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Cellular uptake of oligodeoxyribonucleoside methylphosphonates

J T Levis1, W O Butler, B Y Tseng

  • 1Department of Biochemistry, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.

Antisense Research and Development
|January 1, 1995
PubMed
Summary

Cellular uptake of methylphosphonate oligomers was studied using radiolabeled compounds. Results suggest specific uptake mechanisms for different oligomers, aiding antisense agent delivery research.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Oligodeoxyribonucleoside methylphosphonates are investigated as potential antisense agents.
  • Understanding their cellular uptake is crucial for effective intracellular delivery.

Purpose of the Study:

  • To evaluate the cellular uptake mechanisms of three radiolabeled methylphosphonate oligomers.
  • To compare uptake rates and identify potential entry pathways into various cell types.

Main Methods:

  • Utilized three radiolabeled oligomers: [3H]-T8, [3H]-T16, and EDA-III ([32P]-labeled).
  • Assessed uptake in human erythrocytes, HL-60 cells, K-562 cells, and mouse L cells.
  • Determined octanol/DPBS partition coefficients to predict membrane diffusion.

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Main Results:

  • Oligomers I and II showed low membrane permeability (low partition coefficients).
  • Oligomer I uptake in HL-60 cells was slower than fluid-phase endocytosis.
  • Oligomer II uptake in K-562 cells was concentration-independent and nonsaturable, suggesting a non-receptor-mediated process.
  • EDA-III demonstrated higher initial uptake rates in mouse L cells compared to standard oligodeoxyribonucleotides.

Conclusions:

  • Cellular uptake mechanisms for methylphosphonate oligomers vary.
  • Findings provide insights into the intracellular entry of these antisense agents.
  • Further research can optimize delivery strategies for oligodeoxyribonucleoside methylphosphonates.