Advances in Molecular Imaging: Plaque Imaging

Recent advances in nuclear plaque imaging aim to achieve noninvasive identification of vulnerable atherosclerotic plaques using positron emission tomography (PET) with ¹⁸F-fluorodexoyglucose (FDG) and novel tracers targeting molecular markers of inflammation and other active metabolic processes. Nuclear imaging of atherosclerosis has been demonstrated in multiple vascular beds, including the carotid, aorta, peripheral and coronary arteries—but significant challenges remain, especially for coronary imaging. The advantage of PET over other molecular imaging modalities is its superior sensitivity, however, low spatial resolution means that images must be co-registered with computed tomography (CT) or magnetic resonance imaging (MRI) for precise anatomical localization of the PET signal. Such hybrid techniques provide the best hope for early detection of prospective culprit lesions—which may, in the coronary vasculature, appear falsely low-risk using conventional coronary angiography or stress imaging. Current hot topics in nuclear plaque imaging include the use of FDG-PET for therapeutic monitoring in drug development, identification of imaging biomarkers to evaluate cardiovascular risk, and the development of novel tracers against an array of biologically important markers of atherosclerosis. The purpose of this article is to review these recent advances in nuclear plaque imaging.     

Emerging Molecular Targets for Intravascular Imaging of High-Risk Plaques

Accumulating evidence links catastrophic cardiovascular events to the inflammatory, angiogenic, and apoptotic biological profiles underlying high-risk atherosclerotic plaques. While biological detail is opaque to traditional anatomical imaging readouts, emerging molecular imaging approaches are now yielding significant clinical insights into the biological diagnosis, characterization, and treatment of atherosclerotic vascular disease. Yet, while clinical molecular imaging approaches are available for larger arterial beds such as the carotid arteries or aorta, molecular imaging pathways for human coronary arterial plaques are lacking. Excitingly, the recent advent of intravascular near-infrared fluorescence technology now offers new potential for in vivo molecular imaging of key molecular and cellular targets in coronary-sized vasculature. Here we provide a framework for coronary artery–targeted molecular imaging using intravascular imaging technology, and present key molecular imaging targets relevant to the detection of high-risk, vulnerable coronary plaques.     

Magnetic Resonance Molecular Imaging of Plaque Angiogenesis

Neovascular expansion of the vasa vasorum is an early pathological biomarker of atherosclerosis, preceding endothelial dysfunction. Plaque angiogenesis accompanies intraplaque hemorrhage and plaque rupture, precursors of myocardial infarction and stroke. Molecular imaging of angiogenesis aims to map the expression of neovascular biomarkers on a cellular scale, often utilizing paramagnetic or superparamagnetic MRI contrast agents in order to generate sufficient image enhancement. Both clinically approved extracellular contrast agents and experimental targeted nanoparticles have demonstrated MRI signal enhancement that is proportional to the neovascular density in the vessel wall. Furthermore, targeted contrast agents formulated with anti-angiogenic drugs can be used to quantify drug deposition within the plaque and predict subsequent therapeutic effects. Molecular imaging of plaque angiogenesis has shown promise for interrogating the pathophysiology of atherosclerotic lesions rather than just their physical characteristics, with the ultimate goal of identifying the high-risk plaques that are most likely to cause cardiovascular events.     

MRI of vulnerable plaque

Atherosclerosis is a systemic inflammatory disease resulting in vascular complications such as myocardial infarction or stroke. Noninvasive imaging of early stages of this systemic disease could help guide early interventional or medical therapies. Molecular targeting with MRI using epitope-specific contrast agents has proven to be effective in detection of different stages of atherosclerosis, beginning with an endothelial dysfunction and ending in plaque rupture with superimposed thrombosis. Animal models of atherosclerosis and thrombosis in combination with molecular imaging can help us to understand more about disease progression, therapeutic impact, and molecular mechanisms. This article reviews recent developments in molecular MRI concerning atherosclerosis, highlighting the vulnerable plaque as a key structure of plaque pathology.     

