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Abstract Background Reactive microglia and recruited peripheral macrophages contribute to the pathogenesis of Alzheimer’s dementia (AD). Monocytes, macrophages and microglia all express the marker colony-stimulating factor 1 receptor (CSF1R). 4-Cyano-N-(4-(4-methylpiperazin-1-yl)-2-(4-methylpiperidin-1-yl)phenyl)-1H-pyrrole-2-carboxamide (1) is a high-affinity antagonist for CSF1R. We report the radiosynthesis of both [3H]1 and [11C]1. The PET imaging properties of [11C]1 in mice and baboon were investigated. [3H]1 was studied in Bmax measurement in post-mortem autoradiography in the frontal cortex, inferior parietal cortex and hippocampus from donors diagnosed with AD and age-matched controls. In vitro binding affinity of 1 was measured commercially. Nor-methyl-1 precursor was radiolabeled with [11C]iodomethane or [3H]iodomethane to produce [11C]1 and [3H]1, respectively. Ex vivo brain biodistribution of [11C]1 was compared in normal mice versus lipopolysaccharide-administered (LPS) murine model of neuroinflammation. Dynamic PET imaging was performed in a healthy male Papio anubis baboon. Post-mortem autoradiography with [3H]1 was performed in frozen sections using a standard saturation binding technique. Results Compound 1 exhibits a high in vitro CSF1R binding affinity (0.59 nM). [11C]1 was synthesized with high yield. [3H]1 was synthesized similarly (commercially). Biodistribution of [11C]1 in healthy mice demonstrated moderate brain uptake. In LPS-treated mice the brain uptake of [11C]1 was ~ 50% specific for CSF1R. PET/CT [11C]1 study in baboon revealed low brain uptake (0.36 SUV) of [11C]1. Autoradiography with [3H]1 gave significantly elevated Bmax values in AD frontal cortex versus control (47.78 ± 26.80 fmol/mg vs. 12.80 ± 5.30 fmol/mg, respectively, P = 0.023) and elevated, but not significantly different binding in AD hippocampus grey matter and inferior parietal cortex (IPC) white matter. Conclusions Compound 1 exhibits a high in vitro CSF1R binding affinity. [11C]1 specifically labels CSF1R in the mouse neuroinflammation, but lacks the ability to efficiently cross the blood–brain barrier in baboon PET. [3H]1 specifically labels CSF1R in post-mortem human brain. The binding of [3H]1 is significantly higher in the post-mortem frontal cortex of AD versus control subjects.

Background: Reactive microglia and recruited peripheral macrophages contribute to the pathogenesis of Alzheimer's dementia (AD). Monocytes, macrophages and microglia all express the marker colony-stimulating factor 1 receptor (CSF1R). 4-Cyano-N-(4-(4-methylpiperazin-1-yl)-2-(4-methylpiperidin-1-yl)phenyl)-1H-pyrrole-2-carboxamide (1) is a high-affinity antagonist for CSF1R. We report the radiosynthesis of both [3H]1 and [11C]1. The PET imaging properties of [11C]1 in mice and baboon were investigated. [3H]1 was studied in Bmax measurement in post-mortem autoradiography in the frontal cortex, inferior parietal cortex and hippocampus from donors diagnosed with AD and age-matched controls. In vitro binding affinity of 1 was measured commercially. Nor-methyl-1 precursor was radiolabeled with [11C]iodomethane or [3H]iodomethane to produce [11C]1 and [3H]1, respectively. Ex vivo brain biodistribution of [11C]1 was compared in normal mice versus lipopolysaccharide-administered (LPS) murine model of neuroinflammation. Dynamic PET imaging was performed in a healthy male Papio anubis baboon. Post-mortem autoradiography with [3H]1 was performed in frozen sections using a standard saturation binding technique. Results: Compound 1 exhibits a high in vitro CSF1R binding affinity (0.59 nM). [11C]1 was synthesized with high yield. [3H]1 was synthesized similarly (commercially). Biodistribution of [11C]1 in healthy mice demonstrated moderate brain uptake. In LPS-treated mice the brain uptake of [11C]1 was ~ 50% specific for CSF1R. PET/CT [11C]1 study in baboon revealed low brain uptake (0.36 SUV) of [11C]1. Autoradiography with [3H]1 gave significantly elevated Bmax values in AD frontal cortex versus control (47.78 ± 26.80 fmol/mg vs. 12.80 ± 5.30 fmol/mg, respectively, P = 0.023) and elevated, but not significantly different binding in AD hippocampus grey matter and inferior parietal cortex (IPC) white matter. Conclusions: Compound 1 exhibits a high in vitro CSF1R binding affinity. [11C]1 specifically labels CSF1R in the mouse neuroinflammation, but lacks the ability to efficiently cross the blood–brain barrier in baboon PET. [3H]1 specifically labels CSF1R in post-mortem human brain. The binding of [3H]1 is significantly higher in the post-mortem frontal cortex of AD versus control subjects. [ABSTRACT FROM AUTHOR]

