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Proc Natl Acad Sci U S A. 2017 Feb 21;114(8):2060-2065. doi: 10.1073/pnas.1620874114. Epub 2017 Feb 6.

Barcoded nanoparticles for high throughput in vivo discovery of targeted therapeutics.

Dahlman JE1,2,3,4, Kauffman KJ3,5, Xing Y6,2,3, Shaw TE6,2,3, Mir FF3, Dlott CC3, Langer R6,2,3,5, Anderson DG1,2,3,5, Wang ET7,8.

Author information

1
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139; james.dahlman@bme.gatech.edu rlanger@mit.edu dgander@mit.edu eric.t.wang@ufl.edu.
2
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139.
3
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
4
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332.
5
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
6
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139.
7
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; james.dahlman@bme.gatech.edu rlanger@mit.edu dgander@mit.edu eric.t.wang@ufl.edu.
8
Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32601.

Abstract

Nucleic acid therapeutics are limited by inefficient delivery to target tissues and cells and by an incomplete understanding of how nanoparticle structure affects biodistribution to off-target organs. Although thousands of nanoparticle formulations have been designed to deliver nucleic acids, most nanoparticles have been tested in cell culture contexts that do not recapitulate systemic in vivo delivery. To increase the number of nanoparticles that could be tested in vivo, we developed a method to simultaneously measure the biodistribution of many chemically distinct nanoparticles. We formulated nanoparticles to carry specific nucleic acid barcodes, administered the pool of particles, and quantified particle biodistribution by deep sequencing the barcodes. This method distinguished previously characterized lung- and liver- targeting nanoparticles and accurately reported relative quantities of nucleic acid delivered to tissues. Barcode sequences did not affect delivery, and no evidence of particle mixing was observed for tested particles. By measuring the biodistribution of 30 nanoparticles to eight tissues simultaneously, we identified chemical properties promoting delivery to some tissues relative to others. Finally, particles that distributed to the liver also silenced gene expression in hepatocytes when formulated with siRNA. This system can facilitate discovery of nanoparticles targeting specific tissues and cells and accelerate the study of relationships between chemical structure and delivery in vivo.

KEYWORDS:

barcode; drug delivery; gene therapy; nanoparticle; nanotechnology

PMID:
28167778
PMCID:
PMC5338412
DOI:
10.1073/pnas.1620874114
[Indexed for MEDLINE]
Free PMC Article

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