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: 10480920
• 负责人: Marco Zamora
• 金额: $ 4.68万
• 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/10480920
• 关键词: ANGPT1 gene; Acute; Acute Disease; Acute Respiratory Distress Syndrome; Address; Admission activity; Alveolar; Alveolus; 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; Immunoglobulin G; Inflammatory; Inhalation; Injury; Innate Immune System; Intensive Care Units; Knowledge; Length; Leukocytes; Liquid substance; Luciferases; Lung; 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; Pulmonary Inflammation; 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; hyperoxia induced lung injury; 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.

提案摘要/摘要 急性呼吸窘迫综合征（ARDS）是肺的急性炎症。它代表所有的10％ 美国重症监护室（ICU）入院。尽管进行了数十年的研究和许多大型研究 临床试验，ARDS几乎没有治疗方法。这种缺乏疾病特异性疗法的主要原因是 三个主要因素：首先，由于经常多系统器官衰竭，ARDS患者“脆弱”，因此 无法忍受药物副作用。其次，ARDS在其潜在的病理生理学和 因此，针对单个途径可能不够。第三，该疾病有一个快速发展的时间病程， 这意味着它可以激活以小时数积极改变患者预后的途径，以解决 上述问题，该提案的目的是开发和建立载有mRNA的纳米颗粒（mRNA- LNP）可以针对特定的细胞类型和器官，因此它们可以表达多种疗法 蛋白质作为ARDS的平台技术。我们的实验室以前已经使用了三个我们使用的定位部分 传递纳米载体：与PECAM（内皮细胞表面蛋白）结合的单克隆抗体，ICAM （内皮细胞上的另一种表面蛋白）和非免疫IgG（以下称为“ IgG”）。我们有 进一步表明，用抗PECAM和-ICAM抗体共价覆盖的纳米载体针对 肺部比“免费药物”（无载体）（问题1）高300倍，此外，mRNA负载 纳米颗粒可以用编码各种蛋白质的mRNA加载，以各种途径为目标 （问题2）。另外，mRNA-LNP可以在时间长度（〜48小时）中表达多种蛋白质 与上面的急性重症疾病的高风险时期有关（问题3）。似乎我们开发了 作为直立理论的一种独家传递理论的方法（没有直接的理论 有证据表明肺摄取完全是内皮细胞的。但是，在飞行员实验中，我的赞助商和 我意识到其他细胞居住在肺毛细血管中，中性粒细胞的边缘。我们发现 虽然PECAM涂层颗粒主要由内皮细胞吸收，但我们很有趣，在范式中 降差的转移到肺部，发现抗ICAM的靶向纳米载体被平均地占用 由内皮细胞和白细胞。这导致了该提案的两个关键目标：1）我们想 了解在ARDS期间白细胞增加是否会增加，占用的细胞会发生变化，并且 表达抗CAM靶向mRNA-LNP和2）为ARDS开发了新型的治疗方法。这将是 通过2个特定目标完成。 AIM 1将研究占用并表达mRNA-LNP的细胞类型均在 人类，具有体内人类肺和小鼠ARDS模型。 AIM 2将研究治疗潜力 通过利用Ang-tie途径表达Angiopietin-1来减少肺毛细管 泄漏并最终测试小鼠模型中的表达能力以及离体人肺。结果 该项目将为未来的治疗设计提供信息，并为ARDS开发新的治疗方法，mRNA-LNP。