MULTIMAGE

Nanoparticles for diagnoses in medicine have been proposed since two decades because they present great advantages in comparison with molecular compounds: - multimodality (i.e. the possibility to gather in a same object different properties), - the enhancement of the imaging properties: either by the large number of contrast agents (Gd atoms in MRI) supported per particle or by an increase of the agent efficiency (diminution of the rotational correlation time leading to an increase of relaxivity) , - the capacity to be concentrated in tumours or diseased zones either by passive effect (i.e. Enhanced Permeability and Retention (EPR) Effect) or by an active process via the use of targeting species at the surface of the nanoparticles, - multivalency, i.e., the possibility to use particles as scaffolds for grafting multiple targeting ligands (permitting to increase the fixation to the site of interest by multivalent interactions) and/or to combine multiple types of ligands to augment their specificity of recognition with the diseased areas and - the emergence of new original original properties at the “nano-scale” , One of the major objectives consists in increasing the difference in the particles content between healthy and diseased zones to maximize the contrast in the images acquired. Since only the diseased zones retain the particles, all the healthy regions should eliminate as quickly as possible all circulating particles. It is then preferable that the particles are evacuated exclusively by renal excretion which implies that the size of the nano-objects has to be smaller than 5.5 nm. The development of a particle with a size lesser than 5 nm and still conserving multimodal properties is a real challenge. With the help of MATEIS (Partner 1- coordinator), LPCML (Partner 2) and UTINAM (Partner 3) have developed two types of such particles : (NANOCONSTRUCT 1) small rigid platforms (SRP) of polysiloxane encapsulating fluorophores and grafted by radioactive (111In, 99mTc or 64Cu) or magnetic (Gd3+) complexes allowing magnetic resonance imaging (MRI), optical imaging, scintigraphy and X-ray tomography and (NANOCONSTRUCT 2) gold clusters coated by gadolinium-chelates permiting MRI and X-ray imaging in transmission or in a tomography mode. The aim of this project consists to optimize and develop these new ultrasmall particles in a way that they can be produced by Nano-H S.A. (Partner 4) in large quantities with respect of all the conditions of a good manufacturing process (GMP). Ideally only one type of particles should be retained at the end of the project. With the help of ICMUB (Partner 5) and CheMatech (Partner 6) who develop a certain type of macrocycles (DOTA derivatives) that can act as efficient chelating species for several metal ions, the functionalization of the particles will be optimized in order to ensure (i) a prolonged colloidal stability in biological media and blood stream and (ii) a secure anchorage for contrast agents for MRI and scintigraphy. With the help of IAB and LINA (Partner 8 and 10), the architectures and the process will be optimized to strictly limit the toxicity of particles. At the end of the project, the particles will be ready for the highly expensive toxicity studies required by AFSSAPS in the following step of drug commercialization. Finally, the efficiency of the multi-contrast properties of the particles will be evaluated and proven by imaging the healthy and diseased zones in three pathologies : (i) brain, colorectal or liver cancer with the help of GIN, IAB, UCPGI and LINA (Partners 7,8,9,10), (ii) hepatocellular diseases with the help of UCPGI and LINA (Partners 9 and 10) (iii) diabetes related to amyloid disorders with the help of AFFOND (Partner 11). In all cases, we expect that these combined imaging techniques, still helped by the development of a specific apparatus for scintigraphy by AXINT (Partner 12), will permit an efficient early diagnosis that will save a large number of human lives.