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

项目摘要 在美国，中风是导致残疾的主要原因。尽管溶栓治疗很有效， 血栓切除，卒中后的预后仍然很差，需要有效的脑保护治疗。这 该项目将利用中风神经学家/免疫学家和 生物工程师/成像科学家联合开发和测试通过脂质传递脑保护剂的药物 专门针对脑缺血的纳米颗粒。 血管闭塞后的缺血性卒中显著改变组织代谢。低氧环境随之而来 由于氧气供应减少，代谢转向无氧糖酵解提供能量，这在 转而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， 缺血损伤的低氧和酸性微环境可能被用来指导脑梗塞的特异性治疗。 我们将使用低氧和pH敏感的脂类纳米颗粒，这种纳米颗粒可以穿过血脑屏障，提供高水平的 脑保护和抗炎药的有效负荷，特别是进入缺血的大脑。我们的假设 低氧和pH靶向纳米颗粒将增强药物进入缺血大脑的输送，最大限度地 脑部保护和改善中风预后。 在我们的缺血性中风实验模型中使用这些脂质纳米粒的初步工作表明 纳米颗粒在几分钟内在缺血的大脑中积累，并持续至少两天。这些可以是 由于Gd与脑保护剂共掺而被MRI纵向跟踪 纳米颗粒中的药物。我们提出了两个目标来研究药物的浓度和持续时间。 并测试其对脑梗塞体积、炎症和功能结局的影响。 小鼠大脑中动脉短暂性闭塞后。如果成功，该策略可以应用于其他 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。给定 所有用于合成脂质纳米粒的材料的生物兼容性，我们期望有很高的翻译潜力 这种方法进入更大的物种，并最终进入临床试验。

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.