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Contrast by Quadrupole Enhanced Relaxation

Periodic Reporting for period 1 - CONQUER (Contrast by Quadrupole Enhanced Relaxation)

Reporting period: 2015-09-01 to 2016-08-31

The ageing society and demographic change is one of the major challenges which Europe is facing now, and even more so in the future. Mastering this challenge requires radically new diagnostic and therapeutic treatments as key factors in achieving the healthy well-being of European citizens. Molecular imaging (MI) plays a pivotal role in diagnosis, understanding of disease and in the development of effective treatments.
CONQUER is exploring a fundamentally new contrast mechanism with the potential to push magnetic resonance imaging (MRI) far beyond its limits towards a powerful MI modality. This will be achieved by exploiting the magnetic interaction between 1H and large quadrupolar nuclei (QN) for contrast agent (CA) design. The main objective is to synthesise bio-compatible QN compounds based on high spin nuclei and nano-particles (NPs), high efficiency and manifold degrees of freedom in the design of smart properties, such as the ability to switch the contrast on and off by changing the magnetic field or chemical binding (e.g. targeting). The NPs will be tailored based on quantum-mechanical simulations. Sensitivity and contrast switching will be demonstrated with MRI in cell cultures. This highly interdisciplinary project combines expertise in quantum physics, chemical and biomedical engineering, material characterisation as well as nanotoxicology.
Today, European scientists and companies are already leading global players in CA development. CONQUER will significantly fertilise this field and lay the scientific foundations for a new technology by providing theoretical groundwork, synthesis guidelines, imaging instrumentation and toxicological references. These results will be actively transferred to academia and industry as well in order to strengthen European competitiveness. The combination of a so far unexploited quantum-mechanical phenomenon and cutting-edge imaging technologies has the potential to create MI solutions with significant impact.
(1) Quantum-mechanical simulation programs: The contrasts aimed at are based on a shortening of the so called relaxation time T1 of the protons in water and fat molecules in the human body, i. e. the time the protons need to return to their equilibrium magnetization state after excitation by the MRI radiofrequency pulses. In order to be able to design efficient compounds several parameters must be optimised, e.g. the quadrupole resonance frequencies, the dynamics of the molecules (e.g. rotational tumbling rate) and the exchange rate of water molecules with the quadrupole nucleus. In the first period such a model was developed and programmed for nuclei with spin 9/2, such as Bismuth. The program now allows for the prediction of the relaxation behaviour of simple Bi-Proton-systems. One important result is the prediction of the required particle size for obtaining high relaxation rates at specific frequencies.

(2) Synthesis of candidate organobismuth compounds: In period 1, the target was to synthesise and characterise five organobismuth compounds. This goal was exceeded by far by synthetising a whole family of Bi-aryl compounds with several substituents so as to demonstrate the potential for tuning their quadrupole resonance frequencies. All compounds were characterised with respect to the crystal properties by x-ray diffractometry and compound purity by NMR spectroscopy. All synthesis strategies were thoroughly described. Moreover the quadrupolar properties were characterised by Nuclear Quadrupole Spectroscopy (NQRS). Many of the the compounds already show resonance frequencies close to the target frequency of 123.4 MHz for a clinical MRI scanner, making them good candidates for further fine tuning.

(3) Based on the size recommendations a number of functional polysaccharide nanoparticles (NP) were synthesised. Afterwards, polysaccharide-bismuth composite NPs were produced based on 3 different Bi compounds: The produced functional NPs were characterised in terms of size, surface composition and surface properties by Field Emission-Scanning Electron Microscopy (FE-SEM), ζ-potential and hydrodynamic diameter by dynamic light scattering, Attenuated Total Reflectance-Fourier Transform Infrared spectroscopy (ATR-FTIR) and functional properties such as antioxidant activity. The polymers in the form of polysaccharide-bismuth composite NPs were characterized by NQRS. Many of the particles could be fabricated in the desired range of sizes which was recommended after the simulations in (1).

(4) For the final proof of concept at the end of the project a clinical MRI scanner (SIEMENS Skyra, 3T) must be adapted to be able to shift the magnetic field strength (so-called B0) away from the normal operating value. A special insert was designed and custom-built by an external company and implemented at Graz University of Technology. During the first period the whole process of hardware specification, elaboration of design guidelines, risk analysis and coordination of the information flow between the manufacturers of the insert and the Scanner was carried out so that at the end of the first period the first tests of the insert could be performed. The basic specifications concerning the field shift and the switching speed were met successfully so that in the next period the preparation for the experiments can be undertaken.

(5) Based on the results so far obtained a patent was submitted to the European Patent Office.

(6) Concerning dissemination a Webpage was crated and a plan for the management of open access data and publications was set up. A number of press releases, participations on conferences and activities in pan-European networks can be tracked on the web-page as well as the documents for the open-access reports of non-confidential deliverables.

(7) Publications can be found on the webpage and in the ZENODO database.

(8) Internal communication between the partners was guaranteed by a number of meetings whic
The major scientific breakthroughs beyond state of the art involved the realization of a generic synthetic concept, the generation of bismuth containing nanocomposites involving polysaccharides, and the preparation of polysaccharide based nanoparticles, whose size can be efficiently controlled.
Furthermore a first database on the quadrupole resonance properties of Bismuth-Aryl compounds has been created and will be steadily extended throughout the project lifetime. In the first period, there was a steady and continuous progress of the project, which finally led to the submission of a European patent application (Novel Compounds for Use as Contrast Agents in Magnetic Resonance Imaging). The successful submission is the first step towards the exploitation of the new technology and currently technology offers are under preparation and will be used to identify potential end-users such as high-potential pharmaceutical companies who are leaders in CA production for MRI. Generating and protecting the respective IP will create a unique European selling proposition.

Besides industry, the scientific community will be targeted by the recently granted COST Action CA15209 - ‘European Network on NMR Relaxometry’. CONQUER is represented therein by the leader of WP2, who is the main proposer of the Action, and by the coordinator of CONQUER. Being involved in at least 3 workgroups of the COST Action CONQUER will generate visible impact.
The scientific data produced so far led to the development of improved quantum-physical models which are valuable simulation tools for theoretical physicists interested in spin-relaxation phenomena. CONQUER is also expected to stimulate the development of human field cycling MRI, which is currently only available for basic research.

In the long term, the potential societal impact includes an improvement in theranostic possibilities for patients, the foundation of high-tech enterprises, stimulation of employment, and strengthening of the academic institutions.
general workflow of the project
graphical representation of the iteration loop until, finally, the prototype CA will be tested in an