Flow dynamics, binding and detachment of spherical carriers targeted to ICAM-1 on endothelial cells.
Flow dynamics, binding and detachment of spherical carriers targeted to ICAM-1 on endothelial cells.
复制标题
靶向ICAM-1对内皮细胞上的球形载体的流动动力学，结合和脱离。
DOI：
10.3233/bir-2009-0544
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发表时间：
2009
期刊：
影响因子：
1.1
通讯作者：
Eckmann DM
中科院分区：
文献类型：
--
作者：
Calderon AJ;Muzykantov V;Muro S;Eckmann DM
通过靶向内皮表面决定簇（如细胞间粘附分子（ICAM-1））的载体给药的血管药物递送具有相当大的改善疾病治疗的希望。作为一个模型，以确定控制载体在血流中运动及其与内皮壁中分子靶点相互作用之间相互作用的难以捉摸的因素，我们使用了1 μm的珠粒，这些珠粒包被有ICAM-1单克隆抗体（Ab），抗体浓度为370、1100或4100 Ab/µm2。载体以两种剪切速率灌注在静息或活化的内皮细胞上，表达最小与最大ICAM-1水平，以确定载体滚动、结合和脱离。即使在0.1 Pa和4100 Ab/µm2下，载体也仅附着于活化细胞（比静息细胞增加21倍），非常适合特异性药物靶向病变部位。通过提高载体上的Ab表面密度来增加结合，例如，59.4由于滚动速度降低，4100与1100 Ab/µm2的载体增加± 11.1%。即使在高剪切应力下，载体结合也是稳定的：具有1100和4100 Ab/µm2的载体能够承受超过3 Pa的剪切应力而不会从细胞上脱离。这一点得到了理论模型的进一步支持。这些结果将指导血管靶向药物载体通过合理设计的实验可调参数。
Vascular drug delivery by administration of carriers targeted to endothelial surface determinants, such as intercellular adhesion molecule (ICAM-1), holds considerable promise to improve disease treatment. As a model to define elusive factors controlling the interplay between carrier motion in the bloodstream and its interactions with molecular targets in the endothelial wall, we used 1 µm beads coated with ICAM-1 monoclonal antibody (Ab) at 370, 1100 or 4100 Ab/µm2. Carriers were perfused at two shear rates over resting or activated endothelial cells, expressing minimum vs. maximum ICAM-1 levels, to determine carrier rolling, binding and detachment. Even at 0.1 Pa and 4100 Ab/µm2, carriers attached only to activated cells (21 fold increase over resting cells), ideal for specific drug targeting to sites of pathology. Binding was increased by raising the Ab surface density on the carrier, e.g., 59.4 ± 11.1% increase for carriers having 4100 vs. 1100 Ab/µm2, as a consequence of decreased rolling velocity. Carrier binding was stable even under a high shear stress: carriers with 1100 and 4100 Ab/µm2 withstand shear stress over 3 Pa without detaching from the cells. This is further supported by theoretical modeling. These results will guide vascular targeting of drug carriers via rational design of experimentally tunable parameters.