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WIREs Nanomed Nanobiotechnol
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Molecular imaging of extracellular matrix proteins with targeted probes using magnetic resonance imaging

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Abstract The extracellular matrix (ECM) consists of proteins and carbohydrates that supports different biological structures and processes such as tissue development, elasticity, and preservation of organ structure. Diseases involving inflammation, fibrosis, tumor invasion, and injury are all attributed to the transition of the ECM from homeostasis to remodeling, which can significantly change the biochemical and biomechanical features of ECM components. While contrast agents have played an indispensable role in facilitating clinical diagnosis of diseases using magnetic resonance imaging (MRI), there is a strong need to develop novel biomarker‐targeted imaging probes for in vivo visualization of biological processes and pathological alterations at a cellular and molecular level, for both early diagnosis and monitoring drug treatment. Herein, we will first review the pathological accumulation and characterization of ECM proteins recognized as important molecular features of diseases. Developments in MRI probes targeting ECM proteins such as collagen, fibronectin, and elastin via conjugation of existing contrast agents to targeting moieties and their applications to various diseases, are also reviewed. We have also reviewed our progress in the development of collagen‐targeted protein MRI contrast agent with significant improvement in relaxivity and metal binding specificity, and their applications in early detection of fibrosis and metastatic cancer. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Biology‐Inspired Nanomaterials > Peptide‐Based Structures Biology‐Inspired Nanomaterials > Protein and Virus‐Based Structures
(a) Extracellular matrix components under normal conditions. (b) Extracellular matrix undergoes remodeling which is a sequence of quantitative and qualitative alterations in its composition during disease development and progression. In fibrosis, cancer, and many pathological conditions, this composition becomes dysregulated, stiff and more abundant
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(a) Molecular MR imaging of collagen heterogeneity in liver cirrhosis (three models of NASH, TAA/alcohol, and diethylnitrosamine) with ProCA32.collagen1. (b) Detection of collagen heterogeneity in uveal melanoma liver metastasis using ProCA32.collagen1. Different collagen patterns and distribution in the liver and tumor, and its correlation with histology, can be observed in all four animal models
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Design and development of collagen I targeted protein‐based MRI contrast agent (ProCA32.collagen1) for detection of chronic liver diseases (liver fibrosis and metastasis). ProCA32.collagen1 was developed by covalently linking a collagen type I targeting peptide moiety consisting of natural amino acids to the C‐terminal of protein contrast agent ProCA32 (with two Gd3+ binding sites). PEGylation of the contrast agent was performed to improve protein solubility, blood retention time, and reduce immunogenicity (Salarian, Turaga, et al., ; Salarian, Yang, et al., )
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Development of fibrin‐targeted Gd3+‐based MRI contrast agent and its application in detection of thrombi in patients. (a) Structure of the Gd3+‐based fibrin‐binding probe EP‐2104R. (b) Molecular MR imaging of left ventricular (LV) thrombus. (c) MRI of thrombus in the right atrium (arrow, clot surface; arrowhead, central venous catheter). Clot in the right atrium is shown in CT image. (d) MRI of thrombus in the carotid artery and signal enhancement at the intraluminal clot surface post EP‐2104R injection. (e) MRI of thrombus in the descending thoracic aorta (arrow). CT image demonstrates plaque in the aortic wall. Arrowhead shows a small calcification (Spuentrup et al., )
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(a) Development of a pentapeptide CREKA (Cys‐Arg‐Glu‐Lys‐Ala)‐targeted gadolinium‐based MRI contrast agent, CREKA‐Tris(Gd‐DOTA)3 binding to fibrin–fibronectin complexes and its application for detection of 4T1 breast tumor micrometastasis with MRI in co‐registration with high‐resolution fluorescence cryo‐imaging. (b) MR imaging of 4T1–GFP‐Luc2 breast cancer cells using CREKA‐Tris (Gd‐DOTA)3 (Zhou et al., ; Zhou, Wu, Kresak, Griswold, & Lu, )
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(a) Chemical structure of elastin‐specific magnetic resonance contrast agent (ESMA). (b) DE‐MR and time‐of‐flight (TOF) angiogram images of brachiocephalic artery of a male ApoE−/− mouse with plaque burden in a model of atherosclerosis. Fusion of TOF and high‐resolution DE‐MRI exhibits spatial registration of contrast uptake and luminal anatomy (Makowski et al., )
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(a) Chemical structures of developed collagen‐targeted probes EP‐3533 and CM‐101 for molecular MR imaging of fibrosis. (b) MR images of a control and fibrotic mouse and its correlation with histological characterization (collagen content), post injection of EP‐3533 in CCl4‐induced liver fibrosis mouse model (Desogere, Montesi, & Caravan, )
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Schematic illustration of different strategies for designing targeted contrast agents for extracellular matrix proteins. A targeted MRI contrast agent consists of three main components: The Gd3+ chelate unit, linker, and targeting moiety (small molecule, peptide or antibody)
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Chemical structures of current marketed and clinically approved Gd3+‐based MRI contrast agents as of 2019 with their chemical names, tradenames, generic names and FDA approval year. Eovist and MultiHance have been approved for hepatic and ECF distribution
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