In vitro characterization of leukocyte mimetic for targeting therapeutics to the endothelium using two receptors
In vitro characterization of leukocyte mimetic for targeting therapeutics to the endothelium using two receptors
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DOI：
10.1016/j.biomaterials.2005.05.005
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发表时间：
2005-12-01
期刊：
影响因子：
14
通讯作者：
Hammer, DA
中科院分区：
文献类型：
--
作者：
Eniola, AO;Hammer, DA
选择素（E -选择素和P -选择素）以及其他内皮表达的白细胞黏附分子（ELAMs）由于在血管疾病中具有特异性且受到高度调控的表达，是将治疗药物特异性递送至血管内皮的潜在靶点。最近有研究表明，涂覆有抗E -选择素或其他ELAMs抗体的可降解微球能够在体内靶向炎症部位。然而，仅靶向ELAMs无法区分正常状态和疾病状态，因为在健康组织的内皮上也会表达这些黏附分子的基础水平。此外，白细胞通常并行使用两种不同的黏附分子归巢到病变组织，并且我们最近量化了双受体展示对于白细胞模拟物靶向的优势（Eniola AO，Willcox PJ，Hammer DA。利用由两种不同受体 - 配体对构建的无细胞系统阐明滚动黏附和牢固黏附之间的相互作用。《生物物理学杂志》2003年；85：2720 - 31）。在此，我们描述了一种通过两种受体（选择素和细胞间细胞黏附分子 - 1（ICAM - 1））将治疗药物靶向炎症性疾病血管系统的白细胞模拟物，其中可生物降解的聚合物微球与选择素配体唾液酸化路易斯（x）（sLe(x)）以及抗ICAM - 1抗体（anti - ICAM - 1（aICAM - 1））共同功能化。这些双受体靶向颗粒在给定的sLe(x)/aICAM - 1比例下，只有当两种靶向配体都能与其各自的受体相互作用时，才会在流动状态下牢固地黏附在基质表面，模拟了炎症体内白细胞黏附的多步骤过程。因此，我们在一个能够实现治疗药物局部递送的平台上忠实地重现了白细胞黏附的特异性和程度。（c）2005爱思唯尔有限公司。保留所有权利。
Selectins (E- and P-selectin) and other endothelial expressed leukocyte adhesion molecules (ELAMs) are potential targets for site-specific delivery of therapeutics to the vascular endothelium due to their specific and highly regulated expression in vascular disease. It was recently shown that degradable microspheres coated with antibodies against E-selectin or other ELAMs can target inflammation in vivo. However, targeting ELAMs alone cannot differentiate between normal and diseased state, as a basal level of these LAMs are expressed on endothelium in healthy tissues. Furthermore, leukocytes usually employ two separate adhesion molecules in parallel to home to diseased tissues, and we recently quantified the advantages of a two-receptor display for the targeting of leukocyte mimetics (Eniola AO, Willcox PJ, Hammer DA. Interplay between rolling and firm adhesion elucidated with a cell-free system engineered with two distinct receptor-ligand pairs. Biophys J 2003;85:2720-31). Here, we describe a leukocyte mimetic for targeting therapeutics to the vasculature in inflammatory diseases via two receptors, selectin and intercellular cell adhesion molecule-1 (ICAM-1), where biodegradable, polymer microspheres were co-functionalized with the selectin ligand, sialyl Lewis(x) (sLe(x)), and an antibody against ICAM-1, anti-ICAM-1 (aICAM-1). These two-receptor targeted particles, at given ratios of sLe(x)/aICAM-1, firmly adhere to substrate surface in flow only when both targeting ligands can interact with their respective receptors, mimicking the multi-step in vivo leukocyte adhesion in inflammation. Thus, we have faithfully recreated the specificity and extent of leukocyte adhesion in a platform that can allow for local delivery of therapeutics. (c) 2005 Elsevier Ltd. All rights reserved.