Cellular and molecular imaging with targeted contrast ultrasound

There is growing interest in the availability of methods for imaging disease at the level of the cellular and/or molecular mediators. Techniques for imaging molecular alterations have been develop for essentially all non-invasive cardiac imaging modalities. Molecular imaging with contrast-enhanced ultrasound relies on the detection of novel site-targeted contrast agents. These microbubbles or nanoparticles are retained within regions of a specific disease process, thereby allowing phenotypic characterization of tissue. Since most of these tracers remain within the intravascular space, the disease processes assessed must be characterized by antigens that are expressed within the vascular compartment. Accordingly, the pathologic states that have been targeted include inflammation, ischemia-and tumor-related angiogenesis, and thrombus formation; all of which are mediated in part by molecular events within the vascular space. This review describes: 10 different strategies that have been employed to target ultrasound contrast agents to regions of disease, 2) the unique challenges for imaging targeted ultrasound contrast agents, and 3) some of the early experience imaging molecular events in animal models of disease.     

生物响应MRI对比剂的研究进展

不同组织和疾病都存在特异性的生物信号。开发能对这些生物信号响应的磁共振成像（MRI）对比剂,不仅有望增加MRI检测疾病的灵敏度,而且能够对病变产生的信号进行分子成像,提高疾病诊断的准确度。该文详细综述了白蛋白、pH、金属离子、酶、氧化还原以及其他生物分子等响应对比剂的最新进展,对未来的研究方向做了展望。     

Molecular MRI of Atherosclerosis with USPIO

Inflammation in atherosclerosis is a risk factor for plaque rupture and atherothrombosis. USPIO-enhanced MRI is capable of evaluating the inflammatory activity in vivo on a cellular as well as a sub-cellular level. This paper reviews the recent advances in USPIO-enhanced MRI of atherosclerotic plaque inflammation. Imaging strategies for evidentiating the presence of the USPIO label in plaques take advantage of the susceptibility effect induced by the nanoparticles in their surroundings to obtain a negative contrast (T2* weighted imaging) or a positive contrast (the White Maker and Susceptibility Gradient Mapping). Quantitative methods have more recently been adapted to in vivo imaging of USPIO in atherosclerotic plaques, and showed great promise in detecting treatment responses. When they are not taken up rapidly from blood by the reticulo-endothelial system (RES), USPIOs nanoparticles passively target inflammation in atherosclerosis by engulfment in intra-plaque phagocytic cells. This has been demonstrated in both animal models and human patients. However, by modifying the surface of coating materials, nanoparticles can actively target atherosclerosis molecular and cellular actors in animal models. The goal of molecular imaging of atherosclerotic plaques is to identify events in the early onset of the disease, as well as critical evolution to vulnerable plaques. USPIO agents are preferred as basis to develop targeted agents because of the ability to overcome the toxicity issue of long-term body residence of Gd-based agents, and their lower sensitivity based on their relaxivity properties. MRI agents capable of efficiently targeting oxidized LDL, cell adhesion molecules (VCAM-1, P-selectin, E-selection), apoptosis and activated platelets have been demonstrated in animal models. The use of these methodologies at the clinical level will depend on the availability and toxicity profiles of the agents, and will require standardized state of the art imaging techniques.     

Seeing the Invisible—Ultrasound Molecular Imaging

Ultrasound molecular imaging has been developed in the past two decades with the goal of non-invasively imaging disease phenotypes on a cellular level not depicted on anatomic imaging. Such techniques already play a role in pre-clinical research for the assessment of disease mechanisms and drug effects, and are thought to in the future contribute to earlier diagnosis of disease, assessment of therapeutic effects and patient-tailored therapy in the clinical field. In this review, we first describe the chemical composition and structure as well as the in vivo behavior of the ultrasound contrast agents that have been developed for molecular imaging. We then discuss the strategies that are used for targeting of contrast agents to specific cellular targets and protocols used for imaging. Next we describe pre-clinical data on imaging of thrombosis, atherosclerosis and microvascular inflammation and in oncology, including the pathophysiological principles underlying the selection of targets in each area. Where applicable, we also discuss efforts that are currently underway for translation of this technique into the clinical arena.     

