Using shape effects to target antibody-coated nanoparticles to lung and brain endothelium
Using shape effects to target antibody-coated nanoparticles to lung and brain endothelium
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DOI：
10.1073/pnas.1308345110
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发表时间：
2013-06-25
影响因子：
11.1
通讯作者：
Mitragotri, Samir
中科院分区：
文献类型：
--
作者：
Kolhar, Poornima;Anselmo, Aaron C.;Mitragotri, Samir
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。重要的研究已经集中在开发靶向患病组织中的内皮的药剂上。这包括鉴定抗粘附分子的抗体和使用噬菌体展示发现的新生血管表达标志物或肽。这种靶向分子也已用于将纳米颗粒递送至患病组织的内皮。在这里，我们报告，在体外和体内研究的基础上，内皮靶向的特异性可以通过工程配体展示纳米粒子的形状进一步增强。使用模拟脉管系统（合成微血管网络）的微流体系统进行的体外研究表明，与球形对应物相比，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积聚。粒子-表面相互作用的数学建模表明，纳米棒的更高的亲合力和特异性源自多价相互作用的平衡，该多价相互作用有利于粘附和熵损失以及减少结合的剪切诱导的分离。小鼠体内实验证实，对于展示抗细胞内粘附分子1和抗转铁蛋白受体抗体的纳米颗粒，在肺和脑中的生理条件下也观察到形状诱导的血管靶向增强。
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.