Ultrasmall Iron Oxide Particles Research Articles

Specific nanoprobe design for MRI: Targeting laminin in the blood-brain barrier to follow alteration due to neuroinflammation.

Chronic neuroinflammation is characterized by increased blood-brain barrier (BBB) permeability, leading to molecular changes in the central nervous system that can be explored with biomarkers of active neuroinflammatory processes. Magnetic resonance imaging (MRI) has contributed to detecting lesions and permeability of the BBB. Ultra-small superparamagnetic particles of iron oxide (USPIO) are used as contrast agents to improve MRI observations. Therefore, we validate the interaction of peptide-88 with laminin, vectorized on USPIO, to explore BBB molecular alterations occurring during neuroinflammation as a potential tool for use in MRI. The specific labeling of NPS-P88 was verified in endothelial cells (hCMEC/D3) and astrocytes (T98G) under inflammation induced by interleukin 1β (IL-1β) for 3 and 24 hours. IL-1β for 3 hours in hCMEC/D3 cells increased their co-localization with NPS-P88, compared with controls. At 24 hours, no significant differences were observed between groups. In T98G cells, NPS-P88 showed similar nonspecific labeling among treatments. These results indicate that NPS-P88 has a higher affinity towards brain endothelial cells than astrocytes under inflammation. This affinity decreases over time with reduced laminin expression. In vivo results suggest that following a 30-minute post-injection, there is an increased presence of NPS-P88 in the blood and brain, diminishing over time. Lastly, EAE animals displayed a significant accumulation of NPS-P88 in MRI, primarily in the cortex, attributed to inflammation and disruption of the BBB. Altogether, these results revealed NPS-P88 as a biomarker to evaluate changes in the BBB due to neuroinflammation by MRI in biological models targeting laminin.

A Preclinical Validation of Iron Oxide Nanoparticles for Treatment of Perianal Fistulizing Crohn's Disease.

Fistulizing anoperineal lesions are severe complications of Crohn’s disease (CD) that affect quality of life with a long-term risk of anal sphincter destruction, incontinence, permanent stoma, and anal cancer. Despite several surgical procedures, they relapse in about two-thirds of patients, mandating innovative treatments. Ultrasmall particles of iron oxide (USPIO) have been described to achieve in vivo rapid healing of deep wounds in the skin and liver of rats thanks to their nanobridging capability that could be adapted to fistula treatment. Our main purpose was to highlight preclinical data with USPIO for the treatment of perianal fistulizing CD. Twenty male Sprague Dawley rats with severe 2,4,6-trinitrobenzenesulfonic acid solution (TNBS)-induced proctitis were operated to generate two perianal fistulas per rat. At day 35, two inflammatory fistulas were obtained per rat and perineal magnetic resonance imaging (MRI) was performed. After a baseline MRI, a fistula tract was randomly drawn and topically treated either with saline or with USPIO for 1 min (n = 17 for each). The rats underwent a perineal MRI on postoperative days (POD) 1, 4, and 7 and were sacrificed for pathological examination. The primary outcome was the filling or closure of the fistula tract, including the external or internal openings. USPIO treatment allowed the closure and/or filling of all the treated fistulas from its application until POD 7 in comparison with the control fistulas (23%). The treatment with USPIO was safe, permanently closed the fistula along its entire length, including internal and external orifices, and paved new avenues for the treatment of perianal fistulizing Crohn’s disease.

Ultrasmall Superparamagnetic Particles of Iron Oxide and Cardiac Magnetic Resonance: Novel Imaging in Everyday Conditions

Myocardial inflammation has been hypothesised to be the common underlying mechanism through which several cardiovascular diseases develop and progress. Cardiac magnetic resonance (CMR) has become a powerful non-invasive tool that enables the direct visualisation of the myocardium. The emerging use of ultrasmall superparamagnetic particles of iron oxide (USPIO) and their magnetic properties is gaining a lot of research interest. USPIO-enhanced CMR can provide valuable information, as it allows for the identification of active inflammation in the myocardium, a process that has been hypothesised to be the substrate for adverse remodelling and, eventually, heart failure. In this review, we summarise the properties of USPIO and their role in cardiac magnetic resonance imaging as well as their clinical applications.

