Cellular uptake of antisense oligodeoxynucleotides

Synthetic, chemically modified antisense oligodeoxynucleotides inhibit gene expression in a sequence-specific manner, besides having other, sequence-non-specific effects on cells. In this context, cellular uptake characteristics of these compounds is of particular interest. Radioactive or fluorescence labelling is used to investigate kinetics and intracellular distribution. Oligodeoxynucleotides apparantly enter cells by two mechanisms, an active and a passive; there is evidence for the presence of oligodeoxynucleotide receptors on the surface of cells. Parameters determining cellular uptake are: type of cells and medium from which the uptake takes place, type of oligodeoxynucleotide analog, chain length, and presence of linked groups. In cells, the oligodeoxynucleotides are present mainly in the cytoplasm and in/around the nucleus; the exact distribution pattern appears to vary strongly according to the cellular system and oligodeoxynucleotide analog used. Chemically modified oligodeoxynucleotide analogs remain intact inside the cells for days. Future efforts to increase efficacy of antisense oligodeoxynucleotides should be directed towards design of linked groups increasing and targeting cellular uptake.