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 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.
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.|Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139.|David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.|Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332.
James E
JE
Dahlman
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
Kevin J
KJ
Kauffman
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139.|Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139.|David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
Yiping
Y
Xing
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139.|Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139.|David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
Taylor E
TE
Shaw
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
Faryal F
FF
Mir
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
Chloe C
CC
Dlott
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139.|Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139.|David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
Robert
R
Langer
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.|Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139.|David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
Daniel G
DG
Anderson
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.|Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32601.
Eric T
ET
Wang
D000818:Animals; D002469:Cell Separation; D058893:DNA Barcoding, Taxonomic / Q000379:methods*; D016503:Drug Delivery Systems / Q000379:methods; D055808:Drug Discovery / Q000379:methods*; D005167:Factor VII / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D008099:Liver / Q000166:cytology / Q000187:drug effects; D008168:Lung / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy / Q000379:methods; D053758:Nanoparticles / Q000737:chemistry*; D009696:Nucleic Acids / Q000008:administration & dosage* / Q000627:therapeutic use; D004364:Pharmaceutical Preparations / Q000008:administration & dosage; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000627:therapeutic use; D014018:Tissue Distribution
D009696:Nucleic Acids; D004364:Pharmaceutical Preparations; D034741:RNA, Small Interfering; D005167:Factor VII
barcode; drug delivery; gene therapy; nanoparticle; nanotechnology