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

• 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
• 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

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.

项目概要 中风是美国致残的主要原因。尽管溶栓治疗有效 血栓切除术、中风后的结果仍然很差，需要有效的脑保护疗法。这 项目将利用中风神经学家/免疫学家和中风神经学家/免疫学家的互补专业知识 生物工程师/成像科学家联合开发和测试脂质脑保护剂的药物输送 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显着改变组织代谢。缺氧环境随之而来 由于氧气供应减少，新陈代谢转向无氧糖酵解以提供能量，并且 反过来会产生过量的酸性副产物，这些副产物被挤出到细胞外环境中。因此， 缺血性病变的缺氧和酸性微环境可用于指导梗塞特异性治疗。 我们将使用对缺氧和 pH 敏感的脂质纳米颗粒穿过血脑屏障，以提供高浓度的 脑保护剂和抗炎剂的有效负载专门进入缺血的大脑。我们的假设 缺氧和 pH 值靶向纳米粒子将增强药物输送到缺血性大脑中，从而最大限度地 脑保护和改善中风结果。 我们使用这些脂质纳米粒子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就会在缺血的大脑中积聚，并持续至少两天。这些可以是 由于钆与脑保护剂的共同掺入，通过 MRI 进行纵向追踪 纳米颗粒中的药物。我们提出两个目标来研究药物的浓度和持续时间 递送至缺血大脑并测试对梗死体积、炎症和功能结果的影响 短暂大脑中动脉闭塞后的小鼠。如果成功，该策略可以应用于其他领域 治疗中风以及其他以组织缺氧和酸中毒为特征的疾病的候选药物。鉴于 用于合成脂质纳米粒子的所有材料的生物相容性，我们预计具有较高的转化潜力 这种方法进入更大的物种并最终进入临床测试。