In Vivo Use of a Multi-DNA Aptamer-Based Payload/Targeting System to Study Dopamine Dysregulation in the Central Nervous System
ACS Chemical Neuroscience
The delivery of therapeutics across the blood-brain barrier remains a considerable challenge in investigating central nervous system related processes. In this work, a liposome vehicle was surface-modified with an aptamer that binds to the transferrin receptor and was loaded with two different dopamine-binding aptamer payloads. This system was effectively used to promote the delivery of the aptamer cargo from the peripheral injection site into the brain. The effect of these delivered aptamers on behavior was investigated in vivo in a locomotor task. The first dopamine binding aptamer assessed was a DNA aptamer, the binding of which had been previously validated through the aptamer-based biosensor development reported by several independent research groups. The second aptamer investigated was the result of a novel in vitro selection experiment described herein. Our data suggest that systemic administration of the modified liposomes led to delivery of the dopamine aptamers into the brain. Fluorescence microscopy revealed differential distribution of fluorescence based on the presence or absence of the transferrin receptor aptamer on the surface of fluorescently modified liposomes. In a behavioral experiment using cocaine administration to induce elevated concentrations of neural dopamine, systemic pretreatment with the dopamine aptamer-loaded liposomes reduced cocaine-induced hyperlocomotion. Multiple controls including a transferrin-negative liposome control and transferrin-positive liposomes loaded with either a nonbinding, base-substituted dopamine aptamer or a random oligonucleotide were investigated. None of these controls altered cocaine-induced hyperlocomotion. Chronic systemic administration of the modified liposomes produced no deleterious neurobehavioral or neural degenerative effects. Importantly, this work is one example of an application for this versatile multiaptamer payload/targeting system. Its general application is limited only by the availability of aptamers for specific neural targets.
|blood-brain barrier, DNA aptamer, dopamine, liposome, SELEX, targeted delivery|
|ACS Chemical Neuroscience|
|Organisation||Ottawa-Carleton Chemistry Institute|
McConnell, E.M. (Erin M.), Ventura, K. (Katelyn), Dwyer, Z. (Zach), Hunt, V. (Vernon), Koudrina, A. (Anna), Holahan, M.R, & DeRosa, M.C. (2018). In Vivo Use of a Multi-DNA Aptamer-Based Payload/Targeting System to Study Dopamine Dysregulation in the Central Nervous System. ACS Chemical Neuroscience. doi:10.1021/acschemneuro.8b00292