Molecular Imaging of Vascular Inflammation with Nanoparticles

Innovation in molecular imaging is poised to fundamentally advance the field of diagnostic medical imaging related to atherosclerosis. By detecting molecular signatures and cellular processes in vivo, advanced molecular imaging techniques offer a highly sensitive means to diagnose disease perhaps at preclinical stages. In conjunction with advances in imaging capability, materials science, and synthetic chemistry, nanoparticles have emerged as molecular imaging platforms possessing several salient advantages over traditional molecular imaging probes. Nanoparticle-based imaging platforms may be loaded with therapeutic agents, thereby not only improving detection of pathophysiologic changes in vivo but also limiting off-target toxicity associated with conventional medical therapies through targeted drug delivery. Accordingly, this review details the various advantages associated with nanoparticles in general, as well as highlights recent studies with a diverse collection of multimodal and nuclear nanoparticle imaging agents designed to detect atherosclerotic vascular inflammation in vivo.     

MRI of subclinical coronary atherosclerosis

Coronary artery disease (CAD) is the leading cause of morbidity and mortality in the Western world. Whereas atherosclerosis alone is rarely fatal, sudden luminal thrombosis precipitates life-threatening clinical events such as acute coronary syndromes and stroke. Plaques assumed to cause luminal thrombosis are referred to as vulnerable plaques, which tend to preserve a normal vessel lumen. Today’s clinical assessment of CAD is based on the severity of luminal narrowing or flow restriction and functional indices of cardiac ischemia, thus making a priori detection of vulnerable plaques ambiguous. MRI is an emerging noninvasive imaging modality and is unique in its ability to offer morphologic, functional, and biologic information, including several approaches to detect, quantify, and characterize atherosclerotic plaque burden and composition. These methods, which include noncontrast and contrast-enhanced vessel wall imaging, have shown great promise to assess morphological and biological characteristics of vulnerable plaques, such as inflammatory activity, neovasculature, or positive vessel wall remodeling. Current research that focuses on the development of novel contrast agents for the identification of biologic processes associated with plaque progression and plaque rupture ultimately may facilitate the detection of subclinical disease, enable earlier treatment, and allow imaging-based therapy control.     

分子靶向探针在血栓诊断中的应用

血栓是导致缺血性中风、急性心肌梗死等多种缺血性疾病的主要元凶,每年造成大量的死亡和伤残,是严重危害人类生命健康的致死性病因之一。因此,高效准确的检测血栓在临床上具有很高的研究价值和重要意义。传统影像学技术如CT、MRI和超声等主要依赖非特异性的成像手段进行疾病的检查,不能显示分子改变和疾病的关系,易错过最佳的治疗时期。随着科技的发展和交叉学科的融合,影像学已进入分子影像的时代,即应用影像学方法,对活体状态下的生物过程进行细胞和分子水平的定性和定量研究。分子靶向探针因其对靶点的高特异性,呈现高对比度的显影效果,加之可以实现多模态成像和诊疗一体化的潜力,有望在分子水平发现疾病,真正达到早期诊断和治疗。本综述将对目前已有的分子靶向探针在血栓诊断中的应用研究进行详细的归纳阐述。      

Recent developments and new perspectives on imaging of atherosclerotic plaque: role of anatomical,cellular and molecular MRI part III

Atherosclerotic plaque disruption accounts for the major part of cardiovascular mortality and the risk of disruption appears to depend on plaque composition. Carotid plaques in patients, scheduled for endarterectomy, have been successfully characterised with MRI. MRI has the advantage of combining information about morphology and function. Unfortunately, the tortuosity and size of the coronary arteries, and the respiratory and cardiac motion hinder the in vivo characterisation of human coronary plaque. In addition to plaque composition several molecular markers of the different processes involved in atherosclerosis, such as integrins, matrix metalloproteinases and fibrin seem to correlate with risk of plaque rupture and clinical outcome. These molecular markers can be targeted with antibodies coupled to carriers, which are loaded with gadolinium for detection (molecular MRI). Several cellular/molecular MRI studies in animal models and some in human patients have been conducted with varying levels of success. The advent of clinical high field magnets, the development of contrast agent carriers with high relaxivity and the development of relatively new MR contrast techniques appear to be promising in the field of plaque imaging. Future MRI studies will have to focus on the molecular target of the atherosclerotic process, which has the highest prognostic value with regard to acute coronary syndromes and on the most suitable contrast agent to visualize that target.     

