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Cited by 52RNA Interference and Gene DeliveryBiosimilars and Bioanalytical MethodsNanoparticle-Based Drug Delivery

Pharmacokinetic Profiling of Conjugated Therapeutic Oligonucleotides: A High-Throughput Method Based Upon Serial Blood Microsampling Coupled to Peptide Nucleic Acid Hybridization Assay

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Godinho, Bruno M.D.C., Gilbert, James W., Haraszti, Reka A., Coles, Andrew H., Biscans, Annabelle, Roux, Loic, Nikan, Mehran, Echeverria, Dimas +2 more·2017·Nucleic Acid Therapeutics
DOI 10.1089/nat.2017.0690PMC PMC5706627
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Abstract

Therapeutic oligonucleotides, such as small interfering RNAs (siRNAs), hold great promise for the treatment of incurable genetically defined disorders by targeting cognate toxic gene products for degradation. To achieve meaningful tissue distribution and efficacy in vivo, siRNAs must be conjugated or formulated. Clear understanding of the pharmacokinetic (PK)/pharmacodynamic behavior of these compounds is necessary to optimize and characterize the performance of therapeutic oligonucleotides in vivo. In this study, we describe a simple and reproducible methodology for the evaluation of in vivo blood/plasma PK profiles and tissue distribution of oligonucleotides. The method is based on serial blood microsampling from the saphenous vein, coupled to peptide nucleic acid hybridization assay for quantification of guide strands. Performed with minimal number of animals, this method allowed unequivocal detection and sensitive quantification without the need for amplification, or further modification of the oligonucleotides. Using this methodology, we compared plasma clearances and tissue distribution profiles of two different hydrophobically modified siRNAs (hsiRNAs). Notably, cholesterol-hsiRNA presented slow plasma clearances and mainly accumulated in the liver, whereas, phosphocholine-docosahexaenoic acid-hsiRNA was rapidly cleared from the plasma and preferably accumulated in the kidney. These data suggest that the PK/biodistribution profiles of modified hsiRNAs are determined by the chemical nature of the conjugate. Importantly, the method described in this study constitutes a simple platform to conduct pilot assessments of the basic clearance and tissue distribution profiles, which can be broadly applied for evaluation of new chemical variants of siRNAs and micro-RNAs.

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Cited by

Sorted by citations

Authors
Godinho, B. M. D. C., Gilbert, J. W., Haraszti, R. A., Coles, A. H., Biscans, A., Roux, L., Nikan, M., Echeverria, D., Hassler, M., & Khvorova, A.
Affiliations
  • University of Massachusetts Chan Medical School (US)
  • RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, Massachusetts.
Corresponding author
  • Godinho, Bruno M.D.C.
  • Khvorova, Anastasia
ORCID
Venue
Nucleic Acid Therapeutics
Publisher
SAGE Publications
Published
2017-12
Volume
27
Issue
6
Pages
323-334
ISSN
  • 2159-3337 (ISSN-L)
  • 2159-3345
DOI
10.1089/nat.2017.0690
PMC
PMC5706627
OpenAlex
W2764261280
Cited by
52
References
3
Citations by year
2026: 5 · 2025: 10 · 2024: 6 · 2023: 6 · 2022: 7 · 2021: 3 · 2020: 5 · 2019: 4 · 2018: 6
FWCI
1.68
Type
journal article
Language
en
Open access
Licence
www.liebertpub.com/nv/resources-tools/text-and-data-mining-policy/121/ (tdm)
Locations
  • Nucleic Acid Therapeutics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (1s10od020012-01)
  • National Institute of General Medical Sciences (R01GM108803)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD086111)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Immunology and Microbiology › Immunology › Biosimilars and Bioanalytical Methods
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Keywords
oligonucleotide therapeutics, siRNA, pharmacokinetics, tissue distribution, siRNA conjugates, plasma clearance, liver accumulation, kidney accumulation, microRNA
MeSH terms
Animals, Cholesterol, Docosahexaenoic Acids, Female, Kidney, Liver, Mice, Inbred Strains, Nucleic Acid Hybridization, Oligonucleotides, Phosphorylcholine, Tissue Distribution, Peptide Nucleic Acids, RNA, Small Interfering, Mice, High-Throughput Screening Assays

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