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A Nanoparticle-Based Model Delivery System To Guide the Rational Design of Gene Delivery to the Liver. 2. In Vitro and In Vivo Uptake Results

Popielarski, Stephen R. and Hu-Lieskovan, Siwen and French, Samuel W. and Triche, Timothy J. and Davis, Mark E. (2005) A Nanoparticle-Based Model Delivery System To Guide the Rational Design of Gene Delivery to the Liver. 2. In Vitro and In Vivo Uptake Results. Bioconjugate Chemistry, 16 (5). pp. 1071-1080. ISSN 1043-1802. https://resolver.caltech.edu/CaltechAUTHORS:20170131-080127280

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Abstract

In Part 1 of our work (1), four nanoparticles were synthesized specifically for the purpose of identifying design constraints to guide next generation gene delivery to the liver. The four nanoparticles are Gal-50 and Gal-140 (galactosylated 50 and 140 nm nanoparticles) and MeO-50 and MeO-140 (methoxy-terminated 50 and 140 nm nanoparticles). All four particles have the same surface charge, and Gal-50 and Gal-140 have the same surface galactose density (ca. 25−30 pmol/cm^2). Here, the hepatocyte uptake in vitro and hepatic distribution in vivo of these four nanoparticles is investigated. With freshly isolated hepatocytes, Gal-50 nanoparticles are taken up to a greater extent than are MeO-50, and both 50 nm beads are taken up to a much greater extent than either of the 140 nm nanoparticles. In mice, about 90% of the in vivo dose of Gal-140 nanoparticles is found within the liver 20 min after tail-vein injection. TEM and immunohistochemistry images confirm that Gal-140 nanoparticles are primarily internalized by Kupffer cells, though isolated examples of a few Gal-140 in hepatocytes are also observed. Gal-50 nanoparticles are overwhelmingly found in vesicles throughout the cytoplasm of hepatocytes, with only isolated examples of Kupffer cell uptake 20 min after tail vein injections in mice. Despite similar surface charge and ligand density, 50 nm nanoparticles are primarily found in hepatocytes while 140 nm nanoparticles are primarily observed in Kupffer cells. These results clearly show that slightly anionic, galactose-PEGylated nanoparticles with 25−30 pmol/cm^2 galactose should be about 50 nm in diameter to preferentially target hepatocytes while they should be about 140 nm in diameter to selectively target Kupffer cells.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/bc0501146DOIArticle
http://pubs.acs.org/doi/full/10.1021/bc0501146PublisherArticle
ORCID:
AuthorORCID
Davis, Mark E.0000-0001-8294-1477
Additional Information:© 2005 American Chemical Society. Received 14 April 2005. Published online 31 August 2005. Published in print 1 September 2005. We are grateful to Dr. Hide Tsukamoto for generously offering the services of his lab to isolate nonparenchymal liver cells and for helpful discussions. Dr. Rochelle Diamond went out of her way to assist with in vitro FACS experiments, and we thank George McNamara of the CHLARI Image Core for advice and assistance in acquiring images following immunhistochemical staining.
Issue or Number:5
Record Number:CaltechAUTHORS:20170131-080127280
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170131-080127280
Official Citation:A Nanoparticle-Based Model Delivery System To Guide the Rational Design of Gene Delivery to the Liver. 2. In Vitro and In Vivo Uptake Results Stephen R. Popielarski, Siwen Hu-Lieskovan, Samuel W. French, Timothy J. Triche, and Mark E. Davis Bioconjugate Chemistry 2005 16 (5), 1071-1080 DOI: 10.1021/bc0501146
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:73845
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:31 Jan 2017 17:56
Last Modified:09 Mar 2020 13:18

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