Targeting nanoparticles to the brain by exploiting the blood-brain barrier impermeability to selectively label the brain endothelium
Targeting nanoparticles to the brain by exploiting the blood-brain barrier impermeability to selectively label the brain endothelium
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DOI：
10.1073/pnas.2002016117
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发表时间：
2020-08-11
影响因子：
11.1
通讯作者：
Kataoka, Kazunori
中科院分区：
文献类型：
--
作者：
Gonzalez-Carter, Daniel;Liu, Xueying;Kataoka, Kazunori
目前将载药纳米颗粒直接输送到大脑的策略依赖于功能化纳米颗粒与配体，配体结合与血脑屏障（BBB）相关的靶蛋白。然而，这种策略具有明显的脑特异性局限性，因为靶蛋白并不只在脑微血管中表达。因此，需要利用血脑屏障的替代特性来克服非特异性纳米颗粒靶向外周的新策略，从而提高药物疗效并减少有害的外周副作用。在这里，我们提出了一种简单但违反直觉的脑靶向策略，利用血脑屏障的高不渗透性来选择性地标记脑内皮。这是通过利用脑内皮细胞较低的内噬率（血脑屏障高不渗透性的一个关键特征）来促进与外周内皮细胞相比，脑内皮细胞表面的自由、非偶联蛋白结合配体的选择性保留来实现的。因此，能够有效结合所显示的配体（即标记内皮）的纳米颗粒被特异性地靶向于脑微血管，在周围器官中具有最小的“脱靶”积累。因此，该方法通过实施两步靶向方法彻底改变了脑靶向策略，该方法利用血脑屏障的生理学来产生纳米颗粒递送所需的脑特异性，为克服靶向限制和实现神经治疗的临床转化铺平了道路。此外，这项工作表明，大脑递送的蛋白质靶点可能不是基于组织表达的差异，而是基于大脑和外周细胞之间的不同内吞率。
Current strategies to direct therapy-loaded nanoparticles to the brain rely on functionalizing nanoparticles with ligands which bind target proteins associated with the blood-brain barrier (BBB). However, such strategies have significant brain-specificity limitations, as target proteins are not exclusively expressed at the brain microvasculature. Therefore, novel strategies which exploit alternative characteristics of the BBB are required to overcome nonspecific nanoparticle targeting to the periphery, thereby increasing drug efficacy and reducing detrimental peripheral side effects. Here, we present a simple, yet counterintuitive, brain-targeting strategy which exploits the higher impermeability of the BBB to selectively label the brain endothelium. This is achieved by harnessing the lower endocytic rate of brain endothelial cells (a key feature of the high BBB impermeability) to promote selective retention of free, unconjugated protein-binding ligands on the surface of brain endothelial cells compared to peripheral endothelial cells. Nanoparticles capable of efficiently binding to the displayed ligands (i.e., labeled endothelium) are consequently targeted specifically to the brain microvasculature with minimal "off-target" accumulation in peripheral organs. This approach therefore revolutionizes brain-targeting strategies by implementing a two-step targeting method which exploits the physiology of the BBB to generate the required brain specificity for nanoparticle delivery, paving the way to overcome targeting limitations and achieve clinical translation of neurological therapies. In addition, this work demonstrates that protein targets for brain delivery may be identified based not on differential tissue expression, but on differential endocytic rates between the brain and periphery.