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Fig. 59: Multimodal imaging of neuro-inflammation with

NanoGd. a) Magnetic resonance imaging: signal voids induced by NanoGd (white arrow) are

seen in the ischemic lesion (yellow dashed line); b) Intravital

two-photon microscopy: CXR3CR1-GFP+ cells engulf

NanoGd (arrowheads) in the ischemic core; c) Synchrotron

X-ray phase-contrast imaging: hyperintense signals induced by NanoGd (white arrow) are

seen in the lesion (yellow dashed line); d) Fluorescence

microscopy: NanoGd-laden CXR3CR1-GFP+ cells are seen in the lesion core;

e) Transmission electron microscopy: NanoGd is seen

as dark signals in macrophage lysosomes; f) Upon intravenous

injection (i.v.) after ischemic stroke, NanoGd is engulfed by

activated phagocytic cells such as macrophages, which become detectable with multimodalities and provide a means to image

neuro-inflammation in vivo.

Imaging neuro-inflammation in ischemic stroke

To address the challenge of imaging neuro- inflammation in vivo, magnetic resonance imaging (MRI) was coupled to the administration of a novel hybrid nanoparticle named NanoGd. This innovative imaging approach was validated in a stroke model by combining state-of-the-art complementary and multiscale techniques, including synchrotron X-ray phase-contrast imaging.

Neuro-inflammation is one of the primary pathological features of many brain diseases and thus represents a promising therapeutic target. However, clinical trials employing anti-inflammatory strategies have all been negative to date. Insufficient therapeutic target validation through in-vivo imaging might explain this failure. Therefore, there is an urgent need to couple the search for novel therapeutic approaches with the development of companion imaging tools.

The neuro-inflammatory response to a pathological event involves a number of molecular and cellular actors, amongst which macrophages are key players. Macrophages are white blood cells that specialise in removing pathogens and dying cells, through a process named phagocytosis. This property may be exploited to label macrophages in vivo with superparamagnetic nanoparticles and image them with magnetic resonance imaging (MRI). This innovative imaging approach has already been used to study the neuroinflammatory response following ischemic stroke in rodents and in patients using clinically applicable iron oxide nanoparticles.

However, generalising this approach for diagnosing inflammation in neurological diseases is challenging for three main reasons: (i) the blood-brain barrier limits the accessibility of imaging agents to the brain; (ii) nanoparticles may induce adverse effects; (iii) the biological substrate of signals observed on MRI are still not fully elucidated. As recently summarised [1], answering the question: What are we imaging? is instrumental to fully exploit the potential of this imaging approach.