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。

基本信息

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
项目类别：
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

项目摘要

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.

两个肺界面在细菌和病毒中都起着关键作用（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。由内皮细胞募集和其他宿主防御形成的相邻内部血管界面包括中性粒细胞（PMN）到入侵部位。过度狂热的PMN伤害了内皮。新兴报告在Covid19糟糕的结果中暗示了这种附带损害。抗炎药可以减轻这个问题，但构成感染的风险。保护肺部免受“友好火”而不抑制PMN 战斗感染我们使用亲和力配体的纳米载体载有抗炎剂与肺部内皮上的特定表位结合。幸运的是，试点筛查〜30 纳米颗粒显示，在静脉注射后，一些缺乏亲和力配体的制剂积累发炎的PMN。我们想将这些发现用于双重药物输送到内皮和相邻PMN。在AIM 1中，我们将询问PMN-表面之间的纳米级界面热带纳米载体和微环境，以阐明PMN摄取的机制。在AIM 2中，我们将研究内皮和PMN - 热带纳米载体对微观界面的影响肺微脉管系统。这些研究将阐明基本机制纳米载体材料的特性决定了调子化，而对PMN的质量又是最重要的肺炎的白细胞。我们将确定纳米载体如何定位到两个关键单元格中防御肺炎，从而建立了一种平台药物输送系统来治疗细菌和病毒肺炎。