A5035761451- Barrier Structure and Function Studies
- Extracellular vesicles in disease
- Nanoparticle-Based Drug Delivery
- Monoclonal and Polyclonal Antibodies Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Cell Adhesion Molecules Research
- RNA Interference and Gene Delivery
- Complement system in diseases
- Caveolin-1 and cellular processes
- Inhalation and Respiratory Drug Delivery
- Neonatal Respiratory Health Research
- Graphene and Nanomaterials Applications
- Peptidase Inhibition and Analysis
- Angiogenesis and VEGF in Cancer
- Nanoplatforms for cancer theranostics
- Mechanical Circulatory Support Devices
- Signaling Pathways in Disease
- Acute Ischemic Stroke Management
- Nanopore and Nanochannel Transport Studies
- biodegradable polymer synthesis and properties
- Cancer-related gene regulation
- Ocular Surface and Contact Lens
- Cancer-related molecular mechanisms research
- S100 Proteins and Annexins
- Biochemical and Structural Characterization
Translational Therapeutics (United States)
2017-2024
University of Pennsylvania
2017-2024
Target (United States)
2017-2020
Clemson University
2015
Drug delivery by nanocarriers (NCs) has long been stymied dominant liver uptake and limited target organ deposition, even when NCs are targeted using affinity moieties. Here we report a universal solution: red blood cell (RBC)-hitchhiking (RH), in which adsorbed onto the RBCs transfer from to first downstream of intravascular injection. RH improves for wide range viral vectors. For example, injected intravenously increases liposome organ, lungs, ~40-fold compared with free NCs. Intra-carotid...
The vasculature is an essential component of the circulatory system that plays a vital role in development, homeostasis, and disease various organs human body. ability to emulate architecture transport function blood vessels integrated context their associated represents important requirement for studying wide range physiological processes. Traditional vitro models vasculature, however, largely fail offer such capabilities. Here we combine microfluidic three-dimensional (3D) cell culture...
Significance Drug delivery to the brain is a challenging and elusive goal. Conjugating with ligands of target molecules including transferrin receptor modestly enhances cerebral accumulation drugs drug carriers. We found that conjugating VCAM-1 provides order(s) magnitude higher nanocarriers, especially in inflamed brain. targeted nanocarriers loaded messenger RNA encoding endothelial glycoprotein thrombomodulin cause expression transgene lumen vasculature. This alleviates pathological...
Abstract Molecular targeting of nanoparticle drug carriers promises maximized therapeutic impact to sites disease or injury with minimized systemic effects. Precise demands addressing subcellular features. Caveolae, invaginations in cell membranes implicated transcytosis and inflammatory signaling, are appealing targets. Caveolar geometry has been reported impose a ≈50 nm size cutoff on nanocarrier access plasmalemma vesicle associated protein (PLVAP), marker found caveolae the lungs. The...
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%...
Abstract Endothelial cells actively maintain an anti-thrombotic environment; loss of this protective function may lead to thrombosis and systemic coagulopathy. The transcription factor ERG is essential endothelial homeostasis. Here, we show that inducible deletion ( Erg iEC-KO ) in mice associated with spontaneous thrombosis, hemorrhages We find drives the anticoagulant thrombomodulin (TM), as shown by reporter assays chromatin immunoprecipitation. TM expression regulated shear stress (SS)...
The conjugation of antibodies to drugs and drug carriers improves delivery target tissues. Widespread implementation effective translation this pharmacologic strategy awaits the development affinity ligands capable a defined degree modification highly efficient bioconjugation without loss affinity. To date, such are lacking for targeting therapeutics vascular endothelial cells. enable site-specific, click-chemistry therapeutic cargo, we used bacterial transpeptidase, sortase A, attach short...
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...
Abstract Targeting drugs to endothelial cells has shown the ability improve outcomes in animal models of inflammatory, ischemic and thrombotic diseases. Previous studies have revealed that certain pairs ligands (antibodies antibody fragments) specific for adjacent, but distinct, epitopes on PECAM-1 enhance each other’s binding, a phenomenon dubbed Collaborative Enhancement Paired Affinity Ligands, or CEPAL. This discovery been leveraged enable simultaneous delivery multiple therapeutics...
The pulmonary vasculature plays an important role in many lung pathologies, such as arterial hypertension, primary graft dysfunction of transplant, and acute respiratory distress syndrome. Therapy for these diseases is quite limited, largely due to dose-limiting side effects numerous drugs that have been trialed or approved. High doses targeting the are needed lack specific affinity therapeutic compounds vasculature. To overcome this problem, field targeted drug delivery aims target...
Monoclonal antibodies (mAbs) directed to extracellular epitopes of human and mouse Platelet Endothelial Cell Adhesion Molecule-1 (CD31 or PECAM-1) stimulate binding other mAbs distinct adjacent PECAM-1 epitopes. This effect, dubbed Collaborative Enhancement Paired Affinity Ligands, CEPAL, has been shown enhance delivery mAb-targeted drugs nanoparticles the vascular endothelium. Here we report new insights into mechanism underlying this which demonstrates equivalent amplitude in following...
Targeted drug delivery to the endothelium has potential generate localized therapeutic effects at blood-tissue interface.For some cargoes, it is essential maintain contact with bloodstream exert protective effects.The pharmacokinetics (PK) of endothelial surface-targeted affinity ligands and biotherapeutic cargo remain a largely unexplored area, despite obvious translational implications for this strategy.To bridge gap, we site-specifically radiolabeled mono-(scFv) bivalent (mAb) specific...
Surface plasmon resonance (SPR) was used in this research to investigate the targeting efficacy (i.e., binding affinity) of antibody-modified liposomes. The results indicated that liposomes modified by antibodies exhibited an increase apparent affinity, a result attributed avidity effect. More specifically, effect improved as surface density antibody increased, primarily decrease dissociation rate. However, trend stopped when reached threshold approximately 1.5 × 10(8) antibody/mm(2). This...
Abstract Acute lung inflammation has severe morbidity, as seen in COVID-19 patients. Lung is accompanied or led by massive accumulation of neutrophils pulmonary capillaries (“margination”). We sought to identify nanostructural properties that predispose nanoparticles accumulate marginated neutrophils, and therefore target severely inflamed lungs. designed a library conducted an vivo screen biodistributions naive mice treated with lipopolysaccharides. found supramolecular organization protein...