Nanoscale drug carriers for the treatment of Acute Respiratory Distress Syndrome (ARDS).

用于治疗急性呼吸窘迫综合征（ARDS）的纳米药物载体。

• 批准号: 10461706
• 负责人: Marco Zamora
• 金额: $ 4.6万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461706
• 关键词: ANGPT1 gene; Acute; Acute Disease; Address; Admission activity; Adult Respiratory Distress Syndrome; Alveolar; Angiopoietin-2; Angiopoietins; Animal Model; Antibodies; Awareness; Basic Science; Binding; Biological Assay; Blood Vessels; Blood capillaries; Bronchoalveolar Lavage Fluid; Cell Surface Proteins; Cells; Clinical Treatment; Clinical Trials; Complex; Critical Illness; Development; Disease; Dose; Drug Carriers; Drug Delivery Systems; Drug Side Effects; Drug Targeting; Endothelial Cells; Endothelium; Enzyme-Linked Immunosorbent Assay; Epitopes; Failure; Flow Cytometry; Functional disorder; Future; Goals; Histology; Hour; Human; Hyperoxia; Immunoglobulin G; Inflammatory; Inhalation; Injury; Innate Immune System; Intensive Care Units; Knowledge; Length; Leukocytes; Liquid substance; Luciferases; Lung; Lung Inflammation; Measurement; Measures; Mediating; Membrane Proteins; Messenger RNA; Methods; Modeling; Monoclonal Antibodies; Mus; Nebulizer; Nucleic Acids; Organ; Organ failure; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Play; Problem Solving; Proteins; Publishing; Pulmonary Edema; Recombinants; Research; Role; Route; Serum; Signal Pathway; Signaling Molecule; Site; Solid; Surface; System; Technology; Testing; Therapeutic; Therapeutic Effect; Time; Transplantation; United States; Up-Regulation; Western Blotting; White Blood Cell Count procedure; cell type; cytokine; design; experimental study; high risk; in vivo; intercellular cell adhesion molecule; lipid nanoparticle; lung injury; mortality; mouse model; nanocarrier; nanoparticle; nanoparticle delivery; nanoscale; neutrophil; novel; particle; protein expression; side effect; small molecule; theories; therapeutic development; therapeutic protein; uptake

Proposal Summary/Abstract Acute respiratory distress syndrome (ARDS) is an acute inflammation of the lungs. It represents 10% of all intensive care unit (ICU) admissions in the United States. Despite decades of research and numerous large clinical trials, there are few treatments for ARDS. This lack of disease-specific therapies is primarily due to three main factors: First, ARDS patients are “fragile” due to frequent multi-system organ failure, and thus cannot tolerate drug side effects. Second, ARDS, is very heterogeneous in its underlying pathophysiology, and thus targeting a single pathway may not be sufficient. Third, the disease has a rapidly developing time course, meaning that it can activate pathways that actively change patient outcomes in the order of hours.To solve the above problems, the goal of this proposal is to develop and establish mRNA-loaded nanoparticles (mRNA- LNPs) that can be targeted to specific cell types and organs, whereupon they can express multiple therapeutic proteins as a platform technology for ARDS. Our lab has previously utilized three targeting moieties we use to deliver nanocarriers: monoclonal antibodies binding to PECAM (an endothelial cell surface protein), ICAM (another surface protein abundant on endothelial cells), and non-immune IgG (hereafter called “IgG”). We have further shown that nanocarriers covalently coated with anti-PECAM and -ICAM antibodies are directed to the lungs at levels 300-fold higher than “free drugs” (no carrier) addressing (problem #1), Further, mRNA-loaded nanoparticles can be loaded with mRNA that encodes for various proteins, targeting various pathways (problem #2). Additionally, mRNA-LNPs can express a variety of proteins for the length of time (~48 hours) associated with the high-risk period of acute critical illnesses (problem #3) above. It seemed that we developed a method to exclusively deliver therapeutics to the lung endothelium, as the standing theory was (without direct evidence) that lung uptake was due entirely to endothelial cells. However, in pilot experiments, my sponsor and I became aware that other cells reside in the pulmonary capillaries, marginated neutrophils. We found that while PECAM coated particles are primarily taken up by the endothelial cells, we interestingly, in a paradigm shift for the field of targted delivery to the lungs, found anti-ICAM targeted nanocarriers were taken up equally by endothelial cells and leukocytes. This leads to the two key objectives of this proposal: 1) we want to understand if with increases in leukocytes during ARDS, there will be a change in the cells that take up and express anti-CAM targeted mRNA-LNPs and 2) develop a novel class of therapeutics for ARDS. This will be done via 2 Specific Aims. Aim 1 will investigate the cell types that take up and express mRNA-LNPs both in human, with ex vivo human lungs, and mouse models of ARDS. Aim 2 will investigate the therapeutic potential of mRNA-LNPs by leveraging the Ang-Tie pathway to express Angiopoietin-1 to decrease pulmonary capillary leak and finally testing expression capacity in mouse model as well as with ex vivo human lung. The result of this project will inform future therapeutic design and develop a new class of therapeutic for ARDS, mRNA-LNP.

