INTERACTION OF OLIGONUCLEOTIDE-CONJUGATES WITH THE DIPEPTIDE TRANSPORTER SYSTEM IN CACO-2 CELLS

Oligonucleotide-based therapies represent novel strategies for manipul ating the expression and function of target proteins and are undergoin g clinical evaluation for the treatment of viral diseases and malignan cies. However, poor biological stability and cellular delivery represe nt potential limitations to the therapeutic development of oligonucleo tides. Conjugation of oligonucleotides to lipophilic groups can improv e delivery to cells but the enhanced cellular binding may also facilit ate nonspecific interactions. In this report, we show that phosphoroth ioate oligonucleotides conjugated to lipophilic groups, either tocophe rol (Vitamin E) or 2-Di-O-hexadecyl-3-glycerol, can significantly inhi bit the functioning of the dipeptide transporter system (DTS) in cultu red Caco-2 intestinal cells. Because the DTS mediates the binding and absorption of nutrient peptides and important drugs, such as the cepha losporin and penicillin antibiotics, this finding has important implic ations in relation to the potential toxicity of Lipophilic conjugates in vivo. It also suggests a potential drug interaction with lipophilic oligonucleotide-conjugates if they were to be delivered orally. (C) 1 997 Elsevier Science Inc.