Intravascular Application of Labelled Cell Spheroids: An Approach for Ischemic Peripheral Artery Disease.

Mesenchymal stem cells (MSC) are known for their vascular regeneration capacity by neoangiogenesis. Even though, several delivery approaches exist, particularly in the case of intravascular delivery, only limited number of cells reach the targeted tissue and are not able to remain on site. Applicated cells exhibit poor survival accompanied with a loss of functionality. Moreover, cell application techniques lead to cell death and impede the overall MSC function and survival. 3D cell spheroids mimic the physiological microenvironment, thus, overcoming these limitations. Therefore, in this study we aimed to evaluate and assess the feasibility of 3D MSCs spheroids for endovascular application, for treatment of ischemic peripheral vascular pathologies. Multicellular 3D MSC spheroids were generated at different cell seeding densities, labelled with ultra-small particles of iron oxide (USPIO) and investigated in vitro in terms of morphology, size distribution, mechanical stability as well as ex vivo with magnetic resonance imaging (MRI) to assess their trackability and distribution. Generated 3D spheroids were stable, viable, maintained stem cell phenotype and were easily trackable and visualized via MRI. MSC 3D spheroids are suitable candidates for endovascular delivery approaches in the context of ischemic peripheral vascular pathologies.

Non-invasive monitoring of the kinetic infiltration and therapeutic efficacy of nanoparticle-labeled chimeric antigen receptor T cells in glioblastoma via 7.0-Tesla magnetic resonance imaging

Background aimsChimeric antigen receptor (CAR) T-cell therapy is a promising treatment strategy in solid tumors. In vivo cell tracking techniques can help us better understand the infiltration, persistence and therapeutic efficacy of CAR T cells. In this field, magnetic resonance imaging (MRI) can achieve high-resolution images of cells by using cellular imaging probes. MRI can also provide various biological information on solid tumors. MethodsThe authors adopted the amino alcohol derivatives of glucose-coated nanoparticles, ultra-small superparamagnetic particles of iron oxide (USPIOs), to label CAR T cells for non-invasive monitoring of kinetic infiltration and persistence in glioblastoma (GBM). The specific targeting CARs included anti-human epidermal growth factor receptor variant III and IL13 receptor subunit alpha 2 CARs. ResultsWhen using an appropriate concentration, USPIO labeling exerted no negative effects on the biological characteristics and killing efficiency of CAR T cells. Increasing hypointensity signals could be detected in GBM models by susceptibility-weighted imaging MRI ranging from 3 days to 14 days following the injection of USPIO-labeled CAR T cells. In addition, nanoparticles and CAR T cells were found on consecutive histopathological sections. Moreover, diffusion and perfusion MRI revealed significantly increased water diffusion and decreased vascular permeability on day 3 after treatment, which was simultaneously accompanied by a significant decrease in tumor cell proliferation and increase in intercellular tight junction on immunostaining sections. ConclusionThese results establish an effective imaging technique that can track CAR T cells in GBM models and validate their early therapeutic effects, which may guide the evaluation of CAR T-cell therapies in solid tumors.

Substrate for the Myocardial Inflammation–Heart Failure Hypothesis Identified Using Novel USPIO Methodology

