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Principal Investigator: Dewan Syed Fahmeed Hyder
Organization: YALE UNIVERSITY
Fiscal Year: 2024
Award: $209,375
Funding agency: National Institute of Neurological Disorders and Stroke
Project Summary
Stroke is the leading cause of disability in the United States. Despite the effectiveness of thrombolysis and
thrombectomy, outcomes after stroke remain poor and effective cerebroprotectant therapies are needed. This
project will leverage the complementary expertise of a Stroke Neurologist/Immunologist and a
Bioengineer/Imaging scientist to jointly develop and test drug delivery of cerebroprotectants by lipid
nanoparticles that specifically target the ischemic brain.
Ischemic stroke after vascular occlusion dramatically alters tissue metabolism. A hypoxic environment ensues
due to reduced oxygen supply to shift metabolism towards anaerobic glycolysis for energy supply, and which in
turn produces excessive acidic byproducts which are extruded into the extracellular environment. Thus, the
hypoxic and acidic microenvironment of an ischemic lesion may be exploited to direct infarct-specific therapy.
We will use hypoxia- and pH-sensitive lipid nanoparticles that cross the blood-brain barrier to deliver high
payloads of cerebroprotective and anti-inflammatory agents specifically into the ischemic brain. Our hypothesis
is that hypoxia and pH targeted nanoparticles will enhance drug delivery into the ischemic brain, maximizing
cerebroprotection and improving stroke outcomes.
Preliminary work in our experimental model of ischemic stroke using these lipid nanoparticles show the
nanoparticle accumulate in the ischemic brain within minutes and persist for at least two days. These can be
tracked longitudinally by MRI due to the co-incorporation of gadolinium along with cerebroprotectant
medications in the nanoparticles. We propose two Aims to study the concentration and duration of drug
delivery to the ischemic brain and test the effects on infarct volume, inflammation, and functional outcomes in
mice after transient middle cerebral artery occlusion. If successful, the strategy can be applied to other
candidate drugs for stroke as well as other diseases characterized by tissue hypoxia and acidosis. Given the
biocompatibility of all materials used to synthesize lipid nanoparticles, we expect high translational potential of
this method into larger species and eventually into clinical tests.
Terms: <Acidosis><After Care><After-Treatment><Aftercare><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Apoplexy><BBB crossing><BBB penetration><Biomedical Engineering><Bleeding><Blood - brain barrier anatomy><Blood Vessels><Blood leukocyte><Blood-Brain Barrier><Body Tissues><Brain><Brain Ischemia><Brain Nervous System><Brain Vascular Accident><Brain region><CO2><Carbon Dioxide><Carbonic Anhydride><Cell Body><Cell Death><Cells><Cerebral Ischemia><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Cerebrum><Clinical><D-Glucose><Dextrose><Dimethylbiguanidine><Dimethylguanylguanidine><Disease><Disorder><Dose><Dropsy><Drug Delivery><Drug Delivery Systems><Drug Targeting><Drugs><Edema><Effectiveness><Encapsulated><Encephalon><Energy Supply><Energy-Generating Resources><Environment><Event><Experimental Models><Formulation><Gadolinium><Gd element><Glucose><Goals><Habitats><Hemato-Encephalic Barrier><Hemorrhage><Histology><Hortega cell><Hydrops><Hypoxia><Hypoxic><Immunofluorescence><Immunofluorescence Immunologic><Immunologist><Infarction><Inflammation><Inflammatory><Inflammatory Response><Injections><Injury><Intermediary Metabolism><Ischemia><Ischemic Encephalopathy><Ischemic Stroke><Leukocytes><Leukocytes Reticuloendothelial System><MR Imaging><MR Tomography><MRI><MRI Scans><MRIs><Macrophage><Magnetic Resonance Imaging><Magnetic Resonance Imaging Scan><Marrow leukocyte><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measures><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medication><Metabolic Processes><Metabolism><Metformin><Methods><Mice><Mice Mammals><Microglia><Middle Cerebral Artery Occlusion><Modeling><Murine><Mus><Mφ><N,N-dimethyl-imidodicarbonimidic diamide><NMR Imaging><NMR Tomography><Nervous System Injuries><Nervous System Trauma><Nervous System damage><Neurological Damage><Neurological Injury><Neurological trauma><Neurologist><Nuclear Magnetic Resonance Imaging><O element><O2 element><Outcome><Oxygen><Oxygen Deficiency><Pathway interactions><Pharmaceutical Preparations><Pilot Projects><Pioglitazone><Production><Reperfusion Therapy><Saline><Saline Solution><Stroke><Testing><Therapeutic Intervention><Thrombectomy><Tissues><United States><Validation><White Blood Cells><White Cell><Work><Zeugmatography><after stroke><anaerobic glycolysis><behavior outcome><behavioral outcome><bio-engineered><bio-engineers><biocompatibility><bioengineering><biological engineering><biomaterial compatibility><blood loss><blood-brain barrier crossing><blood-brain barrier penetration><bloodbrain barrier><bloodbrain barrier crossing><bloodbrain barrier penetration><brain attack><brain tissue><cerebral><cerebral vascular accident><cerebroprotection><cerebroprotective><cerebrovascular accident><cognitive assessment><cognitive testing><cohort><cytokine><design><designing><disability><drug candidate><drug detection><drug efficacy><drug testing><drug/agent><efficacy testing><energy source><excitotoxic><excitotoxicity><extracellular><functional outcomes><gitter cell><imaging scientist><improved><improved outcome><in vivo><infarct><inflammatory modulation><injuries><intervention therapy><ischemic lesion><lipid based nanoparticle><lipid nanoparticle><mesoglia><microglial cell><microgliocyte><mortality><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><necrocytosis><neural inflammation><neurobehavioral><neuroinflammation><neuroinflammatory><neurotrauma><novel><oxidative damage><oxidative injury><pathway><perivascular glial cell><pilot study><post stroke><post treatment><poststroke><recruit><reperfusion><stroke outcome><stroked><strokes><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><thrombolysis><translational opportunities><translational potential><translational therapeutics><translational therapy><treatment effect><validations><vascular><white blood cell><white blood corpuscle>