title: Targeted gene silencing of TLR4 using liposomal nanoparticles for preventing liver ischemia reperfusion injury.
abstract: RNAi-based therapy is a promising strategy for the prevention of ischemia-reperfusion injury (IRI). However, systemic administration of small interfering RNA (siRNA) may cause globally nonspecific targeting of all tissues, which impedes clinical use. Here we report a hepatocyte-specific delivery system for the treatment of liver IRI, using galactose-conjugated liposome nanoparticles (Gal-LipoNP). Heptocyte-specific targeting was validated by selective in vivo delivery as observed by increased Gal-LipoNP accumulation and gene silencing in the liver. Gal-LipoNP TLR4 siRNA treatment resulted in a significant decrease of serum alanine transferase (ALT) and aspartate transaminase (AST) in a hepatic IRI model. Histopathology displayed an overall reduction of the injury area in the Gal-LipoNP TLR4 siRNA treated mice. Additionally, neutrophil accumulation and lipid peroxidase-mediated tissue injury, detected by MPO, MDA and ROS respectively, were attenuated after Gal-LipoNP TLR4 siRNA treatment. Moreover, therapeutic effects of Gal-LipoNP TLR4 siRNA were associated with suppression of the inflammatory cytokines IL-1 and TNF-α. Taken together, this study is the first demonstration of liver IRI treatment using liver-specific siRNA delivery.
authors.affiliation: Multi-Organ Transplant Program, London Health Sciences Centre, London, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Jiang
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: X
authors.initials: X
authors.lastname: Zheng
authors.forename: D
authors.initials: D
authors.lastname: Chen
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: L K S
authors.initials: LK
authors.lastname: Siu
authors.forename: H-B
authors.initials: HB
authors.lastname: Xin
authors.forename: R
authors.initials: R
authors.lastname: Li
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.forename: N
authors.initials: N
authors.lastname: Riordan
authors.forename: T E
authors.initials: TE
authors.lastname: Ichim
authors.forename: D
authors.initials: D
authors.lastname: Quan
authors.forename: A M
authors.initials: AM
authors.lastname: Jevnikar
authors.forename: G
authors.initials: G
authors.lastname: Chen
authors.forename: W
authors.initials: W
authors.lastname: Min
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D020868:Gene Silencing; D007150:Immunohistochemistry; D008081:Liposomes; D008099:Liver / Q000098:blood supply*; D051379:Mice; D053758:Nanoparticles; D016133:Polymerase Chain Reaction; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000517:prevention & control*; D051197:Toll-Like Receptor 4 / Q000235:genetics*
chemical_list: D017931:DNA Primers; D008081:Liposomes; D017382:Reactive Oxygen Species; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4