ObjectivesThe purpose of this study was to identify where ultrasmall superparamagnetic particles of iron oxide (USPIO) locate to in myocardium, develop a methodology that differentiates active macrophage uptake of USPIO from passive tissue distribution; and investigate myocardial inflammation in cardiovascular diseases. BackgroundMyocardial inflammation is hypothesized to be a key pathophysiological mechanism of heart failure (HF), but human evidence is limited, partly because evaluation is challenging. USPIO-magnetic resonance imaging (MRI) potentially allows specific identification of myocardial inflammation but it remains unclear what the USPIO-MRI signal represents. MethodsHistological validation was performed using a murine acute myocardial infarction (MI) model. A multiparametric, multi-time-point MRI methodology was developed, which was applied in patients with acute MI (n = 12), chronic ischemic cardiomyopathy (n = 7), myocarditis (n = 6), dilated cardiomyopathy (n = 5), and chronic sarcoidosis (n = 5). ResultsUSPIO were identified in myocardial macrophages and myocardial interstitium. R1 time-course reflected passive interstitial distribution whereas multi-time-point R2* was also sensitive to active macrophage uptake. R2*/R1 ratio provided a quantitative measurement of myocardial macrophage infiltration. R2* behavior and R2*/R1 ratio were higher in infarcted (p = 0.001) and remote (p = 0.033) myocardium in acute MI and in chronic ischemic cardiomyopathy (infarct: p = 0.008; remote p = 0.010), and were borderline higher in DCM (p = 0.096), in comparison to healthy controls, but were no different in myocarditis or sarcoidosis. An R2*/R1 threshold of 25 had a sensitivity and specificity of 90% and 83%, respectively, for detecting active USPIO uptake. ConclusionsUSPIO are phagocytized by cardiac macrophages but are also passively present in myocardial interstitium. A multiparametric multi-time-point MRI methodology specifically identifies active myocardial macrophage infiltration. Persistent active macrophage infiltration is present in infarcted and remote myocardium in chronic ischemic cardiomyopathy, providing a substrate for HF.

Fast field-cycling magnetic resonance detection of intracellular ultra-small iron oxide particles in vitro: Proof-of-concept

PurposeInflammation is central in disease pathophysiology and accurate methods for its detection and quantification are increasingly required to guide diagnosis and therapy. Here we explored the ability of Fast Field-Cycling Magnetic Resonance (FFC-MR) in quantifying the signal of ultra-small superparamagnetic iron oxide particles (USPIO) phagocytosed by J774 macrophage-like cells as a proof-of-principle. MethodsRelaxation rates were measured in suspensions of J774 macrophage-like cells loaded with USPIO (0–200 μg/ml Fe as ferumoxytol), using a 0.25 T FFC benchtop relaxometer and a human whole-body, in-house built 0.2 T FFC-MR prototype system with a custom test tube coil. Identical non-imaging, saturation recovery pulse sequence with 90° flip angle and 20 different evolution fields selected logarithmically between 80 μT and 0.2 T (3.4 kHz and 8.51 MHz proton Larmor frequency [PLF] respectively). Results were compared with imaging flow cytometry quantification of side scatter intensity and USPIO-occupied cell area. A reference colorimetric iron assay was used. ResultsThe T1 dispersion curves derived from FFC-MR were excellent in detecting USPIO at all concentrations examined (0–200 μg/ml Fe as ferumoxytol) vs. control cells, p ≤ 0.001. FFC-NMR was capable of reliably detecting cellular iron content as low as 1.12 ng/µg cell protein, validated using a colorimetric assay. FFC-MR was comparable to imaging flow cytometry quantification of side scatter intensity but superior to USPIO-occupied cell area, the latter being only sensitive at exposures ≥ 10 µg/ml USPIO. ConclusionsWe demonstrated for the first time that FFC-MR is capable of quantitative assessment of intra-cellular iron which will have important implications for the use of USPIO in a variety of biological applications, including the study of inflammation.

Molecular Imaging of Galectin-1 Expression as a Biomarker of Papillary Thyroid Cancer by Using Peptide-Functionalized Imaging Probes

Thyroid cancers are the most frequent endocrine cancers and their incidence is increasing worldwide. Thyroid nodules occur in over 19–68% of the population, but only 7–15% of them are diagnosed as malignant. Diagnosis relies on a fine needle aspiration biopsy, which is often inconclusive and about 90% of thyroidectomies are performed for benign lesions. Galectin-1 has been proposed as a confident biomarker for the discrimination of malignant from benign nodules. We previously identified by phage display two peptides (P1 and P7) targeting galectin-1, with the goal of developing imaging probes for non-invasive diagnosis of thyroid cancer. The peptides were coupled to ultra-small superparamagnetic particles of iron oxide (USPIO) or to a near-infrared dye (CF770) for non-invasive detection of galectin-1 expression in a mouse model of papillary thyroid cancer (PTC, as the most frequent one) by magnetic resonance imaging and fluorescence lifetime imaging. The imaging probes functionalized with the two peptides presented comparable image enhancement characteristics. However, those coupled to P7 were more favorable, and showed decreased retention by the liver and spleen (known for their galectin-1 expression) and high sensitivity (75%) and specificity (100%) of PTC detection, which confirm the aptitude of this peptide to discriminate human malignant from benign nodules (80% sensitivity, 100% specificity) previously observed by immunohistochemistry.

