Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
1] Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland, USA [2] Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland, USA.
Mol Ther Nucleic Acids. 2015 May 12;4:e242. doi: 10.1038/mtna.2015.15.
Alzheimer's disease (AD) is a progressive neurodegenerative disease currently lacking effective treatment. Efficient delivery of siRNA via nanoparticles may emerge as a viable therapeutic approach to treat AD and other central nervous system disorders. We report here the use of a linear polyethyleneimine (LPEI)-g-polyethylene glycol (PEG) copolymer-based micellar nanoparticle system to deliver siRNA targeting BACE1 and APP, two therapeutic targets of AD. Using LPEI-siRNA nanoparticles against either BACE1 or APP in cultured mouse neuroblastoma (N2a) cells, we observe selective knockdown, respectively, of BACE1 or APP. The encapsulation of siRNA by LPEI-g-PEG carriers, with different grafting degrees of PEG, leads to the formation of micellar nanoparticles with distinct morphologies, including worm-like, rod-like, or spherical nanoparticles. By infusing these shaped nanoparticles into mouse lateral ventricles, we show that rod-shaped nanoparticles achieved the most efficient knockdown of BACE1 in the brain. Furthermore, such knockdown is evident in spinal cords of these treated mice. Taken together, our findings indicate that the shape of siRNA-encapsulated nanoparticles is an important determinant for their delivery and gene knockdown efficiency in the central nervous system.
阿尔茨海默病(AD)是一种进行性神经退行性疾病,目前缺乏有效的治疗方法。通过纳米粒子有效递送 siRNA 可能成为治疗 AD 和其他中枢神经系统疾病的可行治疗方法。我们在这里报告了使用基于线性聚乙烯亚胺(LPEI)-g-聚乙二醇(PEG)共聚物的胶束纳米粒子系统递送针对 BACE1 和 APP 的 siRNA,BACE1 和 APP 是 AD 的两个治疗靶点。在培养的小鼠神经母细胞瘤(N2a)细胞中使用针对 BACE1 或 APP 的 LPEI-siRNA 纳米粒子,我们观察到分别对 BACE1 或 APP 的选择性敲低。不同 PEG 接枝度的 LPEI-g-PEG 载体对 siRNA 的包封导致形成具有不同形态的胶束纳米粒子,包括蠕虫状、棒状或球形纳米粒子。通过将这些成型的纳米粒子注入小鼠侧脑室,我们表明棒状纳米粒子在大脑中实现了对 BACE1 的最高效敲低。此外,在这些治疗小鼠的脊髓中也观察到了这种敲低。总之,我们的研究结果表明,封装 siRNA 的纳米粒子的形状是其在中枢神经系统中的递送和基因敲低效率的重要决定因素。