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WIREs Nanomed Nanobiotechnol
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Hot spot 19F magnetic resonance imaging of inflammation

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Abstract Among the preclinical molecular imaging approaches, lately fluorine (19F) magnetic resonance imaging (MRI) has garnered significant scientific interest in the biomedical research community, due to the unique properties of fluorinated materials and the 19F nucleus. Fluorine is an intrinsically sensitive nucleus for MRI—there is negligible endogenous 19F in the body and, thus, no background signal which allows the detection of fluorinated materials as “hot spots” by combined 1H/19F MRI and renders fluorine‐containing molecules as ideal tracers with high specificity. In addition, perfluorocarbons are a family of compounds that exhibit a very high fluorine payload and are biochemically as well as physiologically inert. Perfluorocarbon nanoemulsions (PFCs) are well known to be readily taken up by immunocompetent cells, which can be exploited for the unequivocal identification of inflammatory foci by tracking the recruitment of PFC‐loaded immune cells to affected tissues using 1H/19F MRI. The required 19F labeling of immune cells can be accomplished either ex vivo by PFC incubation of isolated endogenous immune cells followed by their re‐injection or by intravenous application of PFCs for in situ uptake by circulating immune cells. With both approaches, inflamed tissues can unambiguously be detected via background‐free 19F signals due to trafficking of PFC‐loaded immune cells to affected organs. To extend 19F MRI tracking beyond cells with phagocytic properties, the PFC surface can further be equipped with distinct ligands to generate specificity against epitopes and/or types of immune cells independent of phagocytosis. Recent developments also allow for concurrent detection of different PFCs with distinct spectral signatures allowing the simultaneous visualization of several targets, such as various immune cell subtypes labeled with these PFCs. Since ligands and targets can easily be adapted to a variety of problems, this approach provides a general and versatile platform for inflammation imaging which will strongly extend the frontiers of molecular MRI. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease
Initiation of inflammation and the cooperation of innate and adaptive immune responses. (a) Innate immunity is the first line of defense and in most cases sufficient for the removal of pathogens. The first cells that encounter danger signals which are derived from invading pathogens or tissue damage are resident tissue macrophages. This leads to their activation and secretion of cytokines and chemokines into the surrounding tissue and the circulation. These initial signals recruit neutrophils from the bloodstream into the inflamed tissue which eliminate pathogens by phagocytosis and release reactive oxygen species or other antimicrobial molecules. Subsequently, predominantly classical monocytes enter the inflamed area, which differentiate into multiple different macrophage subtypes according to the local inflammatory milieu. Moreover, monocytes can also differentiate into monocyte‐derived dendritic cells (DCs) which capture antigens and migrate into the draining lymph nodes to induce T cell response. The two different endpoints of monocyte to macrophage differentiation are pro‐inflammatory (M1) and anti‐inflammatory M2 macrophages, respectively, whereby the latter foster the resolution and healing process. Of note, apoptosis of neutrophils and subsequent removal by macrophages (efferocytosis) induces M2 polarization into macrophages. (b) The adaptive immune response is exclusively found in vertebrates and is activated if the pathogens are not immediately eliminated. This aims to support the innate immune system but also to enable the generation of a highly effective immune memory. Monocyte‐derived macrophages or DCs migrate toward the nearby lymph nodes to present antigenic peptides via MHC molecules to CD4+ T helper cells or cytotoxic T cells—an interaction which mediates the activation of the T cells. Cytotoxic T cells swarm out to the site of inflammation to kill pathogen‐infected cells whereas T helper cells activate B cells to induce an antibody production, activate macrophages or can also foster the resolution of inflammation via release of anti‐inflammatory cytokines
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The cargo internalization system. (a) All engineered CIRs are composed of an extracellular N‐terminal myc‐tag (white), a GFP nanobody (green) and a linker (black). Intracellular they differ in their transmembrane domains (TMD) and their cytoplasmic domains (CTD). CIR1 consists of the TMD and CTD of the IL6 receptor, CIR2 contains the TMD of the IL6 receptor and the CTD of the Endo180 receptor, and CIR3 comprises the TMD and CTD of the FCγRIIA receptor. (b) To confirm usefulness of the targeting approach CIR‐expressing cells were mixed with matrigel and implanted into the neck of mice. Twenty‐four hours later, GFPPFCs were injected and on the next day the fluorine signal within the matrigel was determined via 1H/19F MRI. (c) The CIR constructs can be cloned into the Rosa locus of mice to be crossed with strains expressing Cre‐recombinase under tissue specific promoters (e.g. CD3‐Cre, CD19‐Cre). This will enable a cell specific targeting of even low phagocytic cells and their imaging in vivo by combined 1H/19F MRI. Source: Adapted from Temme et al., 2018
