Document text
Principal Investigator: Vladimir R Muzykantov
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $698,173
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <Active Oxygen><Affinity><Airway infections><Alveolar><Animal Model><Animal Models and Related Studies><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Anti-viral Agents><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Antibodies><Antigenic Determinants><Antioxidants><Bacteria><Bacterial Pneumonia><Binding><Binding Determinants><Blood><Blood Neutrophil><Blood Plasma><Blood Polymorphonuclear Neutrophil><Blood Reticuloendothelial System><Blood Serum><Blood Vessels><Blood capillaries><Blood leukocyte><Body Tissues><Bypass><C3b><COVID-19><CV-19><Cell Body><Cells><Cessation of life><Clinical><Complement><Complement 3b><Complement C3b><Complement Proteins><Complication><Conjugated Carrier><Coronavirus Infectious Disease 2019><Cryo-electron Microscopy><Cryoelectron Microscopy><Data><Death><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drug Side Effects><Drug Targeting><Drugs><ELISA><Electron Cryomicroscopy><Endothelial Cells><Endothelium><Enzyme-Linked Immunosorbent Assay><Epithelial Cells><Epitopes><Fire - disasters><Fires><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Formulation><Friends><Histology><Host Defense><Human><Immune response><Immunological response><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><In Vitro><Individual><Infection><Inflammatory><Injections><Intervention><Intervention Strategies><Invaded><K pneumoniae><K. pneumoniae><Klebsiella pneumoniae><Leukocytes><Leukocytes Reticuloendothelial System><Ligand Binding><Ligands><Liposomal><Liposomes><Liquid substance><Lung><Lung Alveolar Epithelia><Lung Inflammation><Lung Respiratory System><Lung damage><MOF syndrome><Marrow Neutrophil><Marrow leukocyte><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Mediator><Medication><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Mice><Mice Mammals><Microbe><Microscopy><Miscellaneous Antibiotic><Modern Man><Molecular Interaction><Multiple Organ Dysfunction Syndrome><Multiple Organ Failure><Murine><Mus><Neutrophil Infiltration><Neutrophil Recruitment><Neutrophilic Granulocyte><Neutrophilic Infiltrate><Neutrophilic Leukocyte><Opsonin><Organ><Outcome><Oxygen Radicals><Patients><Pattern><Perfusion><Phagocytosis><Pharmaceutical Preparations><Pharmacokinetics><Phase><Pilot Projects><Plasma><Plasma Serum><Play><Pneumonia><Pneumonitis><Poison><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Pro-Oxidants><Property><Protective Agents><Protective Drugs><Publishing><Pulmonary Inflammation><Reactive Oxygen Species><Reporting><Respiratory Epithelium><Respiratory Infections><Respiratory Tract Infections><Reticuloendothelial System, Serum, Plasma><Roentgen Rays><Scanning><Secondary to><Serum><Site><Sterility><Structure of respiratory epithelium><Surface><Surface Proteins><System><Testing><Tissues><Toxic Chemical><Toxic Substance><Tropism><Variant><Variation><Viral><Viral Pneumonia><Virus><White Blood Cells><White Cell><X-Radiation><X-Ray Radiation><X-ray><Xray><airway epithelium><alveolar epithelium><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><bacteria pneumonia><capillary><cell type><combat><complementation><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><cryo-EM><cryoEM><cryogenic electron microscopy><cytokine><drug/agent><enzyme linked immunoassay><fighting><fire><flow cytophotometry><fluid><high risk><host response><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive response><in vivo><infection risk><interventional strategy><lead candidate><liquid><lung injury><microbial><microcalorimetry><model of animal><monolayer><mouse model><multiorgan failure><multiple organ system failure><murine model><nano formulation><nano meter scale><nano meter sized><nano particle><nano-sized particle><nanocarrier><nanoformulation><nanometer scale><nanometer sized><nanoparticle><nanoscale><nanosized particle><nanovessel><neutrophil><pharmacologic><pilot study><pneumonia therapy><pneumonia treatment><pre-clinical><preclinical><prevent><preventing><pulmonary><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><recruit><respiratory tract epithelium><risk/benefit ratio><screening><screenings><secondary infection><site targeted delivery><sterile><targeted delivery><toxic compound><translational study><treat pneumonia><uptake><vascular><white blood cell><white blood corpuscle>