Periodic Reporting for period 1 - FC-RELAX (NMR relaxometry for biomedicine and advanced materials)
Reporting period: 2023-03-01 to 2025-02-28
The main aim of this multidisciplinary doctoral network is to train a new generation of scientists with outstanding knowledge in the field of field-cycling relaxometry. Field-cycling relaxometry is a versatile tool allowing for the investigation of molecular structure and dynamics on a wide time scale, from picoseconds to milliseconds. This technique provides information which are key in several biomedical applications, as well as in the characterization of advanced materials, thus with a great potential of impact. The knowledge of the molecular dynamics, together with that of the structure, is of central importance to fully understand the mechanisms underlying molecular functions, and field-cycling relaxometry is one of the very few techniques which can provide information on motions occurring on time scales longer than nanoseconds.
In this frame, the fellows are trained to acquire a deep knowledge of the different, possible applications of the technique, ranging from molecular biology and inorganic chemistry to biophysical methods. In addition, they are trained to the mastery of theoretical tools, with a multi-disciplinary integrative view made possible by the different expertise of the consortium partners. A multisectoral training is ensured by the presence in the network of 3 industrial partners and 10 academic partners and by the scheme of planned secondments.
The projects of the recruited DCs focus on different research fields and/or on technological and theoretical developments:
- the improvement of efficacy and safety of magnetic resonance imaging contrast agents and paramagnetic nanosystems for theranostics
- the development of partially crystalline materials and of ionic liquids for their use as electrolytes in energy storage devices
- the exploitation of relaxometry for cancer diagnosis
- the development of the theoretical knowledge of field dependent relaxation processes to unravel dynamic processes occurring in complex systems.
The project thus contributes to a better understanding of key molecular processes occurring in biological systems and in materials to unlock innovations in biomedical technology, medical diagnosis, ionic liquids for energy storage, design of innovative drugs and biologics acting on specific molecular targets.
These scientific achievements may thus open new routes for early detection of diseases by improving the diagnostic methods heavily relying on the efficiency of magnetic resonance imaging (MRI), and to the optimal exploitation of electrolytes, key devices for large-scale energy storage systems.
In this frame, the fellows are trained to acquire a deep knowledge of the different, possible applications of the technique, ranging from molecular biology and inorganic chemistry to biophysical methods. In addition, they are trained to the mastery of theoretical tools, with a multi-disciplinary integrative view made possible by the different expertise of the consortium partners. A multisectoral training is ensured by the presence in the network of 3 industrial partners and 10 academic partners and by the scheme of planned secondments.
The projects of the recruited DCs focus on different research fields and/or on technological and theoretical developments:
- the improvement of efficacy and safety of magnetic resonance imaging contrast agents and paramagnetic nanosystems for theranostics
- the development of partially crystalline materials and of ionic liquids for their use as electrolytes in energy storage devices
- the exploitation of relaxometry for cancer diagnosis
- the development of the theoretical knowledge of field dependent relaxation processes to unravel dynamic processes occurring in complex systems.
The project thus contributes to a better understanding of key molecular processes occurring in biological systems and in materials to unlock innovations in biomedical technology, medical diagnosis, ionic liquids for energy storage, design of innovative drugs and biologics acting on specific molecular targets.
These scientific achievements may thus open new routes for early detection of diseases by improving the diagnostic methods heavily relying on the efficiency of magnetic resonance imaging (MRI), and to the optimal exploitation of electrolytes, key devices for large-scale energy storage systems.
The initial consortium activities focused on the recruitment of the 11 Doctoral Candidates (DCs), the organization of the first- and second-year joint training activities and the definition of the management structure and of the communication and dissemination activities.
After recruitment, the DCs elaborated their initial CDPs, familiarized with their research plans, received training at their Host Institutions and made the scheduled secondments.
Research activities were carried out according to the DC research plans and the project tasks. In particular, the relaxation data collected for a variety of different samples were analysed to better understand which physical model of dynamic processes best fits them, taking into account the different models can be applied to describe molecular mobility. Large effort has been dedicated to the development of software tools optimized for the analysis of relaxation profiles in general and especially of paramagnetic relaxivity. Furthermore, molecular dynamics simulations were performed to validate the employed theoretical models with the experimental relaxation rates (WP1).
Gadolinium(III)-complexes of DOTP and its derivatives were synthesized as pure proton-exchange based MRI relaxation agents, and their thermodynamic and structural features were determined. Since manganese(II)-complexes can represent a safer alternative to Gd-complexes, presently employed in medical diagnosis, new Mn-complexes were synthesized and characterized as potential MRI contrast agents. In order to improve the relaxometer detection system, radiofrequency coils of different geometries were evaluated for the production of more efficient systems (WP2).
