• 3D culture
• Atherosclerosis
• Inflammation
• Liposomes
• Simvastatin
• Spheroids

• Atherosclerosis
• cardiovascular diseases
• diagnosis
• drug delivery system
• nanomedicine
• scaffolds
• theranostics
• treatment.

• anti-inflammation
• atherosclerosis
• corticosteroid
• fluocinolone acetonide
• liposomes

• Dextran
• MRI
• crosslinking
• fucoidan
• human platelets
• submicronic particles

Molecular imaging of atherosclerosis by Magnetic Resonance Imaging (MRI) has been impaired by a lack of validation of the specific substrate responsible for the molecular imaging signal. We therefore aimed to investigate the additive value of mass spectrometry imaging (MSI) of atherosclerosis-affine Gadofluorine P for molecular MRI of atherosclerotic plaques. Atherosclerotic Ldlr^−/− mice were investigated by high-field MRI (7 T) at different time points following injection of atherosclerosis-affine Gadofluorine P as well as at different stages of atherosclerosis formation (4, 8, 16 and 20 weeks of HFD). At each imaging time point mice were immediately sacrificed after imaging and aortas were excised for mass spectrometry imaging: Matrix Assisted Laser Desorption Ionization (MALDI) Imaging and Laser Ablation – Inductively Coupled Plasma – Mass Spectrometry (LA-ICP-MS) imaging. Mass spectrometry imaging allowed to visualize the localization and measure the concentration of the MR imaging probe Gadofluorine P in plaque tissue ex vivo with high spatial resolution and thus adds novel and more target specific information to molecular MR imaging of atherosclerosis.

Polydopamine-coated mesoporous silica nanoparticles loaded with ultrasmall Fe₃O₄ nanoparticles can be prepared for multimodal imaging and combination therapy of tumors.

Molecular MRI is becoming increasingly important for preclinical research. Validation of targeted gadolinium probes in tissue however has been cumbersome up to now. Novel methodology to assess gadolinium distribution in tissue after in vivo application is therefore needed.

To establish combined Magnetic Resonance Imaging (MRI) and Mass Spectrometry Imaging (MSI) for improved detection and quantification of Gadofluorine P deposition in scar formation and myocardial remodeling.

Animal studies were performed according to institutionally approved protocols. Myocardial infarction was induced by permanent ligation of the left ascending artery (LAD) in C57BL/6J mice. MRI was performed at 7T at 1 week and 6 weeks after myocardial infarction. Gadofluorine P was used for dynamic T₁ mapping of extracellular matrix synthesis during myocardial healing and compared to Gd-DTPA. After in vivo imaging contrast agent concentration as well as distribution in tissue were validated and quantified by spatially resolved Matrix-Assisted Laser Desorption Ionization (MALDI) MSI and Laser Ablation – Inductively Coupled Plasma – Mass Spectrometry (LA-ICP-MS) imaging.

Both Gadofluorine P enhancement as well as local tissue content in the myocardial scar were highest at 15 minutes post injection. R₁ values increased from 1 to 6 weeks after MI (1.62 s⁻¹ vs 2.68 s⁻¹, p = 0.059) paralleled by an increase in Gadofluorine P concentration in the infarct from 0.019 mM at 1 week to 0.028 mM at 6 weeks (p = 0.048), whereas Gd-DTPA enhancement showed no differences (3.95 s⁻¹ vs 3.47 s⁻¹, p = 0.701). MALDI-MSI results were corroborated by elemental LA-ICP-MS of Gadolinium in healthy and infarcted myocardium. Histology confirmed increased extracellular matrix synthesis at 6 weeks compared to 1 week.

Adding quantitative MSI to MR imaging enables a quantitative validation of Gadofluorine P distribution in the heart after MI for molecular imaging.

• Biomedical engineering
• Cardiology
• Medical imaging

The aim of the study was to quantify atherosclerotic plaque burden by volumetric assessment and T1 relaxivity measurement at 7T MRI using Gadospin F (GDF) in comparison to en face based measurements.

9-weeks old ApoE^-/- (n = 5 for each group) and wildtype mice (n = 5) were set on high fat diet (HFD). Progression group received MRI at 9, 13, 17 and 21 weeks after HFD initiation. Regression group was reswitched to chow diet (CD) after 13 weeks HFD and monitored with MRI for 12 weeks. MRI was performed before and two hours after iv injection of GDF (100 μmol/kg) at 7T (Clinscan, Bruker) acquiring a 3D inversion recovery gradient echo sequence and T1 Mapping using Saturation Recovery sequences. Subsequently, aortas were prepared for en face analysis using confocal microscopy. Total plaque volume (TPV) and T1 relaxivity were estimated using ImageJ (V. 1.44p, NIH, USA).

