Optimizing endothelial targeting by modulating the antibody density and particle concentration of anti-ICAM coated carriers.
Optimizing endothelial targeting by modulating the antibody density and particle concentration of anti-ICAM coated carriers.
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DOI：
10.1016/j.jconrel.2010.10.025
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发表时间：
2011-02-28
期刊：
影响因子：
--
通讯作者：
Muro S
中科院分区：
文献类型：
--
作者：
Calderon AJ;Bhowmick T;Leferovich J;Burman B;Pichette B;Muzykantov V;Eckmann DM;Muro S
将药物载体靶向内皮细胞（EC）上表达的细胞粘附分子可能会改善涉及血管内皮的疾病的治疗。对于靶向细胞间粘附分子1（ICAM-1）的载体，情况就是如此，ICAM-1是一种在许多病理学中过表达的内皮表面蛋白。为了优化抗ICAM载体的设计，我们在本研究中探索了两个载体设计参数对体外和体内特异性和有效的内皮靶向的影响：载体表面上的靶向分子（抗体-Ab-）的载体剂量和密度。使用放射性同位素示踪，我们评估了这些参数的生物分布的模型聚合物载体靶向ICAM-1（125 I-抗ICAM载体）在小鼠中的作用。增加载体剂量增强了肺血管系统中的特异性蓄积（优先内皮靶点），并降低了非特异性肝和脾摄取。增加Ab密度增强肺蓄积，肝脏和脾脏摄取最低限度降低。这些研究解释了血液流体动力对载体与内皮结合的影响，与小动脉、小静脉和大血管相关。然而，载体可能会结合到广泛的毛细血管床，其中剪切应力最小。我们使用荧光显微镜，以确定在静态条件下，在体内发现的阈值和条件下，模仿低与高ICAM-1表达的静态与激活EC的FITC标记的抗ICAM载体的结合动力学。与活化的EC的结合在所有测试的Ab密度和载体浓度下达到相似的饱和。在静止细胞中，即使在高载体浓度和Ab密度下，载体也达到约3倍低的结合饱和度，并且具有低Ab密度的载体未达到饱和，反映亲合力低于阈值。结合动力学受抗ICAM载体浓度和Ab密度的正调控。与直觉相反，在静止EC中结合更快（除了具有高Ab密度和浓度的载体），可能是由于这些细胞上较少结合位点的快速饱和。这些结果将指导ICAM-1靶向载体的优化，例如，在靶向健康与患病内皮以进行预防性与治疗性干预的背景下。
Targeting of drug carriers to cell adhesion molecules expressed on endothelial cells (ECs) may improve treatment of diseases involving the vascular endothelium. This is the case for carriers targeted to intercellular adhesion molecule 1 (ICAM-1), an endothelial surface protein overexpressed in many pathologies. In order to optimize our design of anti-ICAM carriers, we have explored in this study the influence of two carrier design parameters on specific and efficient endothelial targeting in vitro and in vivo: carrier dose and density of targeting molecules (antibodies -Ab-) on the carrier surface. Using radioisotope tracing we assessed the role of these parameters on the biodistribution of model polymer carriers targeted to ICAM-1 (125I-anti-ICAM carriers) in mice. Increasing the carrier dose enhanced specific accumulation in the lung vasculature (a preferential endothelial target) and decreased non-specific hepatic and splenic uptake. Increasing the Ab density enhanced lung accumulation with minimally reduced liver and spleen uptake. These studies account for the influence of blood hydrodynamic forces on carrier binding to endothelium, relevant to arterioles, venules and larger vessels. Yet, carriers may rather bind to the extensive capillary bed where shear stress is minimal. We used fluorescence microscopy to determine binding kinetics of FITC-labeled anti-ICAM carriers in static conditions, at the threshold found in vivo and conditions mimicking low vs high ICAM-1 expression on quiescent vs activated ECs. Binding to activated ECs reached similar saturation with all tested Ab densities and carrier concentrations. In quiescent cells, carriers reached ~3-fold lower binding saturation, even at high carrier concentration and Ab density, and carriers with low Ab density did not reach saturation, reflecting avidity below threshold. Binding kinetics was positively regulated by anti-ICAM carrier concentration and Ab density. Counterintuitively, binding was faster in quiescent ECs (except for carriers with high Ab density and concentration), likely due to fast saturation of fewer binding sites on these cells. These results will guide optimization of ICAM-1-targeted carriers, e.g., in the context of targeting healthy vs diseased endothelium for prophylactic vs therapeutic interventions.
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