Studies of impending oligonucleotide therapeutics in simulated biofluids

Ivana Domljanovic, Anders Højgaard Hansen, Lykke Haastrup Hansen, Janne Kudsk Klitgaard, Maria Taskova*, Kira Astakhova

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Synthetic oligonucleotides, their complexes and conjugates with other biomolecules represent valuable research tools and therapeutic agents. In spite of growing applications in basic research and clinical science, only few studies have addressed the issue of such compounds’ stability in biological media. Herein, we studied the stability of two therapeutically relevant oligonucleotide probes in simulated biofluids; the 21 nucleotide-long DNA/locked nucleic acid oligonucleotide ON targeted toward cancer-associated BRAF V600E mutation, and a longer DNA analog (TTC) originating from BRAF gene. We found that stability of peptide–oligonucleotide conjugates (POCs) in human serum (HS) was superior compared with the naked or complexed 21mer oligonucleotide, whereas stability of POCs in simulated gastric juice (GJ) was dependent on the peptide sequence. Addition of pepstatin A in general increased the stability of oligonucleotides after 24 h digestion in HS and simulated GJ. Similarly, complexation with optimal amounts of histone proteins was found to rescue oligonucleotide stability after 24 h digestion in hydrochloric acid.
Original languageEnglish
JournalNucleic Acid Therapeutics
Volume28
Issue number6
Pages (from-to)348-356
Number of pages9
ISSN1545-4576
DOIs
Publication statusPublished - 2018

Keywords

  • Stability
  • Oligounucleotide
  • Biofluids
  • Gene therapy

Cite this