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A high r1 relaxivity manganese–gadolinium nanocolloid (α v β 3 -MnOL-Gd NC) was developed and effectively detected atherosclerotic angiogenesis in rabbits fed cholesterol-rich diets for 12 months using a clinical MRI scanner (3 T). 3D mapping of neovasculature signal intensity revealed the spatial coherence and intensity of plaque angiogenic expansion, which may, with other high risk MR bioindicators, help identify high-risk patients with moderate (40% to 60%) vascular stenosis. Microscopy confirmed the predominant media and plaque distribution of fluorescent α v β 3 -MnOL-Gd NC, mirroring the MR data. An expected close spatial association of α v β 3 -integrin neovasculature and macrophages was noted, particularly within plaque shoulder regions. Manganese oleate bioelimination occurred via the biliary system into feces. Gd-DOTA was eliminated through the bile–fecal and renal excretion routes. α v β 3 -MnOL-Gd NC offers an effective vehicle for T1w neovascular imaging in atherosclerosis. From the Clinical Editor Cerebrovascular accidents are a leading cause of mortality and morbidity worldwide. The acute formation of thrombus following atherosclerotic plaque rupture has been well recognized as the etiology of stroke. The authors studied microanatomical features of vulnerable atherosclerotic plaque in this article, in an attempt to identify those with high risk of rupture. Gadolinium-manganese hybrid nanocolloid (MnOL-Gd NC) was developed as a novel contrast agent for MRI. They show that this agent is effective in providing neovascular imaging. [ABSTRACT FROM AUTHOR]

High-relaxivity T1-weighted (T1w) MR molecular imaging nanoparticles typically present high surface gadolinium payloads that can elicit significant acute complement activation (CA). The objective of this research was to develop a high T1w contrast nanoparticle with improved safety. We report the development, optimization, and characterization of a gadolinium–manganese hybrid nanocolloid (MnOL-Gd NC; 138 ± 10 (D av )/nm; PDI: 0.06; zeta: − 27 ± 2 mV). High r1 particulate relaxivity with minute additions of Gd-DOTA-lipid conjugate to the MnOL nanocolloid surface achieved an unexpected paramagnetic synergism. This hybrid MnOL-Gd NC provided optimal MR TSE signal intensity at 5 nM/voxel and lower levels consistent with the level expression anticipated for sparse biomarkers, such as neovascular integrins. MnOL NC produced optimal MR TSE signal intensity at 10 nM/voxel concentrations and above. Importantly, MnOL-Gd NC avoided acute CA in vitro and in vivo while retaining minimal transmetallation risk. From the Clinical Editor The authors developed a gadolinium-manganese hybrid nanocolloid (MnOL-Gd NC) in this study. These were used as a high-relaxivity paramagnetic MR molecular imaging agent in experimental models. It was shown that MnOL-Gd NC could provide high T1w MR contrast for targeted imaging. As the level of gadolinium used was reduced, there was also reduced risk of systemic side effects from complement activation. [ABSTRACT FROM AUTHOR]

Due to their small size, lower cost, short reproduction cycle, and genetic manipulation, rodents have been widely used to test the safety and efficacy for pharmaceutical development in human disease. In this report, MR cholangiography demonstrated an unexpected rapid (< 5 min) biliary elimination of gadolinium–perfluorocarbon nanoparticles (approximately 250 nm diameter) into the common bile duct and small intestine of rats, which is notably different from nanoparticle clearance patterns in larger animals and humans. Unawareness of this dissimilarity in nanoparticle clearance mechanisms between small animals and humans may lead to fundamental errors in predicting nanoparticle efficacy, pharmacokinetics, biodistribution, bioelimination, and toxicity. From the Clinical Editor Comprehensive understanding of nanoparticle clearance is a clear prerequisite for human applications of nanomedicine-based therapeutic approaches. Through a novel use of MR cholangiography, this study demonstrates unusually rapid hepatic clearance of gadolinium-perfluorocarbon nanoparticles in rodents, in a pattern that is different than what is observed in larger animals and humans, raising awareness of important differences between common rodent-based models and larger mammals. [ABSTRACT FROM AUTHOR]

