Browsing by Author "Mendoza, Kimberly"

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    Carbon Nanomaterials and Their Derivatives for Traumatic Brain Injury and Other Biomedical Applications
    (2018-10-23) Mendoza, Kimberly; Tour, James M
    Carbon nanomaterials possess unique chemical and functional properties allowing for their applications across a variety of fields including medicine, energy, materials, mechanics and more. Herein, the synthesis of poly(ethylene glycol) hydrophilic carbon clusters (PEG-HCCs) and poly(ethylene glycol) graphene quantum dots (PEG-GQDs), as well as their biomedical applications as antioxidants is described. Although use of antioxidants has been aimed at reducing the presence of reactive oxygen and nitrogen species (ROS and RNS), success in clinical trials has been disappointing. Traumatic brain injury (TBI) is a leading cause of death and disability in the United States, especially when complicated by secondary trauma, such as hemorrhagic hypotension. Oxidative stress is a prominent feature of TBI that can result in loss of cerebral blood flow (CBF) to the brain causing an increased susceptibility to hypotension and intracranial hypertension. The development of PEG-HCCs through the oxidation of single-walled carbon nanotubes (SWCNTs) has shown its capability to quench SO and HO•. PEG-HCCs are soluble, non-toxic potent antioxidants that are stable in biological media. They can be administered through IV and have been tested in a rat model of TBI. Additionally, the application of PEG-HCCs in a mouse Alzheimer’s disease model was also explored. PEG-HCCs have demonstrated the ability to restore CBF to the brain after injury when administered through IV. Additionally, intranasal administration of PEG-HCCs has been shown to reduce amyloid precursor protein (APP) in the brain. PEG-GQDs, similar to PEG-HCCs, was developed as a derivative and cost-effective antioxidant carbon nanomaterial for the treatment of TBI. Using coal as a starting material (bituminous and anthracite) GQDs were characterized and modified with poly(ethylene glycol). Their intrinsic and chemical properties were evaluated also showing the ability to quench superoxide (SO) and hydroxyl radical (HO•). PEG-GQDs were tested in a rat model of TBI and demonstrated the ability to restore CBF to the brain after injury. PEG-GQDs are water-soluble, non-toxic antioxidants that can be administered intravenously. Overall, PEG-HCCs and PEG-GQDs were studied in vitro and in vivo animal models with novel results that bear further investigation. The need for the development of robust therapy to address oxidative stress is necessary to effectively treat and eliminate damage that otherwise results in devastating outcomes for patients on personal, social and societal levels.
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    Efficacy of Novel Carbon Nanoparticle Antioxidant Therapy in a Severe Model of Reversible Middle Cerebral Artery Stroke in Acutely Hyperglycemic Rats
    (Frontiers, 2018) Fabian, Roderic H.; Derry, Paul J.; Rea, Harriett Charmaine; Dalmeida, William V.; Nilewski, Lizanne G.; Sikkema, William K.A.; Mandava, Pitchaiah; Tsai, Ah-Lim; Mendoza, Kimberly; Berka, Vladimir; Tour, James M.; Kent, Thomas A.
    INTRODUCTION: While oxidative stress can be measured during transient cerebral ischemia, antioxidant therapies for ischemic stroke have been clinically unsuccessful. Many antioxidants are limited in their range and/or capacity for quenching radicals and can generate toxic intermediates overwhelming depleted endogenous protection. We developed a new antioxidant class, 40 nm × 2 nm carbon nanoparticles, hydrophilic carbon clusters, conjugated to poly(ethylene glycol) termed PEG-HCCs. These particles are high-capacity superoxide dismutase mimics, are effective against hydroxyl radical, and restore the balance between nitric oxide and superoxide in the vasculature. Here, we report the effects of PEG-HCCs administered during reperfusion after transient middle cerebral artery occlusion (tMCAO) by suture in the rat under hyperglycemic conditions. Hyperglycemia occurs in one-third of stroke patients and worsens clinical outcome. In animal models, this worsening occurs largely by accelerating elaboration of reactive oxygen species (ROS) during reperfusion. METHODS: PEG-HCCs were studied for their protective ability against hydrogen peroxide in b.End3 brain endothelial cell line and E17 primary cortical neuron cultures. In vivo, hyperglycemia was induced by streptozotocin injection 2 days before tMCAO. 58 Male Sprague-Dawley rats were analyzed. They were injected IV with PBS or PEG-HCCs (4 mg/kg 2×) at the time of recanalization after either 90- or 120-min occlusion. Rats were survived for up to 3 days, and infarct volume characteristics and neurological functional outcome (modified Bederson Score) were assessed. RESULTS: PEG-HCCs were protective against hydrogen peroxide in both culture models. In vivo improvement was found after PEG-HCCs with 90-min ischemia with reduction in infarct size (42%), hemisphere swelling (46%), hemorrhage score (53%), and improvement in Bederson score (70%) (p = 0.068-0.001). Early high mortality in the 2-h in the PBS control group precluded detailed analysis, but a trend was found in improvement in all factors, e.g., reduction in infarct volume (48%; p = 0.034) and a 56% improvement in Bederson score (p = 0.055) with PEG-HCCs. CONCLUSION: This nano-antioxidant showed some improvement in several outcome measures in a severe model of tMCAO when administered at a clinically relevant time point. Long-term studies and additional models are required to assess potential for clinical use, especially for patients hyperglycemic at the time of their stroke, as these patients have the worst outcomes.
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    Oxidized Activated Charcoal Nanozymes: Synthesis, and Optimization for In Vitro and In Vivo Bioactivity for Traumatic Brain Injury
    (Wiley, 2024) McHugh, Emily A.; Liopo, Anton V.; Mendoza, Kimberly; Robertson, Claudia S.; Wu, Gang; Wang, Zhe; Chen, Weiyin; Beckham, Jacob L.; Derry, Paul J.; Kent, Thomas A.; Tour, James M.; Smalley-Curl Institute;NanoCarbon Center;Welch Institute for Advanced Materials
    Carbon-based superoxide dismutase (SOD) mimetic nanozymes have recently been employed as promising antioxidant nanotherapeutics due to their distinct properties. The structural features responsible for the efficacy of these nanomaterials as antioxidants are, however, poorly understood. Here, the process–structure–property–performance properties of coconut-derived oxidized activated charcoal (cOAC) nano-SOD mimetics are studied by analyzing how modifications to the nanomaterial's synthesis impact the size, as well as the elemental and electrochemical properties of the particles. These properties are then correlated to the in vitro antioxidant bioactivity of poly(ethylene glycol)-functionalized cOACs (PEG-cOAC). Chemical oxidative treatment methods that afford smaller, more homogeneous cOAC nanoparticles with higher levels of quinone functionalization show enhanced protection against oxidative damage in bEnd.3 murine endothelioma cells. In an in vivo rat model of mild traumatic brain injury (mTBI) and oxidative vascular injury, PEG-cOACs restore cerebral perfusion rapidly to the same extent as the former nanotube-derived PEG-hydrophilic carbon clusters (PEG-HCCs) with a single intravenous injection. These findings provide a deeper understanding of how carbon nanozyme syntheses can be tailored for improved antioxidant bioactivity, and set the stage for translation of medical applications.