Biomolecular Science and Engineering, University of California Santa Barbara, Santa Barbara, CA 93106, USA.
Proc Natl Acad Sci U S A. 2013 Jun 25;110(26):10753-8. doi: 10.1073/pnas.1308345110. Epub 2013 Jun 10.
Vascular endothelium offers a variety of therapeutic targets for the treatment of cancer, cardiovascular diseases, inflammation, and oxidative stress. Significant research has been focused on developing agents to target the endothelium in diseased tissues. This includes identification of antibodies against adhesion molecules and neovascular expression markers or peptides discovered using phage display. Such targeting molecules also have been used to deliver nanoparticles to the endothelium of the diseased tissue. Here we report, based on in vitro and in vivo studies, that the specificity of endothelial targeting can be enhanced further by engineering the shape of ligand-displaying nanoparticles. In vitro studies performed using microfluidic systems that mimic the vasculature (synthetic microvascular networks) showed that rod-shaped nanoparticles exhibit higher specific and lower nonspecific accumulation under flow at the target compared with their spherical counterparts. Mathematical modeling of particle-surface interactions suggests that the higher avidity and specificity of nanorods originate from the balance of polyvalent interactions that favor adhesion and entropic losses as well as shear-induced detachment that reduce binding. In vivo experiments in mice confirmed that shape-induced enhancement of vascular targeting is also observed under physiological conditions in lungs and brain for nanoparticles displaying anti-intracellular adhesion molecule 1 and anti-transferrin receptor antibodies.
血管内皮为治疗癌症、心血管疾病、炎症和氧化应激提供了多种治疗靶点。大量研究集中于开发针对病变组织内皮的药物。这包括鉴定针对黏附分子和新生血管表达标志物的抗体，或使用噬菌体展示发现的肽。这些靶向分子还被用于将纳米颗粒递送到病变组织的内皮。在这里，我们根据体外和体内研究报告，通过工程化配体展示纳米颗粒的形状，可以进一步增强内皮靶向的特异性。在模拟血管（合成微血管网络）的微流控系统中进行的体外研究表明，与球形纳米颗粒相比，棒状纳米颗粒在目标处的流动下表现出更高的特异性和更低的非特异性聚集。对粒子-表面相互作用的数学建模表明，纳米棒的高亲和力和特异性源于多价相互作用的平衡，这种平衡有利于黏附以及熵损失，同时剪切诱导的脱离减少了结合。在小鼠体内实验中证实，在肺部和大脑中，对于展示抗细胞间黏附分子 1 和抗转铁蛋白受体抗体的纳米颗粒，在生理条件下也观察到形状诱导的血管靶向增强。
