Semi-Automatic Graphical Tool for Measuring Coronary Artery Spatially Weighted Calcium Score from Gated Cardiac Computed Tomography Images

The current standard for measuring coronary artery calcification to determine the extent of atherosclerosis is by calculating the Agatston score from ...

Icahn School of Medicine at Mount Sinai

Nanomedicine research produces hundreds of studies every year, yet very few formulations have been approved for clinical use. This is due in part to a reliance on murine studies, which have limited value in accurately predicting translational efficacy in larger animal models and humans. Here, we report the scale-up of a nanoimmunotherapy from mouse to large rabbit and porcine atherosclerosis models, with an emphasis on the solutions we implemented to overcome production and evaluation challenges. Specifically, we integrated translational imaging readouts within our workflow to both analyze the nanoimmunotherapeutic's in vivo behavior and assess treatment response in larger animals. We observed our nanoimmunotherapeutic's anti-inflammatory efficacy in mice, as well as rabbits and pigs. Nanoimmunotherapy-mediated reduction of inflammation in the large animal models halted plaque progression, supporting the approach's translatability and potential to acutely treat atherosclerosis.

Imaging-assisted nanoimmunotherapy for atherosclerosis in multiple species.

Although the first nanomedicine was clinically approved more than two decades ago, nanoparticles' (NP)  behavior is complex and the immune system's role in their application remains elusive. At present, only passive-targeting nanoformulations have been clinically approved, while more complicated active-targeting strategies typically fail to advance from the early clinical phase stage. This absence of clinical translation is, among others, due to the very limited understanding for  targeting mechanisms. Dynamic  phenomena such as NPs' real-time targeting kinetics and phagocytes' contribution to active NP targeting remain largely unexplored. To better understand  targeting, monitoring NP accumulation and distribution at complementary levels of spatial and temporal resolution is imperative. Here, we integrate  positron emission tomography/computed tomography imaging with intravital microscopy and flow cytometric analyses to study αβ-integrin-targeted cyclic arginine-glycine-aspartate decorated liposomes and oil-in-water nanoemulsions in tumor mouse models. We observed that ligand-mediated accumulation in cancerous lesions is multifaceted and identified "NP hitchhiking" with phagocytes to contribute considerably to this intricate process. We anticipate that this understanding can facilitate rational improvement of nanomedicine applications and that immune cell-NP interactions can be harnessed to develop clinically viable nanomedicine-based immunotherapies.

Tumor Targeting by αβ-Integrin-Specific Lipid Nanoparticles Occurs  Phagocyte Hitchhiking.

Trained immunity, a functional state of myeloid cells, has been proposed as a compelling immune-oncological target. Its efficient induction requires direct engagement of myeloid progenitors in the bone marrow. For this purpose, we developed a bone marrow-avid nanobiologic platform designed specifically to induce trained immunity. We established the potent anti-tumor capabilities of our lead candidate MTP-HDL in a B16F10 mouse melanoma model. These anti-tumor effects result from trained immunity-induced myelopoiesis caused by epigenetic rewiring of multipotent progenitors in the bone marrow, which overcomes the immunosuppressive tumor microenvironment. Furthermore, MTP-HDL nanotherapy potentiates checkpoint inhibition in this melanoma model refractory to anti-PD-1 and anti-CTLA-4 therapy. Finally, we determined MTP-HDL's favorable biodistribution and safety profile in non-human primates. In conclusion, we show that rationally designed nanobiologics can promote trained immunity and elicit a durable anti-tumor response either as a monotherapy or in combination with checkpoint inhibitor drugs.

Trained Immunity-Promoting Nanobiologic Therapy Suppresses Tumor Growth and Potentiates Checkpoint Inhibition.

