Targeted Gene Silencing of TLR4 Using Liposomal Nanoparticles for Preventing Liver Ischemia Reperfusion Injury

被引：42

作者：

Jiang, N. ^{[1
,2
,3
]}

Zhang, X. ^{[1
,2
]}

Zheng, X. ^{[1
,2
]}

Chen, D. ^{[2
]}

Zhang, Y. ^{[2
]}

Siu, L. K. S. ^{[2
]}

Xin, H-B. ^{[4
]}

Li, R. ^{[4
]}

Zhao, H. ^{[5
]}

Riordan, N. ^{[6
]}

Ichim, T. E. ^{[6
]}

Quan, D. ^{[1
,2
]}

Jevnikar, A. M. ^{[1
,2
]}

Chen, G. ^{[3
]}

Min, W. ^{[1
,2
,4
]}

机构：

[1] London Hlth Sci Ctr, Multiorgan Transplant Program, London, ON, Canada

[2] Univ Western Ontario, Dept Surg Pathol & Med, London, ON, Canada

[3] Sun Yat Sen Univ, Affiliated Hosp 3, Liver Transplant Ctr, Transplantat Res Inst, Guangzhou 510275, Guangdong, Peoples R China

[4] Nanchang Univ, Inst Translat Med, Nanchang, Peoples R China

[5] Peking Union Med Coll Hosp, Dept Liver Surg, Beijing, Peoples R China

[6] Medistem Panama City Knowledge, Clayton, Panama

来源：

AMERICAN JOURNAL OF TRANSPLANTATION | 2011年 / 11卷 / 09期

关键词：

Gene silencing; ischemia-reperfusion injury; liposomes; liver; siRNA; TLR4; SMALL INTERFERING RNA; TOLL-LIKE RECEPTORS; INFLAMMATORY RESPONSE; REACTIVE OXYGEN; ACTIVATION; EXPRESSION; COMPLEMENT-3; HEPATOCYTE; CASPASE-3; PROTECTS;

D O I：

10.1111/j.1600-6143.2011.03660.x

中图分类号：

R61 [外科手术学];

学科分类号：

摘要：

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.

引用

页码：1835 / 1844

页数：10

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