Department of Neuroscience, Faculty of Health Sciences, University of Copenhagen, Copenhagen N, Denmark.
Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark.
Nat Commun. 2021 Jul 5;12(1):4121. doi: 10.1038/s41467-021-24323-1.
Effective treatments of neurodegenerative diseases require drugs to be actively transported across the blood-brain barrier (BBB). However, nanoparticle drug carriers explored for this purpose show negligible brain uptake, and the lack of basic understanding of nanoparticle-BBB interactions underlies many translational failures. Here, using two-photon microscopy in mice, we characterize the receptor-mediated transcytosis of nanoparticles at all steps of delivery to the brain in vivo. We show that transferrin receptor-targeted liposome nanoparticles are sequestered by the endothelium at capillaries and venules, but not at arterioles. The nanoparticles move unobstructed within endothelium, but transcytosis-mediated brain entry occurs mainly at post-capillary venules, and is negligible in capillaries. The vascular location of nanoparticle brain entry corresponds to the presence of perivascular space, which facilitates nanoparticle movement after transcytosis. Thus, post-capillary venules are the point-of-least resistance at the BBB, and compared to capillaries, provide a more feasible route for nanoparticle drug carriers into the brain.
神经退行性疾病的有效治疗需要药物主动跨血脑屏障（BBB）转运。然而，为此目的探索的纳米药物载体显示出可忽略不计的脑摄取，而对纳米颗粒与 BBB 相互作用的基本理解缺乏是许多转化失败的基础。在这里，我们使用小鼠的双光子显微镜，在体内描述了递送到大脑的各个步骤中受体介导的纳米颗粒转胞吞作用。我们表明，转铁蛋白受体靶向脂质体纳米颗粒被毛细血管和小静脉的内皮隔离，但不在小动脉中。纳米颗粒在内皮内无障碍移动，但转胞吞介导的脑内进入主要发生在小静脉后，在毛细血管中则微不足道。纳米颗粒进入大脑的血管位置与周细胞外空间的存在相对应，这有助于转胞吞后纳米颗粒的移动。因此，小静脉后是 BBB 上的最小阻力点，与毛细血管相比，为纳米药物载体进入大脑提供了更可行的途径。
