In vivo delivery of antisense oligodeoxynucleotides into rat Kupffer cells

Kupffer cells play a key role in the pathogenesis of liver diseases. Liver injury is believed to result from an excessive release of cytokines and pro stanoids from these cells. A targeted delivery of antisense oligonucleotide s into Kupffer cells might reduce or prevent liver injury. In this report, we describe a method in which anionic liposome-encapsulated antisense phosp horothioate oligodeoxynucleotides (S-Oligos) are delivered to Kupffer cells in vivo. Delivery was assessed using an antisense S-Oligo (TJU-2749) targe ted against the 3' untranslated region of rat tumor necrosis factor-alpha m RNA. At 90 min post-intravenous injection, 90% of the S-Oligo was absorbed from circulation. Of this, 40% was found in the liver and 10% in spleen. Ot her organs, including lungs, kidneys, muscle, stomach, brain, testes and sm all intestine, showed only minor incorporation (<5%). Greater than 65% of t he Liver-associated S-Oligo was found in Kupffer cells. Relative accumulati on of S-Oligo in Kupffer cells was 200-fold that of the combined body tissu es. For an average injected dose of 1.2 mg antisense/Kg body weight, the in tracellular concentration of the S-Oligo attained in Kupffer cells was 65 m u M These studies suggest that Liposome-encapsulated delivery provides an e fficient means of targeting antisense molecules to Kupffer cells in vivo.