Kafa Houmam, Wang Julie Tzu-Wen, Rubio Noelia, Venner Kerrie, Anderson Glenn, Pach Elzbieta, Ballesteros Belén, Preston Jane E, Abbott N Joan, Al-Jamal Khuloud T
Institute of Pharmaceutical Science, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
Biomaterials. 2015;53:437-52. doi: 10.1016/j.biomaterials.2015.02.083. Epub 2015 Mar 19.
Carbon nanotubes (CNTs) are a novel nanocarriers with interesting physical and chemical properties. Here we investigate the ability of amino-functionalized multi-walled carbon nanotubes (MWNTs-NH3(+)) to cross the Blood-Brain Barrier (BBB) in vitro using a co-culture BBB model comprising primary porcine brain endothelial cells (PBEC) and primary rat astrocytes, and in vivo following a systemic administration of radiolabelled f-MWNTs. Transmission Electron microscopy (TEM) confirmed that MWNTs-NH3(+) crossed the PBEC monolayer via energy-dependent transcytosis. MWNTs-NH3(+) were observed within endocytic vesicles and multi-vesicular bodies after 4 and 24 h. A complete crossing of the in vitro BBB model was observed after 48 h, which was further confirmed by the presence of MWNTs-NH3(+) within the astrocytes. MWNT-NH3(+) that crossed the PBEC layer was quantitatively assessed using radioactive tracers. A maximum transport of 13.0 ± 1.1% after 72 h was achieved using the co-culture model. f-MWNT exhibited significant brain uptake (1.1 ± 0.3% injected dose/g) at 5 min after intravenous injection in mice, after whole body perfusion with heparinized saline. Capillary depletion confirmed presence of f-MWNT in both brain capillaries and parenchyma fractions. These results could pave the way for use of CNTs as nanocarriers for delivery of drugs and biologics to the brain, after systemic administration.
碳纳米管（CNTs）是一种具有有趣物理和化学性质的新型纳米载体。在此，我们使用由原代猪脑内皮细胞（PBEC）和原代大鼠星形胶质细胞组成的共培养血脑屏障（BBB）模型，在体外研究氨基功能化多壁碳纳米管（MWNTs-NH3(+)）穿越血脑屏障的能力，并在全身给予放射性标记的f-MWNTs后，在体内进行研究。透射电子显微镜（TEM）证实MWNTs-NH3(+)通过能量依赖性转胞吞作用穿过PBEC单层。在4小时和24小时后，在内吞小泡和多囊泡体中观察到MWNTs-NH3(+)。48小时后观察到体外BBB模型完全被穿越，星形胶质细胞内存在MWNTs-NH3(+)进一步证实了这一点。使用放射性示踪剂对穿过PBEC层的MWNT-NH3(+)进行定量评估。使用共培养模型在72小时后实现了13.0±1.1%的最大转运。在小鼠静脉注射后5分钟，用肝素化盐水进行全身灌注后，f-MWNT在脑中显示出显著摄取（1.1±0.3%注射剂量/克）。毛细血管清除证实f-MWNT存在于脑毛细血管和实质部分。这些结果可能为碳纳米管作为纳米载体在全身给药后将药物和生物制剂递送至脑的应用铺平道路。
