1. Barcoded nanoparticles for high throughput in vivo discovery of targeted therapeutics.
- Author
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Dahlman JE, Kauffman KJ, Xing Y, Shaw TE, Mir FF, Dlott CC, Langer R, Anderson DG, and Wang ET
- Subjects
- Animals, Cell Separation, Drug Delivery Systems methods, Factor VII genetics, Female, Flow Cytometry, Liver cytology, Liver drug effects, Lung cytology, Lung drug effects, Mice, Mice, Inbred C57BL, Molecular Targeted Therapy methods, Nucleic Acids therapeutic use, Pharmaceutical Preparations administration & dosage, RNA Interference, RNA, Small Interfering therapeutic use, Tissue Distribution, DNA Barcoding, Taxonomic methods, Drug Discovery methods, Nanoparticles chemistry, Nucleic Acids administration & dosage, RNA, Small Interfering administration & dosage
- 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.
- Published
- 2017
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