Application of Europium-Doped Very Small Iron Oxide Nanoparticles to Visualize Neuroinflammation with MRI and Fluorescence Microscopy

• Published in: Neuroscience 2019-04, Vol.403, p.136-144
• Main Authors: Millward, Jason M., Ariza de Schellenberger, Angela, Berndt, Dominique, Hanke-Vela, Laura, Schellenberger, Eyk, Waiczies, Sonia, Taupitz, Matthias, Kobayashi, Yuske, Wagner, Susanne, Infante-Duarte, Carmen
• Format: Article
• Language: English
• Subjects: Animals; Brain - diagnostic imaging; Brain - immunology; Brain - pathology; Cell Line; Contrast Media; Encephalomyelitis, Autoimmune, Experimental - diagnostic imaging; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - pathology; Endothelial Cells - immunology; Endothelial Cells - pathology; Europium; experimental autoimmune encephalomyelitis; Female; Ferric Compounds; Inflammation - diagnostic imaging; Inflammation - immunology; Inflammation - pathology; iron oxide nanoparticles; magnetic resonance imaging; Magnetic Resonance Imaging - methods; Mice; Microscopy, Fluorescence - methods; Nanoparticles; neuroinflammation; VSOP
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2017.12.014

[Display omitted] •Eu-VSOP revealed brain lesions in mice with neuroinflammation using T2∗-weighted MRI.•Eu-VSOP signal extinctions were observed at peak disease and during clinical relapse.•Lesions correlated with histological detection of Eu-VSOP by fluorescence microscopy.•In the choroid plexus, Eu-VSOP colocalized with stromal phagocytes and epithelium.•Eu-VSOP are useful for dual MRI/fluorescent detection in experimental neuroinflammation. Our recent studies demonstrated that electrostatically stabilized very small superparamagnetic iron oxide particles (VSOPs) are promising MRI probes for detecting various pathological aspects of autoimmunity in the central nervous system (CNS). However, investigation of the precise tissue and cellular distribution of VSOP has been technically limited due to the need to use iron detection methods for VSOP visualization. Therefore, we assessed here the utility of europium (Eu)-doped VSOP as an MRI tool for in vivo investigations in the animal model experimental autoimmune encephalomyelitis (EAE), and as a tool to investigate histopathological processes in the CNS using fluorescence microscopy. We demonstrated that Eu-VSOP display the same properties as VSOP in terms of revealing inflammation-mediated changes by binding to brain endothelium in vitro, and in terms of visualizing brain lesions in EAE in vivo. MRI examinations with Eu-VSOP confirm that at peak disease particles accumulated inside the choroid plexus, and in cerebellar and meningeal lesions. Importantly, Eu-VSOP-based MRI showed for the first time in a longitudinal setup that particles were absent from the choroid plexus in mice during remission of EAE, but accumulated again during subsequent relapse. Within the choroid plexus, Eu-VSOP were associated both with monocytes/macrophages present in the plexus stroma, and associated with epithelial cells. Using Eu-VSOP, we demonstrated for the first time the involvement of the choroid plexus in relapses. Thus, Eu-VSOP have the potential to reveal various aspects of choroid plexus involvement in neuroinflammation, including monocyte recruitment from the blood and alterations of the choroid plexus epithelium.