Department of Pharmacology and Chemical Biology, Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
J Control Release. 2020 Jun 10;322:31-41. doi: 10.1016/j.jconrel.2020.03.009. Epub 2020 Mar 9.
The elaboration of nanotechnology offers valuable therapeutic options to overcome the blood-brain barrier and enable the treatment of brain diseases. However, to date, limit work has been done to reveal the fate of nanoparticles within the brain, which largely hinders their safe and effective applications. Here we demonstrated that the commonly-used organic nanoparticles reconstituted high density lipoprotein and poly(ethylene glycol)-b-poly(lactic acid) nanoparticles were cleared relatively fast from the brain (half-life <5 h). Notably, through various transgenic mice and pharmacological inhibition approaches, we revealed that the paravascular glymphatic pathway plays a key role (about 80%) in the brain clearance of the nanoparticles, and disclosed that microglia-mediated transportation is essential for facilitating nanoparticles elimination through the paravascular route. In addition, we witnessed a significant decline in the brain clearance of both of the nanoparticles in Alzheimer's model mice where the glymphatic system is impaired. These findings provide insightful data on the fate of nanoparticles in the brain, which would shed new light into the rational design and safe application of nanoparticles for brain drug delivery.
纳米技术的发展为克服血脑屏障并实现脑部疾病的治疗提供了有价值的治疗选择。然而，迄今为止，对于纳米颗粒在大脑内的命运，相关工作仍十分有限，这在很大程度上阻碍了它们的安全有效应用。在这里，我们证明了常用的有机纳米颗粒和聚乙二醇-b-聚乳酸纳米颗粒被快速清除出大脑（半衰期<5 小时）。值得注意的是，通过各种转基因小鼠和药理学抑制方法，我们揭示了脑内的血-脑屏障旁细胞间通路在纳米颗粒的脑内清除中起着关键作用（约 80%），并发现小胶质细胞介导的转运对于通过血-脑屏障旁途径促进纳米颗粒的消除是必不可少的。此外，我们观察到在血脑屏障旁细胞间通路受损的阿尔茨海默病模型小鼠中，这两种纳米颗粒的脑内清除率均显著下降。这些发现为纳米颗粒在大脑中的命运提供了有见地的数据，这将为合理设计和安全应用纳米颗粒进行脑部药物输送提供新的思路。
