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Laboratory | Cell and molecular imaging
Molecular Imaging and Delivery of Active Substances
Presentation of the MIDAS team and the research topics.
Thanks to a previous project called ISEULT, funded by the French Agency for Industrial Innovation (BPIFrance, formerly OSEO), the nuclear magnetic resonance imaging and spectroscopy unit (UNIRS) of NeuroSpin (CEA Saclay) has conducted, in collaboration with the pharmaceutical company Guerbet, a 5 years research program which demonstrated that the use of high field MRI scanners (7 and 17.2 Tesla), combined with the development of new paramagnetic and superparamagnetic functionalized contrast agents exhibiting very high relaxivity, allows to perform molecular imaging of brain pathologies induced in rodents (tumor, stroke). Furthermore, in order to target brain intratissular biomarkers such as amyloid plaques in Alzheimer's disease models, a specific focused ultrasound device working under MRI guidance has been developed to induce temporary permeabilization of the blood-brain barrier (BBB) and thus ensure accessibility for functionalized contrast agent to its target.
In continuity of ISEULT project, the "Molecular Imaging and Delivery of Active Substances" team (MIDAS) of UNIRS focuses its research on developing new quantification strategies and experimental devices dedicated to MR-based molecular imaging at high field (7, 11.7 and 17.2 Tesla). The targeted biomarkers are specific of cerebral pathologies (glioma, glioblastoma, stroke, amyloidosis…), and located on sites either endovascular or intratissular. The different methodological developments mainly consist in optimizing the acquisition of quantitative maps of functionalized MRI contrast agent concentration (relaxometry), in terms of sensitivity detection, spatial and temporal resolutions. These developments include the design of MRI sequences, the implementation of data reconstruction and image post-processing tools, as well as the set-up of in vivo molecular imaging protocols involving murine models of cerebral pathologies. To confirm MRI results, the histology platform of NeuroSpin is in charge of developing immunohistochemical staining protocols dedicated to these animal models, especially to visualize the co-localization of functionalized MRI contrast agent with its biological target. Moreover, in order to control the delivery of functionalized MRI contrast agents to brain tissue (for example to target amyloid plaques in Alzheimer's disease models), a new focused ultrasound device working under MRI guidance has been developed for non-invasive temporary permeabilization of BBB, and validated in vivo on rodent models. Using dedicated motorization system and control software, this device allows monitoring in situ and in real-time the mechanical and electronic trajectories of ultrasound beam, and therefore defining precise locations for molecules delivery to the brain. A feedback loop based on real-time transfer of MRI images is used to record any potential biological effect of ultrasound, and if needed some acoustic parameters can be modified during the imaging session.
The different research projects conducted by the "Molecular Imaging and Delivery of Active Substances" team of UNIRS can be divided in three main topics:
The evaluation of new functionalized contrast agents dedicated to MR-based molecular imaging of brain pathologies: magnetosomes functionalized by genetic modification of magnetotactic bacteria (MEFISTO project), iron oxide nanoparticles functionalized by specific antibodies (TROPICA project), a novel class of paramagnetic MRI contrast agents functionalized to target cerebral amyloidosis (FUSETAD project);
The study of specific animal models of cerebral pathologies in order to identify new therapeutic targets: the tumoral neoangiogenesis in a mouse model of human glioblastoma (MEFISTO project), the tumor-microenvironment interactions in a mouse model of diffuse intrinsic pontine glioma (STROMAD project), the brain tissue infiltration by cancerous human neural stem cells in a mouse model of glioma (TROPICA project), anatomical and functional molecular markers in a rat model of stress (SIGMA project), the appearance of amyloid deposits in transgenic rodent models of Alzheimer's disease (FUSETAD project);
The development of new devices based on transcranial focused ultrasound, working under MRI guidance or not, dedicated to two main applications in rodent and non-human primate models: i) the controlled and localized delivery of diagnostic or therapeutic compounds to brain tissue after an ultrasound induced release of encapsulating drugs and/or a permeabilization of the BBB (MRgFUS, MACAKUS, 3BOPUS and FLUORIMUS projects); ii) the local ultrasound induced neurostimulation combined with functional MRI (NeuroStimUS project).
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.