建议书摘要/摘要 急性呼吸窘迫综合征(ARDS)是一种急性肺部炎症。它占所有总数的10% 美国的重症监护病房(ICU)入院人数。尽管进行了数十年的研究和无数大型 临床试验表明，治疗ARDS的方法很少。这种缺乏针对疾病的治疗方法主要是由于 三个主要因素：第一，由于频繁的多系统器官衰竭，ARDS患者很脆弱，因此 不能忍受药物的副作用。第二，ARDS在其潜在的病理生理学上是非常不同的， 因此，以单一途径为目标可能是不够的。第三，该病具有快速发展的时间进程， 这意味着它可以激活以小时为单位主动改变患者结局的通路。要解决 针对上述问题，本方案的目标是开发和建立信使核糖核酸纳米粒(信使核糖核酸-1)。 LNPs)可以靶向特定的细胞类型和器官，因此它们可以表达多种治疗 蛋白质作为ARDS的平台技术。我们的实验室之前使用了三种靶向部分，我们用来 运送纳米载体：与PECAM(一种内皮细胞表面蛋白)、ICAM结合的单抗 (另一种富含于内皮细胞的表面蛋白)和非免疫性免疫球蛋白(下称“免疫球蛋白”)。我们有 进一步表明，共价包被抗PECAM和-ICAM抗体的纳米载体被定向到 肺中的水平比“游离药物”(无携带者)的水平高出300倍(问题1)，此外，mRNA负载 纳米颗粒可以携带编码各种蛋白质的信使核糖核酸，靶向不同的途径 (问题2)。此外，mRNA-LNPs可以在一定时间内(~48小时)表达多种蛋白质。 与上述急性危重疾病的高危时期(问题3)有关。看起来我们发展了 一种将治疗药物专门输送到肺内皮细胞的方法，正如斯坦德理论所说(没有直接 证据)，肺摄取完全是由于内皮细胞。然而，在试点实验中，我的赞助商和 我意识到其他细胞存在于肺毛细血管中，即有边缘的中性粒细胞。我们发现 虽然PECAM包裹的颗粒主要被内皮细胞吸收，但有趣的是，我们在一个范例中 转移到肺部靶向递送领域，发现抗ICAM靶向纳米载体平均被摄取 由内皮细胞和白细胞引起。这导致了这项建议的两个关键目标：1)我们希望 了解在急性呼吸窘迫综合征期间，随着白细胞的增加，占据和 2)开发一种新的ARDS的治疗方法。这将是 通过两个具体的目标来完成。目标1将研究摄取和表达mRNA-LNPs的细胞类型 人，与体外人肺，和ARDS的小鼠模型。目标2将调查治疗潜力 利用血管紧张素途径表达血管生成素-1减少肺毛细血管生成 泄漏并最终在小鼠模型和体外人肺中测试表达能力。其结果是 该项目将为未来的治疗设计提供参考，并开发一类新的ARDS治疗药物--mRNA-LNP。