Targeted ultrasound contrast agent for molecular imaging of inflammation in high-shear flow
Targeted ultrasound contrast agent for molecular imaging of inflammation in high-shear flow
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DOI：
10.1002/cmmi.113
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发表时间：
2006-11-01
影响因子：
--
通讯作者：
Kaul, S.
中科院分区：
文献类型：
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作者：
Klibanov, A. L.;Rychak, J. J.;Kaul, S.
靶向超声造影剂（带有内皮选择素或整合素配体的充气微泡）已被研究作为潜在的分子显像剂。这种微泡通常在较慢的流动条件下表现出良好的瞄准能力。然而，在剧烈流动的条件下，结合可能是有限的。在这里，我们描述了一种微泡，能够在慢速和快速流动（超过4达因/厘米(2)壁剪切应力）中有效结合靶标，使用快速结合选择配体sialyl Lewis(X)的簇状聚合物形式。以十氟丁烷气体为原料制备微泡，用磷脂酰胆碱、聚乙二醇硬脂酸酯和生物素-聚乙二醇脂质单层进行稳定。生物素化的PSLe(x) （sialyl Lewis(x)聚丙烯酰胺）或生物素化的抗p -选择素抗体（RB40.34）通过链亲和素桥接在微泡上。在平行板流室目标粘附模型中，PSLe(x)气泡在p选择素涂层板上表现出特定的粘附、保留和缓慢滚动。在0.68达因/厘米(2)的剪切应力下，携带抗体的气泡和靶向PSLe(x)的气泡在p -选择素表面的牢固靶向粘附效率（140分子/ μ m(2)）相当。在快速流动（4.45达因/厘米(2)）时，PSLe(x)靶向气泡保持其结合能力，而抗体介导的靶向性下降超过20倍。在较低的p -选择素表面密度（7分子/ μ m(2)）下，在所有测试的流动条件下，通过PSLe(x)靶向比通过抗体靶向更有效。阴性对照酪蛋白涂层板在研究的流动条件范围内不保留气泡。为了确认回声性，使用脉冲倒置模式操作的临床扫描仪，通过超声成像在p选择素涂覆的聚苯乙烯板上显示靶向PSLe(x)气泡；缺乏目标气泡的控制板没有显示出明显的声学后向散射。在体内，在小鼠股静脉炎症模型中，静脉给药PSLe(x)微泡的靶向效果与抗p -选择素抗体介导的靶向效果相当，并显著超过非靶向对照泡的积累。在股动脉炎症情况下，PSLe(x)介导的微泡靶向优于抗体介导的靶向。版权所有(C) 2006 John Wiley & Sons, Ltd。
Targeted ultrasound contrast materials (gas-filled microbubbles carrying ligands to endothelial selectins or integrins) have been investigated as potential molecular imaging agents. Such microbubbles normally exhibit good targeting capability at the slower flow conditions. However, in the conditions of vigorous flow, binding may be limited. Here, we describe a microbubble capable of efficient binding to targets both in slow and fast flow (exceeding 4 dyne/cm(2) wall shear stress) using a clustered polymeric form of the fast-binding selectin ligand sialyl Lewis(X). Microbubbles were prepared from decafluorobutane gas and stabilized with a monolayer of phosphatidylcholine, PEG stearate and biotin-PEG-lipid. Biotinylated PSLe(x) (sialyl Lewis(x) polyacrylamide) or biotinylated anti-P-selectin antibody (RB40.34) was attached to microbubbles via a streptavidin bridge. In a parallel plate flow chamber targeted adhesion model, PSLe(x) bubbles demonstrated specific adhesion, retention and slow rolling on P-selectin-coated plates. Efficiency of firm targeted adhesion to a P-selectin surface (140 molecules/mu m(2)) was comparable for antibody-carrying bubbles and PSLe(x)-targeted bubbles at 0.68 dyne/cm(2) shear stress. At fast flow (4.45 dyne/cm(2)), PSLe(x)-targeted bubbles maintained their ability to bind, while antibody-mediated targeting dropped more than 20-fold. At lower surface density of P-selectin (7 molecules/mu m(2)), targeting via PSLe(x) was more efficient than via antibody under all the flow conditions tested. Negative control casein-coated plates did not retain bubbles in the range of flow conditions studied. To confirm echogenicity, targeted PSLe(x)-bubbles were visualized on P-selectin-coated polystyrene plates by ultrasound imaging with a clinical scanner operated in pulse inversion mode; control plates lacking targeted bubbles did not show significant acoustic backscatter. In vivo, in a murine model of inflammation in the femoral vein setting, targeting efficacy of intravenously administered PSLe(x)-microbubbles was comparable with targeting mediated by anti-P-selectin antibody, and significantly exceeded the accumulation of non-targeted control bubbles. In the inflamed femoral artery setting, PSLe(x)-mediated microbubble targeting was superior to antibody-mediated targeting. Copyright (C) 2006 John Wiley & Sons, Ltd.