Iron oxide nanoparticles for diagnosis and therapy of lymph node metastases

This thesis presents the synthesis, coating and characterization of iron oxide nanoparticles (IONPs) with properties especially designed for the ultimate simultaneous MRI detection and hyperthermia treatment of lymph node metastases, a combination called theranostics. This demanding aim requires to fulfill two different challenges at the same time: (i) synthesis of IONPs with exceptional properties for MRI and hyperthermia obtained with a synthesis method transferable to manufacturing facilities, and (ii) coating of IONPs with molecules, which simultaneously allow their dispersion and ideally have higher affinity to lymph node metastases than to other tissues. We therefore developed a novel simple aqueous method to synthesize IONPs by combining the standard co-precipitation method with a hydrothermal treatment. We studied the influence of the synthesis parameters, especially the hydrothermal treatment duration, on the IONPs' size, morphology, structure, crystallinity, as well as their magnetic, relaxometric and heating properties. As a result, we were able to control simultaneously the studied properties and to obtain IONPs with optimal properties for both MRI and hyperthermia. Subsequently, IONPs were coated in aqueous conditions with nine different molecules considered as biocompatible and non-toxic. In order to preserve the high relaxometric and heating properties of IONPs, we used small molecules to reduce the coating to a minimum. In that case, dispersion of IONPs with the chosen molecules were obtained by electrostatic stabilization. One of the major constraints was to obtain coated IONPs with hydrodynamic diameters smaller than 100 nm and with negative surface charges, both needed to access and be retained in the lymphatic system that is required for the targeting of lymph node metastases. In order to avoid to further enlarge the coating, we also used the available active groups of the coating molecules to target lymph node metastatic cells. In order to confirm the possibility to target such cells, we investigated the uptake of coated IONPs in four tumor cell lines from different cancer stages. Finally, the platform with optimal properties necessary for the targeting, detection and treatment of lymph node metastases was found to be IONPs coated with folic acid or adenosine triphosphate, which are targeting the prostate specific membrane antigen receptors or the highly metabolic nature of tumor cells, respectively. In the last part of this thesis, the interaction of IONPs with blood and lymph, especially the formation of the protein corona around IONPs, was investigated. Our study took into account the complex environment, which IONPs are subjected to in vivo. So far unconsidered in vitro conditions were examined, such as the dynamic variations of the flow or the transition of IONPs from one body fluid to the other.