title: Intraventricular Delivery of siRNA Nanoparticles to the Central Nervous System.
abstract: 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.
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Rishab
authors.initials: R
authors.lastname: Shyam
authors.affiliation: 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.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ren
authors.affiliation: 1] Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA [2] Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Kerstin E
authors.initials: KE
authors.lastname: Braunstein
authors.affiliation: 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 [3] Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA [4] Whitaker Biomedical Engineering Institute, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Hai-Quan
authors.initials: HQ
authors.lastname: Mao
authors.affiliation: 1] Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA [2] Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Wong