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：
10614476
负责人：
Vladimir R Muzykantov
金额：
$ 72.11万
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/10614476
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 Conjugated Carrier 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 Friends 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 Membrane Proteins Microbe Microscopy Multiple Organ Failure Mus Neutrophil Infiltration Opsonin Organ Outcome Patients Pattern Perfusion Phagocytosis Pharmaceutical Preparations Phase Pilot Projects Plasma Play Pneumonia Poison 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 nanoformulation nanoparticle nanoscale neutrophil pharmacologic 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。过度热衷的中性粒细胞会伤害内皮细胞。新出现的报告表明这种附带损害与新冠肺炎的不良结果有关。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。