Nanoparticle Based siRNA Delivery to the Central Nervous System: A Potential Therapeutic Approach
Embargo until
Date
2015-03-26
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Johns Hopkins University
Abstract
Efficient delivery of siRNA via nanoparticles may emerge as a viable therapeutic approach to treat central nervous system disorders including Alzheimer’s Disease (AD), a progressive neurodegenerative disease currently lacking effective treatment. For efficient distribution and cellular uptake of therapeutic nanoparticles, the shape of these delivery vehicles is thought to be a critical determinant. While significant progress has been made to control the morphology of nanoparticles loaded with traditional small molecule drugs, strategies to control the shape of nanoparticles encapsulating siRNAs remain a challenge. Here, we show that a linear polyethyleneimine (LPEI)-g-polyethylene glycol (PEG) copolymer-based micellar nanoparticle system to deliver siRNA, with different grafting degrees of PEG, leads to the formation of micellar nanoparticles with distinct morphologies, including worm-like, rod-like or spherical nanoparticles. In cultured (N2a) cells, we observe robust and selective knockdown of two therapeutic targets of Alzheimer’s disease (namely, BACE1 and APP) using the LPEI polymer complexed with siRNA against either BACE1 or APP. Importantly, by infusing these various shaped nanoparticles into the lateral ventricles of living mice, we show that rod-shaped nanoparticles achieved the most robust knockdown of BACE1 in their brain. Furthermore, by utilizing the circulation of the cerebrospinal fluid we show that such knockdowns can be achieved in spinal cords of these mice as well. These findings collectively indicate that the shape of nanoparticles, encapsulating siRNA, is an important determinant for their ability to efficiently affect gene knockdown and deliver their payload in the central nervous system.
Description
Keywords
Nanoparticles, RNAi, siRNA, Alzheimer's Disease