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Hyperpolarized Biosensors in Molecular Imaging

Final Report Summary - BIOSENSORIMAGING (Hyperpolarized Biosensors in Molecular Imaging)

Basic research has made significant progress in understanding many diseases on a molecular level and triggered the field of molecular imaging and novel targeted drug delivery approaches. Both can be summarized in the concept of “personalized medicine” based on the identification of multiple molecular markers and the delivery of functionalised drug carriers. Techniques for imaging the spatial distribution of such markers and monitoring drug delivery in a living organism are therefore a highly sought-after goal in order to enable early diagnosis and individualized therapy. Nuclear magnetic resonance (NMR), as used for diagnostic imaging, has an outstanding molecular specificity but suffers from low sensitivity. It could contribute significantly to revealing disease-specific markers and implementing the aim of personalized medicine, while being non-invasive and abstaining from using problematic ionizing radiation. Therefore, solving the sensitivity problem of NMR is of major interest for improving early disease detection and optimized monitoring of therapy. The ERC project BiosensorImaging implemented a novel approach to boost the sensitivity of NMR imaging for biomedical applications.
Important improvements have been achieved in the production of laser-polarized xenon, in particular its stability in continuous-flow setups where the gas is used in repetitive delivery for ultra-sensitive detection of targeted xenon hosts in nanomolar concentration ranges. The shot-to-shot noise for gas delivery could be decreased to <0.5% by improved polarizer design. The project also made significant contributions for image encoding procedures within the emerging field of CEST detection (chemical exchange saturation transfer). Optimized use of the available magnetization now allows for snap-shot imaging of nanomolar concentrations – a regime that would require acquisition times of ca. 1100 years with conventional detection techniques.
Following development of the image preparation and acquisition steps, another important component was the development of an NMR-compatible bioreactor that allowed demonstration of xenon NMR studies in live cells. This served as a stepping stone for future biomedical applications in living organisms but also to optimize biosensor design for various molecular targets. An initial study demonstrated untargeted labelling of cells with functionalized xenon. This important intermediate step served as proof for sufficient sensitivity under physiological conditions. With the new tools on hand, the project focused on the development of targeted sensors with biological relevance. We implemented various strategies to use individual xenon hosts (such as cryptophane cages) for the design of targeted contrast agents. These include antibody-based modular approaches with dual-mode reporters (NMR/fluorescence), lipopeptide-functionalized liposomes, and metabolic oligosaccharide engineering (MOE). The MOE approach in particular was considered as a seminal step forward since it could not be realized with other MRI approaches so far.
For advancing the technique further to in vivo applications, we tested alternative xenon hosts, amongst them clinically approved nanodroplets with superior gas-binding properties. This allowed us to demonstrate the first multi-channel MRI of hyperpolarized xenon based on different nanocarriers with unprecedented sensitivity. The project also made important contributions to understand the behavior of functionalized xenon in phospholipid membrane material. This will help to design optimized liposomal carriers for xenon MRI applications and fostered further studies on membrane fluidity and integrity which will be used in studies on antimicrobial peptides.
In summary, BiosensorImaging has contributed significantly to advance the field of xenon MRI and to make it part of the molecular imaging tool box for future applications in improved drug development and therapy monitoring where it is envisioned to close the sensitivity gap between NMR and PET for improved diagnostic imaging.