Preclinical validation of human recombinant glutamate-oxaloacetate transaminase for the treatment of acute ischemic stroke.

The blood enzyme glutamate-oxaloacetate transaminase (GOT) has been postulated as an effective therapeutic to protect the brain during stroke. To demonstrate its potential clinical utility, a new human recombinant form of GOT (rGOT) was produced for medical use. We tested the pharmacokinetics and evaluated the protective efficacy of rGOT in rodent and non-human primate models that reflected clinical stroke conditions.

Lipidomics and biodistribution of extracellular vesicles-secreted by hepatocytes from Zucker lean and fatty rats.

Extracellular vesicles (EVs) have been involved in metabolic syndrome, although their specific role in the development of the pathology is still unknown. To further study the role of EVs, we have analysed by Raman tweezers microspectroscopy and mass spectrometry-based lipidomics the small EVs population secreted by fatty (ZF) and lean (ZL) hepatocytes obtained from Zucker rats. We have also explored in vivo and ex vivo biodistribution of these EVs through fluorine-18-radiolabelling using a positron emission tomography imaging.

The In Vivo Biological Fate of Protein Corona: A Comparative PET Study of the Fate of Soft and Hard Protein Corona in Healthy Animal Models.

Radiolabeling and nuclear imaging techniques are used to investigate the biodistribution patterns of the soft and hard protein corona around poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) after administration to healthy mice. Soft and hard protein coronas of I-labeled BSA or I-labeled serum are formed on PLGA NPs functionalized with either polyehtylenimine (PEI) or bovine serum albumin (BSA). The exchangeability of hard and soft corona is assessed in vitro by gamma counting exposing PLGA NPs with corona to non-labeled BSA, serum, or simulated body fluid.

Anti-seizure effects of JNJ-54175446 in the intra-amygdala kainic acid model of drug-resistant temporal lobe epilepsy in mice.

There remains a need for new drug targets for treatment-resistant temporal lobe epilepsy. The ATP-gated P2X7 receptor coordinates neuroinflammatory responses to tissue injury. Previous studies in mice reported that the P2X7 receptor antagonist JNJ-47965567 suppressed spontaneous seizures in the intraamygdala kainic acid model of epilepsy and reduced attendant gliosis in the hippocampus.

Synthesis and PET Imaging Biodistribution Studies of Radiolabeled Iododiflunisal, a Transthyretin Tetramer Stabilizer, Candidate Drug for Alzheimer's Disease.

The small-molecule iododiflunisal (IDIF) is a transthyretin (TTR) tetramer stabilizer and acts as a chaperone of the TTR-Amyloid beta interaction. Oral administration of IDIF improves Alzheimer's Disease (AD)-like pathology in mice, although the mechanism of action and pharmacokinetics remain unknown. Radiolabeling IDIF with positron or gamma emitters may aid in the in vivo evaluation of IDIF using non-invasive nuclear imaging techniques.

Urease-powered nanobots for radionuclide bladder cancer therapy.

Bladder cancer treatment via intravesical drug administration achieves reasonable survival rates but suffers from low therapeutic efficacy. To address the latter, self-propelled nanoparticles or nanobots have been proposed, taking advantage of their enhanced diffusion and mixing capabilities in urine when compared with conventional drugs or passive nanoparticles. However, the translational capabilities of nanobots in treating bladder cancer are underexplored.

A PEG-assisted membrane coating to prepare biomimetic mesoporous silicon for PET/CT imaging of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) diagnosis remains challenging without expressing critical receptors. Cancer cell membrane (CCm) coating has been extensively studied for targeted cancer diagnostics due to attractive features such as good biocompatibility and homotypic tumor-targeting. However, the present study found that widely used CCm coating approaches, such as extrusion, were not applicable for functionalizing irregularly shaped nanoparticles (NPs), such as porous silicon (PSi).

Multimodal imaging of the role of hyperglycemia following experimental subarachnoid hemorrhage.

Hyperglycemia has been linked to worsening outcomes after subarachnoid hemorrhage (SAH). Nevertheless, the mechanisms involved in the pathogenesis of SAH have been scarcely evaluated so far. The role of hyperglycemia was assessed in an experimental model of SAH by T weighted, dynamic contrast-enhanced magnetic resonance imaging (TW and DCE-MRI), [F]BR-351 PET imaging and immunohistochemistry.

