University of Groningen, University Medical Center Groningen, Department of Pathology & Medical Biology, Medical Biology section, Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, Groningen, the Netherlands.
University of Groningen, University Medical Center Groningen, Department of Pathology & Medical Biology, Medical Biology section, Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, Groningen, the Netherlands; Synvolux Therapeutics, Groningen, the Netherlands.
Int J Pharm. 2014 Jul 20;469(1):121-31. doi: 10.1016/j.ijpharm.2014.04.041. Epub 2014 Apr 18.
In recent years much research in RNA nanotechnology has been directed to develop an efficient and clinically suitable delivery system for short interfering RNA (siRNA). The current study describes the in vivo siRNA delivery using PEGylated antibody-targeted SAINT-based-lipoplexes (referred to as antibody-SAINTPEGarg/PEG2%), which showed superior siRNA delivery capacity and effective down-regulation of VE-cadherin gene expression in vitro in inflammation-activated primary endothelial cells of different vascular origins. PEGylation of antibody-SAINTPEGarg resulted in more desirable pharmacokinetic behavior than that of non-PEGylated antibody-SAINTPEGarg. To create specificity for inflammation-activated endothelial cells, antibodies against vascular cell adhesion molecule-1 (VCAM-1) were employed. In TNFα-challenged mice, these intravenously administered anti-VCAM-1-SAINTPEGarg/PEG2% homed to VCAM-1 protein expressing vasculature. Confocal laser scanning microscopy revealed that anti-VCAM-1-SAINTPEGarg/PEG2% co-localized with endothelial cells in lung postcapillary venules. Furthermore, they did not exert any liver and kidney toxicity. Yet, lack of in vivo gene silencing as assessed in whole lung and in laser microdissected lung microvascular segments indicates that in vivo internalization and/or intracellular trafficking of the delivery system and its cargo in the target cells are not sufficient, and needs further attention, emphasizing the essence of evaluating siRNA delivery systems in an appropriate in vivo animal model at an early stage in their development.
近年来，许多 RNA 纳米技术的研究都致力于开发一种高效且临床适用的短干扰 RNA（siRNA）传递系统。本研究描述了使用聚乙二醇化抗体靶向 SAINT 脂质体（称为抗体-SAINTPEGarg/PEG2%）进行体内 siRNA 传递，该脂质体在体外炎症激活的不同血管来源的原代内皮细胞中表现出优异的 siRNA 传递能力和有效的 VE-钙粘蛋白基因表达下调。与非聚乙二醇化的抗体-SAINTPEGarg 相比，抗体-SAINTPEGarg 的聚乙二醇化导致更理想的药代动力学行为。为了使炎症激活的内皮细胞具有特异性，使用了针对血管细胞粘附分子-1（VCAM-1）的抗体。在 TNFα 挑战的小鼠中，这些静脉内给予的抗 VCAM-1-SAINTPEGarg/PEG2% 归巢到表达 VCAM-1 蛋白的脉管系统。共聚焦激光扫描显微镜显示，抗 VCAM-1-SAINTPEGarg/PEG2% 与肺后毛细血管小静脉中的内皮细胞共定位。此外，它们没有表现出任何肝和肾毒性。然而，如在整个肺和激光微解剖的肺微血管段中评估的那样，体内基因沉默缺乏表明，在靶细胞中，传递系统及其货物的体内内化和/或细胞内转运不足，需要进一步关注，强调了在开发的早期阶段在适当的体内动物模型中评估 siRNA 传递系统的本质。
