Document text
Principal Investigator: Jacob Brenner
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $681,194
Funding agency: National Heart Lung and Blood Institute
ABSTRACT / SUMMARY
Acute critical illnesses rapidly lead to severe organ damage and loss of life. These illnesses include
sepsis, stroke, and acute respiratory distress syndrome (ARDS). Here we focus on ARDS, which is acute
inflammation of the lungs’ air sacs, and the cause of death in COVID-19. For ARDS and these other diseases,
we have developed ligand-targeted nanocarriers that localize drugs to the inflamed microvasculature of affected
organs. As we moved towards clinical translation, we found the key step is gaining control of complement, a set
of plasma proteins that bind microbes and aid their clearance. But we found complement-nanoparticle
interactions are a “double-edged sword”, with both benefits to optimize, and deleterious features to resolve.
First, we found that complement protein C3 rapidly opsonizes particular nanoparticles, and that such C3-
opsonized nanoparticles then act as “decoys” to ameliorate ARDS mouse models (e.g., nebulized LPS) by ~75%.
The C3-coated nanoparticles accumulate in marginated leukocytes, which are key to ARDS pathophysiology,
and cause those cells to leave the lungs. However, C3 opsonization induces an anaphylaxis-like reaction called
CARPA (complement-activation-related pseudo-allergy). Therefore, in Aim 1, we will engineer nanoparticles
that can function like C3-coated decoys to ameliorate ARDS, but without CARPA. We will also investigate the
mechanism underlying nanoparticle decoy therapy. Then we will test the translational potential of these
optimized decoy nanoparticles by testing them in fresh, perfused, ex vivo human lungs.
Second, we found that the ligand-targeted nanoparticles we have been developing for drug delivery for
years also induce CARPA. Therefore, in Aim 2, we will re-engineer our ligand-targeted nanoparticles to prevent
CARPA. We will test a drug carrier we have previously used to concentrate drugs in the alveolar
microvasculature of the lungs: liposomes conjugated to anti-PECAM antibodies that bind endothelial cells. We
will test in vitro and in vivo in mice whether various engineered versions of anti-PECAM liposomes can evade
C3 opsonization and CARPA, and thereby achieve more specific delivery to the lungs. Lastly, we will test these
CARPA-avoiding nanoparticles with plasma from ARDS patients, as such patients have perturbed complement.
Upon completion of these two Aims, we will have developed two technologies that may aid therapy of
ARDS: 1) Decoy nanoparticles that safely cause marginated leukocytes to leave the lungs, and thereby
ameliorate ARDS-like phenotypes; 2) A technology for preventing complement side effects such as CARPA
when delivering ligand-targeted nanoparticles. As marginated leukocytes play pivotal roles in most acute critical
illnesses, and CARPA sensitivity is common to those as well, the technologies developed here may impact not
only ARDS, but also sepsis, stroke, and more.
Terms: <9-Octadecenoic Acid><ARDS><Acute><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adopted><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Affect><Air Bladder><Air Sacs><Allelism Test><Alveolar><Alveolus><Amino Acid Motifs><Anaphylactic Reaction><Anaphylactic Shock><Anaphylaxis><Antibodies><Apoplexy><Artificial nano particles><Artificial nanoparticles><Assay><Binding><Binding Proteins><Bioassay><Biological Assay><Blood><Blood Neutrophil><Blood Plasma><Blood Polymorphonuclear Neutrophil><Blood Proteins><Blood Reticuloendothelial System><Blood Serum><Blood capillaries><Blood leukocyte><Brain Vascular Accident><Bronchial Alveolus><C3 a><C3 regulator><C3a><C3bi><COVID-19><COVID-19 associated death><COVID-19 associated fatality><COVID-19 associated mortality><COVID-19 death><COVID-19 fatality><COVID-19 induced death><COVID-19 induced fatality><COVID-19 induced mortality><COVID-19 mortality><COVID-19 related death><COVID-19 related fatality><COVID-19 related mortality><COVID19 associated death><COVID19 associated fatality><COVID19 associated mortality><COVID19 death><COVID19 fatality><COVID19 induced death><COVID19 induced fatality><COVID19 induced mortality><COVID19 mortality><COVID19 related death><COVID19 related fatality><COVID19 related mortality><CR3><CR3 Receptor><CV-19><Cancers><Cardiac infarction><Cause of Death><Cell Body><Cells><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Cessation of life><Clinical Treatment Moab><Complement><Complement 3 Receptor><Complement 3a><Complement Activation><Complement C3a><Complement Factor H><Complement Factor P><Complement Proteins><Complementation Test><Coronavirus Infectious Disease 2019><Critical Care><Critical Illness><Critically Ill><Da Nang Lung><Death><Disease><Disorder><Drug Carriers><Drug Delivery><Drug Delivery Systems><Drugs><Dysfunction><Endothelial Cells><Endothelium><Engineering><Factor H><Functional disorder><Genetic Complementation Test><Human><Hypotension><Immune><Immunes><In Vitro><Inflammatory><Injections><Integrin alpha-M beta-2><Integrin alphaMbeta2><Knock-out><Knockout><Lead><Leukocytes><Leukocytes Reticuloendothelial System><Life><Ligand