with other hepatic cells have also been observed. To achieve effective cell-specific targeting of drugs through nanoparticle encapsulation, improved mechanistic understanding of nanoparticle-liver interactions is required. Here, we show the caudal vein of the embryonic zebrafish ( Danio rerio) can be used as a model for assessing nanoparticle interactions with mammalian liver sinusoidal (or scavenger) endothelial cells (SECs) and macrophages. We observe that anionic nanoparticles are primarily taken up by SECs and identify an essential requirement for the scavenger receptor, stabilin-2 ( stab2) in this process. Importantly, nanoparticle-SEC interactions can be blocked by dextran sulfate, a competitive inhibitor of stab2 and other scavenger receptors. Finally, we exploit nanoparticle-SEC interactions to demonstrate targeted intracellular drug delivery resulting in the selective deletion of a single blood vessel in the zebrafish embryo. Together, we propose stab2 inhibition or targeting as a general approach for modifying nanoparticle-liver interactions of a wide range of nanomedicines.

KEYWORDS:

endothelial cells; liposomes; nanomedicine; scavenger receptor; stabilin; targeted drug delivery; zebrafish

PMID:
29320626
PMCID:
PMC5876619
DOI:
10.1021/acsnano.7b06995
[Indexed for MEDLINE]
Free PMC Article

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