Dual drug delivery to lung/blood interface in respiratory infections.

两个肺界面在呼吸道感染中发挥关键作用，包括细菌感染和病毒感染(例如， COVID19)。入侵者通过呼吸道和肺泡上皮细胞形成的外部界面进入。 内皮细胞与其他宿主防御形成的邻近内血管界面 包括中性粒细胞(PMN)到侵袭部位。过度热情的中性粒细胞损伤内皮。新兴报告 将这种附带损害牵连到COVID19糟糕的结果中。抗炎药物可以缓解 这一问题，但构成了感染蔓延的风险。在不抑制中性粒细胞的情况下保护肺部免受“友军炮火”的伤害 我们使用亲和配体来对抗感染，目标是负载抗炎剂的纳米载体 与肺内皮细胞上的特定表位结合。幸运的是，飞行员筛查了约30人 纳米粒显示，静脉注射后，一些缺乏亲和力配体的制剂在体内积累 炎症肺中的中性粒细胞。我们希望利用这些发现将药物双重输送到内皮细胞和 相邻的PMN。在目标1中，我们将询问PMN表面之间的纳米级界面- 趋向性纳米载体和微环境，以阐明PMN摄取的机制。在目标2中，我们 将研究内皮亲和性纳米载体对血管内皮细胞和中性粒细胞的微尺度界面的影响 肺微血管系统。这些研究将阐明 纳米载体材料的性质决定了光学电离，进而决定了PMN的取向，这是最重要的 肺炎中的白细胞。我们将确定纳米载体如何定位到以下两种关键细胞类型 预防肺炎，从而创建一个平台药物输送系统，以治疗细菌和 病毒性肺炎。

Two pulmonary interfaces play the key role in respiratory infections, both bacterial and viral (e.g., COVID19). The invaders enter via external interface formed by airway and alveolar epithelial cells. The adjacent internal vascular interface formed by endothelial cells recruits and other host defense including neutrophils (PMN) to invasion site. Overzealous PMN hurt endothelium. Emerging reports implicate this collateral damage in COVID19 poor outcomes. Anti-inflammatory drugs could alleviate this issue, but pose risk of infection spread. To protect lungs from "friendly fire" without inhibiting PMN fighting infection we target nanocarriers loaded with anti-inflammatory agents using affinity ligands binding to specific epitopes on the pulmonary endothelium. Fortuitously, pilot screening of ~30 nanoparticles revealed that after IV injection some formulations lacking affinity ligands accumulate in the PMN in inflamed lungs. We want to use these findings for dual drug delivery to endothelium and adjacent PMN. In Aim 1, we will interrogate the nano-scale interface between the surface of PMN- tropic nanocarriers and microenvironment to elucidate the mechanism of PMN uptake. In Aim 2, we will investigate effect of endothelial- and PMN-tropic nanocarriers on the micro-scale interface of pulmonary microvasculature. These studies will elucidate the fundamental mechanisms by which nanocarrier material properties dictate opsonization, and in turn tropism for PMNs, the most important leukocyte in pneumonia. We will determine how nanocarriers localize to the two key cell types in defense against pneumonia, thus creating a platform drug delivery system to treat both bacterial and viral pneumonia.