Macdonald Joanna, Henri Justin, Goodman Lynda, Xiang Dongxi, Duan Wei, Shigdar Sarah
School of Medicine and ‡Centre for Molecular and Medical Research, Deakin University , Geelong, Victoria 3128, Australia.
ACS Chem Neurosci. 2017 Apr 19;8(4):777-784. doi: 10.1021/acschemneuro.6b00369. Epub 2017 Jan 25.
The treatment of brain disorders is greatly hindered by the presence of the blood-brain barrier, which restricts the overwhelming majority of small molecules from entering the brain. A novel approach by which to overcome this barrier is to target receptor mediated transport mechanisms present on the endothelial cell membranes. Therefore, we fused an aptamer that binds to epithelial cell adhesion molecule-expressing cancer cells to an aptamer targeting the transferrin receptor. This generated a proof of concept bifunctional aptamer that can overcome the blood-brain barrier and potentially specifically target brain disorders. The initial fusion of the two sequences enhanced the binding affinity of both aptamers while maintaining specificity. Additionally, mutations were introduced into both binding loops to determine their effect on aptamer specificity. The ability of the aptamer to transcytose the blood-brain barrier was then confirmed in vivo following a 1 nmol injection. This study has shown that through the fusion of two aptamer sequences, a bifunctional aptamer can be generated that has the potential to be developed for the specific treatment of brain disorders.
血脑屏障的存在极大地阻碍了脑部疾病的治疗，因为它限制了绝大多数小分子进入大脑。一种克服这一屏障的新方法是靶向存在于内皮细胞膜上的受体介导转运机制。因此，我们将一种与表达上皮细胞粘附分子的癌细胞结合的适体与一种靶向转铁蛋白受体的适体融合。这产生了一种概念验证双功能适体，它可以克服血脑屏障，并有可能特异性地靶向脑部疾病。两个序列的初始融合增强了两种适体的结合亲和力，同时保持了特异性。此外，在两个结合环中引入突变以确定它们对适体特异性的影响。在注射1 nmol后，在体内证实了该适体穿越血脑屏障的能力。这项研究表明，通过融合两个适体序列，可以产生一种双功能适体，有潜力被开发用于脑部疾病的特异性治疗。
