Contrast by Quadrupole Enhanced Relaxation

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 will explore 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 cross relaxation between 1H and large quadrupolar nuclei (QN) for contrast agent (CA) design. The main objective is to synthesize bio-compatible QN compounds 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.

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. 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.