Next-generation nanomedicine for acute ischemic stroke

治疗急性缺血性中风的下一代纳米药物

• 批准号: 10603229
• 负责人: Jacob Brenner
• 金额: $ 30.05万
• 依托单位: NANOMUSE, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10603229
• 关键词: Abraxane; Acute; Adrenal Cortex Hormones; American; Anaphylaxis; Animals; Anti-Inflammatory Agents; Antibodies; Arteries; Avidity; Binding; Binding Proteins; Blood; Blood - brain barrier anatomy; Blood Pressure; Blood capillaries; Blood coagulation; Blood flow; Brain; Brain Diseases; Brain Injuries; Brain region; Businesses; COVID-19 vaccine; Capital; Caring; Clinical; Clinical Research; Coagulation Process; Combined Modality Therapy; Complement; Complement Activation; Complement Inactivators; Dangerousness; Data; Dexamethasone; Disease; Drops; Drug Carriers; Drug Delivery Systems; Elderly; Endothelial Cells; Endothelium; Ensure; Enzymes; Epitopes; FDA approved; Fab Immunoglobulins; Fibrinogen; Funding; Genetic Complementation Test; Home; Human; Image; Immunoglobulin Fragments; Infarction; Inflammatory; Injury; Ischemic Stroke; Leukocytes; Liposomes; Macrophage; Measures; Mechanics; Membrane Proteins; Messenger RNA; Microbe; Middle Cerebral Artery Occlusion; Monoclonal Antibodies; Mus; Neuroprotective Agents; Patients; Pennsylvania; Perfusion; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Phase; Physicians; Plasma; Plasma Proteins; Preclinical Drug Development; Production; Proteins; Reaction; Recombinant Proteins; Reperfusion Injury; Reperfusion Therapy; Reporting; Risk; Safety; Secondary to; Serum; Standard Model; Stroke; System; Technology; Testing; Therapeutic; Thrombectomy; Thrombomodulin; Time; Treatment Efficacy; Universities; Vascular Cell Adhesion Molecule-1; anakinra; behavioral outcome; brain endothelial cell; cerebral capillary; comorbidity; complement system; cost; cytokine; design; drug candidate; drug distribution; drug efficacy; efficacy testing; experience; immune activation; improved; improved outcome; innovation; invention; lead candidate; lipid nanoparticle; manufacture; monocyte; mortality; mouse model; nanocarrier; nanomedicine; nanoparticle; nanoscale; neuroinflammation; new technology; next generation; particle; peripheral blood; post stroke; prevent; protein activation; restoration; scale up; screening; side effect; stroke model; stroke patient; stroke trials; technology platform; transcytosis; uptake

ABSTRACT / PROJECT SUMMARY Acute ischemic stroke is poised for a revolution. With the advent of mechanical thrombectomy in the last decade, the worst clots can be removed. While thrombectomy has improved outcomes, most treated patients still have severe deficits, in large part due to secondary injury caused by ischemia-reperfusion injury. To solve this problem, many neuroprotective drugs were trialed, but all failed, largely due to poor drug delivery to at-risk brain. Therefore, a new technology is needed to deliver neuroprotective drugs to re- and under-perfused brain. To meet this challenge, University of Pennsylvania spin-out NanoMuse will build on our two recent breakthroughs: First, we discovered that nano-scale drug carriers (nanocarriers) that bind to the endothelial marker VCAM can concentrate drugs in the brain >30x higher than if delivered without a nanocarrier, and >6x better than the best prior nanocarrier. In the gold-standard stroke model of transient middle cerebral artery occlusion (tMCAO) in mice, VCAM-nanocarriers loaded with the corticosteroid dexamethasone improved mortality and reduced infarct volume 32% (more than the 25% average of drugs that progressed to clinical studies). Second, we found that prior nanocarriers suffered from activation of the complement protein cascade, which limits nanocarrier uptake in the brain and produces an anaphylaxis-like reaction that drops the blood pressure (very dangerous in stroke). Therefore, we conjugated a human complement-inhibitor (Factor I) to the nanocarriers, and completely eliminated these problems. Now we will combine and extend these two innovations to develop our product, a nanocarrier that massively concentrates neuroprotective drugs in at-risk brain, initially in ischemic stroke patients after reperfusion. In Aim 1, we will optimize the nanocarriers (e.g., switching the VCAM-targeting moiety to an Fab antibody fragment) to minimize complement activation and phagocytosis of the particles, using mouse and human serum and leukocytes. In Aim 2, we will use the optimized nanocarriers to test 3 drugs for efficacy in the tMCAO mouse model: dexamethasone (already proven effective with our un-optimized nanocarrier), or mRNAs encoding two anti-inflammatory proteins (which we already showed were effective in other mouse models). We will measure infarct volume, behavioral outcomes, side effects, drug distribution, and mRNA-encoded protein production compared to untargeted or drug-free nanocarriers. The best mono-therapy and a combination therapy will be validated in tMCAO with advanced age. Our deliverable will be a nanocarrier to concentrates one or two anti-inflammatory drugs at the BBB in order to ameliorate infarct volume by > 25%. Our team is poised to do this, with clinicians who take care of stroke, nanotechnologists, business advisors with years of experience in neuro-critical care products, and a supportive university. Together, we will help usher in stroke’s next revolution.

