A5052806309- Barrier Structure and Function Studies
- Extracellular vesicles in disease
- RNA Interference and Gene Delivery
- Lipid Membrane Structure and Behavior
- Acute Ischemic Stroke Management
- Platelet Disorders and Treatments
- Inhalation and Respiratory Drug Delivery
- Neuroinflammation and Neurodegeneration Mechanisms
- Nanoparticle-Based Drug Delivery
- Neonatal Respiratory Health Research
- Intracranial Aneurysms: Treatment and Complications
- Blood properties and coagulation
- Immune cells in cancer
- Phagocytosis and Immune Regulation
- Intracerebral and Subarachnoid Hemorrhage Research
- Galectins and Cancer Biology
- Neurological Disease Mechanisms and Treatments
- Neonatal and fetal brain pathology
- Traumatic Brain Injury and Neurovascular Disturbances
- Respiratory Support and Mechanisms
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
University of Pennsylvania
2022-2024
California University of Pennsylvania
2023-2024
Translational Therapeutics (United States)
2023-2024
Abstract Lipid nanoparticles (LNPs) have become the dominant drug delivery technology in industry, holding promise to deliver RNA up or down‐regulate any protein of interest. LNPs mostly been targeted specific cell types organs by physicochemical targeting which LNP’s lipid compositions are adjusted find mixtures with desired tropism. Here lung‐tropic examined, whose organ tropism derives from containing either a cationic ionizable conferring positive zeta potential. Surprisingly, these...
Abstract Lipid nanoparticles (LNPs) have emerged as the dominant platform for RNA delivery, based on their success in COVID-19 vaccines and late-stage clinical studies other indications. However, we others shown that LNPs induce severe inflammation, massively aggravate pre-existing inflammation. Here, using structure-function screening of lipids analyses signaling pathways, elucidate mechanisms LNP-associated inflammation demonstrate solutions. We show LNPs’ hallmark feature, endosomal...
Ex vivo-loaded white blood cells (WBC) can transfer cargo to pathological foci in the central nervous system (CNS). Here we tested affinity ligand driven vivo loading of WBC order bypass need for ex manipulation. We used a mouse model acute brain inflammation caused by local injection tumor necrosis factor alpha (TNF-α). intravenously injected nanoparticles targeted intercellular adhesion molecule 1 (anti-ICAM/NP). found that (A) at 2 h, >20% anti-ICAM/NP were localized lungs; (B) lungs >90%...
<title>Abstract</title> Intracerebral hemorrhage (ICH) is a lethal and highly morbid form of stroke for which there no disease-specific therapy. Inflammation after ICH an important mechanism secondary damage, the inflamed endothelium in promising therapeutic target as it gateway inflammation brain. Systemic therapies that have been unsuccessful stroke, part due to side effects or poor brain delivery. We hypothesized targeting mRNA encoding IL-10, potent anti-inflammatory cytokine,...
Nanomedicine has long pursued the goal of targeted delivery to specific organs and cell types but yet achieve this with vast majority targets. One rare example success in pursuit been 25+ years studies targeting lung endothelium using nanoparticles conjugated antibodies against endothelial surface molecules. However, here we show that such "endothelial-targeted" nanocarriers also effectively target lungs' numerous marginated neutrophils, which reside pulmonary capillaries patrol for...
Two camps have emerged for targeting nanoparticles to specific organs and cell types: affinity moiety physicochemical tropism. Here we directly compare combine both using intravenous (IV) lipid (LNPs) designed target the lungs. We utilized PECAM antibodies as moieties cationic lipids These methods yield nearly identical lung uptake, but aPECAM LNPs show higher endothelial specificity. combining these had >2-fold uptake than either method alone markedly enhanced epithelial uptake. To...
Lipid nanoparticles (LNPs) have become the dominant drug delivery technology in industry, holding promise to deliver RNA up- or down-regulate any protein of interest. LNPs been targeted specific cell types organs by physicochemical targeting, which LNP's lipid compositions are adjusted find mixtures with desired tropism. In a popular approach, targeting is accomplished formulating charged lipids. Negatively lipids localize spleen, and positively lungs. Here we found that lung-tropic...
Abstract After more than 100 failed drug trials for acute ischemic stroke (AIS), one of the most commonly cited reasons failure has been that drugs achieve very low concentrations in at-risk penumbra. To address this problem, here we employ nanotechnology to significantly enhance concentration penumbra’s blood-brain barrier (BBB), whose increased permeability AIS long hypothesized kill neurons by exposing them toxic plasma proteins. devise drug-loaded nanocarriers targeted BBB, conjugated...
Traumatic brain injury has faced numerous challenges in drug development, primarily due to the difficulty of effectively delivering drugs brain. However, there is a potential solution targeted delivery methods involving antibody-drug conjugates or nanocarriers conjugated with targeting antibodies. Following TBI, blood-brain barrier (BBB) becomes permeable, which can last for years and allow leakage harmful plasma proteins. Consequently, an appealing approach TBI treatment involves using...
Abstract Nanomedicine has long pursued the goal of targeted delivery to specific organs and cell types but not achieved this with vast majority targets. One rare example success in pursuit been 25+ years studies targeting lung endothelium using nanoparticles conjugated antibodies against endothelial surface molecules. However, here we show that such “endothelial-targeted” nanocarriers also effectively target lungs’ numerous marginated neutrophils, which reside pulmonary capillaries patrol...
ABSTRACT Selective drug delivery to injured regions of the brain is an elusive, but biomedically important, goal. It tempting co-opt migrating white blood cells (WBC) carry drugs brain, using natural WBC tropism. Current approaches load cargoes have limited utility, particularly in acute conditions, due need for time consuming ex vivo manipulation and loading cells. Physiological, may be advantageous this scenario. Here we devised such a strategy, capitalizing on unique features direct...
Abstract Two camps have emerged in the targeting of nanoparticles to specific organs and cell types: affinity moiety targeting, which conjugates antibodies or similar molecules that bind known surface markers on cells; physicochemical tropism, achieves organ uptake based nanoparticle’s physical chemical features (e.g., binding endogenous proteins). Because these are largely non-overlapping, two approaches not been directly compared combined. Here we do both, using intravenous (IV) lipid...