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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.

两个肺界面在细菌和病毒的呼吸道感染中起关键作用（例如， COVID 19）。入侵者通过气道和肺泡上皮细胞形成的外部界面进入。内皮细胞募集和其他宿主防御形成的邻近内部血管界面包括中性粒细胞（PMN）到侵袭部位。中性粒细胞过度活跃损伤内皮细胞。新报告这种附带损害与COVID 19的不良结局有关。抗炎药可以缓解这个问题，但构成感染传播的风险。保护肺部免受“友军炮火”伤害，而不抑制PMN 对抗感染，我们使用亲和配体靶向装载有抗炎剂的纳米载体，与肺内皮上的特异性表位结合。幸运的是，试点筛选约30 纳米颗粒显示，在IV注射后，一些缺乏亲和配体的制剂在体内积累，炎症肺部的中性粒细胞我们希望利用这些发现进行双重药物输送到内皮细胞，相邻PMN。在目标1中，我们将询问PMN表面与细胞表面之间的纳米级界面。嗜性纳米载体和微环境来阐明PMN摄取的机制。在目标2中，将研究内皮和嗜中性粒细胞纳米载体对微尺度界面的影响，肺微血管这些研究将阐明纳米载体材料的性质决定了调理作用，反过来又决定了中性粒细胞的向性，这是最重要的肺炎白细胞。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，从而创造了一个平台药物输送系统，以治疗细菌和病毒性肺炎