Barcoded nanoparticles for high throughput in vivo discovery of targeted therapeutics
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 n...
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2018
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| Online Access: | http://hdl.handle.net/1721.1/113871 https://orcid.org/0000-0002-9436-2453 https://orcid.org/0000-0003-4255-0492 https://orcid.org/0000-0001-5629-4798 |
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| author | Kauffman, Kevin John Xing, Yiping Shaw, Taylor E. Mir, Faryal Dlott, Chloe C. Langer, Robert S Anderson, Daniel Griffith Wang, Eric T Dahlman, James E. |
| author2 | Massachusetts Institute of Technology. Institute for Medical Engineering & Science |
| author_facet | Massachusetts Institute of Technology. Institute for Medical Engineering & Science Kauffman, Kevin John Xing, Yiping Shaw, Taylor E. Mir, Faryal Dlott, Chloe C. Langer, Robert S Anderson, Daniel Griffith Wang, Eric T Dahlman, James E. |
| author_sort | Kauffman, Kevin John |
| collection | MIT |
| description | 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 |
| first_indexed | 2024-09-23T09:52:37Z |
| format | Article |
| id | mit-1721.1/113871 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:52:37Z |
| publishDate | 2018 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/1138712022-09-26T14:16:16Z Barcoded nanoparticles for high throughput in vivo discovery of targeted therapeutics Kauffman, Kevin John Xing, Yiping Shaw, Taylor E. Mir, Faryal Dlott, Chloe C. Langer, Robert S Anderson, Daniel Griffith Wang, Eric T Dahlman, James E. Massachusetts Institute of Technology. Institute for Medical Engineering & Science Harvard University--MIT Division of Health Sciences and Technology Massachusetts Institute of Technology. Department of Chemical Engineering Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Koch Institute for Integrative Cancer Research at MIT Dahlman, James Kauffman, Kevin John Xing, Yiping Shaw, Taylor E. Mir, Faryal Dlott, Chloe C. Langer, Robert S Anderson, Daniel Griffith Wang, Eric T 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 Massachusetts Institute of Technology (Presidential Graduate Fellowship) National Science Foundation (U.S.). Graduate Research Fellowship Program David H. Koch Institute for Integrative Cancer Research at MIT. Marble Center for Cancer Nanomedicine National Institutes of Health (U.S.) (Cancer Center Support (Core) Grant P30- CA14051) Massachusetts Institute of Technology. Undergraduate Research Opportunities Program National Institutes of Health (Grant DP5-OD017865) Kathy and Curt Marble Cancer Research Fund (Koch Institute Frontier Grant) 2018-02-22T19:22:58Z 2018-02-22T19:22:58Z 2017-01 2016-10 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/113871 Dahlman, James E., et al. “Barcoded Nanoparticles for High Throughput in Vivo Discovery of Targeted Therapeutics.” Proceedings of the National Academy of Sciences, vol. 114, no. 8, Feb. 2017, pp. 2060–65. © 2017 National Academy of Sciences https://orcid.org/0000-0002-9436-2453 https://orcid.org/0000-0003-4255-0492 https://orcid.org/0000-0001-5629-4798 en_US http://dx.doi.org/10.1073/pnas.1620874114 Proceedings of the National Academy of Sciences Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) PNAS |
| spellingShingle | Kauffman, Kevin John Xing, Yiping Shaw, Taylor E. Mir, Faryal Dlott, Chloe C. Langer, Robert S Anderson, Daniel Griffith Wang, Eric T Dahlman, James E. Barcoded nanoparticles for high throughput in vivo discovery of targeted therapeutics |
| title | Barcoded nanoparticles for high throughput in vivo discovery of targeted therapeutics |
| title_full | Barcoded nanoparticles for high throughput in vivo discovery of targeted therapeutics |
| title_fullStr | Barcoded nanoparticles for high throughput in vivo discovery of targeted therapeutics |
| title_full_unstemmed | Barcoded nanoparticles for high throughput in vivo discovery of targeted therapeutics |
| title_short | Barcoded nanoparticles for high throughput in vivo discovery of targeted therapeutics |
| title_sort | barcoded nanoparticles for high throughput in vivo discovery of targeted therapeutics |
| url | http://hdl.handle.net/1721.1/113871 https://orcid.org/0000-0002-9436-2453 https://orcid.org/0000-0003-4255-0492 https://orcid.org/0000-0001-5629-4798 |
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