Positron Emission Tomography Studies of the Biodistribution, Translocation, and Fate of Poly Allyl Amine-Based Carriers for Sirna Delivery by Systemic and Intratumoral Administration.

Polyamine-based vectors offer many advantages for gene therapy, but they are hampered by a limited knowledge on their biological fate and efficacy for nucleic acid delivery. The F radiolabeled siRNA is complexed with poly(allyl amine) hydrochloride (PAH), PEGylated PAH (PAH ), or oleic acid-modified PAH (PAH ) to form polyplexes, and injected them intravenously into healthy rodents. The biodistribution patterns obtained by positron emission tomography (PET) imaging vary according to the polymer used for complexation.

Ammonium trifluoroborate-modified poly(β-aminoesters): A case study for PET-guided in vivo pharmacokinetic studies of a non-viral gene delivery system.

Nucleic acid-based therapies have become a game-changing player in our way of conceiving pharmacology. Nevertheless, the inherent lability of the phosphodiester bond of the genetic material with respect to the blood nucleases severely hampers its delivery in naked form, therefore making it necessary to use delivery vectors. Among the potential non-viral vectors, polymeric materials such as the poly(β-aminoesters) (PBAEs) stand out as promising gene carriers thanks to their ability to condense nucleic acids in the form of nanometric polyplexes.

Therapeutic effect of 7 nicotinic receptor activation after ischemic stroke in rats.

Nicotinic acetylcholine α7 receptors (α7 nAChRs) have a well-known modulator effect in neuroinflammation. Yet, the therapeutical effect of α7 nAChRs activation after stroke has been scarcely evaluated to date. The role of α7 nAChRs activation with PHA 568487 on inflammation after brain ischemia was assessed with positron emission tomography (PET) using [F]DPA-714 and [F]BR-351 radiotracers after transient middle cerebral artery occlusion (MCAO) in rats.

Pharmacokinetic Evaluation of New Drugs Using a Multi-Labelling Approach and PET Imaging: Application to a Drug Candidate with Potential Application in Neuromuscular Disorders.

Background And Objective: The determination of pharmacokinetic properties of new chemical entities is a key step in the process of drug development. Positron emission tomography (PET) is an ideal technique to obtain both biodistribution and pharmacokinetic parameters of new compounds over a wide range of chemical modalities. Here, we use a multi-radionuclide/multi-position labelling approach to investigate distribution, elimination, and metabolism of a triazole-based FKBP12 ligand (AHK2) with potential application in neuromuscular disorders.

Infection-specific PET imaging with F-fluorodeoxysorbitol and 2-[F]F-ρ-aminobenzoic acid: An extended diagnostic tool for bacterial and fungal diseases.

Introduction: Suspected infectious diseases located in difficult-to-access sites can be challenging due to the need for invasive procedures to isolate the etiological agent. Positron emission tomography (PET) is a non-invasive imaging technology that can help locate the infection site. The most widely used radiotracer for PET imaging (2-deoxy-2[F] fluoro-D-glucose: [F]FDG) shows uptake in both infected and sterile inflammation.

Phase-Separated Liposomes Hijack Endogenous Lipoprotein Transport and Metabolism Pathways to Target Subsets of Endothelial Cells In Vivo.

Plasma lipid transport and metabolism are essential to ensure correct cellular function throughout the body. Dynamically regulated in time and space, the well-characterized mechanisms underpinning plasma lipid transport and metabolism offers an enticing, but as yet underexplored, rationale to design synthetic lipid nanoparticles with inherent cell/tissue selectivity. Herein, a systemically administered liposome formulation, composed of just two lipids, that is capable of hijacking a triglyceride lipase-mediated lipid transport pathway resulting in liposome recognition and uptake within specific endothelial cell subsets is described.

Increased uptake of the P2X7 receptor radiotracer F-JNJ-64413739 in the brain and peripheral organs according to the severity of status epilepticus in male mice.

Objective: The P2X7 receptor (P2X7R) is an important contributor to neuroinflammation, responding to extracellularly released adenosine triphosphate. Expression of the P2X7R is increased in the brain in experimental and human epilepsy, and genetic or pharmacologic targeting of the receptor can reduce seizure frequency and severity in preclinical models. Experimentally induced seizures also increase levels of the P2X7R in blood.

