Targeted gene silencing of TLR4 using liposomal nanoparticles for preventing liver ischemia reperfusion injury.
Am J Transplant. 2011 Sep;11(9):1835-44. doi: 10.1111/j.1600-6143.2011.03660.x. Epub 2011 Jul 27.
Jiang N, Zhang X, Zheng X, Chen D, Zhang Y, Siu LK, Xin HB, Li R, Zhao H, Riordan N, Ichim TE, Quan D, Jevnikar AM, Chen G, Min W.
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.