Molecular Imaging of Inflammatory Disease

biomedicines Review Molecular Imaging of Inflammatory Disease Meredith A. Jones 1,2, William M. MacCuaig 1,2, Alex N. Frickenstein 1,2, Seda Camalan 3 , Metin N. Gurcan 3, Jennifer Holter-Chakrabarty 2,4, Katherine T. Morris 2,5 , Molly W. McNally 2, Kristina K. Booth 2,5, Steven Carter 2,5, William E. Grizzle 6 and Lacey R. McNally 2,5,* 1 Stephenson School of Biomedical Engineering, University of Oklahoma, Norman, OK 73019, USA; [email protected] (M.A.J.); [email protected] (W.M.M.); [email protected] (A.N.F.) 2 Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK 73104, USA; [email protected] (J.H.-C.); [email protected] (K.T.M.); [email protected] (M.W.M.); [email protected] (K.K.B.); [email protected] (S.C.) 3 Department of Internal Medicine, Wake Forest Baptist Health, Winston-Salem, NC 27157, USA; [email protected] (S.C.); [email protected] (M.N.G.) 4 Department of Medicine, University of Oklahoma, Oklahoma City, OK 73104, USA 5 Department of Surgery, University of Oklahoma, Oklahoma City, OK 73104, USA 6 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA; [email protected] * Correspondence: [email protected] Abstract: Inflammatory diseases include a wide variety of highly prevalent conditions with high mortality rates in severe cases ranging from cardiovascular disease, to rheumatoid arthritis, to chronic obstructive pulmonary disease, to graft vs. host disease, to a number of gastrointestinal disorders. Many diseases that are not considered inflammatory per se are associated with varying levels of inflammation. Imaging of the immune system and inflammatory response is of interest as it can give insight into disease progression and severity. Clinical imaging technologies such as computed Citation: Jones, M.A.; MacCuaig, tomography (CT) and magnetic resonance imaging (MRI) are traditionally limited to the visualization W.M.; Frickenstein, A.N.; Camalan, S.; of anatomical information; then, the presence or absence of an inflammatory state must be inferred Gurcan, M.N.; Holter-Chakrabarty, J.; from the structural abnormalities. Improvement in available contrast agents has made it possible Morris, K.T.; McNally, M.W.; Booth, to obtain functional information as well as anatomical. In vivo imaging of inflammation ultimately K.K.; Carter, S.; et al. Molecular facilitates an improved accuracy of diagnostics and monitoring of patients to allow for better patient Imaging of Inflammatory Disease. Biomedicines 2021, 9, 152. https:// care. Highly specific molecular imaging of inflammatory biomarkers allows for earlier diagnosis to doi.org/10.3390/biomedicines9020152 prevent irreversible damage. Advancements in imaging instruments, targeted tracers, and contrast agents represent a rapidly growing area of preclinical research with the hopes of quick translation to Academic Editor: Moritz Wildgruber the clinic. Received: 30 December 2020 Accepted: 31 January 2021 Keywords: molecular imaging; inflammation; cardiovascular disease; rheumatoid arthritis; chronic Published: 4 February 2021 obstructive pulmonary disease; graft vs. host disease; image analysis; machine learning Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- 1. Introduction iations. Inflammation can manifest in all areas of the body and is often the common denomina- tor between a plethora of diseases and infections. There is a current upsurge in preclinical and translation research to uncover the exact role that inflammation may have in disease progression to make a more accurate diagnosis. Much of this research focuses on imaging Copyright: © 2021 by the authors. inflammation by targeting the immune system. When a pathogen elicits an immune re- Licensee MDPI, Basel, Switzerland. sponse, there is an upregulation of immune cells such as macrophages, monocytes, and This article is an open access article lymphocytes [1]. Monocytes and macrophages are recruited to the infection site where distributed under the terms and they proliferate and phagocytose the pathogen; it is through this phagocytotic mechanism conditions of the Creative Commons that exogenous imaging agents can be internalized and the inflammatory response can be Attribution (CC BY) license (https:// imaged [2]. Imaging of lymphocytes is mainly done through radiolabeled antibodies [3–6]. creativecommons.org/licenses/by/ 4.0/). Molecular imaging of these cells allows for the non-invasive, in vivo visualization of these Biomedicines 2021, 9, 152. https://doi.org/10.3390/biomedicines9020152 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, 152 2 of 23 immune cells to characterize the extent and severity of the disease. Visualization of these immune cells as inflammatory biomarkers will have significant