Department of Chemical Engineering, Northeastern University, 360 Huntington Avenue, 313 Snell Engineering Building, Boston, MA, 02115, USA.
Department of Neurology, The Massachusetts General Hospital, Boston, MA, USA.
Ann Biomed Eng. 2020 Jul;48(7):1941-1954. doi: 10.1007/s10439-020-02474-4. Epub 2020 Feb 18.
Therapies for atherosclerotic cardiovascular disease should target early disease stages and specific vascular sites where disease occurs. Endothelial glycocalyx (GCX) degradation compromises endothelial barrier function and increases vascular permeability. This initiates pro-atherosclerotic lipids and inflammatory cells to penetrate vessel walls, and at the same time this can be leveraged for targeted drug delivery. In prior cell culture studies, GCX degradation significantly increased endothelial cell uptake of nanoparticle vehicles that are designed for drug delivery, compared to the effects of intact GCX. The present study assessed if the cell culture findings translate to selective nanoparticle uptake in animal vessels. In mice, the left carotid artery (LCA) was partially ligated to disturb blood flow, which induces GCX degradation, endothelial dysfunction, and atherosclerosis. After ligation, the LCA vessel wall exhibited a loss of continuity of the GCX layer on the intima. 10-nm gold nanospheres (GNS) coated with polyethylene glycol (PEG) were delivered intravenously. GCX degradation in the ligated LCA correlated to increased GNS infiltration of the ligated LCA wall. This suggests that GCX dysfunction, which coincides with atherosclerosis, can indeed be targeted for enhanced drug delivery, offering a new approach in cardiovascular disease therapy.
针对动脉粥样硬化性心血管疾病的治疗方法应该针对早期疾病阶段和发生疾病的特定血管部位。内皮糖萼（GCX）降解会损害内皮屏障功能并增加血管通透性。这会促使促动脉粥样硬化的脂质和炎症细胞穿透血管壁，同时也可以利用这一点进行靶向药物递送。在之前的细胞培养研究中，与完整的 GCX 相比，GCX 降解会显著增加设计用于药物递送的纳米颗粒载体被内皮细胞摄取的数量。本研究评估了这些细胞培养结果是否能转化为动物血管中的选择性纳米颗粒摄取。在小鼠中，左侧颈总动脉（LCA）被部分结扎以干扰血流，从而诱导 GCX 降解、内皮功能障碍和动脉粥样硬化。结扎后，LCA 血管壁在内膜上的 GCX 层连续性丧失。用聚乙二醇（PEG）包裹的 10nm 金纳米球（GNS）经静脉内给药。结扎 LCA 中的 GCX 降解与结扎 LCA 壁中 GNS 渗透的增加相关。这表明，与动脉粥样硬化同时发生的 GCX 功能障碍确实可以作为增强药物递送的靶点，为心血管疾病治疗提供了一种新方法。
