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.

项目摘要 中风是美国残疾的主要原因。尽管溶栓治疗有效， 血栓切除术，中风后的结果仍然很差，需要有效的脑保护剂治疗。这 该项目将利用中风神经学家/免疫学家和 生物工程师/成像科学家共同开发和测试脂质介导的药物输送 专门针对缺血性大脑的纳米颗粒。 血管闭塞后的缺血性卒中显著改变了组织代谢。缺氧环境使 由于氧气供应减少，使新陈代谢转向无氧糖酵解以提供能量， 进而产生过量的酸性副产物，其被挤出到细胞外环境中。因此 缺血性损伤缺氧和酸性微环境可用于指导梗死特异性治疗。 我们将使用缺氧和pH敏感的脂质纳米颗粒，穿过血脑屏障， 有效载荷的脑保护和抗炎剂，特别是进入缺血性脑。我们的假设 缺氧和pH靶向纳米颗粒将增强药物递送到缺血性脑中， 脑保护和改善中风结果。 在我们使用这些脂质纳米颗粒的缺血性中风实验模型中的初步工作显示， 纳米颗粒在几分钟内在缺血性脑中积累并持续至少两天。这些可以 由于钆沿着与抗肿瘤保护剂的共结合，通过MRI纵向追踪 纳米颗粒中的药物。我们提出了两个研究药物浓度和持续时间的目的 递送到缺血性脑，并测试对梗塞体积、炎症和功能结果的影响， 短暂性大脑中动脉闭塞后的小鼠。如果成功的话，该策略可以应用于其他 用于中风以及以组织缺氧和酸中毒为特征的其它疾病的候选药物。鉴于 由于用于合成脂质纳米颗粒的所有材料都具有生物相容性，我们预期 将这种方法应用于更大的物种，并最终用于临床试验。