NFkappaB decoy delivery using dendritic poly(l-lysine) for treatment of endotoxin-induced hepatitis in mice.

Abstract

Mono-dispersed, 6th generation dendritic poly(l-lysine) (KG6) forms a stable complex with plasmid DNA and this complex can circulate in vivo for extended times before the DNA finally accumulates in the liver. In this study, we attempted to use KG6 as a carrier of NFkappaB decoy oligonucleotide to the liver to treat hepatitis, induced by lipopolysaccharide and d-galactosamine. KG6 formed a complex with the NFkappaB decoy. Serum aspartate aminotransferase and alanine aminotransferase were dramatically suppressed in the hepatitis mouse model after intravenous injection of KG6/NFkappaB decoy complexes. Expression levels of several cytokines and proteins related to the inflammatory reaction were also suppressed by intravenous administration of KG6/NFkappaB decoy complexes. Because [(32)P] NFkappaB decoy was found in non-parenchymal cells after intravenous injection, KG6 has been shown to be a promising carrier molecule of various oligonucleotides to non-parenchymal liver cells, including Kupffer cells.

• Authors: Yusuke Sugao, Kazuto Watanabe, Yuriko Higuchi, Ryohsuke Kurihara, Shigeru Kawakami, Mitsuru Hashida, Yoshiki Katayama, Takuro Niidome
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 17 Issue 14 Pg. 4990-5 (Jul 15 2009) ISSN: 1464-3391 [Electronic] England
• PMID: 19539484 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Dendrimers
• Drug Carriers
• Lipopolysaccharides
• NF-kappa B
• Oligonucleotides
• RNA, Messenger
• Polylysine
• Galactosamine
• Transaminases

Topics

• Animals
• Base Sequence
• Chemical and Drug Induced Liver Injury (drug therapy)
• Cytokines (genetics, immunology)
• Dendrimers (chemistry)
• Drug Carriers (chemistry)
• Galactosamine
• Lipopolysaccharides
• Liver (cytology)
• Male
• Mice
• NF-kappa B (genetics)
• Oligonucleotides (administration & dosage, chemistry, pharmacokinetics, therapeutic use)
• Polylysine (chemistry)
• RNA, Messenger (genetics)
• Transaminases (blood, metabolism)