Multi-Organ Transplant Program, London Health Sciences Centre, London, Canada.
Am J Transplant. 2011 Sep;11(9):1835-44. doi: 10.1111/j.1600-6143.2011.03660.x. Epub 2011 Jul 27.
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.
基于 RNAi 的治疗是预防缺血再灌注损伤（IRI）的一种有前途的策略。然而，小干扰 RNA（siRNA）的全身给药可能导致所有组织的非特异性靶向，从而阻碍临床应用。在这里，我们报告了一种用于治疗肝 IRI 的肝细胞特异性递送系统，使用半乳糖偶联脂质体纳米颗粒（Gal-LipoNP）。通过体内选择性递送来验证肝细胞特异性靶向，观察到 Gal-LipoNP 在肝脏中的积累增加和基因沉默。Gal-LipoNP TLR4 siRNA 治疗可显著降低肝 IRI 模型中的血清丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）。组织病理学显示 Gal-LipoNP TLR4 siRNA 处理组的损伤面积总体减少。此外，Gal-LipoNP TLR4 siRNA 处理后，中性粒细胞聚集和丙二醛（MDA）和活性氧（ROS）介导的脂质过氧化引起的组织损伤分别通过 MPO、MDA 和 ROS 检测到，均减弱。此外，Gal-LipoNP TLR4 siRNA 的治疗效果与抑制炎症细胞因子 IL-1 和 TNF-α有关。综上所述，这项研究首次证明了使用肝特异性 siRNA 递送来治疗肝 IRI。
