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

摘要 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3个药理学挑战，特别是ARDS： 患者有多系统器官衰竭，不能耐受脱靶药物副作用; 覆盖肺泡的液体阻止了有效的吸入递送;几十种信号传导途径是ARDS的基础， 因此仅调制一个将不起作用。为了克服这3个挑战，我们设计了M-LAC， 是100纳米的脂质球（脂质体），载有多种药物，并涂有靶向 这些标签导致它们大量积聚在肺泡（肺的气囊）的毛细血管中。 我们之前已经发表了针对肺泡内皮细胞的M-LACs的益处，但 长期以来一直认为需要靶向其他主要肺泡毛细血管细胞类型，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，可以大量集中M-LACs在肺泡 中性粒细胞有了将拉克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， 从根本上改善M-LACs作为ARDS的治疗（目的3）。目的1：体外人肺和体内 在ARDS小鼠模型中，我们定量了与未处理小鼠相比，边缘中性粒细胞的相对数量。 例，我们将测量中性粒细胞和内皮细胞对M-LACs的吸收情况。目标2：我们将测试 靶向药物输送的“仓库理论”，即药物有效地从靶细胞转移到靶细胞， 他们的邻居。我们将测试药物是否作用于中性粒细胞（例如，中性粒细胞弹性蛋白 抑制剂）将改善ARDS样表型，如果靶向内皮细胞，则相同或更差， 反之亦然目的3：我们将确定联合治疗的原则。我们假设， 有效的组合将是一对中性粒细胞和内皮调节药物（例如，作为 与2种内皮调节药物相反）。在这些研究结束时，我们将发现新的 并回答了药理学中的基本问题。此外，我们将有 为ARDS创造了一种高度优化的治疗方法，我们将在多种小鼠模型中进行测试， ARDS和人的肺。

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.