Zukerman Hila, Khoury Maria, Shammay Yosi, Sznitman Josué, Lotan Noah, Korin Netanel
Department of Biomedical Engineering Technion - Israel Institute of Technology Haifa Israel.
Bioeng Transl Med. 2019 Dec 13;5(2):e10151. doi: 10.1002/btm2.10151. eCollection 2020 May.
Local inflammation of the endothelium is associated with a plethora of cardiovascular diseases. Vascular-targeted carriers (VTCs) have been advocated to provide focal effective therapeutics to these disease sites. Here, we examine the design of functionalized nanoparticles (NPs) as VTCs that can specifically localize at an inflamed vessel wall under pathological levels of high shear stress, associated for example with clinical (or in vivo) conditions of vascular narrowing and arteriogenesis. To test this, carboxylated fluorescent 200 nm polystyrene particles were functionalized with ligands to activated endothelium, that is, an E-selectin binding peptide (Esbp), an anti ICAM-1 antibody, or using a combination of both. The functionalized NPs were investigated in vitro using microfluidic models lined with inflamed (TNF-α stimulated) and control endothelial cells (EC). Specifically, their adhesion was monitored under different relevant wall shear stresses (i.e., 40-300 dyne/cm) via real-time confocal microscopy. Experiments reveal a significantly higher specific adhesion of the examined functionalized NPs to activated EC for the window of examined wall shear stresses. Moreover, particle adhesion correlated with the surface coating density whereby under high surface coating (i.e., ~10,000 molecule/particle), shear-dependent particle adhesion increased significantly. Altogether, our results show that functionalized NPs can be designed to target inflamed endothelial cells under high shear stress. Such VTCs underscore the potential for attractive avenues in targeting drugs to vasoconstriction and arteriogenesis sites.
内皮细胞的局部炎症与多种心血管疾病相关。血管靶向载体（VTCs）已被提倡用于为这些疾病部位提供局部有效的治疗方法。在此，我们研究了作为VTCs的功能化纳米颗粒（NPs）的设计，这些纳米颗粒能够在高剪切应力的病理水平下特异性地定位于炎症血管壁，例如与血管狭窄和动脉生成的临床（或体内）情况相关。为了验证这一点，用与活化内皮细胞结合的配体对羧化荧光200纳米聚苯乙烯颗粒进行功能化，即E-选择素结合肽（Esbp）、抗ICAM-1抗体，或两者结合使用。使用内衬炎症（TNF-α刺激）和对照内皮细胞（EC）的微流控模型在体外研究功能化的NPs。具体而言，通过实时共聚焦显微镜在不同的相关壁面剪切应力（即40 - 300达因/平方厘米）下监测它们的粘附情况。实验表明，在所研究的壁面剪切应力范围内，所检测的功能化NPs对活化EC的特异性粘附显著更高。此外，颗粒粘附与表面涂层密度相关，在高表面涂层（即~10,000分子/颗粒）下，剪切依赖性颗粒粘附显著增加。总之，我们的结果表明，可以设计功能化的NPs在高剪切应力下靶向炎症内皮细胞。这种VTCs强调了在将药物靶向血管收缩和动脉生成部位方面具有吸引人的途径的潜力。
