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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.

摘要