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Barcoded nanoparticles for high throughput in vivo discovery of targeted therapeutics

James E. Dahlman, Kevin J. Kauffman, Yiping Xing, Taylor E. Shaw, Faryal F. Mir, Chloe C. Dlott, Robert Langer, Daniel G. Anderson, and Eric T. Wang
PNAS published ahead of print February 6, 2017 https://doi.org/10.1073/pnas.1620874114
James E. Dahlman
aHarvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139;bInstitute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139;cDavid H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;dWallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332;
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  • For correspondence: james.dahlman@bme.gatech.edurlanger@mit.edudgander@mit.edueric.t.wang@ufl.edu
Kevin J. Kauffman
cDavid H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;eDepartment of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139;
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Yiping Xing
aHarvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139;bInstitute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139;cDavid H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
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Taylor E. Shaw
aHarvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139;bInstitute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139;cDavid H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
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Faryal F. Mir
cDavid H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
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Chloe C. Dlott
cDavid H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;
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Robert Langer
aHarvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139;bInstitute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139;cDavid H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;eDepartment of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139;
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Daniel G. Anderson
aHarvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139;bInstitute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139;cDavid H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;eDepartment of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139;
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  • For correspondence: james.dahlman@bme.gatech.edurlanger@mit.edudgander@mit.edueric.t.wang@ufl.edu
Eric T. Wang
cDavid H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139;fDepartment of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32601
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  • For correspondence: james.dahlman@bme.gatech.edurlanger@mit.edudgander@mit.edueric.t.wang@ufl.edu
  1. Contributed by Robert Langer, January 3, 2017 (sent for review October 28, 2016; reviewed by Charles A. Gersbach and David Putnam)

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Significance

The effectiveness of nucleic acid drugs is limited by inefficient delivery to target tissues and cells and by unwanted accumulation in off-target organs. Although thousands of chemically distinct nanoparticles can be synthesized, nanoparticles designed to deliver nucleic acids in vivo were first tested in cell culture, yielding poor predictions for delivery in vivo. To facilitate testing of many nanoparticles in vivo, we designed and optimized a high-throughput DNA barcoding system to simultaneously measure nucleic acid delivery mediated by dozens of distinct nanoparticles in a single mouse. This nano-barcoding system can be used to study hundreds, or even thousands, of nanoparticles directly in vivo and could dramatically accelerate the discovery and understanding of nanoparticle drug delivery systems.

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.

  • barcode
  • nanotechnology
  • nanoparticle
  • drug delivery
  • gene therapy

Footnotes

  • ↵1J.E.D., K.J.K., and Y.X. contributed equally to this work.

  • ↵2To whom correspondence may be addressed. Email: james.dahlman{at}bme.gatech.edu, rlanger{at}mit.edu, dgander{at}mit.edu, and eric.t.wang{at}ufl.edu.
  • Author contributions: J.E.D., K.J.K., Y.X., T.E.S., F.F.M., R.L., D.G.A., and E.T.W. designed research; J.E.D., K.J.K., Y.X., T.E.S., F.F.M., C.C.D., and E.T.W. performed research; J.E.D., K.J.K., Y.X., R.L., D.G.A., and E.T.W. contributed new reagents/analytic tools; J.E.D., K.J.K., Y.X., T.E.S., C.C.D., R.L., D.G.A., and E.T.W. analyzed data; and J.E.D., K.J.K., R.L., D.G.A., and E.T.W. wrote the paper.

  • Reviewers: C.A.G., Duke University; and D.P., Cornell University.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1620874114/-/DCSupplemental.

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Barcoded nanoparticles to study targeting in vivo
James E. Dahlman, Kevin J. Kauffman, Yiping Xing, Taylor E. Shaw, Faryal F. Mir, Chloe C. Dlott, Robert Langer, Daniel G. Anderson, Eric T. Wang
Proceedings of the National Academy of Sciences Feb 2017, 201620874; DOI: 10.1073/pnas.1620874114

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Barcoded nanoparticles to study targeting in vivo
James E. Dahlman, Kevin J. Kauffman, Yiping Xing, Taylor E. Shaw, Faryal F. Mir, Chloe C. Dlott, Robert Langer, Daniel G. Anderson, Eric T. Wang
Proceedings of the National Academy of Sciences Feb 2017, 201620874; DOI: 10.1073/pnas.1620874114
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