Although much of the research on atherosclerosis has focused on the intimal accumulation of lipids and inflammatory cells, there is an increasing amount of interest in the role of the adventitia in coordinating the immune response in atherosclerosis. In this review of the contributions of the adventitia and adventitial lymphocytes to the development of atherosclerosis, we discuss recent research on the formation and structural nature of adventitial immune aggregates, potential mechanisms of crosstalk between the intima, media, and adventitia, specific contributions of B lymphocytes and T lymphocytes, and the role of the vasa vasorum and surrounding perivascular adipose tissue. Furthermore, we highlight techniques for the imaging of lymphocytes in the vasculature.

Lymphocytes and the Adventitial Immune Response in Atherosclerosis

Despite recent progress, cardiovascular and allied metabolic disorders remain a worldwide health challenge. We must identify new targets for therapy, develop new agents for clinical use, and deploy them in a clinically effective and cost-effective manner. Molecular imaging of atherosclerotic lesions has become a major experimental tool in the last decade, notably by providing a direct gateway to the processes involved in atherogenesis and its complications. This review summarizes the current status of molecular imaging approaches that target the key processes implicated in plaque formation, development, and disruption and highlights how the refinement and application of such tools might aid the development and evaluation of novel therapeutics.

Molecular Imaging of Atherosclerosis for Improving Diagnostic and Therapeutic Development

An understanding of neovascularization and/or angiogenesis in cancer is acutely required for effective cancer therapy due to concerns about tumor growth and metastasis. In particular, integrin αvβ3 is closely associated with cell migration and invasion during angiogenesis. Hence, we developed aptamer(αvβ3)-conjugated magnetic nanoparticles (Apt(αvβ3)-MNPs) to enable precise detection of integrin-expressing cancer cells using magnetic resonance imaging. Apt(αvβ3)-MNPs exhibited not only cytocompatibility, but also an efficient targeting ability with high magnetic sensitivity through in vitro/in vivo studies. The results of this study demonstrate that Apt(αvβ3)-MNPs have the potential to be used for accurate tumor diagnosis and therapy.

Aptamer-conjugated magnetic nanoparticles enable efficient targeted detection of integrin αvβ3 via magnetic resonance imaging.

68Ga-NODAGA-THERANOST™ is an αvβ3 integrin antagonist and the first radiolabeled peptidomimetic to reach clinical development for targeting integrin receptors. In this first-in-human study, the feasibility of integrin receptor peptidomimetic positron emission tomography/computed tomography (PET/CT) imaging was confirmed in patients with non-small-cell lung cancer and breast cancer. Methods: Patients underwent PET/CT imaging with 68Ga NODAGA-THERANOST. PET images were analyzed qualitatively and quantitatively and compared to 2-deoxy-2-(18F) fluoro-d-glucose (18F-FDG) findings. Images were obtained 60 minutes postinjection of 300–500 MBq of 68Ga-NODAGA-THERANOST. Results: 68Ga-NODAGA-THERANOST revealed high tumor-to-background ratios (SUVmax=4.8) and uptake at neoangiogenesis sites. Reconstructed fused images distinguished cancers with high malignancy potential and enabled enhanced bone metastasis detection. 18F-FDG-positive lung and lymph node metastases did not show uptake, indicating the absence...

First-In-Human Study Demonstrating Tumor-Angiogenesis by PET/CT Imaging with 68Ga-NODAGA-THERANOST, a High-Affinity Peptidomimetic for αvβ3 Integrin Receptor Targeting

Vascular lesion formation and collagen presentation are key events leading to the development of vulnerable plaques. Glycoprotein VI (GPVI) significantly contributes to plaque-associated collagen binding and thrombus formation. The aim of this study was to image endothelial injury using fluorescence-labelled GPVI-Fc (Fc, fragment crystallized), a soluble form of GPVI that was generated by cloning and fusing GPVI to an Fc-domain, in an ex-vivo rabbit model. This study serves as a proof-of-principle study to demonstrate that GPVI-Fc is a useful tool for detecting endothelial damage. The carotid and femoral arteries and the aorta abdominalis were isolated from rabbits and perfused with phosphate buffered saline (PBS) to remove all blood, and a catheter was placed into the vessels in situ. Endothelial damage was achieved by pulling an inflated balloon approximately 1 inch through the vessels, while control vessels were not balloon-treated. After balloon deflation, the catheter was removed. Fluorescence-labell...

Ex vivo imaging of injured arteries in rabbits using fluorescence-labelled glycoprotein VI-Fc

Purpose
A newly developed synthetic αvβ3 integrin targeted optical probe (ITOP) has been demonstrated to target cancer cells, in vivo. Compared to the commercially available cyclic peptide c[RGDfv], this optical probe has at least 20 times better binding affinity for the αvβ3 receptor. The present in vitro study was designed to investigate the possibility of detecting early atherosclerotic plaque by using this ITOP.

/pdf/high-affinity-avb3-integrin-targeted-optical-probe-as-a-new-4a4wtmhz2d.pdf

High-Affinity αvβ3 Integrin Targeted Optical Probe as a New Imaging Biomarker for Early Atherosclerosis: Initial Studies in Watanabe Rabbits

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High-Affinity αvβ3 Integrin Targeted Optical Probe as a New Imaging Biomarker for Early Atherosclerosis: Initial Studies in Watanabe Rabbits