Interaction of oligonucleotide-conjugates with the dipeptide transporter system in Caco-2 cells.
Oligonucleotide-based therapies represent novel strategies for manipulating the expression and function of target proteins and are undergoing clinical evaluation for the treatment of viral diseases and malignancies. However, poor biological stability and cellular delivery represent potential limitations to the therapeutic development of oligonucleotides. Conjugation of oligonucleotides to lipophilic groups can improve delivery to cells but the enhanced cellular binding may also facilitate nonspecific interactions. In this report, we show that phosphorothioate oligonucleotides conjugated to lipophilic groups, either tocopherol (Vitamin E) or 2-Di-O-hexadecyl-3-glycerol, can significantly inhibit the functioning of the dipeptide transporter system (DTS) in cultured Caco-2 intestinal cells. Because the DTS mediates the binding and absorption of nutrient peptides and important drugs, such as the cephalosporin and penicillin antibiotics, this finding has important implications 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.
Moore
V A
VA
Pharmaceutical Sciences Institute, Aston University, Birmingham, UK.
Dunnion
D J
DJ
Brown
T
T
Irwin
W J
WJ
Akhtar
S
S
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells / Q000187:drug effects*; D004151:Dipeptides / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005995:Glyceryl Ethers / Q000494:pharmacology; D006801:Humans; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology*; D014810:Vitamin E / Q000494:pharmacology
C107392:2-di-O-hexadecyl-3-glycerol; D000806:Angiotensin-Converting Enzyme Inhibitors; D004151:Dipeptides; D005995:Glyceryl Ethers; D009838:Oligodeoxyribonucleotides; D009943:Organophosphorus Compounds; D013873:Thionucleotides; D014810:Vitamin E; C015248:glycylproline; D011392:Proline; C054518:ceronapril