Recently developed molecular imaging approaches can be used to visualize specific host responses and pathology in a quest to image infections where few microbe-specific tracers have been developed and in recognition that host responses contribute to morbidity and mortality in their own right. Here we highlight several recent examples of these imaging approaches adapted for imaging infections. The early successes and new avenues described here encompass diverse imaging modalities and leverage diverse aspects of the host response to infection—including inflammation, tissue injury and healing, and key nutrients during host-pathogen interactions. Clearly, these approaches merit further preclinical and clinical study as they are complementary and orthogonal to the pathogen-focused imaging modalities currently under investigation. [ABSTRACT FROM AUTHOR]

Abstract Carbon nanogels (CNGs) with dual ability of reactive oxygen species (ROS) imaging and photodynamic therapy have been designed with self‐assembled chemiluminescent carbonized polymer dots (CPDs). With efficient deep‐red/near‐infrared chemiluminescence (CL) emission and distinctive photodynamic capacity, the H2O2‐driven chemiluminescent CNGs are further designed by assembling the polymeric conjugate and CL donors, enabling an in vitro and in vivo ROS bioimaging capability in animal inflammation models and a high‐performance therapy for xenograft tumors. Mechanistically, ROS generated in inflammatory sites or tumor microenvironment can trigger the chemically initiated electron exchange luminescence in the chemical reaction of peroxalate and H2O2, enabling in vivo CL imaging. Meanwhile, part of the excited‐state electrons will transfer to the ambient H2O or dissolved oxygen and in turn lead to the type I and type II photochemical ROS production of hydroxyl radicals or singlet oxygen, endowing the apoptosis of tumor cells and thus enabling cancer therapy. These results open up a new avenue for the design of multifunctional nanomaterials for bioimaging and antienoplastic agents.

Abstract Purpose In the characterization of severe lung diseases, early detection of specific inflammatory cells could help to monitor patients’ response to therapy and increase chances of survival. Macrophages contribute to regulating the resolution and termination of inflammation and have increasingly been of interest for targeted therapies. [68Ga]Ga-DOTA-TATE is an established clinical radiopharmaceutical targeting somatostatin receptor subtype 2 (SSTR 2). Since activated macrophages (M1) overexpress SSTR 2, the aim of this study was to investigate the applicability of [68Ga]Ga-DOTA-TATE for positron emission tomography (PET) imaging of M1 macrophages in pulmonary inflammation. Methods Inflammation in the pig lungs was induced by warm saline lavage followed by injurious ventilation in farm pigs (n = 7). Healthy pigs (n = 3) were used as control. A 60-min dynamic PET scan over the lungs was performed after [68Ga]Ga-DOTA-TATE injection and [18F]FDG scan was executed afterward for comparison. The uptake of both tracers was assessed as mean standardized uptake values (SUVmean) 30–60-min post-injection. The PET scans were followed by computed tomography (CT) scans, and the Hounsfield units (HU) were quantified of the coronal segments. Basal and apical segments of the lungs were harvested for histology staining. A rat lung inflammation model was also studied for tracer specificity using lipopolysaccharides (LPS) by oropharyngeal aspiration. Organ biodistribution, ex vivo autoradiography (ARG) and histology samples were conducted on LPS treated, octreotide induced blocking and control healthy rats. Results The accumulation of [68Ga]Ga-DOTA-TATE on pig lavage model was prominent in the more severely injured dorsal segments of the lungs (SUVmean = 0.91 ± 0.56), compared with control animals (SUVmean = 0.27 ± 0.16, p

Abstract Background Ulcerative colitis (UC), a subtype of inflammatory bowel disease (IBD), has evolved into a global burden given its high incidence. There is a clinical need to create better diagnostic and therapeutic approaches to UC. Results We fabricated P-selectin binding peptide-decorated poly lactic-co-glycolic acid (PBP-PLGA-NP) doped with two lipophilic dyes, DiL and DiD. Meanwhile, two low-toxic anti-inflammatory natural products (betulinic acid [BA] and resveratrol [Res]) were co-loaded in the PBP-PLGA-NP system. The BA/Res-loaded NPs had an average size of around 164.18 nm with a negative zeta potential (− 25.46 mV). Entrapment efficiencies of BA and Res were 74.54% and 52.33%, respectively, and presented a sustained drug release profile. Further, the resulting PBP-PLGA-NP could be internalized by RAW 264.7 cells and Colon-26 cells efficiently in vitro and preferentially localized to the inflamed colon. When intravenously injected with luminol, MPO-dependent bioluminescence imaging to visualize tissue inflammation was activated by the bioluminescence and fluorescence resonance energy transfer (BRET-FRET) effect. Importantly, injected NPs could remarkably alleviate UC symptoms yet maintain intestinal microbiota homeostasis without inducing organ injuries in the mice models of colitis. Conclusions This theranostic nano-platform not only serves as a therapeutic system for UC but also as a non-invasive and highly-sensitive approach for accurately visualizing inflammation. Graphical Abstract