Recent developments and new perspectives on imaging of atherosclerotic plaque: role of anatomical,cellular and molecular MRI Part I and II

Atherosclerotic plaque disruption accounts for the major part of cardiovascular mortality and the risk of disruption appears to depend on plaque composition. Carotid plaques in patients, scheduled for endarterectomy, have been successfully characterised with MRI. MRI has the advantage of combining information about morphology and function. Unfortunately, the tortuosity and size of the coronary arteries, and the respiratory and cardiac motion hinder the in vivo characterisation of human coronary plaque. In addition to plaque composition several molecular markers of the different processes involved in atherosclerosis, such as integrins, matrix metalloproteinases and fibrin seem to correlate with risk of plaque rupture and clinical outcome. These molecular markers can be targeted with antibodies coupled to carriers, which are loaded with gadolinium for detection (molecular MRI). Several cellular/molecular MRI studies in animal models and some in human patients have been conducted with varying levels of success. The advent of clinical high field magnets, the development of contrast agent carriers with high relaxivity and the development of relatively new MR contrast techniques are promising in the field of plaque imaging. Future MRI studies will have to focus on the molecular target of the atherosclerotic process, which has the highest prognostic value with regard to acute coronary syndromes and on the most suitable contrast agent to visualize that target.     

Quantitative cardiovascular magnetic resonance for molecular imaging

Cardiovascular magnetic resonance (CMR) molecular imaging aims to identify and map the expression of important biomarkers on a cellular scale utilizing contrast agents that are specifically targeted to the biochemical signatures of disease and are capable of generating sufficient image contrast. In some cases, the contrast agents may be designed to carry a drug payload or to be sensitive to important physiological factors, such as pH, temperature or oxygenation. In this review, examples will be presented that utilize a number of different molecular imaging quantification techniques, including measuring signal changes, calculating the area of contrast enhancement, mapping relaxation time changes or direct detection of contrast agents through multi-nuclear imaging or spectroscopy. The clinical application of CMR molecular imaging could offer far reaching benefits to patient populations, including early detection of therapeutic response, localizing ruptured atherosclerotic plaques, stratifying patients based on biochemical disease markers, tissue-specific drug delivery, confirmation and quantification of end-organ drug uptake, and noninvasive monitoring of disease recurrence. Eventually, such agents may play a leading role in reducing the human burden of cardiovascular disease, by providing early diagnosis, noninvasive monitoring and effective therapy with reduced side effects.     

Microparticle-Based Molecular MRI of Atherosclerosis, Thrombosis, and Tissue Ischemia

MRI is well suited for imaging vascular disease as it provides excellent soft tissue contrast and spatial resolution of the vessel wall. By generating potent contrast effects, iron oxide particles further enhance the ability of MRI to deliver functional information in a range of vascular syndromes. Larger microparticles of iron oxide (MPIO) generate sufficient contrast to enable detection of low-abundance vascular targets in vivo. Ligand-conjugated MPIO confer molecular specificity, facilitating molecular imaging of a range of specific endovascular targets. This review discusses the application of iron oxide particles in the molecular imaging of a variety of vascular syndromes. In particular, ligand-conjugated MPIO have been used for targeted molecular imaging in experimental models of atherosclerosis, thrombosis, and tissue ischemia syndromes. This provides a platform for vascular molecular imaging that could accelerate diagnosis, characterize disease progression, and measure response to treatment in a clinical setting.     

Noninvasive imaging of atherosclerotic vessels by MRI for clinical assessment of the effectiveness of therapy

Atherosclerosis and its thrombotic complications are the major cause of morbidity and mortality in the industrialized countries. Despite advances in our understanding of the mechanisms of pathogenesis and new treatment modalities, the absence of an adequate noninvasive method for early detection limits prevention or treatment of patients with various degrees and localizations of atherothrombotic disease. The ideal clinical imaging modality for atherosclerosis should be safe, inexpensive, noninvasive or minimally invasive, accurate, and reproducible, thus allowing longitudinal studies in the same patients. Additionally, the results should correlate with the extent of atherosclerotic disease and have high predictive values for clinical events. In vivo, high-resolution magnetic resonance imaging (MRI) has recently emerged as one of the most promising techniques for the noninvasive study of atherothrombotic disease in several vascular beds such as the aorta, the carotid arteries, and the coronary arteries. Most importantly MRI can be used to characterize plaque composition as it allows the discrimination of lipid core, fibrosis, calcification, and intra-plaque hemorrhage deposits. MRI findings have been extensively validated against pathology in ex vivo studies of carotid, aortic, and coronary artery specimens obtained at autopsy and using experimental models of atherosclerosis. In vivo MRI of carotid arteries of patients referred for endarterectomy has shown a high correlation with pathology and with previous ex vivo results. A recent study in patients with plaques in the thoracic aorta showed that compared with transesophageal echocardiography plaque composition and size are more accurately characterized and measured using in vivo MRI. The composition of the plaque rather than the degree of stenosis determines the patient outcome. Therefore, a reliable noninvasive imaging tool able to detect early atherosclerotic disease in the various regions and identify the plaque composition is clinically desirable. MRI has potential in the detection arterial thrombi and in the definition of thrombus age. MRI has been used to monitor plaque progression and regression in several animal model of atherosclerosis and more recently in human. Advances in diagnosis prosper when they march hand-in-hand with advances in treatment. We stand at the threshold of accurate noninvasive assessment of atherosclerosis. Thus, MRI opens new strategies ranging from screening of high-risk patients for early detection and treatment as well as monitoring the target areas for pharmacological intervention.     

