期刊
AMERICAN JOURNAL OF TRANSPLANTATION
卷 11, 期 9, 页码 1835-1844出版社
WILEY
DOI: 10.1111/j.1600-6143.2011.03660.x
关键词
Gene silencing; ischemia-reperfusion injury; liposomes; liver; siRNA; TLR4
资金
- Heart and Stroke Foundation of Canada
- CIHR
- Department of Surgery Institute Scientist, University of Western Ontario
- Pfizer-CIHR
- Major State Basic Research Development Program (973 Program) of China [2009CB522404]
- National 11th Five-Year Science and Technology Plan major projects of China [2008ZX10002-026]
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-alpha. Taken together, this study is the first demonstration of liver IRI treatment using liver-specific siRNA delivery.
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