Purpose of Review: This focused report aims to discuss and summarize the use of conventional and emerging methods using cardiovascular magnetic resonance (CMR) imaging in cardiomyopathy patients with implanted cardiac devices to identify diffuse and focal inflammation and fibrosis. Recent Findings: Many cardiomyopathy patients with diffuse and focal myocardial fibrosis have a unique need for cardiac imaging that is complicated by cardiovascular implantable electronic devices (CIEDs). CMR imaging can accurately image myocardial fibrosis and inflammation using T1 mapping and late gadolinium enhancement (LGE) imaging. CMR imaging in CIED patients, however, has been limited due to severe imaging artifacts associated with the devices. The emergence of wideband imaging variants of LGE and T1 mapping techniques can successfully reduce or eliminate CIED artifacts for the evaluation of myocardial substrate in cardiomyopathy patients. Summary: Wideband imaging variants of LGE and T1 mapping techniques provide new tools for imaging focal and diffuse fibrosis and imaging in cardiomyopathy patients with implanted cardiac devices. These emerging techniques have the potential for great impact in clinical care of such patients as well as clinical research where imaging endpoints are desired. [ABSTRACT FROM AUTHOR]

To enable patients with rheumatoid arthritis (RA) and their healthcare professionals to choose the optimal treatment, it is crucial to accurately assess the current state of inflammatory activity. The objectives of this study were to (1) investigate the perspective of RA patients on their insight into the current status of their disease, and to (2) investigate the patients' perspective on the possible added value of a monitoring device based on optical spectral transmission—called the HandScan—that measures the location and severity of joint inflammation. A survey was distributed online among patients with RA in the Netherlands. Four-hundred and eight patients with RA completed the survey. Of these, 298 (73%) felt they have sufficient insight into their current disease status. Most respondents perceived either a large (n = 242; 59%) or small (n = 148; 36%) added value of the HandScan in their monitoring process, mostly because the device provides additional knowledge on the presence of inflammation. This perceived added value was higher for respondents experienced with the device (n = 46; p =.04). Respondents preferred monitoring with the device on every (n = 192; 47%) or most (n = 171; 42%) visits to the outpatient clinic, or even more often than on every visit (n = 17; 4%). Monitoring RA using an optical spectral transmission device is seen by patients as a possibly valuable addition to the monitoring process of inflammatory activity during visits to an outpatient clinic. Their main reason was that the device can increase insight into their current disease status. More insight may support patients in discussing treatment options with their rheumatologist. [ABSTRACT FROM AUTHOR]

Background: Sjögren's syndrome (SS) is a progressive autoimmune disease characterized by local mononuclear cell infiltration of the salivary and lachrymal glands. Labial biopsy demonstrates local infiltration by Th1 cells that produce pro-inflammatory cytokines, such as interleukin-2 (IL2). The aim of this study was to assess the utility of 99mTc-labelled-IL2 (99mTc-IL2) in evaluating in vivo the extent and severity of lympho-mononuclear cell infiltration in the salivary glands of patients with SS. Methods: We investigated 48 patients with primary SS and 27 control subjects using 99mTc-IL2 scintigraphy. Furthermore, in a subgroup of 30 patients, we also performed 99mTc-pertechnetate scintigraphy (99mTcO4−) for evaluation of the salivary gland function. Results: 99mTc-IL2 uptake in the salivary glands of SS patients was higher than in the control subjects (1.30 ± 0.16 vs. 0.83 ± 0.08 for parotids and 1.36 ± 0.15 vs. 1.16 ± 0.07 for submandibular glands; p < 0.0001). The salivary gland uptake of 99mTc-IL2 in patients with a longer history of disease was lower compared with the recently diagnosed patients. A significant direct correlation was found between the uptake of 99mTc-IL2 and histology. Conclusions: 99mTc-IL2 scintigraphy showed that the degree of lymphocytic infiltration of major salivary glands is variable in patients with different disease durations. Patients with a high 99mTc-IL2 uptake could be efficiently treated with immuno-modulatory drugs and the efficacy of treatment could be followed-up by 99mTc-IL2 scintigraphy. [ABSTRACT FROM AUTHOR]

Carbon nanogels (CNGs) with dual ability of reactive oxygen species (ROS) imaging and photodynamic therapy have been designed with self‐assembled chemiluminescent carbonized polymer dots (CPDs). With efficient deep‐red/near‐infrared chemiluminescence (CL) emission and distinctive photodynamic capacity, the H2O2‐driven chemiluminescent CNGs are further designed by assembling the polymeric conjugate and CL donors, enabling an in vitro and in vivo ROS bioimaging capability in animal inflammation models and a high‐performance therapy for xenograft tumors. Mechanistically, ROS generated in inflammatory sites or tumor microenvironment can trigger the chemically initiated electron exchange luminescence in the chemical reaction of peroxalate and H2O2, enabling in vivo CL imaging. Meanwhile, part of the excited‐state electrons will transfer to the ambient H2O or dissolved oxygen and in turn lead to the type I and type II photochemical ROS production of hydroxyl radicals or singlet oxygen, endowing the apoptosis of tumor cells and thus enabling cancer therapy. These results open up a new avenue for the design of multifunctional nanomaterials for bioimaging and antienoplastic agents. [ABSTRACT FROM AUTHOR]

