Ultrasensitive molecular magnetic resonance imaging to unmask intestinal inflammation – MAD-GUT

Our objective is to develop the first molecular MRI method of intestinal inflammation and provide preclinical evidence of its diagnostic performance in several experimental models of IBD. The novelty of the present project relies on the use of a new contrast agent that is innovative both by its target (MAdCAM-1, a mucosal specific endothelial adhesion molecule) and by the nature of its contrast-carrying particle (MPIO). This imaging strategy has the potential to over-perform clinically used diagnostic procedures.
To date, several imaging methods are available for imaging of the gastrointestinal tract, including MRI, positron-emission tomography (PET) and ultrasounds. A few targeted contrast agents for ultrasounds have been developed (including microbubbles targeted to adhesion molecules), but there are several drawbacks that disqualify ultrasound as a universally suitable method for detecting mucosal inflammation, such as an exploration limited to superficial intestinal loops and the frequent presence of obstacles that preclude evaluation of some intestinal segments (such as gas). Positron-emission tomography using 18F-Fluorodeoxyglucose or immuno-PET techniques is suitable for imaging of the whole gastrointestinal tract but is limited by its low spatial resolution, its long acquisition time and its use of ionizing radiation, that precludes its frequent use in IBD patients. Although MRI is devoid of these drawbacks, it is limited by its low sensitivity to contrast agents that requires concentrations in the micromolar range to induce contrast changes (versus picomolar for PET).
The use of large contrast-carrying particles allows breaking this limitation. This is exemplified by the fact that MRI can detect a single MPIO at clinically relevant field strengths. The large size of the contrast agent comes at the cost of a strictly intravascular distribution of MPIO after intravenous injection. Therefore, only vascular targets are appropriate for molecular imaging using MPIO. In line with this constraint, we will image an adhesion molecule that is expressed by endothelial cells and exposed at the luminal surface. In the context of IBD, the large size of MPIO is also an advantage since it prevents their passive extravasation through the permeated endothelial barrier of inflammatory tissues and therefore, increases the specificity of the imaging method.

We report a new MRI contrast agent allowing non-invasive detection of mucosal inflammation in an ultrasensitive manner. The technique presented herein, if successfully applied in humans, holds potential for early diagnosis, longitudinal follow-up and therapeutic response monitoring in diseases involving mucosal tissue, such as IBD. In clinical settings, morphological MRI coupled to molecular imaging of MAdCAM-1 could allow fast, sensitive and non-invasive evaluation of mucosal lesions, thereby alleviating the need for endoscopy and improving patient comfort and safety. The ability to detect MAdCAM-1 could also be key for the identification of patients candidate for MAdCAM-1 targeted therapies such as vedolizumab. Beyond mucosal lesions, this method has also the potential to improve the diagnosis of other disorders involving dysregulation of MAdCAM-1 such as pancreatic cancers or chronic inflammatory liver disease. The main limitation is the lack of direct clinical translatability of the particles and antibodies that were used in the present study. However, biodegradable MPIOs are now available and anti-human MAdCAM-1 antibodies are currently under clinical investigation, opening the way for clinical translation of our imaging method by coupling the two constructs.

Since MRI is a widely available technique that is routinely performed in patients affected by mucosal disorders and since our contrast agent can be detected using standard sequences and magnets, the potential impact in patient care could be significant. Only a minor modification of currently performed imaging protocols would be necessary to include a T2*-weighted sequence and therefore to allow MPIO-aMAdCAM-1 detection. Notably, in the context of mucosal inflammation, MRI compares favorably to the other non-invasive methods available for molecular imaging such as positron-emission tomography and ultrasounds. A few targeted contrast agents for ultrasounds have been developed (including microbubbles targeted to adhesion molecules), but there are several drawbacks that disqualify ultrasound as a universally suitable method for detecting mucosal inflammation, such as an exploration limited to superficial tissues and the frequent presence of obstacles (such as gas) that precludes evaluation of some organs or intestinal segments. Combining ultrasounds with laser light stimulation, photoacoustic imaging allows imaging of mucosal inflammation in Crohn’s disease without exogenous contrast but remains impaired by the same limitations than ultrasounds. Positron-emission tomography, using 18F-Fluorodeoxyglucose or immuno-PET techniques, is theoretically suitable for imaging of mucosal tissue in the whole body but is limited by its low spatial resolution, its long acquisition time and its use of ionizing radiation, that precludes its repeated use in patients with chronic diseases. MRI is devoid of these drawbacks and the use of MPIO as contrast-carrying particles compensates for its low sensitivity, thus allowing sensitive imaging of mucosal inflammation.

We published the first part of our work in science translational medicine (Fournier et al., 2020). No patent has been filed regarding this work.

Inflammatory bowel disease (IBD) is the second most common chronic inflammatory disease worldwide. It is characterized by an inflamed mucosa in the gastrointestinal tract. Ileocolonoscopy with biopsies is considered the diagnostic gold standard in IBD, but this procedure causes significant patient discomfort and can only explore the distal end of the gastrointestinal tract. In the present project, we plan to develop a new contrast agent for molecular magnetic resonance imaging (MRI) which is targeted to proteins that are specifically expressed by the inflamed intestinal mucosa. To this aim, we will use macro-sized iron oxide particles (MPIO) coupled to monoclonal antibodies targeted to activated intestinal endothelial cells, in order to achieve sensitive, specific and non-invasive molecular imaging of intestinal inflammation. This method could have the potential to replace ileocolonoscopy during the follow up of IBD patients.