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Contrast by Quadrupole Enhanced Relaxation

Periodic Reporting for period 2 - CONQUER (Contrast by Quadrupole Enhanced Relaxation)

Reporting period: 2016-09-01 to 2018-08-31

The ageing society and demographic change is a major challenge 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 has explored quadrupole-enhanced relaxation (QRE) as a fundamentally new contrast mechanism with the potential to push magnetic resonance imaging (MRI) far beyond its limits towards a powerful MI modality. QRE exploits magnetic interaction between protons (1H) and high spin quadrupolar nuclei (QN) for contrast agent (CA) design. The aim was to synthesise bio-compatible nano-particles (NPs) containing Bismuth (Bi) as QN with high freedom in the design of smart properties, e.g. the ability to switch the contrast on and off by changing the magnetic field (B0) or chemical binding (e.g. targeting). The feasibility of QRE should be demonstrated in aqueous solutions. 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 in that it has provided theoretical groundwork, synthesis guidelines, imaging instrumentation and toxicological data. These results have been actively transferred to academia and industry in order to strengthen European competitiveness.
The proof of concept for QRE has been clearly provided for the first time in aqueous dispersions of crystalline Triaryl-Bi NPs, coated with a hydrophilic polymer. The observed signals occur close to the B0 of a clinical 3T MRI scanner. As predicted by theory the B0 at which the effect appears depends on subtle changes of the chemical structure and also the interaction of the Bi-centres with the molecular environment. This makes the compounds excellent candidates to be exploited for responsive CAs in MI.
Quantum-mechanical simulation programs for the relaxation of Bi-1H-systems have been developed to study the dependence of QRE efficiency on design parameters like quadrupole resonance frequencies, dynamics of the molecules and exchange rate of water molecules with the QN. In addition simple, fast applicable tools were developed for a coarse prediction of QRE frequencies as well as quadrupolar relaxation in solid precursors. Calculations predict a theoretical relaxivity enhancement of 5-10 compared to water for 10mMol concentration after full optimization of the NPs. DFT calculations have shown the dependence of NQR frequencies on bound ligands and also long-ranging structural effects, e.g. subtle changes of binding angles, thus supporting the fine tuning of the CAs.
A family of Bi-aryl compounds with several substituents was synthesised and an extremely versatile strategy for covalently bonding them onto different NPs was elaborated. All compounds were characterised with respect to crystal properties and purity. Nuclear Quadrupole Spectroscopy (NQRS) revealed resonance frequencies close to target values for clinical scanners and showed the relevance of structural order of the Bi centres.
A number of highly biocompatible functional NPs based on polysaccharide (PS), especially ethyl cellulose and Dextran, were synthesised. Then composite NPs with selected Bi compounds as well as polymer-coated Bi-Aryl nanocrystallites were produced.
Triaryl-Bi-compounds were also successfully bonded to cyclodextrin, thus providing a well-reproducible model-system for basic investigations and highly ordered Bi-centres.
All NPs were comprehensively characterised in terms of the physical and chemical properties relevant for QRE. Finally solids as well as liquid dispersions were investigated for QRE of intrinsic and solvent 1H, respectively, by Fast Field Cycling (FFC) NMR relaxometry.
For testing QRE imaging, a clinical 3T MRI scanner was equipped with an insert for FFC to shift B0 away from the nominal value. Technical challenges comprising installation, correction of system imperfections and sequence design were tackled to make the system fully operative. The capability of generating contrast from relaxivity dispersion has been proven for the first time at 3T. Actual QRE imaging was not yet possible because of still insufficient signal from the available samples.
A patent was submitted to the European Patent Office.
General information as well as access to open data and publications including press releases and activities in pan-European networks can be found on the Webpage http://www.conquer.at. Meetings for the internal communication and participation in international conferences can be tracked on the web-page. Details on ethical issues, potential environmental risks and guidelines for health and safety procedures were elaborated and documented in non-public deliverables.
The observation of QRE in liquids is a remarkable breakthrough beyond state of the art. CONQUER has provided a unique and comprehensive knowledge-base for transferring the pioneering findings to the design of optimized NPs in order to reach maximum contrast enhancement as predicted by theory. Scientific progress involves a generic synthetic concept for the Bi-compounds and the bonding strategy as well as unique experience in the preparation of the most promising PS-based carriers. For NQRS a novel type of custom-built, fast scanning and sensitive wideband cryo-probeheads has been developed. Powerful numeric models are now available for supporting the next decisive step, i.e. the optimization of NPs for size, water approach and exchange rate with the QNs, structural order and quadrupolar relaxation times. Predictions and experimental evidence strongly suggest further research to push QRE towards a clinically applicable CA.
Patenting has been started as an important step for the exploitation of the new technology. Technology offers have been prepared to identify potential end-users such as high-potential pharmaceutical companies. Generating and protecting the respective IP has created a unique European selling proposition.
The scientific community was targeted by the COST Action CA15209 - ‘European Network on NMR Relaxometry’ (EURELAX). Its action coordinator is, at the same time, workgroup leader in CONQUER , and the coordinator of CONQUER is involved in 3 workgroups of EURELAX. This situation has generated significant visibility of CONQUER and led to several cooperations and joint publications as well as invited lectures. Good connections could also be built up with the EU project IDENTIFY which aims at bringing FFC-MRI to the stage where it can be used as a routine tool for clinical diagnosis. There is continuous exchange of information between IDENTIFY and CONQUER which is thus actively stimulating the development of human field cycling MRI.
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.
graphical representation of the iteration loop until, finally, the prototype CA will be tested in an
general workflow of the project