A tetrameric protein, identified as a possible carrier for the delivery of cytotoxic drugs to cancer cells, was tagged with a Gd-complex, and its efficiency as possible MRI contrast agent was evaluated from the acquired relaxivity profiles. The relaxation profiles of model tissues are investigated to evaluate the possibility of obtaining information about their biological structure or function. Metabolite interactions are studied with high resolution relaxometry by adding phosphorus-containing metabolites to blood serum (WP3).
Molecular dynamics simulations performed for ionic liquid systems were validated against NMR measurements and relaxation models. Dynamics in polymeric materials and semicrystalline solids were studied with time-domain NMR experiments. The influence of surfactants in the wettability of nanoparticles was investigated. Software packages for automated analysis are under development (WP4).
After recruitment, the DCs elaborated their initial CDPs, familiarized with their research plans, received training at their Host Institutions and made the scheduled secondments.
Research activities were carried out according to the DC research plans and the project tasks. In particular, the relaxation data collected for a variety of different samples were analysed to better understand which physical model of dynamic processes best fits them, taking into account the different models can be applied to describe molecular mobility. Large effort has been dedicated to the development of software tools optimized for the analysis of relaxation profiles in general and especially of paramagnetic relaxivity. Furthermore, molecular dynamics simulations were performed to validate the employed theoretical models with the experimental relaxation rates (WP1).
Gadolinium(III)-complexes of DOTP and its derivatives were synthesized as pure proton-exchange based MRI relaxation agents, and their thermodynamic and structural features were determined. Since manganese(II)-complexes can represent a safer alternative to Gd-complexes, presently employed in medical diagnosis, new Mn-complexes were synthesized and characterized as potential MRI contrast agents. In order to improve the relaxometer detection system, radiofrequency coils of different geometries were evaluated for the production of more efficient systems (WP2).
A tetrameric protein, identified as a possible carrier for the delivery of cytotoxic drugs to cancer cells, was tagged with a Gd-complex, and its efficiency as possible MRI contrast agent was evaluated from the acquired relaxivity profiles. The relaxation profiles of model tissues are investigated to evaluate the possibility of obtaining information about their biological structure or function. Metabolite interactions are studied with high resolution relaxometry by adding phosphorus-containing metabolites to blood serum (WP3).
Molecular dynamics simulations performed for ionic liquid systems were validated against NMR measurements and relaxation models. Dynamics in polymeric materials and semicrystalline solids were studied with time-domain NMR experiments. The influence of surfactants in the wettability of nanoparticles was investigated. Software packages for automated analysis are under development (WP4).
Also thanks to the research work performed by the 11 enrolled DCs several scientific results of potential impact have already been achieved.
New software tools optimized for the analysis of the relaxation data, web-accessible and with graphical interfaces, have been developed. The availability of these tools will facilitate the analysis of the relaxation profiles and therefore potentially increase the number of possible users of this technique.
An improved radiofrequency coil was produced, more compact and with a higher efficiency.
New Mn-complexes have been characterized as possible safer alternatives to the Gd-complexes presently employed as MRI contrast agents. New Gd(III)-complexes have been characterized to evaluate the contribution of proton-exchange based relaxation, as an additional strategy for improving the efficacy of MRI contrast agents.
A tetrameric protein with Gd(III) complexes attached to it has been produced, with a very good mobility and exchange rate of the Gd-coordinated water molecule, so that the efficiency of this nanoparticle as contrast agent is potentially very high; the presence of a pendant linker for the binding to the cysteine amino acids of the protein allows the easy conjugation of this Gd(III) complex to a variety of biomolecular platforms.
Five articles coauthored by at least one of the DCs have already been published in peer-reviewed journals, and several DCs have already material for further publications.
New software tools optimized for the analysis of the relaxation data, web-accessible and with graphical interfaces, have been developed. The availability of these tools will facilitate the analysis of the relaxation profiles and therefore potentially increase the number of possible users of this technique.
An improved radiofrequency coil was produced, more compact and with a higher efficiency.
New Mn-complexes have been characterized as possible safer alternatives to the Gd-complexes presently employed as MRI contrast agents. New Gd(III)-complexes have been characterized to evaluate the contribution of proton-exchange based relaxation, as an additional strategy for improving the efficacy of MRI contrast agents.
A tetrameric protein with Gd(III) complexes attached to it has been produced, with a very good mobility and exchange rate of the Gd-coordinated water molecule, so that the efficiency of this nanoparticle as contrast agent is potentially very high; the presence of a pendant linker for the binding to the cysteine amino acids of the protein allows the easy conjugation of this Gd(III) complex to a variety of biomolecular platforms.
Five articles coauthored by at least one of the DCs have already been published in peer-reviewed journals, and several DCs have already material for further publications.