Oligodeoxynucleotides (ONs) are a powerful new class of drugs whose transport to the cytoplasm or nucleus inefficient and incompletely defined. Thus, to further extend our understanding of the mechanism of ON cellular uptake, the role of multivalent cations in ON cellular uptake was examined. All the multivalent cations tested, except magnesium, significantly increase ON uptake and was predictably related to the cation's electronegativity but only partially due to an increase in surface-binding. In addition, the primary mechanism of uptake is largely independent of trypsin-sensitive surface components, cellular energy, and several specific, calcium-dependent cellular processes. Therefore, ON cellular uptake may involve an interaction between multivalent cations and either the ON, the cell membrane, or both.
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