A useful preparation of ultrasmall iron oxide particles by using arc plasma deposition.

Ultrasmall particles, different from the larger size nanoparticles, have recently attracted significant attention in the scientific community in nanotechnology for catalytic, electronic and optical applications; however, their magnetic properties remain unexplored due to the difficult structural analysis. A challenging issue is to develop a preparation method for iron oxide particles (IOPs) with fine size control, and to determine the dependence of magnetic properties on the morphology and crystallinity of the magnetic particles. However, synthetic approaches to obtain IOPs, regarded as one of the new fields of magnetic nanoparticles, have been significantly limited. This article reported a developed synthetic method to prepare IOPs on carbon supports using pulsed arc plasma deposition (APD) in flowing oxygen gas, which clarified the finely-controlled formation of IOPs on graphene nanosheets. Structural characterization of the IOPs revealed the formation of crystalline γ-Fe2O3 ultrasmall particles with oxygen deficiency. The pulsed APD method for IOPs is the first simple and convenient technique to not only prevent significant aggregation and contamination by organic compounds and avoid the need for thermal pretreatment, but also provide uniform crystalline nano-order particles.

MRI Relaxometry for Quantitative Analysis of USPIO Uptake in Cerebral Small Vessel Disease.

A protocol for evaluating ultrasmall superparamagnetic particles of iron oxide (USPIO) uptake and elimination in cerebral small vessel disease patients was developed and piloted. B1-insensitive R1 measurement was evaluated in vitro. Twelve participants with history of minor stroke were scanned at 3-T MRI including structural imaging, and R1 and R2* mapping. Participants were scanned (i) before and (ii) after USPIO (ferumoxytol) infusion, and again at (iii) 24–30 h and (iv) one month. Absolute and blood-normalised changes in R1 and R2* were measured in white matter (WM), deep grey matter (GM), white matter hyperintensity (WMH) and stroke lesion regions. R1 measurements were accurate across a wide range of values. R1 (p < 0.05) and R2* (p < 0.01) mapping detected increases in relaxation rate in all tissues immediately post-USPIO and at 24–30 h. R2* returned to baseline at one month. Blood-normalised R1 and R2* changes post-infusion and at 24–30 h were similar, and were greater in GM versus WM (p < 0.001). Narrower distributions were seen with R2* than for R1 mapping. R1 and R2* changes were correlated at 24–30 h (p < 0.01). MRI relaxometry permits quantitative evaluation of USPIO uptake; R2* appears to be more sensitive to USPIO than R1. Our data are explained by intravascular uptake alone, yielding estimates of cerebral blood volume, and did not support parenchymal uptake. Ferumoxytol appears to be eliminated at 1 month. The approach should be valuable in future studies to quantify both blood-pool USPIO and parenchymal uptake associated with inflammatory cells or blood-brain barrier leak.

Stimulating brain recovery after stroke using theranostic albumin nanocarriers loaded with nerve growth factor in combination therapy

For many years, delivering drug molecules across the blood brain barrier has been a major challenge. The neuropeptide nerve growth factor is involved in the regulation of growth and differentiation of cholinergic neurons and holds great potential in the treatment of stroke. However, as with many other compounds, the biomolecule is not able to enter the central nervous system. In the present study, nerve growth factor and ultra-small particles of iron oxide were co-encapsulated into a chemically crosslinked albumin nanocarrier matrix which was modified on the surface with apolipoprotein E. These biodegradable nanoparticles with a size of 212 ± 1 nm exhibited monodisperse size distribution and low toxicity. They delivered NGF through an artificial blood brain barrier and were able to induce neurite outgrowth in PC12 cells in vitro. In an animal model of stroke, the infarct size was significantly reduced compared to the vehicle control. The combination therapy of NGF and the small-molecular MEK inhibitor U0126 showed a slight but not significant difference compared to U0126 alone. However, further in vivo evidence suggests that successful delivery of the neuropeptide is possible as well as the synergism between those two treatments.