2D and 3D en face analysis showed a strong and exponential increase of plaque burden over time, while plaque burden in regression group was less pronounced. Correspondent in vivo MRI measurements revealed a more linear increase of TPV and T1 relaxivity for regression group. A significant correlation was observed between 2D and 3D en face analysis (r = 0.79; p<0.001) as well as between 2D / 3D en face analysis and MRI (r = 0.79; p<0.001; r = 0.85; p<0.001) and delta R1 (r = 0.79; p<0.001; r = 0.69; p<0.01).

GDF-enhanced in vivo MRI is a powerful non-invasive imaging technique in mice allowing for reliable estimation of atherosclerotic plaque burden, monitoring of disease progression and regression in preclinical studies.

• Animals
• Apolipoproteins E/deficiency
• Apolipoproteins E/genetics
• Gene Knockout Techniques
• Lipids/blood
• Magnetic Resonance Imaging/methods
• Mice
• Plaque, Atherosclerotic/blood
• Plaque, Atherosclerotic/diagnostic imaging
• Plaque, Atherosclerotic/genetics

• EU FP7 project RESOLVE

Contrast agents for Cardiovascular Magnetic Resonance (CMR) play a major role in research and clinical cardiology.

• Angiotensin-Converting Enzyme Inhibitors/therapeutic use
• Cilostazol
• Clopidogrel
• Factor V/genetics
• Heparin, Low-Molecular-Weight/therapeutic use
• Hot Temperature/therapeutic use
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Metabolic Syndrome/therapy
• Mutation
• Nitric Oxide/therapeutic use
• Phosphodiesterase Inhibitors/therapeutic use
• Piperazines/therapeutic use
• Platelet Aggregation Inhibitors/therapeutic use
• Purines
• Sildenafil Citrate
• Sulfones
• Tetrazoles/therapeutic use
• Thrombin
• Ticlopidine/analogs & derivatives
• Ticlopidine/therapeutic use
• Vascular Diseases/diagnosis
• Vascular Diseases/drug therapy
• Vascular Diseases/surgery
• Vascular Diseases/therapy
• Vascular Surgical Procedures

• Animals
• Apolipoproteins E/deficiency
• Atherosclerosis/diagnostic imaging
• Atherosclerosis/genetics
• Atherosclerosis/pathology
• Contrast Media/administration & dosage
• Coordination Complexes/administration & dosage
• Gadolinium/administration & dosage
• Magnetic Resonance Imaging
• Mice
• Mice, Inbred C57BL
• Microscopy, Electron, Transmission
• Microscopy, Fluorescence
• Radiography

Crohn's disease (CD) is a chronic inflammatory condition with relapsing-remitting behavior, often causing strictures or penetrating bowel damage. Its lifelong clinical course necessitates frequent assessment of disease activity and complications. Computed tomography (CT) enterography has been used as primary imaging modality; however, the concern for radiation hazard limits its use especially in younger population. Magnetic resonance (MR) imaging has advantages of avoiding radiation exposure, lower incidence of adverse events, ability to obtain dynamic information, and good soft-tissue resolution. MR enterography (MRE) with oral contrast agent has been used as primary MR imaging modality of CD with high sensitivity, specificity, and interobserver agreement. The extent of inflammation as well as transmural ulcers and fibrostenotic diseases can be detected with MRE. Novel MR techniques such as diffusion-weighted MRI (DWI), motility study, PET-MRI, and molecular imaging are currently investigated for further improvement of diagnosis and management of CD. MR spectroscopy is a remarkable molecular imaging tool to analyze metabolic profile of CD with human samples such as plasma, urine, or feces, as well as colonic mucosa itself.

AIM: To investigate the performance of Gadofluorine P-enhanced magnetic resonance imaging (MRI) on the diagnosis of diabetes in a streptozotocin (STZ) -induced diabetic rat model.

