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Nanomedicine for ARDS: A new paradigm to target drugs to multiple cell types within alveolar capillaries

ARDS 纳米医学：将药物靶向肺泡毛细血管内多种细胞类型的新范例

基本信息

批准号：
10466854
负责人：
Jacob Brenner
金额：
$ 40.63万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10466854
关键词：
Acute Acute Respiratory Distress Syndrome Address Air Sacs Alveolar Alveolar Cell Alveolus American Antibodies Binding Biology Blood Blood capillaries Cells Clinical Trials Combined Modality Therapy Dose Drug Carriers Drug Combinations Drug Delivery Systems Drug Side Effects Drug Synergism Drug Targeting Drug toxicity Endothelial Cells Endothelium Failure Functional disorder Goals Human Imatinib Impairment Inhalation Label Left Lipids Liposomes Liquid substance Lung Measures Mediating Mediator of activation protein Modeling Mus Nanotechnology Nebulizer Organ Organ failure Pathway interactions Patients Pharmaceutical Preparations Pharmacology Pharmacotherapy Phenotype Publishing Pulmonary Artery Branch Role Signal Pathway Structure of parenchyma of lung Testing Therapeutic Therapeutic Effect Therapeutic Index Time Tissue Banks Toxic effect Transplantation Treatment Efficacy Work base cell type design human model improved in vivo inflammatory lung disease invention mouse model nanocarrier nanomedicine nanometer neutrophil neutrophil elastase inhibitor novel novel therapeutics pharmacokinetic model prevent response screening side effect small molecule synergism theories tool treatment optimization uptake

项目摘要

ABSTRACT Dozens of drugs have failed in clinical trials for the inflammatory lung disease ARDS (acute respiratory distress syndrome), largely due to 3 pharmacological challenges particular to ARDS: ARDS patients have multi-system organ failure, so cannot tolerate off-target drug side effects; the column of liquid covering alveoli prevents effective inhaled delivery; dozens of signaling pathways underlie ARDS, so modulating just one will not work. To overcome these 3 challenges, we designed M-LACs, which are 100-nanometer lipid spheres (liposomes), loaded with multiple drugs, and coated with targeting tags that cause them to massively accumulate in the capillaries of the alveoli (air sacs of the lungs). We have previously published on the benefits of M-LACs targeted to alveolar endothelial cells, but have long seen the need to target the other major alveolar capillary cell type, alveolar marginated neutrophils. Here we introduce new targeting tags that can massively concentrate M-LACs in alveolar neutrophils. With the new ability to target LACs to both endothelium and neutrophils, we can now answer fundamental questions in ARDS biology (Aim 1) and general pharmacology (Aim 2), while radically improving M-LACs as a therapy for ARDS (Aim 3). Aim 1: In ex vivo human lungs and in vivo mouse models of ARDS, we quantify the relative number of marginated neutrophils compared to naive cases, and we will measure how well neutrophils and endothelial take up M-LACs. Aim 2: We will test the “depot theory” of targeted drug delivery, which says drugs efficiently elute from targeted cells to their neighbors. We will test whether drugs meant to act in neutrophils (e.g., neutrophil elastase inhibitors) will ameliorate ARDS-like phenotypes the same or worse if targeted to endothelial cells, and vice versa. Aim 3: We will identify the principles of combination therapy. We hypothesize that the most efficacious combinations will be a pair of neutrophil- and endothelial-modulating drugs (e.g., as opposed to 2 endothelial-modulating drugs). By the end of these studies, we will have uncovered new ARDS biology and answered fundamental questions in pharmacology. Additionally, we will have created a highly optimized therapy for ARDS that we will have tested in multiple mouse models of ARDS and in human lungs.

抽象的数十种药物在治疗炎症性肺病 ARDS（急性呼吸窘迫综合征）的临床试验中失败。呼吸窘迫综合征），主要是由于 ARDS 特有的 3 种药理学挑战： ARDS 患者有多系统器官衰竭，不能耐受脱靶药物副作用；的专栏液体覆盖肺泡阻碍有效的吸入输送； ARDS 背后有数十种信号通路，所以只调制一个是行不通的。为了克服这 3 个挑战，我们设计了 M-LAC，是100纳米脂质球（脂质体），负载多种药物，并涂有靶向药物导致它们大量积聚在肺泡（肺的气囊）毛细血管中的标签。我们之前曾发表过关于针对肺泡内皮细胞的 M-LAC 的益处，但长期以来一直认为需要针对其他主要的肺泡毛细血管细胞类型，即肺泡边缘细胞中性粒细胞。在这里，我们介绍了新的靶向标签，可以将 M-LAC 大量集中在肺泡中中性粒细胞。凭借将 LAC 靶向内皮细胞和中性粒细胞的新能力，我们现在可以回答 ARDS 生物学（目标 1）和一般药理学（目标 2）的基本问题，同时从根本上改善 M-LAC 作为 ARDS 的治疗方法（目标 3）。目标 1：离体人肺和体内 ARDS 小鼠模型中，我们量化了边缘中性粒细胞与幼稚粒细胞相比的相对数量情况下，我们将测量中性粒细胞和内皮细胞吸收 M-LAC 的程度。目标 2：我们将进行测试靶向药物递送的“仓库理论”，该理论认为药物有效地从靶向细胞洗脱到他们的邻居。我们将测试药物是否对中性粒细胞起作用（例如，中性粒细胞弹性蛋白酶如果针对内皮细胞，则可以相同或更差地改善 ARDS 样表型，并且反之亦然。目标 3：我们将确定联合治疗的原则。我们假设最有效的组合将是一对中性粒细胞和内皮细胞调节药物（例如，与 2 种内皮调节药物相反）。到这些研究结束时，我们将发现新的 ARDS 生物学并回答了药理学的基本问题。此外，我们还将有为 ARDS 创建了一种高度优化的疗法，我们将在多种小鼠模型中进行测试 ARDS 和人类肺部。