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:
  • 金额:
    $ 40.63万
  • 依托单位:
  • 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

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

项目成果

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Jacob Brenner其他文献

Jacob Brenner的其他文献

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{{ truncateString('Jacob Brenner', 18)}}的其他基金

miRNA-Nanotechnology as a novel regenerative therapy for lymphangioleiomyomatosis
miRNA-纳米技术作为淋巴管平滑肌瘤病的新型再生疗法
  • 批准号:
    10761353
  • 财政年份:
    2023
  • 资助金额:
    $ 40.63万
  • 项目类别:
The DOVE Device to Prevent Opioid Overdose Deaths: An Armband That Senses Overdose and Automatically Injects Naloxone
防止阿片类药物过量死亡的 DOVE 装置:可感应过量并自动注射纳洛酮的臂带
  • 批准号:
    10485568
  • 财政年份:
    2023
  • 资助金额:
    $ 40.63万
  • 项目类别:
mRNA-LNPs for ARDS
ARDS 的 mRNA-LNP
  • 批准号:
    10659792
  • 财政年份:
    2023
  • 资助金额:
    $ 40.63万
  • 项目类别:
Next-generation nanomedicine for acute ischemic stroke
治疗急性缺血性中风的下一代纳米药物
  • 批准号:
    10603229
  • 财政年份:
    2023
  • 资助金额:
    $ 40.63万
  • 项目类别:
Controlling complement to unleash nanomedicine for acute critical illnesses
控制补体释放纳米药物治疗急性危重疾病
  • 批准号:
    10557895
  • 财政年份:
    2022
  • 资助金额:
    $ 40.63万
  • 项目类别:
Controlling complement to unleash nanomedicine for acute critical illnesses
控制补体释放纳米药物治疗急性危重疾病
  • 批准号:
    10340537
  • 财政年份:
    2022
  • 资助金额:
    $ 40.63万
  • 项目类别:
RBC-mediated mopping of cytokines for the treatment of pneumonia
红细胞介导的细胞因子清除治疗肺炎
  • 批准号:
    10495259
  • 财政年份:
    2021
  • 资助金额:
    $ 40.63万
  • 项目类别:
RBC-mediated mopping of cytokines for the treatment of pneumonia
红细胞介导的细胞因子清除治疗肺炎
  • 批准号:
    10353073
  • 财政年份:
    2021
  • 资助金额:
    $ 40.63万
  • 项目类别:
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
  • 批准号:
    10678910
  • 财政年份:
    2020
  • 资助金额:
    $ 40.63万
  • 项目类别:
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
  • 批准号:
    10030992
  • 财政年份:
    2020
  • 资助金额:
    $ 40.63万
  • 项目类别:

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机械建模与机器学习相结合诊断急性呼吸窘迫综合征
  • 批准号:
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