New radiotracers for imaging of vascular targets in angiogenesis-related diseases

Abstract

Tremendous advances over the last several decades in positron emission tomography (PET) and single photon emission computed tomography (SPECT) allow for targeted imaging of molecular and cellular events in the living systems. Angiogenesis, a multistep process regulated by the network of different angiogenic factors, has attracted world-wide interests, due to its pivotal role in the formation and progression of different diseases including cancer, cardiovascular diseases (CVD), and inflammation. In this review article, we will summarize the recent progress in PET or SPECT imaging of a wide variety of vascular targets in three major angiogenesis-related diseases: cancer, cardiovascular diseases, and inflammation. Faster drug development and patient stratification for a specific therapy will become possible with the facilitation of PET or SPECT imaging and it will be critical for the maximum benefit of patients.

Introduction

Angiogenesis is critical for various growth and development relevant events including embryogenesis, tissue remodeling, and wound healing [1]. The sophisticated process is usually regulated in a spatial and temporal manner via active interactions between angiogenic factors, extracellular matrix (ECM) components, and various types of cells. Imbalanced angiogenesis will lead to angiogenic disorders and destructive process of diseases, such as cardiovascular diseases (CVD, e.g. atherosclerosis), inflammation, and tumor growth/metastasis [2].

The pivotal process of angiogenesis can be divided into multiple stages. At the initial stage, the angiogenic stimuli activate the endothelial cells (ECs, the essential building blocks of all vessels) by enhancing their permeability and proliferation, resulting in new capillary sprout elongation [3]. The following stage involves the degradation of membrane matrix components to promote the invasion of ECs into the stroma from the proximal tissue [4], where matrix metalloproteinases (MMPs) are of critical importance. After the migration of ECs, the buildup of lumen is confirmed with the formation of multicellular vessel sprout. The final stage of angiogenesis is the stabilization of newly formed capillary. Disruption of angiogenesis is a critical factor of many pathological disorders, such as insufficient vascular density observed in myocardial or limb ischemia [5], [6] or irregular vascular growth and abnormal remodeling in primarily tumor [7] development.

In normal conditions, angiogenesis and inflammation are collaborators in tissue repair and remodeling following tissue damage or destructive process of disease. In contrast, a detrimental relationship between angiogenesis and inflammation can result in diseases like asthma, atherosclerosis, diabetes, abdominal aortic aneurysm, inflammatory bowel diseases, and rheumatoid arthritis (RA) [8], [9], [10], [11], [12]. Acute inflammation usually triggers a protective defense against the “intruders”, which involves rapid recruitment and activation of various immune/inflammatory cells to fight against pathogens [13], [14]. On the other hand, chronic inflammation can cause substantial tissue damage which might facilitate carcinogenicity [15], where pathological angiogenesis (i.e. angiogenesis process under pathological states, e.g. tumorigenesis and inflammation) promotes a continuous recruitment of inflammatory cells, exacerbating inflammation and damage [16]. A number of inflammatory cells (e.g. neutrophils, eosinophils, mast cells, natural killer (NK) cells, macrophages, and dendritic cells (DCs)) are involved in inducing and promoting angiogenesis. Under hypoxia condition, these inflammatory cells can secrete a plethora of angiogenesis-boosting molecules, including vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), and various cytokines, resulting in enhanced vascular permeability and additional recruitment of immune cells. Multiple types of leukocytes and macrophages are also involved in the proteolytic remodeling of the ECM by releasing different types of proteases (MMPs, cathepsins, plasminogen, urokinase etc.) to stimulate blood vessel formation. Activation of these inflammatory cells will also lead to the production of reactive oxygen species (ROS), important stimuli of angiogenesis.

The interactions between these constituents result in an intricate and heterogeneous complex of cells and matrix in the pathological angiogenesis. To explore the mechanisms of angiogenesis in molecular level and identify potential targets for disease therapy/prevention, precise knowledge about the role/network of these molecules (e.g. pro- or anti-angiogenic factors, vascular targets) inside the angiogenic cascades will be extremely beneficial.

With an aim to demonstrate the pros and cons of the different vascular targets (Scheme 1 and Table 1) in the diagnosis and therapy of various diseases, herein we will summarize newly developed radiotracers for positron emission tomography (PET) or single-photon emission computed tomography (SPECT) imaging of these vascular targets in three major angiogenesis-related diseases (i.e. cancer, cardiovascular diseases, and inflammation). Future research directions in the field of molecular imaging of angiogenesis will also be discussed.