METHODS: Fischer 344 rats were treated with STZ. Rats not treated with STZ served as controls. T1-weighted MRI was performed using a 3T scanner before and after the injection of Gd-DOTA or Gadofluorine P (6 diabetic rats, 5 controls). The normalized signal intensity (SI) and the enhancement ratio (ER) of the pancreas were measured at each time point, and the values were compared between the normal and diabetic rats using the Mann-Whitney test. In addition, the values were correlated with the mean islet number. Optimal cut-off values were calculated using a positive test based on receiver operating characteristics. Intrapancreatic Gd concentration after the injection of each contrast media was measured using laser ablation-inductively coupled plasma-mass spectrometry in a separate set of rats (4 diabetic rats, 4 controls for Gadofluorine P; 2, 2 for Gd-DOTA).

RESULTS: The normalized SI and ER of the pancreas using Gd-DOTA were not significantly different between diabetic rats and controls. With Gadofluorine P, the values were significantly higher in the diabetic rats than in the control rats 30 min after injection (P < 0.05). The area under the receiver operating characteristic curve that differentiated diabetic rats from the control group was greater for Gadofluorine P than for Gd-DOTA (0.967 vs 0.667, P = 0.085). An increase in normalized SI 30 min after Gadofluorine P was correlated with a decrease in the mean number of islets (r² = 0.510, P = 0.014). Intra-pancreatic Gd was higher in rats with Gadofluorine P injection than Gd-DOTA injection (Gadofluorine P vs Gd-DOTA, 7.37 vs 0.00, P < 0.01). A significant difference in the concentration of intrapancreatic Gd was observed between the control and diabetic animals that were sacrificed 30 min after Gadofluorine P injection (control vs diabetic, 3.25 ng/g vs 10.55 ng/g, P < 0.05)

CONCLUSION: In this STZ-induced diabetes rat model, Gadofluorine P-enhanced MRI of the pancreas showed high accuracy in the diagnosis of diabetes.

• Gadofluorine P
• Gd-DOTA
• Magnetic resonance contrast media
• Type 1 diabetes
• Pancreas

• Animals
• Area Under Curve
• Biopsy
• Contrast Media
• Coordination Complexes
• Diabetes Mellitus, Experimental/pathology
• Female
• Fluorocarbons
• Heterocyclic Compounds
• Magnetic Resonance Imaging
• Organometallic Compounds
• Pancreas/pathology
• Predictive Value of Tests
• ROC Curve
• Rats, Inbred F344
• Time Factors

• biochemistry
• gadolinium
• imaging agents
• kinetics
• mass spectrometry

• Activatable
• Cancer
• DDS
• In vivo imaging
• MRI
• Multimodal
• Nanoparticles
• Theranostics

• (000.1430) Biology and medicine
• (120.3890) Medical optics instrumentation
• (170.4500) Optical coherence tomography
• (350.5340) Photothermal effects

Neuroinflammation plays a central role in a variety of neurological diseases, including stroke, multiple sclerosis, Alzheimer’s disease, and malignant CNS neoplasms, among many other. Different cell types and molecular mediators participate in a cascade of events in the brain that is ultimately aimed at control, regeneration and repair, but leads to damage of brain tissue under pathological conditions. Non-invasive molecular imaging of key players in the inflammation cascade holds promise for identification and quantification of the disease process before it is too late for effective therapeutic intervention. In this review, we focus on molecular imaging techniques that target inflammatory cells and molecules that are of interest in neuroinflammation, especially those with high translational potential. Over the past decade, a plethora of molecular imaging agents have been developed and tested in animal models of (neuro)inflammation, and a few have been translated from bench to bedside. The most promising imaging techniques to visualize neuroinflammation include MRI, positron emission tomography (PET), single photon emission computed tomography (SPECT), and optical imaging methods. These techniques enable us to image adhesion molecules to visualize endothelial cell activation, assess leukocyte functions such as oxidative stress, granule release, and phagocytosis, and label a variety of inflammatory cells for cell tracking experiments. In addition, several cell types and their activation can be specifically targeted in vivo, and consequences of neuroinflammation such as neuronal death and demyelination can be quantified. As we continue to make progress in utilizing molecular imaging technology to study and understand neuroinflammation, increasing efforts and investment should be made to bring more of these novel imaging agents from the “bench to bedside.”

