Theranostic Oxygen Reactive Polymers for Treatment of Traumatic Brain Injury

Abstract

4124 wileyonlinelibrary.com IntroductionTraumatic brain injury (TBI) is a serious medical condition that may occur after the brain sustains a signifi cant impact via linear or rotational forces. TBI is the leading cause of disability and death in people under 45 with approximately ten million new cases each year worldwide. [ 1 ] The effects of TBI can be severe, including severe neurocognitive, physical, and psychosocial impairment. [ 2 ] Only incremental improvements in treatment have been made over the past century, and there remains a signifi cant 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. [ 3 ] Secondary injury [ 3,4 ] occurs later via such mechanisms as reperfusion injury, delayed cortical edema, blood-brain barrier (BBB) breakdown, and local electrolyte imbalance. [4][5][6] These disturbances themselves result in reactive oxygen species (ROS)-mediated neurodegeneration through calcium release, glutamate toxicity, lipid peroxidation, and mitochondrial dysfunction. [ 7 ] Such secondary injury may occur in brain adjacent to the site of initial supposed injury, yielding the potential for unexpected spread of the zone of damage over months postinjury.With the goal of treating secondary brain injury, ROS scavengers have become an increasingly popular potential treatment option. The compounds poly(ethylene glycol)-conjugated superoxide dismutase and tirilizad have been considered for use in free-radical scavenging, but both antioxidant formulations did not show positive results in improving patient outcome after TBI, [ 3 ] likely because of poor delivery into brain. Preclinical studies suggest progesterone has neuroprotective effects in brain injury models likely by modulating native antioxidant activity levels. [ 8 ] However, other central nervous system injuries treated with progesterone have not shown any improvement, and Phase III clinical trails have shown limited success. [ 9 ] Cyclosporine A is being tested for its neuroprotective properties following TBI in an ongoing phase II study (NeuroSTAT) because of its ability to stabilize mitochondrial function. [ 10 ] Cyclosporin A is thought to decrease excitotoxic and oxidative stress that occurs in secondary damage by stabilizing

Oxidation‐Responsive Materials: Biological Rationale, State of the Art, Multiple Responsiveness, and Open Issues

“…It is therefore of little surprise to realize that synthetic ROS scavengers, sometimes also similar in composition (e.g., sulfur(II)‐based systems) are also inherently endowed with anti‐inflammatory properties. The recent literature provides a certain number of cases where this feature has been exploited; for example, PPS‐PEG diblock copolymers used to alleviate the symptoms of sepsis, or for the cytoprotection of stem cell in injectable formulations, PPS microparticles for those of ischemia, poly(ester sulfide) nanoparticles and copolymers of 2‐(methylthio)ethyl methacrylate for those of traumatic brain injury, boronated cyclodextrins for those of peritonitis, and PEGylated bilirubin nanoparticles for colon inflammation . It is worth mentioning that ROS scavenging are not a prerogative of oxidation‐responsive polymers: a number of organic materials can remove ROS/radicals without significantly changing their properties, but produce anti‐inflammatory effects, for example, carbon particles and above all 2,2,6,6‐tetramethylpiperidine‐N‐oxyl (TEMPO)‐containing systems (see also a recent review on the latter materials).…”

Nanoparticle-Based Technology Approaches to the Management of Neurological Disorders

“…Xu et al developed oxygen reactive polymeric NPs to ameliorate secondary injuries associated with ROS [ 179 ]. They copolymerized polyethylene glycol methacrylate with monomer 2-(methylthio)ethyl methacrylate (MEM) and methacrylic acid N-hydroxysuccinimide ester (MNHS) to form the oxygen reactive polymer (ORP).…”

Cell and Tissue Instructive Materials for Central Nervous System Repair

“…Although BBB dysfunction following TBI leads to the uncontrolled infiltration of inflammatory cells and may compromise nutrient and oxygen exchanges, it may provide an opportunity for the therapeutic delivery of NPs due to increased endothelial permeability. [117][118][119] Nevertheless, trauma severity, the extent of BBB damage, and the level of glial cell activation may [111] still compromise NPs uptake. [120] A possible way to circumvent this is by controlling NP size, having been demonstrated in some studies that this feature influences both the passage of NPs across the barrier and the accumulation at the lesion site.…”

“…To neutralize this damaging event, a study from 2016 developed oxygen reactive polymeric (ORP) NPs based on PEG and a thioether (responsible for ROS scavenging). [118] PEGylated ORP NPs also contained gadolinium, to provide contrast in magnetic resonance imaging, and a thioether containing unit, responsible for ROS scavenging. [127] The intravenous delivery of these NPs in an animal model of TBI, effectively sequestered ROS while remaining biocompatible even at high concentrations.…”