Imaging of distant metastases of prostate cancer.

The detection of distant metastases at the initial diagnosis of prostate cancer (PCa) establishes the treatment approach and has a prognostic value, nevertheless it is not well established. Since proposed staging approaches often contradict each other, we aimed to compare the current imaging techniques for staging of advanced PCa, including future applications of the most innovative methods. Conventional imaging techniques, including computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) have been employed for metastatic staging (both N and M staging) of men with high-risk PCa, but surgical pelvic dissection remains the gold standard for N staging. However, functional MRI by using diffusion-weighted imaging, MR lymphography (MRL) with ultra-small paramagnetic iron oxide particles (USPIO), and hybrid PET/MRI imaging showed both high sensitivity and high specificity for nodal staging and depicting metastases. The standard of practice for M staging in PCa includes the radionuclide bone scan and targeted X-ray film, but their performance has generally been poor. Recently, MRI showed promising results with applications in both local and distant staging. Finally, with the development of new PET tracers, PET/CT and PET/MRI offer a combination of excellent pharmacokinetic characteristics, functional information, and precise anatomic localization and morphological correlation of tumor lesions.

Magnetic resonance imaging using ultrasmall superparamagnetic particles of iron oxide for abdominal aortic aneurysm: a risk prediction study

Background Abdominal aortic aneurysm (AAA) rupture is a common cause of sudden death. Pre-emptive elective surgical repair can prevent aneurysm rupture and be life-saving. Ultrasmall superparamagnetic particles of iron oxide (USPIO) detect cellular inflammation using magnetic resonance imaging (MRI) in patients with AAAs. For this reason, USPIO-enhanced MRI represents a promising new technique that could improve risk prediction and better guide surgical intervention. Objectives To assess whether or not USPIO-enhanced MRI can predict aneurysm growth rates and clinical outcomes in patients with AAAs. Design A prospective multicentre open-label observational cohort study. Setting Three secondary and tertiary care hospitals in Scotland. Participants Patients (n = 342) aged &gt; 40 years with a maximum anteroposterior AAA diameter of ≥ 40 mm confirmed by abdominal ultrasonography, and under ultrasonographic surveillance as part of routine clinical care. Interventions USPIO-enhanced MRI of AAA. Main outcome measures The primary end point was the composite of aneurysm rupture or repair. Secondary outcomes included rate of aneurysm growth, all-cause mortality and aneurysm-related mortality. Results Participants (85% male, aged 73.1 ± 7.2 years) had a baseline aneurysm diameter of 49.6 ± 7.7 mm, and USPIO enhancement was identified in 146 participants (42.7%), absent in 191 participants (55.8%) and indeterminate in 5 participants (1.5%). During follow-up (1005 ± 280 days), there were 17 AAA ruptures (5.0%), 126 AAA repairs (36.8%) and 48 deaths (14.0%). Compared with those without uptake, patients with USPIO enhancement have increased rates of aneurysm expansion (3.1 ± 2.5 vs. 2.5 ± 2.4 mm/year; p = 0.0424), although this was not independent of current smoking habits (p = 0.1993). The primary end point (aneurysm rupture or repair) occurred more frequently in participants with USPIO enhancement [69/146 (47.3%) vs. 68/191 (35.6%), difference 11.7%, 95% confidence interval 1.1% to 22.2%; p = 0.0308]: this was similar for each component of rupture (6.8% vs. 3.7%; p = 0.1857) or repair (41.8% vs. 32.5%; p = 0.0782). USPIO enhancement was associated with reduced event-free survival for aneurysm rupture or repair (p = 0.0275). Baseline AAA diameter (p &lt; 0.0001) and current smoking habits (p = 0.0446) also predicted the primary outcome, and the addition of USPIO enhancement to the multivariate model did not improve event prediction (c-statistic 0.7935 to 0.7936). Conclusions USPIO-enhanced MRI is a novel approach to the identification of aortic wall cellular inflammation in patients with AAAs, and predicts the rate of aneurysm growth and clinical outcome. USPIO-enhanced MRI does not provide independent prediction of aneurysm expansion or clinical outcomes in a model incorporating known clinical risk factors. Larger trials are now needed to explore the prediction of emergent aneurysm events to establish the added benefit of USPIO-enhanced MRI. Comparative outcome studies should determine whether or not using other imaging biomarkers that track alternative disease processes have better predictive capability than USPIO-enhanced MRI. Trial registration Current Controlled Trials ISRCTN76413758. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership.