摘要/项目摘要 急性缺血性中风即将迎来一场革命。随着机械血栓切除术的出现 过去十年，最严重的血栓可以被清除。虽然血栓切除术改善了结果，但大多数治疗 患者仍然存在严重的缺陷，很大程度上是由于缺血再灌注损伤引起的继发性损伤。 为了解决这个问题，尝试了许多神经保护药物，但都失败了，很大程度上是由于药物输送不良 到有风险的大脑。因此，需要一种新技术来向患者提供神经保护药物 大脑灌注不足。为了应对这一挑战，宾夕法尼亚大学的衍生产品 NanoMuse 将在我们的基础上发展 最近的两个突破：首先，我们发现纳米级药物载体（nanocarrier）可以与药物结合 内皮标记物 VCAM 可以将药物在大脑中的浓度比不使用药物时高出 30 倍以上 纳米载体，比现有最佳纳米载体好 6 倍以上。在瞬态的金标准中风模型中 小鼠大脑中动脉闭塞（tMCAO），VCAM-纳米载体负载皮质类固醇 地塞米松可降低死亡率并减少梗塞体积 32%（高于其他药物 25% 的平均水平） 已进入临床研究）。其次，我们发现先前的纳米载体受到激活的影响 补体蛋白级联，限制纳米载体在大脑中的摄取并产生类似过敏反应 降低血压的反应（中风非常危险）。因此，我们将人类 将补体抑制剂（因子I）添加到纳米载体上，完全消除了这些问题。现在我们将 结合并扩展这两项创新来开发我们的产品，一种大规模浓缩的纳米载体 针对高危脑部的神经保护药物，最初用于再灌注后的缺血性中风患者。在目标 1 中，我们将 优化纳米载体（例如，将 VCAM 靶向部分切换为 Fab 抗体片段）以最大限度地减少 使用小鼠和人血清以及白细胞进行补体激活和颗粒吞噬作用。在 目标 2，我们将使用优化的纳米载体在 tMCAO 小鼠模型中测试 3 种药物的疗效： 地塞米松（已被证明对我们未优化的纳米载体有效），或编码两种的 mRNA 抗炎蛋白（我们已经证明其在其他小鼠模型中有效）。我们将测量 梗塞体积、行为结果、副作用、药物分布和 mRNA 编码的蛋白质产生 与非靶向或无药物的纳米载体相比。最好的单一疗法和联合疗法是 在高龄 tMCAO 中得到验证。我们的交付成果将是一种纳米载体，可浓缩一种或两种 BBB 处使用抗炎药物，可将梗塞体积改善 > 25%。我们的团队已做好准备 与治疗中风的临床医生、纳米技术专家、具有多年经验的商业顾问一起， 神经重症监护产品和支持性大学。我们将共同帮助迎来下一次中风 革命。