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Imaging of early venous thrombosis by 19F MRI with targeted PFCs. (a) Schematic drawing showing the principle of targeted 19F MRI for visualization of acutely formating thrombi. (b) In vivo 1H and 19F MRI after thrombus induction (arrows) in the inferior vena cava. Dashed lines represent the magnified areas below with 1H (left) and merged images (middle; 19F, red) of mice that received α2AP‐PFCs (top) or Q3A‐PFCs as control (bottom). (c) 19F MRI of pulmonary embolism. Combined in vivo 1H/19F MRI of the mouse thorax showing strong 19F signals within the lung after thrombin and α2AP‐PFC injection. The white line within the axial image (top) indicates the location of the corresponding coronal slice shown at the bottom. LV indicates left ventricle; PV, pulmonary vessels; RV, right ventricle; and SC, spinal cord. Source: Adapted from Temme et al., 2015
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Comparison of cryo‐coils with RT‐coils. Horizontal (a) and coronal (b) ex vivo images of mice undergoing EAE and injection of PFCs on five consecutive days. The increase in the SNR from the cryo‐coil (CRP) is nearly 15‐fold compared to the RT‐coil. (c) 3D reconstruction of the fluorine signal within the brain of the EAE mice conducted by the RT‐coil (upper panel) or the cryo‐coil. Source: Lower panel, reprinted from Waiczies et al., 2017
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In vivo multicolor 19F MRI. (a) 19F spectra of different perfluorocarbons. Arrows indicate the specific 19F peaks used for imaging the respective perfluorocarbon. Three of these (PFCE, PFTBA, TPFBME) were used for in vivo imaging. (b) As a proof‐of‐concept the perfluorocarbons were injected subcutaneously at the indicated sites followed by their detection via 19F multicolor MRI. Source: Reprinted from Akazawa et al., 2018
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Visualization of inflammation after myocardial infarction by 19F MRI in vivo. (a) Scheme of the in situ labeling approach for 19F MR inflammation imaging after myocardial infarction. (b) Imaging of monocyte infiltration into the heart after myocardial infarction by 1H/19F MRI 4 days after injection of PFCs (I = infarct, T = thoracotomy). (c) Merged 1H and 19F images 1, 3 and 6 days after MI indicating time dependent infiltration of immune cells into the infarcted area of the heart. (d) Cellular uptake of PFCs was validated by i. v. injection of rhodamine‐labeled PFCs and subsequent flow cytometry. A clear rhodamine PFC‐signal was observed in peripheral blood mononuclear cells upon PFC‐injection (left) whereas no rhodamine label was found in control cells (right). (e) Determination of the cell type by which the PFCs are taken up in vivo. The strongest signal belongs to CD11b+ cells (monocytes/macrophages) and only minor signal to B cells (B220+). T cells (CD3+) show no signal at all. Source: Adapted from Flögel et al., 2008
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Tracking of reimplanted dendritic cells in human patients via 19F MRI. (a) NMR spectroscopy of labeled human dendritic cells. (b) Statistic of the labeled dendritic cells. The labeling efficiency is quite comparable between the different donors. (c) Cell viability of the labeled dendritic cells in comparison to untreated cells. There is no major influence measurable on the viability by the labeling. (d) Surface expression of different dendritic markers with no major differences between controls and labeled cells. (e) Visualization of PFC‐labeled and re‐implanted dendritic cells in the quadriceps of three different human patients 4 hours after injection. (f) NMR spectroscopy of labeled dendritic cells within the human patients. (g) Statistical analysis of the number of cells found at the site of injection 2 and 24 hours after injection into the quadriceps of the patients. Source: Reprinted from Ahrens, Helfer, O'Hanlon, & Schirda, 2014
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Preparation of PFCs and their use for cell tracking. (a) Perfluorocarbons are mixed with phospholipids and isotonic buffer to generate a crude emulsion. By high‐pressure homogenization PFCs of roughly 100–200 nm are formed. Isolated cells can be incubated ex vivo with PFCs and injected into the animal to follow their fate by 19F MRI. (b) In vivo detection of ex vivo labeled T cells 4 days (left and middle) and 21 days (right) after injection showing homing of the labeled cells into the lymph nodes of mice. Source: Adapted from Srinivas et al., 2009
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Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease
Therapeutic Approaches and Drug Discovery > Emerging Technologies

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