Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Hepatology. 2012 Jul;56(1):259-69. doi: 10.1002/hep.25607. Epub 2012 Jun 6.
Hepatitis is often associated with the overexpression of various adhesion molecules. In particular, intracellular adhesion molecule-1 (ICAM-1), which is expressed on hepatic endothelial cells (HECs) in the early stage of inflammation, is involved in serious illnesses. Therefore, ICAM-1 suppression in HECs enables the suppression of inflammatory responses. Here, we developed an ICAM-1 small interfering RNA (siRNA) transfer method using ultrasound (US)-responsive and mannose-modified liposome/ICAM-1 siRNA complexes (Man-PEG(2000) bubble lipoplexes [Man-PEG(2000) BLs]), and achieved efficient HEC-selective ICAM-1 siRNA delivery in combination with US exposure. Moreover, the sufficient ICAM-1 suppression effects were obtained via this ICAM-1 siRNA transfer in vitro and in vivo, and potent anti-inflammatory effects were observed in various types of inflammation, such as lipopolysaccharide, dimethylnitrosamine, carbon tetrachloride, and ischemia/reperfusion-induced inflammatory mouse models.
HEC-selective and efficient ICAM-1 siRNA delivery using Man-PEG(2000) BLs and US exposure enables suppression of various types of acute hepatic inflammation. This novel siRNA delivery method may offer a valuable system for medical treatment where the targeted cells are HECs.
肝炎通常与各种粘附分子的过度表达有关。特别是细胞间粘附分子-1（ICAM-1），在炎症的早期阶段表达于肝内皮细胞（HEC），与严重疾病有关。因此，抑制 HEC 中的 ICAM-1 能够抑制炎症反应。在这里，我们开发了一种使用超声（US）响应和甘露糖修饰的脂质体/ICAM-1 siRNA 复合物（Man-PEG（2000）泡脂质体[Man-PEG（2000）BLs]）的 ICAM-1 小干扰 RNA（siRNA）转移方法，并结合 US 暴露实现了高效的 HEC 选择性 ICAM-1 siRNA 传递。此外，通过这种 ICAM-1 siRNA 传递在体外和体内均获得了足够的 ICAM-1 抑制作用，并在各种类型的炎症中观察到了有效的抗炎作用，例如脂多糖、二甲基亚硝胺、四氯化碳和缺血/再灌注诱导的炎症小鼠模型。
使用 Man-PEG（2000）BLs 和 US 暴露进行 HEC 选择性和高效的 ICAM-1 siRNA 传递能够抑制各种类型的急性肝炎症。这种新型的 siRNA 传递方法可能为以 HEC 为靶向细胞的治疗提供有价值的系统。
