PHARMACOKINETICS, TISSUE DISTRIBUTION, AND SAFETY OF P-ETHOXY OLIGONUCLEOTIDES INCORPORATED IN LIPOSOMES

P-ethoxy oligonucleotides (oligos) are lipophilic analogs of phosphodi esters. We have used liposomes to increase the intracellular uptake of P-ethoxy oligos, and demonstrated that liposomal P-ethoxy antisense o ligos specific for Bcr-Abl, Grb2, Crkl or Bcl-2 mRNA could selectively inhibit the production of the corresponding proteins, thereby inducin g growth inhibition in leukemia and lymphoma cell lines. In support of studying the effectiveness of liposomal P-ethoxy antisense oligos in animal models, we had conducted a series of studies to evaluate the ph armacokinetics, tissue distribution and safety of intravenous injectio n of liposomal P-ethoxy oligos in normal mice. The pharmacokinetics an d tissue distribution of liposomal P-ethoxy oligos are very similar to those of other liposomal compounds. The plasma clearance rate of lipo somal P-ethoxy oligos was biphasic; the t(1/2)alpha and t(1/2)beta wer e approximately 6.7 min and 7 h, respectively. The highest concentrati ons of liposomal P-ethoxy oligos were found in spleen and liver, with a t(1/2) of approximately 48 h. When up to 180 mg of P-ethoxy oligos p er kg of mice's body weight were used, the administration of liposomal P-ethoxy oligos had no adverse effects on renal and hepatic functions , or on the hematological parameters studied. No major organ pathologi c changes were observed. Our studies suggested that, at the doses stud ied, liposomal P-ethoxy oligos could be safely used in animal studies. Since liposomal P-ethoxy oligos were found to accumulate mainly in sp leen and liver, which are the major organs of leukemic and lymphoma di sease manifestation, we are currently investigating the use of liposom al P-ethoxy antisense oligos in experimental leukemia and lymphoma ani mal models.