Binding Protein><Ligand Binding Protein Gene><Ligands><Liposomal><Liposomes><Low Blood Pressure><Lung><Lung Inflammation><Lung Respiratory System><Lung damage><Mac 1><Mac-1 Adhesive Receptor><Mac-1 Antigen><Mac-1 Receptor><Macrophage-1 Antigen><Malignant Neoplasms><Malignant Tumor><Marrow Neutrophil><Marrow leukocyte><Measures><Medication><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Mice><Mice Mammals><Microbe><Mo1 Antigen Receptor><Mo1 Glycoprotein Receptor><Modeling><Modern Man><Molecular Interaction><Monoclonal Antibodies><Murine><Mus><Myocardial Infarct><Myocardial Infarction><Nanotechnology><Nebulizer><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Oleic Acids><Organ><Out-patients><Outcome><Outpatients><Patients><Pb element><Perfusion><Pharmaceutical Preparations><Phenotype><Physicians><Physiopathology><Plasma><Plasma Proteins><Plasma Serum><Play><Pneumonitis><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Properdin><Protein Binding><Protein Motifs><Pulmonary Inflammation><Reaction><Receptor Protein><Recombinants><Reporting><Reticuloendothelial System, Serum, Plasma><Role><SARS-CoV-2 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 death><SARS-CoV-2 fatality><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 mortality><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><Sepsis><Serum><Shock Lung><Side><Spleen><Spleen Reticuloendothelial System><Stiff lung><Stroke><Surface Proteins><Swimbladder><Technology><Testing><Therapeutic><Therapeutic Effect><Trans Test><Vascular Hypotensive Disorder><White Blood Cells><White Cell><Wild Type Mouse><Work><antibody conjugate><blood infection><bloodstream infection><bound protein><brain attack><capillary><cardiac infarct><cerebral vascular accident><cerebrovascular accident><cis-9-Octadecenoic Acid><clinical translation><clinically translatable><complement 3 regulator><complement pathway><complement pathway regulation><complementation><complementation analysis><complementation approach><coronary attack><coronary infarct><coronary infarction><coronavirus disease 2019><coronavirus disease 2019 associated death><coronavirus disease 2019 associated fatality><coronavirus disease 2019 associated mortality><coronavirus disease 2019 death><coronavirus disease 2019 fatality><coronavirus disease 2019 induced death><coronavirus disease 2019 induced fatality><coronavirus disease 2019 induced mortality><coronavirus disease 2019 mortality><coronavirus disease 2019 related death><coronavirus disease 2019 related fatality><coronavirus disease 2019 related mortality><coronavirus disease-19><coronavirus disease-19 mortality><coronavirus infectious disease-19><cytokine><death due to COVID-19><death due to COVID19><death due to SARS-CoV-2><death due to coronavirus disease 2019><death due to severe acute respiratory syndrome coronavirus 2><death in COVID><death in COVID-19><death in SARS-CoV-2><death in coronavirus disease><death in coronavirus disease 2019><death in severe acute respiratory syndrome coronavirus 2><density><design><designing><drug/agent><engineered nano particle><engineered nanoparticle><ex vivo perfusion><experiment><experimental research><experimental study><experiments><factor P><fatality due to COVID-19><fatality due to COVID19><fatality due to SARS-CoV-2><fatality due to coronavirus disease 2019><fatality due to severe acute respiratory syndrome coronavirus 2><heart attack><heart infarct><heart infarction><heavy metal Pb><heavy metal lead><human tissue><iC3b><improved><in vitro testing><in vivo><inhibitor><lung injury><mAbs><malignancy><migration><monoclonal Abs><mortality due to COVID-19><mortality due to COVID19><mortality due to SARS-CoV-2><mortality due to coronavirus disease 2019><mortality due to severe acute respiratory syndrome coronavirus 2><mouse model><murine model><nano medicinal><nano medicine><nano particle><nano tech><nano technology><nano-sized particle><nano-technological><nanocarrier><nanomedicinal><nanomedicine><nanoparticle><nanosized particle><nanotech><nanotechnological><nanovessel><nebulization><nebulize><neoplasm/cancer><neutralizing antibody><neutrophil><pathophysiology><prevent><preventing><pulmonary><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><receptor><severe acute respiratory syndrome coronavirus 2 associated death><severe acute respiratory syndrome coronavirus 2 associated fatality><severe acute respiratory syndrome coronavirus 2 associated mortality><severe acute respiratory syndrome coronavirus 2 death><severe acute respiratory syndrome coronavirus 2 fatality><severe acute respiratory syndrome coronavirus 2 induced death><severe acute respiratory syndrome coronavirus 2 induced fatality><severe acute respiratory syndrome coronavirus 2 induced mortality><severe acute respiratory syndrome coronavirus 2 mortality><severe acute respiratory syndrome coronavirus 2 related death><severe acute respiratory syndrome coronavirus 2 related fatality><severe acute respiratory syndrome coronavirus 2 related mortality><side effect><social role><standard measure><stroked><strokes><tissue resource><translational opportunities><translational potential><uptake><wet lung><white blood cell><white blood corpuscle><wildtype mouse><αMβ2>