Pharmacokinetics, Tissue Distribution, and Safety of P-Ethoxy Oligonucleotides Incorporated in Liposomes

P-ethoxy oligonucleotides (oligos) are lipophilic analogs of phospho-diesters. We have used liposomes to increase the intracellular uptake of P-ethoxy oligos, and demonstrated that liposomal P-ethoxy antisense oligos specific for Bcr-Abl, Grb2, Crkl or Bcl-2 mRNA could selectively inhibit the production of the corresponding proteins, thereby inducing 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 pharmacokinetics, tissue distribution and safety of intravenous injection of liposomal P-ethoxy oligos in normal mice. The pharmacokinetics and tissue distribution of liposomal P-ethoxy oligos are very similar to those of other liposomal compounds. The plasma clearance rate of liposomal P-ethoxy oligos was biphasic; the t1/2 α and t1/2 β were approximately 6.7 min and 7 h, respectively. The highest concentrations of liposomal P-ethoxy oligos were found in spleen and liver, with a t1/2 of approximately 48 h. When up to 180 mg of P-ethoxy oligos per 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 pathologic changes were observed. Our studies suggested that, at the doses studied, liposomal P-ethoxy oligos could be safely used in animal studies. Since liposomal P-ethoxy oligos were found to accumulate mainly in spleen and liver, which are the major organs of leukemic and lymphoma disease manifestation, we are currently investigating the use of liposomal P-ethoxy antisense oligos in experimental leukemia and lymphoma animal models.