RESUMEN
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.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Portadores de Fármacos/química , FN-kappa B/genética , Oligonucleótidos/administración & dosificación , Oligonucleótidos/uso terapéutico , Polilisina/química , Animales , Secuencia de Bases , Citocinas/genética , Citocinas/inmunología , Dendrímeros/química , Galactosamina , Lipopolisacáridos , Hígado/citología , Masculino , Ratones , Oligonucleótidos/química , Oligonucleótidos/farmacocinética , ARN Mensajero/genética , Transaminasas/sangre , Transaminasas/metabolismoRESUMEN
Intravenous delivery of apolipoprotein B-specific siRNA with a sixth-generation of dendritic poly(L-lysine) (KG6) resulted in siRNA-mediated knockdown of ApoB in healthy C57BL/6 mice without hepatotoxicity, and with a significant reduction of serum low-density lipoprotein cholesterol in apolipoprotein E-deficient mice.