Acute bacterial endocarditis is a rapid, difficult to manage, and frequently lethal disease. Potent antibiotics often cannot efficiently kill  that colonizes the heart's valves.  relies on virulence factors to evade therapeutics and the host's immune response, usurping the host's clotting system by activating circulating prothrombin with staphylocoagulase and von Willebrand factor-binding protein. An insoluble fibrin barrier then forms around the bacterial colony, shielding the pathogen from immune cell clearance. Targeting virulence factors may provide previously unidentified avenues to better diagnose and treat endocarditis. To tap into this unused therapeutic opportunity, we codeveloped therapeutics and multimodal molecular imaging to probe the host-pathogen interface. We introduced and validated a family of small-molecule optical and positron emission tomography (PET) reporters targeting active thrombin in the fibrin-rich environment of bacterial colonies. The imaging agents, based on the clinical thrombin inhibitor dabigatran, are bound to heart valve vegetations in mice. Using optical imaging, we monitored therapy with antibodies neutralizing staphylocoagulase and von Willebrand factor-binding protein in mice with  endocarditis. This treatment deactivated bacterial defenses against innate immune cells, decreased in vivo imaging signal, and improved survival. Aortic or tricuspid  endocarditis in piglets was also successfully imaged with clinical PET/magnetic resonance imaging. Our data map a route toward adjuvant immunotherapy for endocarditis and provide efficient tools to monitor this drug class for infectious diseases.

Multimodal imaging of bacterial-host interface in mice and piglets with  endocarditis.

This study aimed to (i) develop Magnetization-Prepared Golden-angle RAdial Sparse Parallel (MP-GRASP) MRI using a stack-of-stars trajectory for rapid free-breathing T1 mapping and (ii) extend MP-GRASP to multi-echo acquisition (MP-Dixon-GRASP) for fat/water-separated (water-specific) T1 mapping.

Magnetization-prepared GRASP MRI for rapid 3D T1 mapping and fat/water-separated T1 mapping.

Subject motion in positron emission tomography (PET) is a key factor that degrades image resolution and quality, limiting its potential capabilities. Correcting for it is complicated due to the lack of sufficient measured PET data from each position. This poses a significant barrier in calculating the amount of motion occurring during a scan. Motion correction can be implemented at different stages of data processing either during or after image reconstruction, and once applied accurately can substantially improve image quality and information accuracy. With the development of integrated PET-MRI (magnetic resonance imaging) scanners, internal organ motion can be measured concurrently with both PET and MRI. In this review paper, we explore the synergistic use of PET and MRI data to correct for any motion that affects the PET images. Different types of motion that can occur during PET-MRI acquisitions are presented and the associated motion detection, estimation and correction methods are reviewed. Finally, some highlights from recent literature in selected human and animal imaging applications are presented and the importance of motion correction for accurate kinetic modelling in dynamic PET-MRI is emphasized. This article is part of the theme issue 'Synergistic tomographic image reconstruction: part 2'.

Synergistic motion compensation strategies for positron emission tomography when acquired simultaneously with magnetic resonance imaging.

This study investigated whether pulmonary artery (PA) F-FDG uptake is associated with hypertension, and if it correlates to elevated pulmonary pressures.

Pulmonary Artery F-Fluorodeoxyglucose Uptake by PET/CMR as a Marker of Pulmonary Hypertension in Sarcoidosis.

This study aimed to explore the radiomic features from PET images to detect active cardiac sarcoidosis (CS).

Exploring the Utility of Radiomic Feature Extraction to Improve the Diagnostic Accuracy of Cardiac Sarcoidosis Using FDG PET.