• Brain
• CNS
• Inflammation
• MRI
• Molecular imaging
• Neuroinflammation
• PET

Acute rupture of vulnerable plaques frequently leads to myocardial infarction and stroke. Within the last decades, several cellular and molecular players have been identified that promote atherosclerotic lesion formation, maturation and plaque rupture. It is now widely recognized that inflammation of the vessel wall and distinct leukocyte subsets are involved throughout all phases of atherosclerotic lesion development. The mechanisms that render a stable plaque unstable and prone to rupture, however, remain unknown and the identification of the vulnerable plaque remains a major challenge in cardiovascular medicine. Imaging technologies used in the clinic offer minimal information about the underlying biology and potential risk for rupture. New imaging technologies are therefore being developed, and in the preclinical setting have enabled new and dynamic insights into the vessel wall for a better understanding of this complex disease. Molecular imaging has the potential to track biological processes, such as the activity of cellular and molecular biomarkers in vivo and over time. Similarly, novel imaging technologies specifically detect effects of therapies that aim to stabilize vulnerable plaques and silence vascular inflammation. Here we will review the potential of established and new molecular imaging technologies in the setting of atherosclerosis, and discuss the cumbersome steps required for translating molecular imaging approaches into the clinic.

• Atherosclerosis
• Inflammation
• Molecular imaging

• Atherosclerosis
• Contrast agent
• Dextran sulfate
• Double hydrophilic copolymer
• Magnetic resonance imaging

• Atherosclerosis
• CE-MRI
• Contrast agent
• DCE-MRI
• Gadolinium
• Gd
• Imaging
• MRI
• Magnetic resonance imaging
• Non-specific contrast agents
• Specific non-targeted contrast agents
• Specific targeted contrast agents

• cell therapy
• critical limb ischemia
• imaging
• peripheral arterial disease

• Animals
• Cell Survival
• Cell Tracking/methods
• Clinical Trials as Topic/methods
• Humans
• Neovascularization, Physiologic
• Peripheral Arterial Disease/physiopathology
• Peripheral Arterial Disease/therapy
• Regeneration
• Research Design
• Stem Cell Transplantation/methods

• R01 EB009689 NIBIB NIH HHS
• RC1 HL099117 NHLBI NIH HHS
• EB009689 NIBIB NIH HHS
• HL099117 NHLBI NIH HHS

• Analysis of Variance
• Animals
• Biocompatible Materials
• Cells, Cultured
• Chitosan
• Contrast Media
• Guided Tissue Regeneration
• Magnetic Resonance Imaging/methods
• Mesenchymal Stem Cells/physiology
• Nerve Regeneration/physiology
• Organometallic Compounds
• Peripheral Nerve Injuries/therapy
• Rats
• Rats, Sprague-Dawley
• Tissue Engineering
• Tissue Scaffolds

Inflammatory activity in atherosclerotic plaque is a risk factor for plaque rupture and atherothrombosis and may direct interventional therapy. Inflammatory activity can be evaluated at the (sub)cellular level using in vivo molecular MRI. This paper reviews recent progress in contrast-enhanced molecular MRI to visualize atherosclerotic plaque inflammation. Various MRI contrast agents, among others ultra-small particles of iron oxide, low-molecular-weight Gd-chelates, micelles, liposomes, and perfluorocarbon emulsions, have been used for in vivo visualization of various inflammation-related targets, such as macrophages, oxidized LDL, endothelial cell expression, plaque neovasculature, MMPs, apoptosis, and activated platelets/thrombus. An enzyme-activatable magnetic resonance contrast agent has been developed to study myeloperoxidase activity in inflamed plaques. Agents creating contrast based on the chemical exchange saturation transfer mechanism were used for thrombus imaging. Transfer of these molecular MRI techniques to the clinic will critically depend on the safety profiles of these newly developed magnetic resonance contrast agents.

• Atherosclerotic plaque
• Magnetic resonance imaging
• Multidetector row computed tomography
• Single photon emission computed tomography

• Animals
• Contrast Media/administration & dosage
• Coronary Vessels/injuries
• Coronary Vessels/pathology
• Coronary Vessels/physiopathology
• Disease Models, Animal
• Endothelium, Vascular/injuries
• Endothelium, Vascular/pathology
• Endothelium, Vascular/physiopathology
• Female
• Gadolinium/administration & dosage
• Heart Injuries/pathology
• Heart Injuries/physiopathology
• Image Interpretation, Computer-Assisted
• Injections, Intravenous
• Magnetic Resonance Angiography
• Microvessels/pathology
• Microvessels/physiopathology
• Neovascularization, Physiologic
• Observer Variation
• Organometallic Compounds/administration & dosage
• Predictive Value of Tests
• Reproducibility of Results
• Swine
• Time Factors

