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In Vitro Characterization Of Sophisticated Leukocyte Mimetic For Targeting Therapeutics To The Vasculature Via Two Receptors

机译:通过两种受体靶向靶向脉管系统的精致白细胞模拟物的体外表征

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The site-specific expression of selectins (E- and P-selectin) on endothelial cells of blood vessels during inflammation provides an opportunity for the targeted delivery of anti-inflammatory drugs to the vascular endothelium in chronic inflammatory diseases. We previously described a targeted delivery system were biotinylated-sialyl lewis X (sLe~X), a carbohydrate that serves as a ligand to selectins, was attached to the surface of avidin-linked poly-lactic-co-glycolic-acid (PLGA) microspheres. These carbohydrate-coated microspheres mimic the adhesive behavior of leukocytes on P-selectin in flow chambers, displaying slow rolling under flow. Since the selectinligand bond is weak, it cannot sufficiently maintain either firm leukocyte-endothelial interaction or cell transmigration. Firm arrest of leukocytes to the endothelium in vivo is mediated by intercellular and vascular adhesion molecules (ICAMs and VCAMs) binding to activated β2-integrin. Similarly, it is expected that selectin-ligand interaction alone would not support firm binding of targeted, drug delivery vehicle to the endothelium. To this end, we explored the possibility of two-receptor, selectin and ICAM-1, targeting by functionalizing microspheres with both sLeX and anti-ICAM-1. We show that at particular sLe~X/anti-ICAM-1 ratios, these two-receptor microspheres must roll via selectin-sLe~X interaction prior to firm binding, mimicking the in vivo leukocyte adhesion in inflammation.
机译:炎症期间血管内皮细胞的选择汀(E-和P-SELECTIN)的特异性特异性表达为慢性炎症疾病中针对血管内皮进行靶向抗炎药的机会。我们以前描述了靶向递送系统是生物素化 - 唾液酸的X(SLE〜X),用作配体的碳水化合物与选择素的配体,连接到抗生物素蛋白连接的多乳酸共聚糖酸(PLGA)的表面上。微球。这些碳水化合物涂覆的微球模仿白细胞在流量室中的白细胞上的粘合剂行为,在流动下显示缓慢轧制。由于选择性吲哚氏键弱,因此不能充分维持坚固的白细胞 - 内皮相互作用或细胞迁移。将白细胞的牢固逮捕对体内内皮细胞的内皮(ICAMS和VCAM)介导与活化β2-整联蛋白的结合。类似地,预期单独选择的选择蛋白 - 配体相互作用将不支持靶向药物递送型载体与内皮的结合。为此,我们探讨了双受体,选择素和ICAM-1的可能性,通过用Slex和抗ICAM-1官能化微球来靶向。我们表明,特别是SLE〜X /抗ICAM-1比率,这些双受体微球必须在坚固的结合之前通过选择素-LE〜X相互作用滚动,模拟炎症中的体内白细胞粘附。

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