PHARMACOKINETICS, TISSUE DISTRIBUTION, AND STABILITY OF ANTISENSE OLIGODEOXYNUCLEOTIDE PHOSPHOROTHIOATE ISIS-3466 IN MICE

Phosphorothioate oligonucleotides have a potential as therapeutic agen ts. The pharmacokinetics, tissue distribution, stability, and cellular uptake by LOX ascites tumor of p120 antisense phosphorothioate oligon ucleotide, ISIS 3466, were studied in vivo. The oligonucleotide, which was quickly cleared from the circulation in the normal mice after TV injection, was readily absorbed into the systemic circulation from the peritoneum. The oligonucleotide was found in most tissues 48 h after IP administration. The highest concentrations were in kidney and liver but the brain had a very low concentration. The phosphorothioate olig onucleotide was intact even after 48 h. When the oligonucleotide was c omplexed with cationic lipid DOTMA, the DOTMA did not affect the oligo nucleotide uptake or tissue distribution in normal mice. However, DOTM A significantly increased the oligonucleotide cellular uptake (4-10 ti mes) in LOX ascites tumors in an IP/IP model. These results indicate t hat the phosphorothioate oligonucleotide is stable, has favourable kin etics for use as an therapeutic agent, and that DOTMA could be useful in local delivery of the oligonucleotide in vivo.