Seven Elif S, Seven Yasin B, Zhou Yiqun, Poudel-Sharma Sijan, Diaz-Rucco Juan J, Kirbas Cilingir Emel, Mitchell Gordon S, Van Dyken J David, Leblanc Roger M
Department of Chemistry, University of Miami 1301 Memorial Dr. Coral Gables FL 33146 USA
Department of Physical Therapy, University of Florida 101 Newell Dr. Gainesville FL 32603 USA.
Nanoscale Adv. 2021 May 31;3(13):3942-3953. doi: 10.1039/d1na00145k. eCollection 2021 Jun 30.
The blood-brain barrier (BBB) is a major obstacle for drug delivery to the central nervous system (CNS) such that most therapeutics lack efficacy against brain tumors or neurological disorders due to their inability to cross the BBB. Therefore, developing new drug delivery platforms to facilitate drug transport to the CNS and understanding their mechanism of transport are crucial for the efficacy of therapeutics. Here, we report (i) carbon dots prepared from glucose and conjugated to fluorescein (GluCD-F) cross the BBB in zebrafish and rats without the need of an additional targeting ligand and (ii) uptake mechanism of GluCDs is glucose transporter-dependent in budding yeast. Glucose transporter-negative strain of yeast showed undetectable GluCD accumulation unlike the glucose transporter-positive yeast, suggesting glucose-transporter-dependent GluCD uptake. We tested GluCDs' ability to cross the BBB using both zebrafish and rat models. Following the injection to the heart, wild-type zebrafish showed GluCD-F accumulation in the central canal consistent with the transport of GluCD-F across the BBB. In rats, following intravenous administration, GluCD-F was observed in the CNS. GluCD-F was localized in the gray matter ( ventral horn, dorsal horn, and middle grey) of the cervical spinal cord consistent with neuronal accumulation. Therefore, neuron targeting GluCDs hold tremendous potential as a drug delivery platform in neurodegenerative disease, traumatic injury, and malignancies of the CNS.
血脑屏障（BBB）是药物输送至中枢神经系统（CNS）的主要障碍，以至于大多数治疗药物由于无法穿过血脑屏障而对脑肿瘤或神经系统疾病缺乏疗效。因此，开发新的药物递送平台以促进药物向中枢神经系统的转运并了解其转运机制对于治疗药物的疗效至关重要。在此，我们报告：（i）由葡萄糖制备并与荧光素偶联的碳点（GluCD-F）在斑马鱼和大鼠中可穿过血脑屏障，无需额外的靶向配体；（ii）在出芽酵母中，GluCDs的摄取机制依赖于葡萄糖转运蛋白。与葡萄糖转运蛋白阳性的酵母不同，葡萄糖转运蛋白阴性的酵母菌株未检测到GluCD的积累，这表明GluCD的摄取依赖于葡萄糖转运蛋白。我们使用斑马鱼和大鼠模型测试了GluCDs穿过血脑屏障的能力。向心脏注射后，野生型斑马鱼在中央管中显示出GluCD-F的积累，这与GluCD-F穿过血脑屏障的转运一致。在大鼠中，静脉给药后，在中枢神经系统中观察到了GluCD-F。GluCD-F定位于颈脊髓的灰质（腹角、背角和中间灰质），与神经元积累一致。因此，靶向神经元的GluCDs作为神经退行性疾病、创伤性损伤和中枢神经系统恶性肿瘤的药物递送平台具有巨大潜力。