Purpose: In the characterization of severe lung diseases, early detection of specific inflammatory cells could help to monitor patients' response to therapy and increase chances of survival. Macrophages contribute to regulating the resolution and termination of inflammation and have increasingly been of interest for targeted therapies. [68Ga]Ga-DOTA-TATE is an established clinical radiopharmaceutical targeting somatostatin receptor subtype 2 (SSTR 2). Since activated macrophages (M1) overexpress SSTR 2, the aim of this study was to investigate the applicability of [68Ga]Ga-DOTA-TATE for positron emission tomography (PET) imaging of M1 macrophages in pulmonary inflammation. Methods: Inflammation in the pig lungs was induced by warm saline lavage followed by injurious ventilation in farm pigs (n = 7). Healthy pigs (n = 3) were used as control. A 60-min dynamic PET scan over the lungs was performed after [68Ga]Ga-DOTA-TATE injection and [18F]FDG scan was executed afterward for comparison. The uptake of both tracers was assessed as mean standardized uptake values (SUVmean) 30–60-min post-injection. The PET scans were followed by computed tomography (CT) scans, and the Hounsfield units (HU) were quantified of the coronal segments. Basal and apical segments of the lungs were harvested for histology staining. A rat lung inflammation model was also studied for tracer specificity using lipopolysaccharides (LPS) by oropharyngeal aspiration. Organ biodistribution, ex vivo autoradiography (ARG) and histology samples were conducted on LPS treated, octreotide induced blocking and control healthy rats. Results: The accumulation of [68Ga]Ga-DOTA-TATE on pig lavage model was prominent in the more severely injured dorsal segments of the lungs (SUVmean = 0.91 ± 0.56), compared with control animals (SUVmean = 0.27 ± 0.16, p < 0.05). The tracer uptake corresponded to the damaged areas assessed by CT and histology and were in line with HU quantification. The [68Ga]Ga-DOTA-TATE uptake in LPS treated rat lungs could be blocked and was significantly higher compared with control group. Conclusion: The feasibility of the noninvasive assessment of tissue macrophages using [68Ga]Ga-DOTA-TATE/PET was demonstrated in both porcine and rat lung inflammation models. [68Ga]Ga-DOTA-TATE has a great potential to be used to study the role and presence of macrophages in humans in fight against severe lung diseases. [ABSTRACT FROM AUTHOR]

Background: Ulcerative colitis (UC), a subtype of inflammatory bowel disease (IBD), has evolved into a global burden given its high incidence. There is a clinical need to create better diagnostic and therapeutic approaches to UC. Results: We fabricated P-selectin binding peptide-decorated poly lactic-co-glycolic acid (PBP-PLGA-NP) doped with two lipophilic dyes, DiL and DiD. Meanwhile, two low-toxic anti-inflammatory natural products (betulinic acid [BA] and resveratrol [Res]) were co-loaded in the PBP-PLGA-NP system. The BA/Res-loaded NPs had an average size of around 164.18 nm with a negative zeta potential (− 25.46 mV). Entrapment efficiencies of BA and Res were 74.54% and 52.33%, respectively, and presented a sustained drug release profile. Further, the resulting PBP-PLGA-NP could be internalized by RAW 264.7 cells and Colon-26 cells efficiently in vitro and preferentially localized to the inflamed colon. When intravenously injected with luminol, MPO-dependent bioluminescence imaging to visualize tissue inflammation was activated by the bioluminescence and fluorescence resonance energy transfer (BRET-FRET) effect. Importantly, injected NPs could remarkably alleviate UC symptoms yet maintain intestinal microbiota homeostasis without inducing organ injuries in the mice models of colitis. Conclusions: This theranostic nano-platform not only serves as a therapeutic system for UC but also as a non-invasive and highly-sensitive approach for accurately visualizing inflammation. [ABSTRACT FROM AUTHOR]

Intracranial aneurysms (IA) are often asymptomatic and have a prevalence of 3 to 5% in the adult population. The risk of IA rupture is low, however when it occurs half of the patients dies from subarachnoid hemorrhage (SAH). To avoid this fatal evolution, the main treatment is an invasive surgical procedure, which is considered to be at high risk of rupture. This risk score of IA rupture is evaluated mainly according to its size and location. Therefore, angiography and anatomic imaging of the intracranial aneurysm are crucial for its diagnosis. Moreover, it has become obvious in recent years that several other factors are implied in this complication, such as the blood flow complexity or inflammation. These recent findings lead to the development of new IA imaging tools such as vessel wall imaging, 4D-MRI, or molecular MRI to visualize inflammation at the site of IA in human and animal models. In this review, we will summarize IA imaging techniques used for the patients and those currently in development.

