Magnetic nanoparticles for brain diseases

The present dissertation presents my doctoral work developed during the last three years at the Italian Institute of Technology (IIT) and the University of Genoa. The work was focused on the development of different ferrite nanoparticles and their magnetic characterization. Another objective of this work was the use of these magnetic nanoparticles for magnetic hyperthermia as a suitable mean to enhance the blood brain barrier passage. The first chapter deals with the synthesis and characterization of different divalent ions substituted ferrite nanocubes (NCs). In particular, trough non-hydrolytic synthesis, cobalt ferrite, zinc ferrite and mixed ferrite NCs, i.e. cobalt-manganese and cobalt-zinc, were obtained. The size and the composition were controlled by modifying the synthesis parameters, obtaining cubic-shaped nanoparticles with a cube edge ranging from 5 nm to 65 nm at different ions stoichiometry. The full characterization of these NCs was carried out to find the combination of composition and size that better suits their application in magnetic hyperthermia treatment (MHT), magnetic resonance imaging (MRI) and magnetic particle imaging (MPI). Additionally, their use to prepare magnetic clusters by controlling the aggregation of these nanocubes into polymeric beads, here named magnetic nanobeads, was also studied. In chapter 1 is shown that these nanocubes, especially cobalt ferrite and zinc ferrite, revealed outstanding heating properties in magnetic hyperthermia. The same nanocubes were showing good performances as MRI contrast agent and generates MPI signals that were better than commercially available Resovist magnetic nanoparticles. Thanks to the large portfolio of NCs here prepared, it was possible to correlate their structural and chemical properties to the hysteresis loops measured under alternating magnetic field (AMF), probing heat losses as a function of media viscosity, concentration and aggregation status. The results obtained revealed that among all the different compositions, the zinc ferrite NCs are the most promising material for MHT, MPI and MRI applications, thanks also to his biocompatibility. In the second chapter, the functionalization and the exploitation of magnetic nanoparticles for enhancing central nervous system delivery is reported. In particular, the main goal of this study was to increase the NCs transportation through the blood-brain barrier (BBB) for the treatment of neurodegenerative diseases and brain tumors by using magnetic hyperthermia and molecular targeting. To reach this scope two strategies were followed. The first approach consists on the temporary and local damage of the BBB driven by the heat properties of the iron oxide and cobalt ferrite NCs thus increasing the para-cellular transportation through the BBB. The second approach consists on the functionalization of the same NCs with the trans-activating transcriptional activator peptide (TAT) to enhance the trans-cellular transportation through the BBB. The experiments were carried on a functional in vitro model of BBB using bEnd3 cells. First a suitable coating for the nanoparticles was developed. The results showed the importance of coating the NPs with polyethylene glycol (PEG) to increase the stability in biological media, enhancing the passive passage through the BBB. Then, the heating performances of both iron oxide and cobalt ferrite NCs were compared to induce thermal damage to the BBB. Due to their ability to heat up using lower NPs dose, cobalt ferrite NCs were chosen over iron oxide ones for further studies. The experiments of BBB transportation of these nanoparticles in presence of magnetic hyperthermia revealed a double fold dose increase in the passage when the barrier was thermally damaged. Nevertheless, the complete recovery from the temporarily induced damage was demonstrated. Concerning the second BBB transportation approach, the TAT coated NPs were successfully prepared. Further experiments will be done to test them on the BBB model. Finally, being most of the neurodegenerative disorders characterized by peptide fibrils accumulation in to the brain, a preliminary study focused on the use of Ferulic acid (FA) as a potential compound for disassembling aggregated insulin fibrils in a protein plaque model was followed. The effect of the FA on the fibrils was found to be concentration dependent, increasing with the increase of compound concentration. Further studies should be done to delivery this compound to the brain.