Hypoxia and pH Responsive Nanoparticles for Targeted Drug Delivery to Ischemic Stroke

用于缺血性中风靶向药物输送的缺氧和 pH 响应纳米颗粒

基本信息

批准号：
10681846
负责人：
Dewan Syed Fahmeed Hyder
金额：
$ 25.13万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10681846
关键词：
Acidosis Aftercare Anti-Inflammatory Agents Biomedical Engineering Blood - brain barrier anatomy Blood Vessels Brain Brain Ischemia Brain region Carbon Dioxide Cell Death Cells Cerebral Ischemia Cerebrum Clinical Disease Dose Drug Delivery Systems Drug Targeting Edema Effectiveness Encapsulated Energy Supply Energy-Generating Resources Environment Event Experimental Models Formulation Gadolinium Glucose Goals Habitats Hemorrhage Histology Hypoxia Immunofluorescence Immunologic Immunologist Infarction Inflammation Inflammatory Inflammatory Response Injections Injury Ischemia Ischemic Stroke Leukocytes MRI Scans Macrophage Magnetic Resonance Imaging Mass Spectrum Analysis Measures Metabolism Metformin Methods Microglia Middle Cerebral Artery Occlusion Modeling Mus Nervous System Trauma Neurologist Outcome Oxygen Pathway interactions Pharmaceutical Preparations Pilot Projects Pioglitazone Production Reperfusion Therapy Saline Stroke Testing Therapeutic Intervention Thrombectomy Tissues United States Validation Work anaerobic glycolysis behavioral outcome biomaterial compatibility blood-brain barrier crossing blood-brain barrier penetration brain tissue cerebroprotection cognitive testing cohort cytokine design disability drug candidate drug efficacy drug testing efficacy testing excitotoxicity extracellular functional outcomes imaging scientist improved improved outcome in vivo inflammatory modulation ischemic lesion lipid nanoparticle mortality mouse model nanoparticle neurobehavioral neuroinflammation novel oxidative damage post stroke recruit stroke outcome targeted treatment thrombolysis translational potential translational therapeutics treatment effect

项目摘要

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.

项目摘要中风是美国残疾的主要原因。尽管溶栓和血栓切除术，中风后的结局仍然很差，需要有效的脑保护剂疗法。这项目将利用中风神经科医生/免疫学家的互补专业知识和生物工程师/成像科学家通过脂质共同开发和测试药物递送脑保护剂专门针对缺血大脑的纳米颗粒。血管闭塞后的缺血性中风会极大地改变组织代谢。随之而来的缺氧环境由于氧气供应减少以将代谢转移到厌氧性糖酵解中的能源供应，并且转弯会产生过多的酸性副产品，这些副产品被挤出到细胞外环境中。因此，缺血性病变的低氧和酸性微环境可以利用直接梗死特异性治疗。我们将使用横穿血脑屏障的低氧和pH敏感的脂质纳米颗粒以提供高脑外保护和抗炎剂的有效载荷专门针对缺血性大脑。我们的假设是缺氧和pH靶向纳米颗粒会增强药物输送到缺血性脑中，最大化脑保护和改善中风结果。我们使用这些脂质纳米颗粒的缺血性中风实验模型的初步工作表明纳米颗粒在几分钟内积聚在缺血性大脑中，持续至少两天。这些可以由于Gadolinium与脑保护剂的合并，由MRI纵向跟踪纳米颗粒中的药物。我们提出了两个目标，以研究药物的浓度和持续时间输送到缺血性大脑并测试对梗塞体积，炎症和功能结果的影响瞬时脑动脉阻塞后的小鼠。如果成功，该策略可以应用于其他以组织缺氧和酸中毒为特征的中风以及其他疾病的候选药物。鉴于用于合成脂质纳米颗粒的所有材料的生物相容性，我们期望该方法进入较大的物种，并最终进入临床测试。