Synthetic antimicrobial peptide fragment, 99mTc-Ubiquicidin 29-41, is shown to be sensitive and also specific for imaging bacterial infections. We undertook this study to explore the advantage of using a positron emission agent, 68Ga-DOTA-Ubiquicidin 29-41 (68Ga-DOTA-UBI), for detecting Staph-A infection in an animal model, and also evaluated its ability to distinguish a turpentine-induced sterile inflammation in an animal model. Pure Ga-68 was freshly eluted from a 68Ge/68Ga generator (IGG-100). DOTA-UBI (50 μg) was radiolabeled with pure Ga-68 (500MBq) by incubating the reaction mixture at pH 4.5 for 10 min, 95°C. Rats were infected with Staph-A at the hind leg joint of rats to form bacterial abscess. Sterile inflammation was induced in the right thigh muscle by injecting 200 μl of 100% turpentine oil. Rats were injected intravenously with 10-15 MBq of tracer, and images were acquired at different time intervals with Siemens (Biograph mCT) positron emission tomography computed tomography scanner. The early images at 6 min postinjection clearly indicated mild uptake of the agent corresponding to the infection site, which increased dramatically at 20, 30, and 60 min postinjection. The target to background ratio (T/B) increased significantly over the same time period of study (1.6, 4.2, and 6.1, respectively). There was a mild uptake of 68Ga-DOTA-UBI at the site corresponding to sterile inflammation at 6 min postinjection, which was rapidly washed off as seen at 25 and 45 min images. The images indicated fast clearance of the agent from liver and soft tissues within 6 min. Control rats showed similar biodistribution of activity. The mild uptake of 68Ga-DOTA-UBI at the corresponding Staph-A infection lesion and very fast kinetics of clearance from the blood pool and soft tissues suggested a very high clinical potential for this agent. The absence of uptake of the agent at sterile inflammation site suggests that the agent may be useful in distinguishing infection from inflammation. [ABSTRACT FROM AUTHOR]

Abstract As a basic innate immune response to the disordered tissue homeostasis, inflammation is related to the pathogenesis of multiple diseases, including bacterial infections, atherosclerosis, neurodegenerative diseases, and cancers. It is also a pivotal feature of some metabolic disorders such as diabetes and obesity. The visualization of in vivo inflammations can help us to comprehend the pathogenesis of these diseases and develop new solutions to diagnose them. Over the past few decades, a variety of strategies (eg, computed tomography, magnetic resonance imaging [MRI], and ultrasound [US] imaging) have been utilized for visualizing inflammations by imaging the structural changes of inflammatory tissues. Moreover, many recent studies have focused on some probes that can target or localize the inflammatory sites by specific binding to inflammation‐related molecules, being internalized by inflammatory cells, or becoming detectable only under inflammatory conditions. These probes can also be applied to visualize inflammations by MRI, positron emission tomography, single‐photon emission computed tomography, photoacoustic imaging, optical imaging (eg, fluorescence imaging, bioluminescence imaging, and chemiluminescence imaging), contrast‐enhanced US imaging, and the combined use of the abovementioned methods. This review not only summarizes the existing strategies for visualizing inflammations, but also discusses the limitations of the present strategies and the future directions on the development of new strategies for realizing the in vivo inflammation visualization.

As a basic innate immune response to the disordered tissue homeostasis, inflammation is related to the pathogenesis of multiple diseases, including bacterial infections, atherosclerosis, neurodegenerative diseases, and cancers. It is also a pivotal feature of some metabolic disorders such as diabetes and obesity. The visualization of in vivo inflammations can help us to comprehend the pathogenesis of these diseases and develop new solutions to diagnose them. Over the past few decades, a variety of strategies (eg, computed tomography, magnetic resonance imaging [MRI], and ultrasound [US] imaging) have been utilized for visualizing inflammations by imaging the structural changes of inflammatory tissues. Moreover, many recent studies have focused on some probes that can target or localize the inflammatory sites by specific binding to inflammation‐related molecules, being internalized by inflammatory cells, or becoming detectable only under inflammatory conditions. These probes can also be applied to visualize inflammations by MRI, positron emission tomography, single‐photon emission computed tomography, photoacoustic imaging, optical imaging (eg, fluorescence imaging, bioluminescence imaging, and chemiluminescence imaging), contrast‐enhanced US imaging, and the combined use of the abovementioned methods. This review not only summarizes the existing strategies for visualizing inflammations, but also discusses the limitations of the present strategies and the future directions on the development of new strategies for realizing the in vivo inflammation visualization. [ABSTRACT FROM AUTHOR]

The study of blood brain barrier (BBB) functions is important for neurological disorder research. However, the lack of suitable tools and methods has hampered the progress of this field. Herein, we present a hybrid nanodot strategy, termed AIE-Gd dots, comprising of a fluorogen with aggregation-induced emission (AIE) characteristics as the core to provide bright and stable fluorescence for optical imaging, and gadolinium (Gd) for accurate quantification of vascular leakage via inductively-coupled plasma mass spectrometry (ICP-MS). In this report, we demonstrate that AIE-Gd dots enable direct visualization of brain vascular networks under resting condition, and that they form localized punctate aggregates and accumulate in the brain tissue during experimental cerebral malaria, indicative of hemorrhage and BBB malfunction. With its superior detection sensitivity and multimodality, we hereby propose that AIE-Gd dots can serve as a better alternative to Evans blue for visualization and quantification of changes in brain barrier functions. [ABSTRACT FROM AUTHOR]

