Combination-targeting to multiple endothelial cell adhesion molecules modulates binding, endocytosis, and in vivo biodistribution of drug nanocarriers and their therapeutic cargoes.
Combination-targeting to multiple endothelial cell adhesion molecules modulates binding, endocytosis, and in vivo biodistribution of drug nanocarriers and their therapeutic cargoes.
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DOI：
10.1016/j.jconrel.2014.06.008
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发表时间：
2014-08-28
期刊：
影响因子：
--
通讯作者：
Muro S
中科院分区：
文献类型：
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作者：
Papademetriou I;Tsinas Z;Hsu J;Muro S
设计药物纳米载体以帮助治疗药物的递送是一个不断扩大的领域，可以改善医学治疗。纳米载体通常具有识别参与亚细胞运输的细胞表面分子的功能，以提高治疗药物的靶向性和内吞作用。使用几个亲和元素的组合靶向进一步调节了这一结果。研究最多的例子是通过多细胞粘附分子（CAMs）靶向内皮细胞，它模仿白细胞粘附和穿过血管内皮的策略。然而，这一策略对细胞内运输和体内生物分布的影响仍不明确。我们使用功能化的纳米载体对细胞间、血小板内皮和/或血管cam （ICAM-1、PECAM-1、VCAM-1）进行双重或三重靶向研究。这些分子在表达水平、位置、病理刺激和/或内吞途径上存在差异。在内皮细胞中，PECAM-1/ vcam -1靶向纳米载体的结合介于单靶向载体之间，并在疾病样条件下增强。ICAM-1/PECAM-1靶向纳米载体在对照中优于PECAM-1/VCAM-1，但对类疾病条件的选择性较低。三重靶向导致与ICAM-1/PECAM-1联合类似的结合，并且在疾病样条件下显示出最高的选择性。所有的组合都被细胞有效地内化，当靶向不同的内吞途径的受体时，表现稍好。在体内，ICAM-1/PECAM-1靶向纳米载体在对照和疾病样条件下优于PECAM-1/VCAM-1，而三靶向纳米载体在某些器官中略微增强了这一结果。因此，通过三重靶向纳米载体，特别是在疾病样条件下，模型治疗货物（酸性鞘磷脂酶，缺乏尼曼-匹克病a - b）被增强到所有受影响的器官。因此，多cam靶向可能有助于优化一些治疗性纳米载体，其中利用亲和部分的组合和多样性可以调节靶向性能。
Designing of drug nanocarriers to aid delivery of therapeutics is an expanding field that can improve medical treatments. Nanocarriers are often functionalized with elements that recognize cell-surface molecules involved in subcellular transport to improve targeting and endocytosis of therapeutics. Combination-targeting using several affinity elements further modulates this outcome. The most studied example is endothelial targeting via multiple cell adhesion molecules (CAMs), which mimics the strategy of leukocytes to adhere and traverse the vascular endothelium. Yet, the implications of this strategy on intracellular transport and in vivo biodistribution remain uncharacterized. We examined this using nanocarriers functionalized for dual- or triple- targeting to intercellular, platelet-endothelial, and/or vascular CAMs (ICAM-1, PECAM-1, VCAM-1). These molecules differ in expression level, location, pathological stimulation, and/or endocytic pathway. In endothelial cells, binding of PECAM-1/VCAM-1-targeted nanocarriers was intermediate to single-targeted counterparts and enhanced in disease-like conditions. ICAM-1/PECAM-1-targeted nanocarriers surpassed PECAM-1/VCAM-1 in control, but showed lower selectivity toward disease-like conditions. Triple-targeting resulted in binding similar to ICAM-1/PECAM-1 combination and displayed the highest selectivity in disease-like conditions. All combinations were effectively internalized by cells, with slightly better performance when targeting receptors of different endocytic pathways. In vivo, ICAM-1/PECAM-1-targeted nanocarriers outperformed PECAM-1/VCAM-1 in control and disease-like conditions, and triple-targeted counterparts slightly enhanced this outcome in some organs. As a result, delivery of a model therapeutic cargo (acid sphingomyelinase, deficient in Niemann-Pick disease A-B) was enhanced to all affected organs by triple-targeted nanocarriers, particularly in disease-like conditions. Therefore, multi-CAM targeting may aid optimization of some therapeutic nanocarriers, where the combination and multiplicity of the affinity moieties utilized allow modulation of targeting performance.