OA197] Normal ranges of cardiac imaging radiomic metrics in healthy volunteers 24 h post ultra-small particles of iron oxide (USPIO) administration

Purpose Radiomics is a novel post-processing imaging methodology by which statistical features are extracted from medical images. The radiomic features of a myocardial region of interest open the possibility that novel descriptive patterns, found in images, may selectively identify phenotypic features of myocardial disease. Ultra-small particles of iron oxide (USPIO) uptake in the myocardium may show insights into a variety of pathologies that involve macrophage activation. While myocardial uptake may be low, any MRI signal changes due to USPIO uptake may be difficult to detect using global measures. Hence the potential need for more subtle metrics. The study aims to investigate USPIO uptake by innate macrophages resistant in normal myocardium using radiomics. Methods 11 healthy volunteers were imaged using a 3T Philips MRI scanner pre and exactly 24 h post administration of 2 (n = 7) or 4 mg/kg (n = 4) of USPIO. A short axis stack of entire left ventricular myocardium was acquired using a multi-echo gradient sequence (10 mm thickness, 0 mm gap). To delineate the myocardium, endocardial and epicardial border contours were manually traced on the first echo in the sequence (TE = 1.15 ms). First order and second order radiomic features were extracted from each slice of the stacks. Differences between feature values pre and post USPIO administration were calculated using paired samples t-test. Results In the 4 mg/kg USPIO group significant differences were found in Mean (p = 0.027), Large Area Emphasis (LAE) (p = 0.027), Zone Variance (ZV) (p = 0.027), Large Area Low Gray Level Emphasis (LALGLE) (p = 0.027), and Large Area High Gray Level Emphasis (LAHGLE) (p = 0.027). For the 2 mg/kg group, significant differences were found for Informal Measure of Correlation 1 (p = 0.009), LAE (p = 0.014), ZV (p = 0.014), Zone Percentage (p = 0.014), LALGLE (p = 0.014), and LAHGLE (p = 0.014). Conclusions Radiomics assessment of multi-echo gradient magnetic resonance images of the myocardium is feasible. Compared to pre USPIO images, post USPIO radiomics was able to detect a reduction in voxel intensity, an increase in intensity and run length homogeneity, and an increase in coarseness; with a smaller distribution of shorter run lengths.

The Diagnostic Performance of MRI for Detection of Lymph Node Metastasis in Bladder and Prostate Cancer: An Updated Systematic Review and Diagnostic Meta-Analysis.

The purpose of this article is to review the diagnostic performance of MRI for the detection of pelvic lymph node (LN) metastasis in patients with bladder and prostate cancer. MEDLINE and EMBASE were searched up to January 13, 2017. We included diagnostic accuracy studies that used MRI for pelvic LN detection in patients with bladder or prostate cancer, using histopathologic analyses published since 2000 as the reference standard. Two independent reviewers assessed the methodologic quality using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Sensitivity and specificity of all studies were calculated. Per-patient and per-LN results were pooled and plotted in a hierarchic summary ROC plot. Metaregression, sensitivity, and subgroup analyses were performed. Twenty-four studies (2928 patients) were included. Pooled per-patient sensitivity (n = 21) was 0.56 (95% CI, 0.42-0.69) with a specificity of 0.94 (95% CI, 0.90-0.96). Per-LN pooled estimates (n = 9) showed consistent results: sensitivity of 0.57 (95% CI, 0.29-0.82) and specificity of 0.97 (95% CI, 0.94-0.98). At metaregression analysis, type of cancer, magnet field strength, and use of ultrasmall superparamagnetic particles of iron oxide (USPIO) were significant factors affecting heterogeneity (p ≤ 0.01). Sensitivity analyses showed that specificity estimates were comparable (range, 0.87-0.95), but sensitivity estimates showed significant differences. Studies that used USPIO (n = 4) had higher sensitivity (0.86; 95% CI, 0.62-0.96) than did those not using USPIO (n = 17; 0.46; 95% CI, 0.35-0.58). MRI shows high specificity but poor and heterogeneous sensitivity for detecting pelvic LN metastasis in patients with bladder and prostate cancer. Using USPIO can improve sensitivity.

