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: 10693409
• 负责人: Marco Zamora
• 金额: $ 4.77万
• 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/10693409
• 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; Proteins; Publishing; Pulmonary Edema; Pulmonary Inflammation; Recombinants; Regional Perfusion; Research; Role; Route; Serum; Signal Pathway; Signaling Molecule; Site; Solid; System; Technology; Testing; Therapeutic; Therapeutic Effect; Time; Transplantation; United States; Up-Regulation; Western Blotting; White Blood Cell Count procedure; body system; cell type; cytokine; design; ex vivo perfusion; experimental study; high risk; hyperoxia induced lung injury; improved; 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; surface coating; technology platform; 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）是一种急性肺部炎症。它代表了10% 重症监护病房（ICU）在美国的招生。尽管数十年的研究和许多大型 在临床试验中，ARDS的治疗方法很少。这种缺乏疾病特异性治疗的主要原因是， 主要有三个因素：一是ARDS患者多系统器官功能衰竭频繁，属于“脆弱型”， 不能忍受药物的副作用。其次，ARDS在其基础病理生理学上是非常异质的， 因此靶向单一途径可能是不够的。第三，疾病具有快速发展的时间过程， 这意味着它可以激活在数小时内积极改变患者结果的途径。 针对上述问题，本提案的目标是开发和建立载有mRNA的纳米颗粒（mRNA- LNP），其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活性。 蛋白质作为治疗ARDS的平台技术。我们的实验室以前使用了三种靶向部分， 递送纳米载体：结合PECAM（内皮细胞表面蛋白）、ICAM （内皮细胞上丰富的另一种表面蛋白）和非免疫IgG（下文称为“IgG”）。我们有 进一步表明，用抗PECAM和抗ICAM抗体共价包被的纳米载体针对 肺中的水平比“游离药物”（无载体）高300倍，解决了（问题#1）。 纳米颗粒可以装载编码各种蛋白质的mRNA，靶向各种途径 （问题#2）。此外，mRNA-LNP可以表达多种蛋白质的时间长度（约48小时） 与上述急性危重病（问题3）的高风险期相关。似乎我们发展了 一种专门向肺内皮递送治疗剂的方法，如现有理论所述（没有直接的 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 我开始意识到，其他细胞居住在肺毛细血管，边缘中性粒细胞。我们发现 尽管PECAM包被的颗粒主要被内皮细胞吸收，但有趣的是， 转移到肺部的靶向递送领域，发现抗ICAM靶向纳米载体同样被采用 由内皮细胞和白细胞组成。这就引出了本提案的两个关键目标：1）我们希望 了解在ARDS期间白细胞的增加，是否会有细胞的变化， 表达抗CAM靶向mRNA-LNP和2）开发用于ARDS的新型治疗剂。这将是 通过两个具体目标。目的1将研究细胞类型，采取和表达mRNA-LNPs都在 人，具有离体人肺和ARDS的小鼠模型。目的2将研究治疗潜力 通过利用Ang-Tie途径表达血管生成素-1来减少肺毛细血管 泄漏，最后测试小鼠模型以及离体人肺中的表达能力。的结果 该项目将为未来的治疗设计提供信息，并开发一种新的ARDS治疗药物mRNA-LNP。

项目成果

Monoclonal antibody 2C5 specifically targets neutrophil extracellular traps.

• DOI: 10.1080/19420862.2020.1850394
• 发表时间: 2020-01
• 期刊: mAbs
• 影响因子: 5.3
• 作者: Mendes LP;Rostamizadeh K;Gollomp K;Myerson JW;Marcos-Contreras OA;Zamora M;Luther E;Brenner JS;Filipczak N;Li X;Torchilin VP
• 通讯作者: Torchilin VP

Physicochemical Targeting of Lipid Nanoparticles to the Lungs Induces Clotting: Mechanisms and Solutions.

脂质纳米颗粒的物理化学靶向肺部诱导凝血：机制和解决方案。

• DOI: 10.1101/2023.07.21.550080
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Omo-Lamai,Serena;Zamora,MarcoE;Patel,ManthanN;Wu,Jichuan;Nong,Jia;Wang,Zhicheng;Peshkova,Alina;Chase,LiamS;Essien,Eno-Obong;Muzykantov,Vladimir;Marcos-Contreras,Oscar;Myerson,JacobW;Brenner,JacobS
• 通讯作者: Brenner,JacobS

Mechanisms by Which Liposomes Improve Inhaled Drug Delivery for Alveolar Diseases.

• DOI: 10.1002/anbr.202200106
• 发表时间: 2023-03
• 期刊: ADVANCED NANOBIOMED RESEARCH
• 影响因子: 3.4
• 作者: Ferguson, Laura T;Ma, Xiaonan;Myerson, Jacob W;Wu, Jichuan;Glassman, Patrick M;Zamora, Marco E;Hood, Elizabeth D;Zaleski, Michael;Shen, Mengwen;Essien, Eno-Obong;Shuvaev, Vladimir V;Brenner, Jacob S
• 通讯作者: Brenner, Jacob S