Objectives: The objectives of this study were to use magnetic resonance (MR) molecular imaging to 1) characterize the aortic neovascular development in a rat model of atherosclerosis and 2) monitor the effects of an appetite suppressant on vascular angiogenesis progression. Background: The James C. Russell:LA corpulent rat strain (JCR:LA-cp) is a model of metabolic syndrome characterized by obesity, insulin resistance, hyperlipidemia, and vasculopathy, although plaque neovascularity has not been reported in this strain. MR molecular imaging with ανβ3-targeted nanoparticles can serially map angiogenesis in the aortic wall and monitor the progression of atherosclerosis. Methods: Six-week old JCR:LA-cp (+/?; lean, n = 5) and JCR:LA-cp (cp/cp; obese, n = 5) rats received standard chow, and 6 obese rats were fed the appetite suppressant benfluorex over 16 weeks. Body weight and food consumption were recorded at baseline and weeks 4, 8, 12, and 16. MR molecular imaging with ανβ3-targeted paramagnetic nanoparticles was performed at weeks 0, 8, and 16. Fasted plasma triglyceride, cholesterol, and glucose were measured immediately before MR scans. Plasma insulin and leptin levels were assayed at weeks 8 and 16. Results: Benfluorex reduced food consumption (p < 0.05) to the same rate as lean animals, but had no effect on serum cholesterol or triglyceride levels. MR (3-T) aortic signal enhancement with ανβ3-targeted nanoparticles was initially equivalent between groups, but increased (p < 0.05) in the untreated obese animals over 16 weeks. No signal change (p > 0.05) was observed in the benfluorex-treated or lean rat groups. MR differences paralleled adventitial microvessel counts, which increased (p < 0.05) among the obese rats and were equivalently low in the lean and benfluorex-treated animals (p > 0.05). Body weight, insulin, and leptin were decreased (p < 0.05) from the untreated obese animals by benfluorex, but not to the lean control levels (p < 0.05). Conclusions: Neovascular expansion is a prominent feature of the JCR:LA-cp model. MR imaging with ανβ3-targeted nanoparticles provided a noninvasive assessment of angiogenesis in untreated obese rats, which was suppressed by benfluorex. [Copyright &y& Elsevier]

Objectives: Studies were performed to develop a prolonged antiangiogenesis therapy regimen based on theranostic ανβ3-targeted nanoparticles. Background: Antiangiogenesis therapy may normalize atherosclerotic plaque vasculature and promote plaque stabilization. ανβ3-targeted paramagnetic nanoparticles can quantify atherosclerotic angiogenesis and incorporate fumagillin to elicit acute antiangiogenic effects. Methods: In the first experiment, hyperlipidemic rabbits received ανβ3-targeted fumagillin nanoparticles (0, 30, or 90 μg/kg) with either a continued high fat diet or conversion to standard chow. The antiangiogenic response was followed for 4 weeks by cardiac magnetic resonance (CMR) molecular imaging with ανβ3-targeted paramagnetic nanoparticles. In a second 8-week study, atherosclerotic rabbits received atorvastatin (0 or 44 mg/kg diet) alone or with ανβ3-targeted fumagillin nanoparticles (only week 0 vs. weeks 0 and 4), and angiogenesis was monitored with CMR molecular imaging. Histology was performed to determine the location of bound nanoparticles and to correlate the level of CMR enhancement with the density of angiogenic vessels. Results: The ανβ3-targeted fumagillin nanoparticles reduced the neovascular signal by 50% to 75% at 1 week and maintained this effect for 3 weeks regardless of diet and drug dose. In the second study, atherosclerotic rabbits receiving statin alone had no antineovascular benefit over 8 weeks. The ανβ3-targeted fumagillin nanoparticles decreased aortic angiogenesis for 3 weeks as in study 1, and readministration on week 4 reproduced the 3-week antineovascular response with no carry-over benefit. However, atorvastatin and 2 doses of ανβ3-targeted fumagillin nanoparticles (0 and 4 weeks) achieved marked and sustainable antiangiogenesis. Microscopic studies corroborated the high correlation between CMR signal and neovessel counts and confirmed that the ανβ3-targeted nanoparticles were constrained to the vasculature of the aortic adventia. Conclusions: The CMR molecular imaging with ανβ3-targeted paramagnetic nanoparticles demonstrated that the acute antiangiogenic effects of ανβ3-targeted fumagillin nanoparticles could be prolonged when combined with atorvastatin, representing a potential strategy to evaluate antiangiogenic treatment and plaque stability. [Copyright &y& Elsevier]

