Differential intra-endothelial delivery of polymer nanocarriers targeted to distinct PECAM-1 epitopes
Differential intra-endothelial delivery of polymer nanocarriers targeted to distinct PECAM-1 epitopes
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DOI：
10.1016/j.jconrel.2008.06.007
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发表时间：
2008-09-24
影响因子：
10.8
通讯作者：
Muro, Silvia
中科院分区：
文献类型：
--
作者：
Garnacho, Carmen;Albelda, Steven M.;Muro, Silvia
将药物载体偶联到靶向内皮细胞（EC）的抗体可以改善血管和肺部疾病的治疗。选择将载体递送至细胞表面或细胞内的抗体可以进一步优化干预的特异性。我们研究了抗体导向的靶向纳米载体的血小板内皮细胞粘附分子（PECAM）-1，内皮糖蛋白含有6个Ig样胞外结构域。PECAM-1抗体与EC结合而不内化，但EC通过携带多个拷贝的抗PECAM（抗PECAM/NC）的内吞作用纳米载体内化。为了确定抗PECAM/NC的结合和细胞内转运是否依赖于所接合的表位，我们靶向五个PECAM-1表位：mAb 35、mAb 37和mAb 62（膜远端IG结构域1）、mAb G134（IG结构域2/3）和mAb 4G 6（膜近端IG结构域6）。抗体与EC结合，而不管表位与质膜的接近度如何，而130 nm直径的纳米载体仅有效靶向远端结构域（mAb 4G 6/NC不与EC结合）。EC内化mAb 35、mAb 62和mAbGi 34载体，无论其大小（直径0.13至5 μ M），但它们不内化mAb 37/NC。内化后，mAb 62/NC在2-3小时内运输至溶酶体，而mAb 35/NC在前溶酶体囊泡中具有延长的停留。因此，抗PECAM/NC的内皮结合、内吞作用和细胞内转运是表位特异性的。这种模式将指导设计的内皮药物输送系统提供特定的细胞定位。(C)2008 Elsevier B. V.保留所有权利。
Coupling drug carriers to antibodies for targeting endothelial cells (ECs) may improve treatment of vascular and pulmonary diseases. Selecting antibodies that deliver carriers to the cell surface or intracellularly may further optimize specificity of interventions. We studied antibody-directed targeting of nanocarriers to platelet-endothelial cell adhesion molecule (PECAM)-1, an endothelial glycoprotein containing 6 Ig-like extracellular domains. PECAM-1 antibodies bind to ECs without internalization, but ECs internalize by endocytosis nanocarriers carrying multiple copies of anti-PECAM (anti-PECAM/NCs). To determine whether binding and intracellular transport of anti-PECAM/NCs depend on the epitope engaged, we targeted five PECAM-1 epitopes: mAb35, mAb37 and mAb62 (membrane-distal Ig domain 1), mAbGi34 (Ig domains 2/3), and mAb4G6 (membrane-proximal Ig domain 6). The antibodies bound to ECs regardless of the epitope proximity to the plasmalemma, whereas 130 nm diameter nanocarriers only targeted effectively distal domains (mAb4G6/NCs did not bind to ECs). ECs internalized mAb35, mAb62, and mAbGi34 carriers regardless of their size (0.13 to 5 mu M diameter), yet they did not internalize mAb37/NCs. After internalization, mAb62/NCs trafficked to lysosomes within 2-3 h, whereas mAb35/NCs had prolonged residence in pre-lysosomal vesicles. Therefore, endothelial binding, endocytosis, and intracellular transport of anti-PECAM/NCs are epitope-specific. This paradigm will guide the design of endothelial drug delivery systems providing specific cellular localizations. (C) 2008 Elsevier B.V. All rights reserved.