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Multi-functional drugs with imaging labels targeted at tumour angiogenesis – GLYCO-PROBES

Submission summary

The design of new radiopharmaceuticals and contrast agents (CA) represents an important field of research. These classes of compounds are valuable tools for non-invasive diagnosis of numerous diseases such as cancers. Two different techniques are currently used for in vivo imaging. 1-Magnetic Resonance Imaging (MRI) has become a powerful tool in diagnostic medicine. Nowadays, an important part of clinical scans are performed with the administration of CA which are chemicals able to amplify the contrast in the image to obtain a better discrimination between pathological regions and normal tissues. The contrast agents that are routinely used in clinical practice are mainly paramagnetic chelates of Gd3+ ions. 2-SPECT (Single Photon Emission Computed Tomography) is a diagnosis technique involving administration of a radiopharmaceutical to the patient. For SPECT imaging, a gamma ray emitting radionuclide such as technetium (Tc99m) is vectorized to pathological tissus. SPECT is particularly important in nuclear medicine for diagnosis of small tumors. Increasing the sensitivity of these techniques for early diagnosis of cancers is a major aspiration of the scientific community. SPECT imaging technique suffers from low concentration of the radiopharmaceutical inside tumours. This phenomenon leads to a low resolution of images and to a non specific irradiation. To date, In MRI techniques, all commercially approved gadolinium (Gd) compounds are extracellular agents with an aspecific biodistribution. The next generation of contrast agents will include systems able to recognize specific molecules on the cellular surface. New radiopharmaceuticals able to target most efficiently tumours and new CA probes with higher sensitivity would have a very important impact in the field of medical imaging. We propose two different ways, respectively for increasing the efficiency in tumours targeting for SPECT imaging and the sensitivity in MRI techniques. • In order to increase the efficiency in tumour targeting for SPECT, we propose to developp new multivalent probes. Affinity of a multivalent ligand for its receptors is generally much higher than monovalent one. • To overcome the problem of the relatively low sensitivity of MRI techniques, we propose to develop new probes with increased number of gadolinium ions per molecules. High molecular weight multi-gadolinium(III) chelates is anticipated to have increased rotational correlation time and, hence, to improve the relaxivity per gadolinium atom. The goal of this project is to develop and test a new class of multifunctional radiopharmaceuticals and contrast agents for medical imaging. New drugs will be based on a carbohydrate scaffold on which will be attached either technetium (SPECT) or gadolinium (IRM) chelates and specific ligands for targeting angiogenesis. This multidisciplinary approach will require scientific complementarity of the different partners. Partner 1 (Laboratoire Des Glucides, Dr Sébastien Gouin and Dr. Vincent Moreau) has an experience in the field of carbohydrate chemistry and more precisely have conduced previous work on the functionalization of carbohydrates scaffolds. Molecular dynamics of new probes will be also conducted by Partner 1 (Prof. François-Yves Dupradeau) who has developed new force field for carbohydrates. Partner 2, (SPCMIB, Chantal Galaup, ERIC Benoist) have a strong experience in coordination and physical chemistry of transition metals and lanthanide ions. They will be in charge of the synthesis, structural characterisation of gadolinium and technetium chelates, and biological evaluation of new radioimaging agents. The last partner of this project (CNAB) has developped a cyclopeptide (cyclo-VEGI) having a high affinity for the VEGF receptor. Dr Victor Maurizot will synthesize cyclo-VEGI comporting a grafting function and will evaluate affinity of the synthetic probes for VEGFr. This project that represents a new field of research in the laboratory shows different original aspects in regards to previous work. Radiopharmaceuticals and contrast agents will be easily tuneable. The synthetic strategy will allow easy variation of the multivalency and distance between ligands in order to design optimized probes. Furthermore, carbohydrate chemistry has not been much employed in the field of medical imaging despite expected adequate physical properties offered by sugars scaffolds such as hydrophilic entities and improved biokinetics. High complementarity of the different partners respectively involved in the field of carbohydrate chemistry, coordination chemistry for medical imaging, and in the design and evaluation of anti-angiogenic ligands, should allow the generation of a new family of chemical probes for medical imaging based on carbohydrate scaffold.

Project coordination

Sébastien GOUIN (Université)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

Help of the ANR 149,000 euros
Beginning and duration of the scientific project: - 36 Months

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