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Shape effect in active targeting of nanoparticles to inflamed cerebral endothelium under static and flow conditions.
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2019-07-19 , DOI: 10.1016/j.jconrel.2019.07.026 A Da Silva-Candal 1 , T Brown 2 , V Krishnan 2 , I Lopez-Loureiro 1 , P Ávila-Gómez 1 , A Pusuluri 2 , A Pérez-Díaz 3 , C Correa-Paz 1 , P Hervella 1 , J Castillo 1 , S Mitragotri 2 , F Campos 1
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2019-07-19 , DOI: 10.1016/j.jconrel.2019.07.026 A Da Silva-Candal 1 , T Brown 2 , V Krishnan 2 , I Lopez-Loureiro 1 , P Ávila-Gómez 1 , A Pusuluri 2 , A Pérez-Díaz 3 , C Correa-Paz 1 , P Hervella 1 , J Castillo 1 , S Mitragotri 2 , F Campos 1
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Endothelial cells represent the first biological barrier for compounds, including nanoparticles, administered via the intravascular route. In the case of ischemic stroke and other vascular diseases, the endothelium overexpresses specific markers, which can be used as molecular targets to facilitate drug delivery and imaging. However, targeting these markers can be quite challenging due to the presence of blood flow and the associated hydrodynamic forces, reducing the likelihood of adhesion to the vessel wall. To overcome these challenges, various parameters including size, shape, charge or ligand coating have been explored to increase the targeting efficiency. Geometric shape can modulate nanoparticle binding to the cell, especially by counteracting part of the hydrodynamic forces of the bloodstream encountered by the classical spherical shape. In this study, the binding affinity of polystyrene nanoparticles with two different shapes, spherical and rod-shaped, were compared. First, vascular adhesion molecule-1 (VCAM-1) was evaluated as a vascular target of inflammation, induced by lipopolysaccharide (LPS) stimulation. To evaluate the effect of nanoparticle shape on particle adhesion, nanoparticles were coated with anti-VCAM-1 and tested under static conditions in cell culture dishes coated with cerebral microvasculature cells (bEnd.3) and under dynamic flow conditions in microfluidic channels lined with hCMEC/D3 cells. Effect of particle shape on accumulation was also assessed in two in vivo models including systemic inflammation and local brain inflammation. The elongated rod-shaped particles demonstrated greater binding ability in vitro, reaching a 2.5-fold increase in the accumulation for static cultures and 1.5-fold for flow conditions. Anti-VCAM-1 coated rods exhibited a 3.5-fold increase in the brain accumulation compared to control rods. These results suggest shape offers a useful parameter in future design of drug delivery nanosystems or contrast agents for neurovascular pathologies.
中文翻译：
在静态和流动条件下，将纳米粒子主动靶向发炎的脑内皮的形状效应。
内皮细胞代表化合物（包括纳米颗粒）通过血管内途径给药的第一个生物屏障。在缺血性中风和其他血管疾病的情况下，内皮过表达特定的标志物，这些标志物可用作分子靶标，以促进药物递送和成像。但是，由于存在血流和相关的流体动力，因此靶向这些标记可能非常具有挑战性，从而降低了粘附在血管壁上的可能性。为了克服这些挑战，已经探索了各种参数，包括尺寸，形状，电荷或配体涂层，以提高靶向效率。几何形状可以调节纳米粒子与细胞的结合，特别是通过抵消经典球形所遇到的一部分血液流的流体动力。在这项研究中，比较了球形和棒形两种不同形状的聚苯乙烯纳米颗粒的结合亲和力。首先，通过脂多糖（LPS）刺激，将血管粘附分子1（VCAM-1）评估为炎症的血管靶标。为了评估纳米颗粒形状对颗粒附着力的影响，将纳米颗粒涂有抗VCAM-1并在静态条件下在涂有脑微血管细胞的细胞培养皿中进行测试（bEnd.3），并在动态流动条件下在衬有hCMEC的微流体通道中进行测试/ D3单元格。在两个体内模型（包括全身性炎症和局部脑部炎症）中也评估了颗粒形状对累积的影响。细长的棒状颗粒在体外显示出更大的结合能力，达到了2。对于静态培养物，其积累量增加5倍，对于流动条件，其积累量增加1.5倍。与对照棒相比，涂有抗VCAM-1的棒显示出3.5倍的大脑积聚。这些结果表明形状为神经血管病理学的药物输送纳米系统或造影剂的未来设计提供了有用的参数。
更新日期：2019-07-19
中文翻译：
在静态和流动条件下，将纳米粒子主动靶向发炎的脑内皮的形状效应。
内皮细胞代表化合物（包括纳米颗粒）通过血管内途径给药的第一个生物屏障。在缺血性中风和其他血管疾病的情况下，内皮过表达特定的标志物，这些标志物可用作分子靶标，以促进药物递送和成像。但是，由于存在血流和相关的流体动力，因此靶向这些标记可能非常具有挑战性，从而降低了粘附在血管壁上的可能性。为了克服这些挑战，已经探索了各种参数，包括尺寸，形状，电荷或配体涂层，以提高靶向效率。几何形状可以调节纳米粒子与细胞的结合，特别是通过抵消经典球形所遇到的一部分血液流的流体动力。在这项研究中，比较了球形和棒形两种不同形状的聚苯乙烯纳米颗粒的结合亲和力。首先，通过脂多糖（LPS）刺激，将血管粘附分子1（VCAM-1）评估为炎症的血管靶标。为了评估纳米颗粒形状对颗粒附着力的影响，将纳米颗粒涂有抗VCAM-1并在静态条件下在涂有脑微血管细胞的细胞培养皿中进行测试（bEnd.3），并在动态流动条件下在衬有hCMEC的微流体通道中进行测试/ D3单元格。在两个体内模型（包括全身性炎症和局部脑部炎症）中也评估了颗粒形状对累积的影响。细长的棒状颗粒在体外显示出更大的结合能力，达到了2。对于静态培养物，其积累量增加5倍，对于流动条件，其积累量增加1.5倍。与对照棒相比，涂有抗VCAM-1的棒显示出3.5倍的大脑积聚。这些结果表明形状为神经血管病理学的药物输送纳米系统或造影剂的未来设计提供了有用的参数。
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