• Animals
• Apolipoproteins E/genetics
• Contrast Media/chemistry
• Contrast Media/pharmacokinetics
• Electron Spin Resonance Spectroscopy/methods
• Female
• Half-Life
• Image Enhancement/methods
• Liposomes/pharmacokinetics
• Magnetic Resonance Imaging/methods
• Mice
• Mice, Knockout
• Phenotype
• Plaque, Atherosclerotic/diagnostic imaging
• Plaque, Atherosclerotic/genetics
• Plaque, Atherosclerotic/metabolism
• Plaque, Atherosclerotic/pathology
• Radiography
• Tissue Distribution

• PG/09/090/28065 British Heart Foundation

Circumventricular organs (CVO) are cerebral areas with incomplete endothelial blood-brain barrier (BBB) and therefore regarded as "gates to the brain". During inflammation, they may exert an active role in determining immune cell recruitment into the brain.

In a longitudinal study we investigated in vivo alterations of CVO during neuroinflammation, applying Gadofluorine M- (Gf) enhanced magnetic resonance imaging (MRI) in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. SJL/J mice were monitored by Gadopentate dimeglumine- (Gd-DTPA) and Gf-enhanced MRI after adoptive transfer of proteolipid-protein-specific T cells. Mean Gf intensity ratios were calculated individually for different CVO and correlated to the clinical disease course. Subsequently, the tissue distribution of fluorescence-labeled Gf as well as the extent of cellular inflammation was assessed in corresponding histological slices.

We could show that the Gf signal intensity of the choroid plexus, the subfornicular organ and the area postrema increased significantly during experimental autoimmune encephalomyelitis, correlating with (1) disease severity and (2) the delay of disease onset after immunization. For the choroid plexus, the extent of Gf enhancement served as a diagnostic criterion to distinguish between diseased and healthy control mice with a sensitivity of 89% and a specificity of 80%. Furthermore, Gf improved the detection of lesions, being particularly sensitive to optic neuritis. In correlated histological slices, Gf initially accumulated in the extracellular matrix surrounding inflammatory foci and was subsequently incorporated by macrophages/microglia.

Gf-enhanced MRI provides a novel highly sensitive technique to study cerebral BBB alterations. We demonstrate for the first time in vivo the involvement of CVO during the development of neuroinflammation.

• Animals
• Apolipoproteins E/genetics
• Biomarkers/metabolism
• Gadolinium/metabolism
• Humans
• Image Enhancement/methods
• Magnetic Resonance Imaging/instrumentation
• Magnetic Resonance Imaging/methods
• Mice
• Mice, Knockout
• Micelles
• Nitric Oxide Synthase Type III/genetics
• Plaque, Atherosclerotic/metabolism
• Plaque, Atherosclerotic/pathology
• Receptor, Cannabinoid, CB2/metabolism
• Time Factors
• Tissue Distribution

• carotid artery mri
• clinical trial
• atherosclerotic plaque
• stroke

• Accreditation
• Biomarkers
• Cardiovascular Diseases/diagnosis
• Diagnostic Imaging/methods
• Education, Medical, Continuing
• Humans
• Magnetic Resonance Angiography/methods
• Magnetic Resonance Imaging/methods
• Radiopharmaceuticals
• United States

• R29 HL056874 NHLBI NIH HHS
• HL56874 NHLBI NIH HHS
• R01 HL076378 NHLBI NIH HHS
• HL076378 NHLBI NIH HHS
• R01 HL056874 NHLBI NIH HHS

• Cardiovascular
• MRI
• atherosclerosis
• gadolinium
• iron oxide nanoparticles
• micelles
• molecular imaging
• smart probes
• targeted peptides

• Amino Acid Sequence
• Apoptosis
• Cardiovascular System/anatomy & histology
• Cardiovascular System/pathology
• Contrast Media/chemistry
• Ferric Compounds/chemistry
• Gadolinium/chemistry
• Magnetic Resonance Imaging/methods
• Metal Nanoparticles/chemistry
• Molecular Probes/chemistry
• Molecular Sequence Data
• Molecular Structure
• Myocytes, Cardiac/cytology
• Myocytes, Cardiac/physiology
• Peptides/chemistry
• Peptides/genetics

• R01 EB009062 NIBIB NIH HHS
• R21 EB009738 NIBIB NIH HHS
• R01EB009062 NIBIB NIH HHS
• R21EB009738 NIBIB NIH HHS

• Humans
• Magnetic Resonance Imaging/methods
• Magnetic Resonance Imaging/trends
• Multiple Sclerosis/diagnosis