In recent years, cardiovascular immuno-imaging by positron emission tomography (PET) has undergone tremendous progress in preclinical settings. Clinically, two approved PET tracers hold great potential for inflammation imaging in cardiovascular patients, namely FDG and DOTATATE. While the former is a widely applied metabolic tracer, DOTATATE is a relatively new PET tracer targeting the somatostatin receptor 2 (SST2). In the current study, we performed a detailed, head-to-head comparison of DOTATATE-based radiotracers and [F]F-FDG in mouse and rabbit models of cardiovascular inflammation. For mouse experiments, we labeled DOTATATE with the long-lived isotope [Cu]Cu to enable studying the tracer's mode of action by complementing in vivo PET/CT experiments with thorough ex vivo immunological analyses. For translational PET/MRI rabbit studies, we employed the more widely clinically used [Ga]Ga-labeled DOTATATE, which was approved by the FDA in 2016. DOTATATE's pharmacokinetics and timed biodistribution were determined in control and atherosclerotic mice and rabbits by ex vivo gamma counting of blood and organs. Additionally, we performed in vivo PET/CT experiments in mice with atherosclerosis, mice subjected to myocardial infarction and control animals, using both [Cu]Cu-DOTATATE and [F]F-FDG. To evaluate differences in the tracers' cellular specificity, we performed ensuing ex vivo flow cytometry and gamma counting. In mice subjected to myocardial infarction, in vivo [Cu]Cu-DOTATATE PET showed higher differential uptake between infarcted (SUV 1.3, IQR, 1.2-1.4, N = 4) and remote myocardium (SUV 0.7, IQR, 0.5-0.8, N = 4, p = 0.0286), and with respect to controls (SUV 0.6, IQR, 0.5-0.7, N = 4, p = 0.0286), than [F]F-FDG PET. In atherosclerotic mice, [Cu]Cu-DOTATATE PET aortic signal, but not [F]F-FDG PET, was higher compared to controls (SUV 1.1, IQR, 0.9-1.3 and 0.5, IQR, 0.5-0.6, respectively, N = 4, p = 0.0286). In both models, [Cu]Cu-DOTATATE demonstrated preferential accumulation in macrophages with respect to other myeloid cells, while [F]F-FDG was taken up by macrophages and other leukocytes. In a translational PET/MRI study in atherosclerotic rabbits, we then compared [Ga]Ga-DOTATATE and [F]F-FDG for the assessment of aortic inflammation, combined with ex vivo radiometric assays and near-infrared imaging of macrophage burden. Rabbit experiments showed significantly higher aortic accumulation of both [Ga]Ga-DOTATATE and [F]F-FDG in atherosclerotic (SUV 0.415, IQR, 0.338-0.499, N = 32 and 0.446, IQR, 0.387-0.536, N = 27, respectively) compared to control animals (SUV 0.253, IQR, 0.197-0.285, p = 0.0002, N = 10 and 0.349, IQR, 0.299-0.423, p = 0.0159, N = 11, respectively). In conclusion, we present a detailed, head-to-head comparison of the novel SST2-specific tracer DOTATATE and the validated metabolic tracer [F]F-FDG for the evaluation of inflammation in small animal models of cardiovascular disease. Our results support further investigations on the use of DOTATATE to assess cardiovascular inflammation as a complementary readout to the widely used [F]F-FDG.

Systematically evaluating DOTATATE and FDG as PET immuno-imaging tracers of cardiovascular inflammation.

The aim of this study is to explore the utility of cardiac magnetic resonance (CMR) imaging of radiomic features to distinguish active and inactive cardiac sarcoidosis (CS).

Exploring the Utility of Cardiovascular Magnetic Resonance Radiomic Feature Extraction for Evaluation of Cardiac Sarcoidosis.

In the past 2 decades, research on atherosclerotic cardiovascular disease has uncovered inflammation to be a key driver of the pathophysiological process. A pressing need therefore exists to quantitatively and longitudinally probe inflammation, in preclinical models and in cardiovascular disease patients, ideally using non-invasive methods and at multiple levels. Here, we developed and employed  multiparametric imaging approaches to investigate the immune response following myocardial infarction. The myocardial infarction models encompassed either transient or permanent left anterior descending coronary artery occlusion in C57BL/6 and Apoemice. We performed nanotracer-based fluorine magnetic resonance imaging and positron emission tomography (PET) imaging using a CD11b-specific nanobody and a C-C motif chemokine receptor 2-binding probe. We found that immune cell influx in the infarct was more pronounced in the permanent occlusion model. Further, using F-fluorothymidine and F-fluorodeoxyglucose PET, we detected increased hematopoietic activity after myocardial infarction, with no difference between the models. Finally, we observed persistent systemic inflammation and exacerbated atherosclerosis in  mice, regardless of which infarction model was used. Taken together, we showed the strengths and capabilities of multiparametric imaging in detecting inflammatory activity in cardiovascular disease, which augments the development of clinical readouts.

Georgios Soultanidis

BioMedical Engineering and Imaging Institute

Icahn School of Medicine at Mount Sinai

Semi-Automatic Graphical Tool for Measuring Coronary Artery Spatially Weighted Calcium Score from Gated Cardiac Computed Tomography Images

Georgios Soultanidis

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Icahn School of Medicine at Mount Sinai

Semi-Automatic Graphical Tool for Measuring Coronary Artery Spatially Weighted Calcium Score from Gated Cardiac Computed Tomography Images

BioMedical Engineering and Imaging Institute