In Vivo Neuroimaging of Exosomes Using Gold Nanoparticles
In Vivo Neuroimaging of Exosomes Using Gold Nanoparticles
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DOI：
10.1021/acsnano.7b04495
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发表时间：
2017-11-01
期刊：
影响因子：
17.1
通讯作者：
Popovtzer, Rachela
中科院分区：
文献类型：
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作者：
Betzer, Oshra;Perets, Nisim;Popovtzer, Rachela
外来体正在成为各种病理学的有效治疗工具。这些细胞外囊泡可以绕过生物屏障，包括血脑屏障，并可以作为强大的药物和基因治疗转运蛋白。然而，治疗开发的进展受到几个挑战的阻碍，包括外泌体运输和生物分布的数据不足以及难以在体内对深部脑结构进行成像。在此，我们建立了一种基于葡萄糖包被的金纳米颗粒（GNP）标记和计算机断层扫描成像的非侵入性体内神经成像和外泌体跟踪的方法。与通过亲本细胞的典型且效率较低的间接标记模式相反，直接实现了用GNP标记外泌体。在机制水平上，我们发现葡萄糖包被的GNP通过由葡萄糖转运蛋白GLUT-1介导并涉及内吞蛋白的主动的能量依赖性机制被摄取到MSC衍生的外泌体中。接下来，我们确定了大小和给药途径的最佳参数;我们证明了5 nm GNP能够改善外泌体标记，并且与静脉内相比，鼻内给药导致上级脑积累，从而增强体内神经成像。此外，使用局灶性脑缺血的小鼠模型，我们非侵入性地跟踪鼻内施用的GNP标记的外泌体，其显示出在24小时内在病变部位的累积增加，与同期对照脑的非特异性迁移和清除相比。因此，这种外泌体标记技术可以作为一种强有力的诊断工具，用于各种大脑。疾病，并可能增强基于外泌体的治疗神经元的恢复。
Exosomes are emerging as effective therapeutic tools for various pathologies. These extracellular vesicles can bypass biological barriers, including the blood brain barrier, and can serve as powerful drug and gene therapy transporters. However, the progress of therapy development is impeded by several challenges, including insufficient data on exosome trafficking and biodistribution and the difficulty to image deep brain structures in vivo. Herein, we established a method for noninvasive in vivo neuroimaging and tracking of exosomes, based on glucose-coated gold nanoparticle (GNP) labeling and computed tomography imaging. Labeling of exosomes with the GNPs was achieved directly, as opposed to the typical and less efficient indirect labeling mode through parent cells. On the mechanistic level, we found that the glucose-coated GNPs were uptaken into MSC-derived exosomes via an active, energy-dependent mechanism that is mediated by the glucose transporter GLUT-1 and involves endocytic proteins. Next, we determined optimal parameters of size and administration route; we demonstrated that 5 nm GNPs enabled improved exosome labeling and that intranasal, compared to intravenous, administration led to superior brain accumulation and thus enhanced in vivo neuroimaging. Furthermore, using a mouse model of focal brain ischemia, we noninvasively tracked intranasally administered GNP-labeled exosomes, which showed increased accumulation at the lesion site over 24 h, as compared to nonspecific migration and clearance from control brains over the same period. Thus, this exosome labeling technique can serve as a powerful diagnostic tool for various brain. disorders and could potentially enhance exosome-based treatments for neuronal recovery.