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