Myocardial inflammation, injury and infarction during on-pump coronary artery bypass graft surgery

BackgroundMyocardial inflammation and injury occur during coronary artery bypass graft (CABG) surgery. We aimed to characterise these processes during routine CABG surgery to inform the diagnosis of type 5 myocardial infarction.MethodsWe assessed 87 patients with stable coronary artery disease who underwent elective CABG surgery. Myocardial inflammation, injury and infarction were assessed using plasma inflammatory biomarkers, high-sensitivity cardiac troponin I (hs-cTnI) and cardiac magnetic resonance imaging (CMR) using both late gadolinium enhancement (LGE) and ultrasmall superparamagnetic particles of iron oxide (USPIO).ResultsSystemic humoral inflammatory biomarkers (myeloperoxidase, interleukin-6, interleukin-8 and c-reactive protein) increased in the post-operative period with C-reactive protein concentrations plateauing by 48 h (median area under the curve (AUC) 7530 [interquartile range (IQR) 6088 to 9027] mg/L/48 h). USPIO-defined cellular myocardial inflammation ranged from normal to those associated with type 1 myocardial infarction (median 80.2 [IQR 67.4 to 104.8] /s). Plasma hs-cTnI concentrations rose by ≥50-fold from baseline and exceeded 10-fold the upper limit of normal in all patients. Two distinct patterns of peak cTnI release were observed at 6 and 24 h. After CABG surgery, new LGE was seen in 20% (n = 18) of patients although clinical peri-operative type 5 myocardial infarction was diagnosed in only 9% (n = 8). LGE was associated with the delayed 24-h peak in hs-cTnI and its magnitude correlated with AUC plasma hs-cTnI concentrations (r = 0.33, p < 0.01) but not systemic inflammation, myocardial inflammation or bypass time.ConclusionPatients undergoing CABG surgery invariably have plasma hs-cTnI concentrations >10-fold the 99th centile upper limit of normal that is not attributable to inflammatory or ischemic injury alone. Peri-operative type 5 myocardial infarction is often unrecognised and is associated with a delayed 24-h peak in plasma hs-cTnI concentrations.

Validation by Magnetic Resonance Imaging of the Diagnostic Potential of a Heptapeptide-Functionalized Imaging Probe Targeted to Amyloid-β and Able to Cross the Blood-Brain Barrier.

The diagnosis of Alzheimer's disease (AD) is a critical step in the management of patients. We have developed a non-invasive diagnosis tool based on magnetic resonance molecular imaging (MRMI) of amyloid-β peptide using ultra-small particles of iron oxide (USPIO) functionalized with a disulfide constrained cyclic heptapeptide (PHO) identified by phage display (USPIO-PHO). After previously demonstrating the optimal pharmacologic properties of USPIO-PHO and its capacity to cross the blood-brain barrier (BBB), the ability of USPIO-PHO to target amyloid plaques (AP) by MRMI has been validated in the present work on AD transgenic mice. The immunohistochemistry and immunofluorescent detection of USPIO-PHO on brain sections collected after in vivo MRMI studies enabled its colocalization with AP, confirming the BBB passage and specific targeting. The AP targeting by USPIO-PHO has been moreover corroborated by the good correlation between the number of AP detected with anti-amyloid β antibody and Perls'-DAB staining. Finally, the crossing mechanism of USPIO-PHO through the BBB was elucidated, revealing the involvement of non-degradation pathway of caveolae, while the control contrast agent USPIO-PEG was not endocytosed by the human brain endothelial cells.