Molecular MRI of Atherosclerosis Burden

Atherosclerosis is a systemic vascular disease predominantly affecting the intima of central and peripheral arteries. Its complications, myocardial infarction and stroke, remain the leading cause of morbidity and mortality in the Western world and developing countries. Angiographic imaging methods are the current gold standard for the clinical graduation of coronary and carotid artery disease and the guidance of treatment. These techniques are however limited to the assessment of the extent of luminal narrowing. MRI is a noninvasive modality, which allows the direct evaluation of the thin arterial vessel wall with excellent soft tissue contrast and high spatial resolution. Targeted MR contrast agents enable the evaluation of specific cellular and subcellular markers on a molecular level. This review will introduce and discuss novel molecular MR imaging techniques for the assessment of plaque and inflammatory burden in the context of atherosclerosis. Both measures can provide additional information beyond the assessment of luminal stenosis alone.     

Main applications of hybrid PET‐MRI contrast agents: a review

In medical imaging, the continuous quest to improve diagnostic performance and optimize treatment strategies has led to the use of combined imaging modalities. Positron emission tomography (PET) and computed tomography (CT) is a hybrid imaging existing already for many years. The high spatial and contrast resolution of magnetic resonance imaging (MRI) and the high sensitivity and molecular information from PET imaging are leading to the development of this new hybrid imaging along with hybrid contrast agents. To create a hybrid contrast agent for PET‐MRI device, a PET radiotracer needs to be combined with an MRI contrast agent. The most common approach is to add a radioactive isotope to the surface of a small superparamagnetic iron oxide (SPIO) particle. The resulting agents offer a wide range of applications, such as pH variation monitoring, non‐invasive angiography and early imaging diagnosis of atherosclerosis. Oncology is the most promising field with the detection of sentinel lymph nodes and the targeting of tumor neoangiogenesis. Oncology and cardiovascular imaging are thus major areas of development for hybrid PET‐MRI imaging systems and hybrid contrast agents. The aim is to combine high spatial resolution, high sensitivity, morphological and functional information. Future prospects include the use of specific antibodies and hybrid multimodal PET‐MRI‐ultrasound‐fluorescence imaging with the potential to provide overall pre‐, intra‐ and postoperative patient care. Copyright © 2015 John Wiley & Sons, Ltd.     

Design of ProCAs (Protein‐Based Gd3+ MRI Contrast Agents) with High Dose Efficiency and Capability for Molecular Imaging of Cancer Biomarkers

Magnetic resonance imaging (MRI) is the leading imaging technique for disease diagnostics, providing high resolution, three‐dimensional images noninvasively. MRI contrast agents are designed to improve the contrast and sensitivity of MRI. However, current clinically used MRI contrast agents have relaxivities far below the theoretical upper limit, which largely prevent advancing molecular imaging of biomarkers with desired sensitivity and specificity. This review describes current progress in the development of a new class of protein‐based MRI contrast agents (ProCAs) with high relaxivity using protein design to optimize the parameters that govern relaxivity. Further, engineering with targeting moiety allows these contrast agents to be applicable for molecular imaging of prostate cancer biomarkers by MRI. The developed protein‐based contrast agents also exhibit additional in vitro and in vivo advantages for molecular imaging of disease biomarkers, such as high metal‐binding stability and selectivity, reduced toxicity, proper blood circulation time, and higher permeability in tumor tissue in addition to improved relaxivities.