publisher‐imprint‐name Springer volume‐issue‐count 1 issue‐article‐count 0 issue‐toc‐levels 0 issue‐pricelist‐year 2017 issue‐copyright‐holder The Author(s) issue‐copyright‐year 2017 article‐contains‐esm No article‐numbering‐style Unnumbered article‐registration‐date‐year 2016 article‐registration‐date‐month 12 article‐registration‐date‐day 22 article‐toc‐levels 0 toc‐levels 0 volume‐type Regular journal‐product ArchiveJournal numbering‐style Unnumbered article‐grants‐type OpenChoice metadata‐grant OpenAccess abstract‐grant OpenAccess bodypdf‐grant OpenAccess bodyhtml‐grant OpenAccess bibliography‐grant OpenAccess esm‐grant OpenAccess online‐first false pdf‐file‐reference BodyRef/PDF/40169_2016_Article_134.pdf target‐type OnlinePDF issue‐type Regular article‐type OriginalPaper journal‐subject‐primary Medicine & Public Health journal‐subject‐secondary Medicine/Public Health, general journal‐subject‐collection SC11 open‐access true --> Background: There is currently no clinical imaging technique available to assess the degree of inflammation associated with atherosclerotic plaques. This study aims to develop targeted superparamagnetic particles of iron oxide (SPIO) as a magnetic resonance imaging (MRI) probe for detecting inflamed endothelial cells. Methods: The in vitro study consists of the characterisation and detection of inflammatory markers on activated endothelial cells by immunocytochemistry and MRI using biotinylated anti‐P‐selectin and anti‐VCAM‐1 (vascular cell adhesion molecule 1) antibody and streptavidin conjugated SPIO. Results: Established an in vitro cellular model of endothelial inflammation induced with TNF‐α (tumor necrosis factor alpha). Inflammation of endothelial cells was confirmed with both immunocytochemistry and MRI. These results revealed both a temporal and dose dependent expression of the inflammatory markers, P‐selectin and VCAM‐1, on exposure to TNF‐α. Conclusion: This study has demonstrated the development of an in vitro model to characterise and detect inflamed endothelial cells by immunocytochemistry and MRI. This will allow the future development of contrast agents and protocols for imaging vascular inflammation in atherosclerosis. This work may form the basis for a translational study to provide clinicians with a novel tool for the in vivo assessment of atherosclerosis. [ABSTRACT FROM AUTHOR]

Positron Emission Tomography is an attractive imaging modality for monitoring the migration of cells to pathological tissue. We evaluated a new method for radiolabelling leukocytes with zirconium-89 ( 89 Zr) using chitosan nanoparticles (CN, Z-average size 343 ± 210 nm and zeta potential +46 ± 4 mV) as the carrier. We propose that cell uptake of 89 Zr-loaded CN occurred in a two-step process; cell membrane interaction with 89 Zr-loaded CN was followed by a slower cell internalisation step. [ABSTRACT FROM AUTHOR]

The expression level of neutrophil elastase (NE) is closely related to the occurrence of inflammation. This enzyme has been identified as a research target for the development of anti-inflammatory drugs and for the early diagnosis and treatment of many diseases. This work developed the first near-infrared ratiometric fluorescence sensor (TMNF) for monitoring and imaging NE i n vivo and in vitro. Cell imaging results showed that NE was highly expressed in cells treated with pro-inflammatory factors, whereas NE activity was significantly reduced after pretreatment with the enzyme inhibitor. Relevant experiments have shown that inflammation can lead to increased expression of NE in vivo. The imaging of the probe in inflammation mouse shows excellent practicality, making the probe an effective tool for the early diagnosis and treatment of diseases related to inflammatory lesions. • One near-infrared sensor TMNF for Neutrophil elastase (NE) detection both in vivo and in vitro was designed. • TMNF shows highly sensitive (DL is 32 ng/mL), fast response time (18 min) and good biocompatibility. • Under stimulation, the imaging of TMNF in cells indicate that the high expression of NE is associated with inflammation. • This is the first time to confirm that NE expression in inflammatory mice is much higher than that in normal mice. [ABSTRACT FROM AUTHOR]

Mixed leukocyte (white blood cells [WBCs]) trafficking using positron emission tomography (PET) is receiving growing interest to diagnose and monitor inflammatory conditions. PET, a high sensitivity molecular imaging technique, allows precise quantification of the signal produced from radiolabelled moieties. We have evaluated a new method for radiolabelling WBCs with either zirconium-89 (89Zr) or copper-64 (64Cu) for PET imaging. Chitosan nanoparticles (CNs) were produced by a process of ionotropic gelation and used to deliver radiometals into WBCs. Experiments were carried out using mixed WBCs freshly isolated from whole human blood. WBCs radiolabelling efficiency was higher with [89Zr]-loaded CN (76.8 ± 9.6% ( n = 12)) than with [64Cu]-loaded CN (26.3 ± 7.0 % ( n = 7)). [89Zr]-WBCs showed an initial loss of 28.4 ± 5.8% ( n = 2) of the radioactivity after 2 h. This loss was then followed by a plateau as 89Zr remains stable in the cells. [64Cu]-WBCs showed a loss of 85 ± 6% ( n = 3) of the radioactivity after 1 h, which increased to 96 ± 6% ( n = 3) loss after 3 h. WBC labelling with [89Zr]-loaded CN showed a fast kinetic of leukocyte association, high labelling efficiency and a relatively good retention of the radioactivity. This method using 89Zr has a potential application for PET imaging of inflammation. [ABSTRACT FROM AUTHOR]