effects on the fields of personalized medicine and early diagnostics of inflammatory disease. Molecular imaging relies on the presence of endogenous or exogenous contrast agents for the identification of inflamed tissue. While reliance on endogenous contrast is of interest due to decreased risk to patients, lack of specificity in regard to molecular processes limits the accuracy and application of such agents such as hemoglobin and deoxyhemoglobin [7,8]. As a result, molecular imaging has traditionally required tracer molecules specific for bio- logical processes. These tracers consist of a contrast-generating agent, e.g., fluorescent dye, which is targeted for a molecule/function within the body. Such tracers offer high, control- lable, and specific contrast, which is unachievable with endogenous contrast alone. Tracers have been utilized across many modalities; examples include radioactive atoms applied to sugars for metabolism tracking with positron emission tomography (PET)/SPECT [9], iodine-labeled tracers for X-ray-based imaging [10], and lanthanides that respond to an external magnetic field for MRI [11]. However, further development of small molecule tracers has slowed significantly due to toxicity concerns and poor sensitivity as a result of weak signal specificity and rapid bodily clearance [1]. The utilization of nanoparticles is a potentially viable method to add exogenous contrast for the purpose of molecular imaging in efforts to overcome limitations that often plague fluorescent probes. While many types of nanoparticles have shown potential, nanoparticles consistently miss expectations in a clinical setting, owing to poor target specificity. Recent advancements in active targeting have improved such outlooks [12]. Approaches to functionalize nanoparticles provide increased specificity through targeting extracellular receptors or key features of the target environment. Identification and exploitation of the molecular signature of diseases allows for the development of novel imaging probes to reveal pathological information about the tissue without the need for invasive biopsies. Standard clinical imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound (US) are traditionally used to reveal anatomical information, providing information required for diagnosis but do not yield molecular information that could be critical for identifying appropriate treatments. For example, the monitoring of response of tumors to therapy uses the Response Evaluation Criteria in Solid Tumors (RECIST) score, which is reliant on changes in tumor size [13]. It may take multiple weeks for a measurable change in tumor size to be observed; however, molecular changes will precede anatomical changes. Recent advancements in contrast agents allows for the extraction of functional and molecular information as well as anatomical information from standard imaging modalities. The choice of contrast agent for MRI is dependent on the objective of the imaging session. T1-weighted MRI involves the injection of a paramagnetic metal agent, often gadolinium based, which shortens the T1 relaxation time resulting in an enhanced signal [14]. The low sensitivity and limited specificity of gadolinium-based contrast agents renders T1-weighted MRI suboptimal for molecular imaging [15]. T2-weighted MRI most often involves the injection of superparamagnetic iron oxide nanoparticles (SPIONs), resulting in negative contrast enhancement. SPIONs usually range in size from 10 to 100 nm and are often dextran-coated to increase biocompatibility [16,17]. The uptake of SPIONs by active macrophages at sites of inflammation make T2-weighted MRI an appropriate choice for molecular imaging of inflammation [16,18]. MR spectroscopy is another MR technique that acquires the molecular spectra of the tissue of interest in order to reveal information about the concentration and presence of different metabolites in the tissue [19]. While MR spectroscopy provides more information than standard MRI, it is limited by poor spatial resolution and low sensitivity, since the agents of interest exist in very low concentrations [20]. Chemical exchange saturation transfer (CEST) MR imaging involves the exchange of magnetization from the target agent to the surrounding water molecules so that the signal reduction through the saturation effect is seen only on the water molecules and not on the target agent. CEST imaging is dependent on the chemical composition of Biomedicines 2021, 9, 152 3 of 23 the target metabolite and the radiofrequency pulse that initiates the chemical exchange of the proton [20]. Then, the sensitivity of CEST imaging is directly related to the chemical exchange

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