Objective: The Cox maze procedure is the most effective surgical treatment for atrial fibrillation; however, its complexity has limited its clinical utility. The purpose of this study was to simplify the procedure by using an irrigated bipolar radiofrequency ablation device on the beating heart without cardiopulmonary bypass. Methods: Six domestic pigs underwent median sternotomy. The pulmonary veins were circumferentially ablated. Electrical isolation was confirmed by pacing. Eight lesions were performed epicardially, and three lesions were performed through purse-string sutures with one of the jaws of the device introduced into the right atrium. After 30 days, magnetic resonance imaging was performed to assess atrial function, pulmonary vein anatomy, and coronary artery patency. Cholinergic stimulation and burst pacing were administered to induce atrial fibrillation. Histologic assessment of the heart was performed after the animal was killed. Results: A modified Cox maze procedure was successfully performed with the irrigated bipolar radiofrequency device with no deaths. In every instance, the pulmonary veins were electrically isolated. Cholinergic stimulation with burst pacing failed to produce atrial fibrillation. Imaging studies revealed tricuspid regurgitation without evidence of pulmonary vein stenosis, coronary artery stenosis, or intra-atrial thrombus. Total atrial ejection fraction was 16.9% ± 7.5%, a significant reduction. Histologically, 99% of the lesions were transmural, and there was no evidence of coronary sinus injury. Conclusion: Lesions on both the right and left atria can be created successfully on the beating heart with irrigated bipolar radiofrequency. The great majority of lesions with this device were transmural. This device should not be used on valvular tissue. [Copyright &y& Elsevier]

Rationale and Objectives: We studied preparatory strategies for high-resolution human eye in vivo imaging with commercially available magnets and coils. Materials and Methods: We imaged normal volunteers on 1.5T systems by Philips, GE, and Siemens, using commercial ∼9 cm temporomandibular joint receive coils. Subjects fixated the nonimaged eye on a target. We compared signal (S) to tissue noise (Nt) and system noise (Ns) between images acquired with the imaged eye: 1) open, 2) held closed, 3) taped closed, and 4) taped closed with overlying water-soaked gauze. We standardized technique 4 to compare studies between manufacturers using T1-weighted parameters (repetition time/echo time/flip angle/number of signal averages = 400 ms/10–17ms/90°/4–6, in-plane resolution ∼250 × 250 μm2; 2–3 mm slices, image time = 4.3–5.2 min). We obtained similar images of an enucleated human eye to estimate in vivo effects of microsaccades and ocular pulsations. Results: Measurements of S/Nt and S/Ns gave surprising results of Nt < Ns in some instances. Ns/Nt was ≅ 1, varying ∼20%, when the eye was taped shut and covered with water-soaked gauze. T1-weighted spin echo sequences, using technique 4, produced high-quality images with good S/Nt on all systems. Images from the three manufacturers were comparable when parameters were normalized for pulse repetition time, echo time, number of signal averages, bandwidth in Hz/pixel, and reconstruction matrix. Images of the enucleated eye produced S/Nt ratios that were comparable to in vivo images in some structures. Conclusions: Our best preparatory technique produced images with in-plane resolution of ∼250 μm in 4–5 minutes with three commercial 1.5T systems. The in vivo S/Nt was comparable to in vitro values in most solid tissues but decreased in most fluid compartments. [Copyright &y& Elsevier]

An abstract of the article "F Magnetic Resonance Molecular Imaging With Perfluorocarbon Nanoparticles," by Gregory M. Lanza and colleagues is presented.