Flow shear stress differentially regulates endothelial uptake of nanocarriers targeted to distinct epitopes of PECAM-1.
Flow shear stress differentially regulates endothelial uptake of nanocarriers targeted to distinct epitopes of PECAM-1.
复制标题
DOI：
10.1016/j.jconrel.2015.05.006
复制
发表时间：
2015-07-28
期刊：
影响因子：
--
通讯作者：
Muzykantov VR
中科院分区：
文献类型：
--
作者：
Han J;Shuvaev VV;Davies PF;Eckmann DM;Muro S;Muzykantov VR
靶向纳米载体(NC到包括血小板-内皮细胞黏附分子-1(PECAM-1或CD31)在内的内皮细胞黏附分子)在动物模型中改善了炎症、氧化应激、血栓形成和缺血的药物传递和药物治疗。最近的研究表明，流体动力学条件可调节针对PECAM-1的NC的内皮内吞作用，但其作用的特异性和机制尚不清楚。在这里，我们研究了针对PECAM远端胞外区不同表位的单抗Ab62和Ab37对NC人内皮细胞内吞作用的影响。在1-8dyne/cm2的范围内，静脉血管系统的典型流量刺激了携带~50的球形抗体/NC(~180 nm直径)的摄取，分别为200Ab62和Ab37/NC。富含胆固醇的质膜结构域的破坏和PECAM-1胞浆尾部的缺失抑制了Flow的作用。Flow通过分别通过RhoA/ROCK和Src家族激酶介导的不同信号通路刺激Ab62/NC和Ab37/NC的内吞作用。因此，FLOW以PECAM-1表位特异性的方式刺激抗体/NC的内皮内吞作用。使用与同一靶分子上不同表位结合的配体，可以基于感兴趣的血管区域的血流动力学条件来微调细胞内的递送。
Targeting nanocarriers (NC to endothelial cell adhesion molecules including Platelet-Endothelial Cell Adhesion Molecule-1 (PECAM-1 or CD31) improves drug delivery and pharmacotherapy of inflammation, oxidative stress, thrombosis and ischemia in animal models. Recent studies unveiled that hydrodynamic conditions modulate endothelial endocytosis of NC targeted to PECAM-1, but the specificity and mechanism of effects of flow remain unknown. Here we studied the effect of flow on endocytosis by human endothelial cells of NC targeted by monoclonal antibodies Ab62 and Ab37 to distinct epitopes on the distal extracellular domain of PECAM. Flow in the range of 1 – 8 dyne/cm2, typical for venous vasculature, stimulated the uptake of spherical Ab/NC (~180 nm diameter) carrying ~50 vs 200 Ab62 and Ab37 per NC, respectively. Effect of flow was inhibited by disruption of cholesterol-rich plasmalemma domains and deletion of PECAM-1 cytosolic tail. Flow stimulated endocytosis of Ab62/NC and Ab37/NC via eliciting distinct signaling pathways mediated by RhoA/ROCK and Src Family Kinases, respectively. Therefore, flow stimulates endothelial endocytosis of Ab/NC in a PECAM-1 epitope specific manner. Using ligands of binding to distinct epitopes on the same target molecule may enable fine-tuning of intracellular delivery based on the hemodynamic conditions in the vascular area of interest.