Nanoparticle-mediated reduction of oxidative stress for the treatment of traumatic brain injury - PROJECT SUMMARY/ABSTRACT
Traumatic brain injury (TBI) is the leading cause of disability and death in people under 45 with
approximately 10 million new cases each year worldwide. The effects of TBI can be severe, including
neurocognitive, physical, and psychosocial impairment. There remains a significant unmet need to develop
strategies to avoid long-term damage from TBI. The primary phase of TBI describes immediate neuronal
damage from contusions or oxygen deprivation caused by global mass effect. Secondary injury occurs later via
such mechanisms as reperfusion injury, delayed cortical edema, blood-brain barrier (BBB) breakdown, and
local electrolyte imbalance. These disturbances result in increased reactive oxygen species (ROS), calcium
release, glutamate toxicity, lipid peroxidation (LP), and mitochondrial dysfunction that lead to a vicious positive
feedback loop of progressive oxidative stress-mediated neurodegeneration and neuroinflammation. Such
secondary injury may occur in brain adjacent to the site of initial supposed injury, yielding unexpected spread
of the zone of damage over months post-injury.
With the goal of treating secondary brain injury, ROS scavengers and LP product inhibitors have become
increasingly popular. However, there are still no effective treatment options demonstrating improved outcome
in a large, multi-center Phase III trial, which can be partially attributed to poor delivery to and retention in the
brain. Our overall goal is to reduce the long-term secondary injury phase of TBI using ROS and LP product
reactive nanoparticles (NPs) that can quickly accumulate and be retained in damaged tissue to reduce post-
traumatic oxidative stress. We have previously developed multifunctional, reactive NPs that aid in imaging
distribution within the injury and result in reduced neuroinflammation and neurobehavioral deficits in a mouse
model of TBI.
We hypothesize that NP-mediated reduction oxidative stress in TBI will reduce long-term damage and
improve recovery. This is based on the scientific premise of preclinical efficacy shown with ROS and LP
product inhibitors as well as NP accumulation and retention in a TBI. To address our hypothesis, we will refine
and optimize our modular, image-guided NPs to maximize uptake and retention within damaged brain in a
controlled cortical impact mouse model of TBI in Aim 1. In Aim 2, we will study the effects of NP-mediated
reduction in post-traumatic oxidative stress on the spread of secondary injury that will provide us a therapeutic
index for these NPs and, and then in Aim 3 test neurobehavioral outcome. This proposal capitalizes on
advances in nanotechnology that facilitate the development of novel approaches to treat and image TBI. If
successful, these NPs could be further developed for other pathologies that involve progressive
neuroinflammation and neurodegeneration.
