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

在呼吸道感染中向肺/血液界面双重给药。

• 批准号: 10179690
• 负责人: Vladimir R Muzykantov
• 金额: $ 74.23万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-20 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10179690
• 关键词: Affinity; Alveolar; Animal Model; Anti-Inflammatory Agents; Antibiotics; Antibodies; Antioxidants; Antiviral Agents; Bacteria; Bacterial Pneumonia; Binding; Blood; Blood Vessels; Blood capillaries; Bypass; COVID-19; Cells; Cessation of life; Clinical; Complement; Complement 3b; Complication; Cryoelectron Microscopy; Data; Drug Delivery Systems; Drug Kinetics; Drug Side Effects; Drug Targeting; Endothelial Cells; Endothelium; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Epitopes; Fire - disasters; Flow Cytometry; Formulation; Histology; Host Defense; Human; Immune response; Immunosuppression; In Vitro; Individual; Infection; Inflammatory; Injections; Intervention; Invaded; Klebsiella pneumoniae; Leukocytes; Ligand Binding; Ligands; Liposomes; Liquid substance; Lung; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Membrane Proteins; Microbe; Microscopy; Multiple Organ Failure; Mus; Neutrophil Infiltration; Opsonin; Organ; Outcome; Patients; Pattern; Perfusion; Phagocytosis; Pharmaceutical Preparations; Pharmacology; Phase; Pilot Projects; Plasma; Play; Pneumonia; Poison; Problem Solving; Property; Protective Agents; Publishing; Pulmonary Inflammation; Reactive Oxygen Species; Reporting; Respiratory Tract Infections; Roentgen Rays; Scanning; Secondary to; Serum; Site; Sterility; Surface; System; Testing; Tissues; Tropism; Variant; Viral; Viral Pneumonia; Virus; airway epithelium; alveolar epithelium; cell type; combat; cytokine; fighting; high risk; in vivo; infection risk; lead candidate; lung injury; microbial; microcalorimetry; monolayer; mouse model; nanocarrier; nanoparticle; nanoscale; neutrophil; pneumonia treatment; pre-clinical; prevent; recruit; risk benefit ratio; screening; secondary infection; targeted delivery; translational study; uptake

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.

两个肺界面在细菌性和病毒性呼吸道感染中发挥着关键作用（例如， 新冠肺炎）。入侵者通过气道和肺泡上皮细胞形成的外部界面进入。 由内皮细胞形成的相邻内部血管界面招募和其他宿主防御 包括中性粒细胞 (PMN) 到侵袭部位。过度热衷的 PMN 会伤害内皮细胞。新出现的报告 表明这种附带损害与新冠肺炎的不良后果有关。消炎药可以缓解 这个问题，但会带来感染传播的风险。在不抑制 PMN 的情况下保护肺部免受“友军火力”的伤害 对抗感染，我们使用亲和配体靶向负载抗炎剂的纳米载体 与肺内皮上的特定表位结合。幸运的是，试点筛选了约 30 纳米颗粒显示，静脉注射后，一些缺乏亲和配体的制剂会在 发炎肺部的 PMN。我们希望利用这些发现将药物双重递送至内皮细胞和 相邻的 PMN。在目标 1 中，我们将研究 PMN-表面之间的纳米级界面 热带纳米载体和微环境阐明 PMN 摄取机制。在目标 2 中，我们 将研究内皮亲和中性粒细胞亲和性纳米载体对微尺度界面的影响 肺微血管。这些研究将阐明其基本机制 纳米载体材料特性决定了调理作用，进而决定了 PMN 的趋向性，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于两种关键细胞类型 防御肺炎，从而创建一个治疗细菌和肺炎的平台药物输送系统 病毒性肺炎。