PET Imaging of Self-Assembled F-Labelled Pd L Metallacages for Anticancer Drug Delivery.

To advance the design of self-assembled metallosupramolecular architectures as new generation theranostic agents, the synthesis of F-labelled [Pd L ] metallacages is reported. Different spectroscopic and bio-analytical methods support the formation of the host-guest cage-cisplatin complex. The biodistribution profiles of one of the cages, alone or encapsulating cisplatin have been studied by PET/CT imaging in healthy mice in vivo, in combination to ICP-MS ex vivo.

Assessment of Regional Lung Ventilation with Positron Emission Tomography Using the Radiofluorinated Gas [F]SF: Application to an Animal Model of Impaired Ventilation.

Purpose: Clinical ventilation studies are primarily performed with computerized tomography (CT) and more often with single-photon emission Computerized tomography (SPECT) using radiolabelled aerosols, both presenting certain limitations. Here, we investigate the use of the radiofluorinated gas [F]SF as a positron emission tomography (PET) ventilation marker in an animal model of impaired lung ventilation.

Procedures: Sprague-Dawley rats (n = 15) were randomly assigned to spontaneous ventilation (sham group), endotracheal administration of phosphate-buffered saline (PBS group), or endotracheal administration of lipopolysaccharide (LPS group).

Core surface labelling of mesoporous silica nanoparticles: advancing the understanding of nanoparticle fate and design of labelling strategies.

Despite great interest in the use of silica mesoporous nanoparticles (MSNs) in drug delivery little is known on their biological fate. Positron emission tomography (PET) studies of radiolabelled MSNs face a major difficulty due to the degradation of the MSNs during circulation as it is difficult to assign activity values to either the MSNs or their degradation products. Here, a PET study is conducted using two strategies of labelling.

Decellularization of xenografted tumors provides cell-specific 3D environment.

cell culture studies are common in the cancer research field, and reliable biomimetic 3D models are needed to ensure physiological relevance. In this manuscript, we hypothesized that decellularized xenograft tumors can serve as an optimal 3D substrate to generate a top-down approach for tumor modeling. Multiple tumor cell lines were xenografted and the formed solid tumors were recovered for their decellularization by several techniques and further characterization by histology and proteomics techniques.

The Replica Set Method is a Robust, Accurate, and High-Throughput Approach for Assessing and Comparing Lifespan in Experiments.

The advent of feeding based RNAi in led to an era of gene discovery in aging research. Hundreds of gerogenes were discovered, and many are evolutionarily conserved, raising the exciting possibility that the underlying genetic basis for healthy aging in higher vertebrates could be quickly deciphered. Yet, the majority of putative gerogenes have still only been cursorily characterized, highlighting the need for high-throughput, quantitative assessments of changes in aging.

NSI and PCL-5 Normative Tables for Active Duty Service Members Affected by Traumatic Brain Injury.

Introduction: Many service members (SMs) have been diagnosed with traumatic brain injury. Currently, military treatment facilities do not have access to established normative tables which can assist clinicians in gauging and comparing patient-reported symptoms. The aim of this study is to provide average scores for both the Neurobehavioral Symptom Inventory (NSI) and Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5) for active duty SMs based upon varying demographic groups.

Longitudinal evaluation of neuroinflammation and oxidative stress in a mouse model of Alzheimer disease using positron emission tomography.

Background: Validation of new biomarkers of Alzheimer disease (AD) is crucial for the successful development and implementation of treatment strategies. Additional to traditional AT(N) biomarkers, neuroinflammation biomarkers, such as translocator protein (TSPO) and cystine/glutamine antiporter system (x), could be considered when assessing AD progression. Herein, we report the longitudinal investigation of [F]DPA-714 and [F]FSPG for their ability to detect TSPO and x biomarkers, respectively, in the 5xFAD mouse model for AD.

Catalytic alkene skeletal modification for the construction of fluorinated tertiary stereocenters.

Herein we describe the first construction of fluorinated tertiary stereocenters based on an alkene C(sp)-C(sp) bond cleavage. The new process, that takes advantage of a Rh-catalyzed carbyne transfer, relies on a branched-selective fluorination of tertiary allyl cations and is distinguished by a wide scope including natural products and drug molecule derivatives as well as adaptability to radiofluorination.