Influence of base composition on membrane binding and cellular uptake of 10-mer phosphorothioate oligonucleotides in Chinese hamster ovary (CHRC5) cells.

A key problem in antisense therapeutics is the relatively poor cell uptake of oligonucleotides and subsequent transport to the cytoplasm and nucleus. Although the chemical characteristics of oligonucleotides seem likely to affect their uptake by cells, little is known about this issue. In this article we explore the effect of base composition on oligonucleotide uptake. We show that phosphorothioate homo-G oligomers have a distinctly greater cellular uptake than other phosphorothioate homooligomers. This is probably due to a greater initial association with the plasma membrane, because homo-G oligomers show the greatest binding to liposome membranes, when tested at physiological ionic strength. Under different buffer conditions appreciable differences in membrane binding to liposomes were detected for the various homooligonucleotides.