Bacterial infection is one of the major causes of morbidity and mortality especially in developing countries. The aim of this study was to develop a new radiopharmaceutical for imaging infection. The labeling conditions were optimized, and lyophilized kits were developed for instant preparing. The stability of Tc-AMOX in human serum was identified, sterility and pyrogenicity of the radiopharmaceutical were estimated, gamma scintigraphy and in vivo biodistribution with infected rats were investigated. The promising properties of Tc-AMOX combined with the development of reliable and instant lyophilized kit afford the opportunity of inflammatory process imaging. [ABSTRACT FROM AUTHOR]

99mTc-cefotaxime sodium (99mTc-CEF) was developed and standardized under varying conditions of reducing and antioxidant agent concentration, pH, radioactivity dose, and reducing agent type. Labeling studies were performed by changing the selected parameters one by one, and optimum labeling conditions were determined. After observing the conditions for maximum labeling efficiency and stability, lyophilized freeze dry kits were prepared accordingly. Simple method for radiolabeling of CEF with 99mTc has been developed and standardized. Labeling efficiency of 99mTc-CEF was assessed by both radio thin-layer chromatography and radio high-performance liquid chromatography and found higher than 90%. The labeled compound was found to be stable in saline and human serum up to 24 h. Two different freeze dry kits were developed and evaluated. Based on the data obtained from this study, both products were stable for 6 months with high labeling efficiency. The prepared cold kit was found sterile and pyrogen free. The bacterial infection and sterile inflammation imaging capacity of 99mTc-CEF was evaluated. Based on the in vivo studies, 99mTc-CEF has higher uptake in infected and inflamed thigh muscle than healthy thigh muscle. [ABSTRACT FROM AUTHOR]

Inflammatory processes can reliably be assessed by 19F MRI using perfluorocarbons (PFCs), which is primarily based on the efficient uptake of emulsified PFCs by circulating cells of the monocyte-macrophage system and subsequent infiltration of the 19F-labeled cells into affected tissue. An ideal candidate for the sensitive detection of fluorine-loaded cells is the biochemically inert perfluoro-15-crown-5 ether (PFCE), as it contains 20 magnetically equivalent 19F atoms. However, the biological half-life of PFCE in the liver and spleen is extremely long, and so this substance is not suitable for future clinical applications. In the present study, we investigated alternative, nontoxic PFCs with predicted short biological half-lives and high fluorine content: perfluorooctyl bromide (PFOB), perfluorodecalin (PFD) and trans-bis-perfluorobutyl ethylene (F-44E). Despite the complex spectra of these compounds, we obtained artifact-free images using sine-squared acquisition-weighted three-dimensional chemical shift imaging and dedicated reconstruction accomplished with in-house-developed software. The signal-to-noise ratio of the images was maximized using a Nutall window with only moderate localization error. Using this approach, the retention times of the different PFCs in murine liver and spleen were determined at 9.4 T. The biological half-lives were estimated to be 9 days (PFD), 12 days (PFOB) and 28 days (F-44E), compared with more than 250 days for PFCE. In vivo sensitivity for inflammation imaging was assessed using an ear clip injury model. The alternative PFCs PFOB and F-44E provided 37% and 43%, respectively, of the PFCE intensities, whereas PFD did not show any signal in the ear model. Thus, for in vivo monitoring of inflammatory processes, PFOB emerges as the most promising candidate for possible future translation of 19F MR inflammation imaging to human applications. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The rising interest in using functional cells for diagnosis and treatment has created an urgent need for in vivo cell-tracking techniques. Certain advanced techniques, such as those involving reporter genes or nanoparticles, are still awaiting confirmation of their safety and feasibility in human patients. Tracking cells by labeling them with 18F-fluorodeoxyglucose, a tracer clinically used in positron emission tomography (PET), may be one way to rapidly translate some of these principles from bench to bedside. The preliminary results are exciting, although further development, optimization, and validation are required. Here, several applications of the technique are surveyed: finding inflammatory foci, targeting cancer immunotherapies, tracking transplanted islet cells, and monitoring cardiac stem cells. Advantages, limitations, and prospects of the technique are discussed. These early experiences only highlight the existing need to improve cell-labeling techniques using PET tracers. This method may finally lead to the development of effective and convenient methods for clinical cell-tracking techniques involving PET/computed tomography. [ABSTRACT FROM AUTHOR]

Celecoxib was labelled effectively with Tc. The labeling yield was found to be influenced by the amount of celecoxib, the amount of stannous chloride dihydrate, the reaction time, the temperature and the pH of the reaction mixture. The importance of stannous chloride dihydrate arises from its function as a reducing agent for pertechnetate to form complex celecoxib. The suitable amount required to produce high labeling yield of Tc-celecoxib was 500 μg SnCl·2HO. The pH of the reaction medium was found to play a significant role in this labeling process. The labeling reaction was performed at a neutral medium (pH 7). The labeling reaction proceeds well at room temperature (25 ± 1 °C) and the complex decomposes by heat. The labeled celecoxib (Tc-celecoxib) showed a good localization in inflamed foci and a good imaging must be taken 4 h post injection. [ABSTRACT FROM AUTHOR]