Toward a new and noninvasive diagnostic method of papillary thyroid cancer by using peptide vectorized contrast agents targeted to galectin-1.

The incidence of papillary thyroid cancer has increased these last decades due to a better detection. High prevalence of nodules combined with the low incidence of thyroid cancers constitutes an important diagnostic challenge. We propose to develop an alternative diagnostic method to reduce the number of useless and painful thyroidectomies using a vectorized contrast agent for magnetic resonance imaging. Galectin-1 (gal-1), a protein overexpressed in well-differentiated thyroid cancer, has been targeted with a randomized linear 12-mer peptide library using the phage display technique. Selected peptides have been conjugated to ultrasmall superparamagnetic particles of iron oxide (USPIO). Peptides and their corresponding contrast agents have been tested in vitro for their specific binding and toxicity. Two peptides (P1 and P7) were selected according to their affinity toward gal-1. Their binding has been revealed by immunohistochemistry on human thyroid cancer biopsies, and they were co-localized with gal-1 by immunofluorescence on TPC-1 cell line. Both peptides induce a decrease in TPC-1 cells' adhesion to gal-1 immobilized on culture plates. After coupling to USPIO, the peptides preserved their affinity toward gal-1. Their specific binding has been corroborated by co-localization with gal-1 expressed by TPC-1 cells and by their ability to compete with anti-gal-1 antibody. The peptides and their USPIO derivatives produce no toxicity in HepaRG cells as determined by MTT assay. The vectorized contrast agents are potential imaging probes for thyroid cancer diagnosis. Moreover, the two gal-1-targeted peptides prevent cancer cell adhesion by interacting with the carbohydrate-recognition domain of gal-1.

Exploring the Biological and Mechanical Properties of Abdominal Aortic Aneurysms Using USPIO MRI and Peak Tissue Stress: A Combined Clinical and Finite Element Study

Inflammation detected through the uptake of ultrasmall superparamagnetic particles of iron oxide (USPIO) on magnetic resonance imaging (MRI) and finite element (FE) modelling of tissue stress both hold potential in the assessment of abdominal aortic aneurysm (AAA) rupture risk. This study aimed to examine the spatial relationship between these two biomarkers. Patients (n = 50) > 40 years with AAA maximum diameters > = 40 mm underwent USPIO-enhanced MRI and computed tomography angiogram (CTA). USPIO uptake was compared with wall stress predictions from CTA-based patient-specific FE models of each aneurysm. Elevated stress was commonly observed in areas vulnerable to rupture (e.g. posterior wall and shoulder). Only 16% of aneurysms exhibited co-localisation of elevated stress and mural USPIO enhancement. Globally, no correlation was observed between stress and other measures of USPIO uptake (i.e. mean or peak). It is suggested that cellular inflammation and stress may represent different but complimentary aspects of AAA disease progression.

Imaging pathobiology of carotid atherosclerosis with ultrasmall superparamagnetic particles of iron oxide: an update.

Purpose of reviewTo provide brief overview of the developments regarding use of ultrasmall superparamagnetic particles of iron oxide in imaging pathobiology of carotid atherosclerosis.Recent findingsMRI is a promising technique capable of providing morphological and functional information about atheromatous plaques. MRI using iron oxide particles, called ultrasmall superparamagnetic iron oxide (USPIO) particles, allows detection of macrophages in atherosclerotic tissue. Ferumoxytol has emerged as a new USPIO agent, which has an excellent safety profile. Based on the macrophage-selective properties of ferumoxytol, there is increasing number of recent reports suggesting its effectiveness to detect pathological inflammation.SummaryUSPIO particles allow magnetic resonance detection of macrophages in atherosclerotic tissue. Ferumoxytol has emerged as a new USPIO agent, with an excellent safety profile. This has the potential to be used for MRI of the pathobiology of atherosclerosis.