Antioxidant-loaded nanoparticles for the treatment of excitotoxicity in neurological disease

Abstract

In the United States alone, neurological diseases affect tens of millions of people, costing $800 billion annually. In acute neurological injury, a process known as excitotoxicity manifests from energy failure or direct trauma, causing overexcitation of neurons that leads to neuronal toxicity. Following neuronal death, toxic metabolites and cellular debris accumulate in the brain, perpetuating excitotoxicity to neighboring neurons. Despite the heavy social and economic toll and extensive research into neurotherapeutic development, there are currently no approved therapeutics for targeting excitotoxicity after acute neurological injury. The difficulty in clinical translation is largely attributed to several barriers intrinsic to the brain, including traversing the blood-brain barrier (BBB) and diffusion through the brain parenchyma. Therefore, in addition to understanding the biological complexity of the brain, developing effective therapeutics is a drug delivery problem. To expedite the pre-clinical research process, we have developed a tailorable organotypic whole hemisphere (OWH) brain slice model, capable of mimicking in vivo processes including excitotoxity and neuroinflammation. Using OWH models, we can systematically study disease processes and screen therapeutics in a high-throughput fashion, bypassing delivery obstacles. To improve therapeutic enzyme delivery, we have developed brain-penetrating antioxidant enzyme-loaded polymeric nanoparticles that inhibit enzymatic degradation. Furthermore, via nanoparticle screening on the OWH model, we have elucidated the toxicity of a common polymeric nanoparticle formulation involving poly(ethylene glycol) (PEG) and sonication, and developed alternative biocompatible nanoparticle formulations. Finally, the OWH model has enabled detailed observation of disease-dependent nanoparticle-microglia interactions that can better inform drug delivery strategies. Throughout these studies, we have implemented a transdisciplinary approach that emphasizes thorough understanding of the neurobiology of disease and leverages chemical engineering fundamentals, to ultimately advance neurotherapeutic development.