This study describes a fast and efficient method for radiolabeling of etodolac with iodine-125 [I], where both chloramine-T and iodogen were used as oxidizing agents. The labeling reaction was carried out via electrophilic substitution of hydrogen atom with the iodonium cation I. The labeling yield was found to be influenced by different factors such as drug concentration, pH of the reaction mixtures, different oxidizing agents, reaction time, temperature and different organic media. The radiochemical yield (RCY) was determined by TLC system using methylene chloride:ethyl acetate (3:7 v/v) as a developing solvent and by electrophoresis using cellulose acetate moistened with 0.02 M phosphate buffer pH 7. The maximum radiochemical yield of [I]Etodolac (87.7%) was obtained. Labeled etodolac shows a good localization in inflamed muscle. It excretes mainly via kidney and to some via liver. [ABSTRACT FROM AUTHOR]

An emerging suite of new imaging techniques offer the ability to monitor and quantify molecular and cellular processes in the lungs noninvasively. These techniques take advantage of dramatic advances in both imaging technology as well as molecular and cell biology. Molecular imaging is being used with increasing regularity in research protocols, and forms of molecular imaging have found their way into the patient care setting (eg, positron emission tomography imaging in cancer). Such techniques will afford the basic scientist as well as the clinician an unprecedented opportunity for in vivo study of the lung biology that drives normal pulmonary physiology as well as pathophysiology. [Copyright &y& Elsevier]

Nuclear medicine examinations hold an important position in the diagnosis of diseases of the spine. During the las decade, decisive progress has been made in the field of instrumentation and radiopharmaceutical techniques: the use of high resolution collimators and the introduction of emission computer tomography as examples of improved instrumentation as well as 99m-Technetium red blood cell labelling as a new radiopharmaceutical technique. These present some of the developments responsible for the growing importance of scintigraphical diagnosis. Inflammatory processes of the vertebrae and the surrounding soft tissues can be detected or excluded with high reliability by the use of radionuclide-labelled granulocytes. The important role of bone scintigraphy in the differential diagnosis of neoplastic bone disease relies on its high sensitivity combined with the quantitative analysis of increased bone metabolism. Furthermore, it provides exact information about the extent and a possible metastatic spread of bone tumours. In the field of orthopaedy and surgery, skeletal scintigraphy is of growing importance as a highly sensitive procedure in the detection of special traumatic lesions such as acute vertebral compression fractures and in the follow-up of patients after bone surgical interventions. Despite the progress of other imaging modalities such as computer tomography and magnetic resonance imaging, nuclear medicine today is well-established in the assessment of diseases of the vertebral column. Among all scintigraphical diagnostic procedures, bone scintigraphy and the different techniques of inflammation imaging are of special importance. [ABSTRACT FROM AUTHOR]

Labeling of macrophages with perfluorocarbon (PFC)-based compounds allows the visualization of inflammatory processes by 19F-magnetic resonance imaging (19F-MRI), due to the absence of endogenous background. Even if PFC-labeling of monocytes/macrophages has been largely investigated and used, information is lacking about the impact of these agents over the polarization towards one of their cell subsets and on the best way to image them. In the present work, a PFC-based nanoemulsion was developed to monitor the course of inflammation in a model of spinal cord injury (SCI), a pathology in which the understanding of immunological events is of utmost importance to select the optimal therapeutic strategies. The effects of PFC over macrophage polarization were studied in vitro, on cultured macrophages, and in vivo, in a mouse SCI model, by testing and comparing various cell tracking protocols, including single and multiple administrations, the use of MRI or Point Resolved Spectroscopy (PRESS), and application of pre-saturation of Kupffer cells. The blood half-life of nanoemulsion was also investigated by 19F Magnetic Resonance Spectroscopy (MRS). In vitro and in vivo results indicate the occurrence of a switch towards the M2 (anti-inflammatory) phenotype, suggesting a possible theranostic function of these nanoparticles. The comparative work presented here allows the reader to select the most appropriate protocol according to the research objectives (quantitative data acquisition, visual monitoring of macrophage recruitment, theranostic purpose, rapid MRI acquisition, etc.). Finally, the method developed here to determine the blood half-life of the PFC nanoemulsion can be extended to other fluorinated compounds. [ABSTRACT FROM AUTHOR]

Abstract: A neutrophil-binding peptide, cinnamoyl-F(D)LF(D)LF (cFLFLF), was labeled with the near infrared (NIR) fluorophore, Cyanine 7 (Cy7). This construct was modified with a polyethylene glycol (PEG, M W 3.4kDa) moiety in order to increase its solubility and bioavailability to circulating neutrophils. A preliminary noninvasive fluorescence imaging of a mouse model of ear inflammation with the fluorescent probe is presented. [Copyright &y& Elsevier]

Abstract: A neutrophil-specific peptide, cinnamoyl-F(D)LF(D)LFK (cFLFLFK), was conjugated consecutively with a polyethylene glycol moiety (3.4K) and 2,2′,2″,2‴-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA) to form cFLFLFK-PEG-DOTA. After 64Cu labeling, Positron Emission Tomography (PET) imaging was successfully able to detect mouse lung inflammation. [Copyright &y& Elsevier]