Antisense oligonucleotides provide useful tools in cell function studies and in therapy of various disorders. They are designed for specific reactions with their targets in order to regulate cellular activities. One of the drawbacks of the application of antisense oligonucleotides is their low penetration into cells and instability within cells. Cellular uptake can be facilitated by application together with cationic lipids. Another approach is lipid modification of oligonucleotides. In this study, oligonucleotides covalently linked to sphingophospholipids will be synthesised. Attachment of ceramides phosphate to one or both ends of the oligonucleotide should not only facilitate cellulare uptake but also protect the oligonucleotide against attack by exonucleases. Efficiency and mechanism of uptake will be tested with the use of fluorescently labelled derivatives. Biological activity will be tested by determining the effect of antisense olideoxynucleotides on the expression of the Sry gene (linked to the Y-chromosome) in mice preimplantation embryos, and on viral proliferation. Tissue distribution in mice after intravenous administration of fluorescently labelled substances will also be determined.
|Effective start/end date||1/10/01 → 31/01/03|