Department of Pathology & Medical Biology, Medical Biology section, Laboratory for Endothelial Biomedicine & Vascular Drug Targeting Research, University Medical Center, University of Groningen, The Netherlands.
IUBMB Life. 2011 Aug;63(8):648-58. doi: 10.1002/iub.487. Epub 2011 Jul 15.
Increased insight in the role of endothelial cells in the pathophysiology of cancer, inflammatory and cardiovascular diseases, has drawn great interest in pharmacological interventions aiming at the endothelium in diseased sites. Their location in the body makes them suitable targets for therapeutic approaches based on targeted drug delivery. Functional heterogeneity of the microvascular bed in normal organ homeostasis has been appreciated for a long time, and more recent studies have revealed heterogeneity in endothelial reactivity to inflammatory stimuli as well. Upon stimulation, each organ displays a vascular bed specific pattern of cell adhesion molecules providing challenging opportunities to deliver drugs or small RNAs to organ specific (micro)vascular endothelial subsets. In this review we introduce general concepts of endothelial heterogeneity in relation to disease state and its consequences for targeted therapeutic interventions. Furthermore, we will describe novel approaches to interfere with endothelial cell engagement in disease with a main focus on siRNA therapeutics and currently used nonviral lipid and polymer-based siRNA delivery systems. The last part of this review addresses some technical issues that are essential in proving the concept of target mRNA knock down in a vascular bed specific manner, and the further development of effective endothelial cell specific drug delivery devices.
内皮细胞在癌症、炎症和心血管疾病病理生理学中的作用的深入了解，引起了人们对针对病变部位内皮细胞的药理学干预的极大兴趣。它们在体内的位置使它们成为基于靶向药物输送的治疗方法的合适靶点。正常器官稳态中小血管床的功能异质性已经被人们认识了很长时间，最近的研究也揭示了内皮细胞对炎症刺激的反应性存在异质性。受到刺激后，每个器官都会显示出特定的细胞黏附分子模式的血管床，为向器官特异性（微）血管内皮亚群输送药物或小 RNA 提供了具有挑战性的机会。在这篇综述中，我们介绍了内皮细胞异质性的一般概念，以及它与疾病状态的关系及其对靶向治疗干预的影响。此外，我们将描述干扰内皮细胞参与疾病的新方法，主要集中在 siRNA 治疗和目前使用的非病毒脂质和聚合物基 siRNA 递送系统上。这篇综述的最后一部分讨论了一些在以血管床特异性方式证明靶 mRNA 敲低的概念和有效内皮细胞特异性药物输送装置的进一步发展中至关重要的技术问题。
