Pharmacokinetics in mice of a [H-3]-labeled phosphorothioate oligonucleotide formulated in the presence and absence of a cationic lipid

Formulation of phosphorothioate oligonucleotides with cationic lipids enhances the pharmacological activity of the oligonucleotide in cellular based assay systems. The effect of cationic lipid formulation on the pharmacokinetic behavior of a phosphorothioate oligodeoxynucleotide in mice was investigated in the present study. In the absence of any formulation, the phosphorothioate oligonucleotide exhibited a plasma T-1/2 of 10.2 min and was broadly distributed to many peripheral tissues with liver, kidney, skeletal muscle and skin being the major organs of disposition. Formulating the oligonucleotide with a DMRIE/DOPE (50:50) formulation, such that there was a 2.5:1 positive charge excess on the lipidic structure, resulted in marked changes in the distribution of the oligonucleotide. Significant increases in the amount of oligonucleotide distributed to liver, lung and spleen were observed when the oligonucleotide was formulated with cationic lipids. These results suggest that it is possible to change the biodistribution of phosphorothioate oligodeoxynucleotides by formulating with cationic liposomes.