Influence of Combinations of Lipophilic and Phosphate Backbone Modifications on Cellular Uptake of Modified Oligonucleotides

Abstract

Numerous types of oligonucleotide modifications have been developed since automated synthesis of DNA/RNA became a common instrument in the creation of synthetic oligonucleotides. Despite the growing number of types of oligonucleotide modifications under development, only a few of them and, moreover, their combinations have been studied widely enough in terms of their influence on the properties of corresponding NA constructions. In the present study, a number of oligonucleotides with combinations of 3′-end lipophilic (a single cholesteryl or a pair of dodecyl residues) and phosphate backbone modifications were synthesized. The influence of the combination of used lipophilic groups with phosphate modifications of various natures and different positions on the efficiency of cell penetration was evaluated. The obtained results indicate that even a couple of phosphate modifications are able to affect a set of oligonucleotide properties in a complex manner and can remarkably change cellular uptake. These data clearly show that the strategy of using different patterns of modification combinations has great potential for the rational design of oligonucleotide structures with desired predefined properties.