Center for Disease Biology and Integrative Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Institute of Engineering Innovation, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
Sci Rep. 2020 Oct 26;10(1):18220. doi: 10.1038/s41598-020-75253-9.
The blood-brain barrier (BBB) has hampered the efficiency of nanoparticle delivery into the brain via conventional strategies. The widening of BBB tight junctions via focused ultrasound (FUS) offers a promising approach for enhancing the delivery of nanoparticles into the brain. However, there is currently an insufficient understanding of how nanoparticles pass through the opened BBB gaps. Here we investigated the size-dependence of nanoparticle delivery into the brain assisted by FUS-induced BBB opening, using gold nanoparticles (AuNPs) of 3, 15, and 120 nm diameter. For 3- and 15-nm AuNPs, FUS exposure significantly increased permeation across an in vitro BBB model by up to 9.5 times, and the permeability was higher with smaller diameter. However, in vivo transcranial FUS exposure in mice demonstrated that smaller particles were not necessarily better for delivery into the brain. Medium-sized (15 nm) AuNPs showed the highest delivery efficiency (0.22% ID), compared with 3- and 120-nm particles. A computational model suggested that this optimum size was determined by the competition between their permeation through opened BBB gaps and their excretion from blood. Our results would greatly contribute to designing nanoparticles for their delivery into the brain for the treatment of central nervous system diseases.
血脑屏障（BBB）一直阻碍着传统策略通过纳米颗粒向大脑的有效传递。聚焦超声（FUS）可使 BBB 紧密连接增宽，为增强纳米颗粒向大脑的传递提供了一种很有前景的方法。然而，目前对于纳米颗粒如何通过打开的 BBB 间隙仍然缺乏足够的了解。在这里，我们研究了 FUS 诱导的 BBB 开放辅助下纳米颗粒进入大脑的尺寸依赖性，使用了 3、15 和 120nm 直径的金纳米颗粒（AuNPs）。对于 3nm 和 15nm 的 AuNP，FUS 暴露使体外 BBB 模型的通透性增加了高达 9.5 倍，且直径越小通透性越高。然而，在小鼠的经颅 FUS 暴露实验中，较小的颗粒不一定更有利于进入大脑。与 3nm 和 120nm 颗粒相比，中等大小（15nm）的 AuNP 显示出最高的传递效率（0.22%ID）。计算模型表明，这种最佳尺寸是由它们通过打开的 BBB 间隙的渗透能力和从血液中排泄的能力之间的竞争决定的。我们的研究结果将极大地有助于设计用于治疗中枢神经系统疾病的向大脑传递的纳米颗粒。
