Hot spot ¹⁹F magnetic resonance imaging of inflammation

Abstract

Among the preclinical molecular imaging approaches, lately fluorine (19 F) magnetic resonance imaging (MRI) has garnered significant scientific interest in the biomedical research community, due to the unique properties of fluorinated materials and the 19 F nucleus. Fluorine is an intrinsically sensitive nucleus for MRI-there is negligible endogenous 19 F in the body and, thus, no background signal which allows the detection of fluorinated materials as "hot spots" by combined 1 H/ 19 F 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 1 H/ 19 F MRI. The required 19 F 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 19 F signals due to trafficking of PFC-loaded immune cells to affected organs. To extend 19 F 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

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“…Based on light irradiation from the ultraviolet, visible, and near-infrared spectrums, optical imaging techniques have high detection sensitivity but are limited by quenching and the photo-bleaching effect. Magnetic resonant imaging (MRI) is a radiation-free and non-invasive technique based on magnetic contrast agents such as Gadolinium (III), superparamagnetic iron oxide nanoparticles (SPIO), or perfluorocarbons (PFCs), and is characterized by high spatial resolution but with very low sensitivity 185 , 186 , 187 , 188 . Ionizing radiation such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are based on the use of high-energy elements (radioisotopes) characterized by high-detection sensitivity (from nanomolar to picomolar) but with low spatial resolution 189 , 190 .…”

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“…19 F has a high relative sensitivity comparable to 1 H (83% of 1 H), and the 19 F signal can be more directly related to the presence of the label, compared to the T2* approaches described above with SPIOs. This quantifiable signal obtained from 19 F-based contrast agents is highly specific due to the lack of endogenous 19 F in biological tissues and provides positive rather than negative contrast which facilitates detection [56]. Perfluorocarbons (PFC) have been used for 19 F-MRI tracking of immune cells both clinically and preclinically.…”

“…PFCs can be emulsified into lipid nanoemulsions or incorporated into the synthetic amino acid poly(lactide-co-glycolide) or PLGA to improve biocompatibility for imaging applications [57,58]. Commonly used PFCs include perfluoro-15-crown-5 ether and perfluoropolyether [56]. Perfluoro-15-crown-5 ether has been used for imaging neutrophils and monocyte infiltration in a preclinical model of lipopolysaccharide (LPS) bacterial endotoxininduced inflammation [40].…”

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“…In the past, it has been shown that intravenous injection of PFCs results in cellular uptake by circulating monocytes and macrophages that leads to an accumulation of 19 F atoms at sites of inflammation 19 . This technology has been successfully used for imaging a variety of different inflammatory diseases like myocardial infarction, myocarditis, transplant rejection and pneumonia 21 . To further enhance the specificity of PFCs, and to expand the repertoire of target cells and structures we have recently established a platform to functionalize PFCs with specific ligands 30 , 32 , 44 .…”

“…Perfluorocarbons are not soluble in water and instead are emulsified with lipids to form stable perfluorocarbon nanoemulsions (PFCs) with droplet sizes of 100–200 nm. Intravenous administration of PFCs leads to strong phagocytic uptake by monocytes and macrophages that accumulate at inflammatory lesions which has been successfully used for imaging inflammation in diseases like myocardial infarction, myocarditis, transplant rejection or pneumonia by combined 1 H/ 19 F MRI 20 , 21 . Interestingly, 19 F MRI has also been used in theranostic applications since combining targeted drug delivery with imaging offers the unique possibility to determine if and how much of the therapeutic agent reaches the desired target tissue and how this impacts disease development 22 .…”