Periodic Reporting for period 1 - NOVA-MRI (Novel Applications in 19F Magnetic Resonance Imaging)
Reporting period: 2020-02-01 to 2022-01-31
Magnetic resonance imaging (MRI) is a leading clinical diagnostic technique that is able to provide whole body imaging, and when individual cells are imaged in living animals, it can provide new insights into the biology of cell trafficking and migration. For cells to be visualized by MRI, they generally must be labelled to enable their discrimination from surrounding tissue.
Problem/issue being addressed : Currently the agents of choice are gadolinium-based contrast agents (GBCAs). Until recently, these contrast agents were considered historically safe and well tolerated. However, they have been found to accumulate in various tissues of patients who do not have renal impairment, including bone, brain and kidneys. Also, in 2015 the FDA released a new safety announcement regarding GBCAs and the risk of accumulated deposits in the brain following repeated use. This led to the search for a new generation of safer MRI contrast reagents using perfluorocarbon (19F) being incorporated inside smart nanoparticles, which can offer unique quantitative signatures for molecular MRI with no competing background signal.
Importance for society: The goal of NOVA-MRI is to produce the next generation of MRI contrast agents, based on nanomaterials, which can provide sensitive detection during scanning and will lack the safety issues around currently established contrast agents like GBCAs. There is negligible endogenous 19F MRI signal from the body since the physiological concentrations of detectable mobile fluorine are below the detection limit. This lack of background signal means that the use of fluorinated compounds can potentially provide both high sensitivity (high signal-to-noise ratio) and specificity.
Overall objectives: 1) The training of a new generation of researchers in the field of imaging of cell-based inflammation with 19F MRI through individual research projects, sharing all the same main challenges, intra- and intersectoral secondments, local, and network-wide training. 2) Completion of all ESR projects with focus on the development of i) Nanomaterials and PFC contrast reagents for 19F MRI, ii) Development of dual modality (optical and 19F) fluorophore and PFC-NE (nano-emulsion) imaging, iii) Development of novel 19F MRI applications relevant for clinical translation. 3) The creation of an efficient network of researchers from academia and industry, working closely together towards the success of NOVA-MRI that will be reflected by the foreseen dissemination, outreach, and communication activities. 4) To ensure effective and appropriate management and coordination of NOVA-MRI and adopting an interdisciplinary and intersectoral approach through the composition of this expert consortium together with the associated partners.
Problem/issue being addressed : Currently the agents of choice are gadolinium-based contrast agents (GBCAs). Until recently, these contrast agents were considered historically safe and well tolerated. However, they have been found to accumulate in various tissues of patients who do not have renal impairment, including bone, brain and kidneys. Also, in 2015 the FDA released a new safety announcement regarding GBCAs and the risk of accumulated deposits in the brain following repeated use. This led to the search for a new generation of safer MRI contrast reagents using perfluorocarbon (19F) being incorporated inside smart nanoparticles, which can offer unique quantitative signatures for molecular MRI with no competing background signal.
Importance for society: The goal of NOVA-MRI is to produce the next generation of MRI contrast agents, based on nanomaterials, which can provide sensitive detection during scanning and will lack the safety issues around currently established contrast agents like GBCAs. There is negligible endogenous 19F MRI signal from the body since the physiological concentrations of detectable mobile fluorine are below the detection limit. This lack of background signal means that the use of fluorinated compounds can potentially provide both high sensitivity (high signal-to-noise ratio) and specificity.
Overall objectives: 1) The training of a new generation of researchers in the field of imaging of cell-based inflammation with 19F MRI through individual research projects, sharing all the same main challenges, intra- and intersectoral secondments, local, and network-wide training. 2) Completion of all ESR projects with focus on the development of i) Nanomaterials and PFC contrast reagents for 19F MRI, ii) Development of dual modality (optical and 19F) fluorophore and PFC-NE (nano-emulsion) imaging, iii) Development of novel 19F MRI applications relevant for clinical translation. 3) The creation of an efficient network of researchers from academia and industry, working closely together towards the success of NOVA-MRI that will be reflected by the foreseen dissemination, outreach, and communication activities. 4) To ensure effective and appropriate management and coordination of NOVA-MRI and adopting an interdisciplinary and intersectoral approach through the composition of this expert consortium together with the associated partners.
The project started successfully but experienced very soon considerable delays due to the COVID-19 pandemic. Recruitment of staff was delayed due to travel restrictions. Research could initially not at all be performed due to measures to work from home, limited access to lab space, and worldwide problems in availability of lab consumables. Fortunately, the ESRs have now fully started, however some with a delay, and for all problems solutions have been found that comply with the aims of the project.
The ESRs 1 -5, 15 have focused on the synthesis, preparation, and characterization of nanomaterials that have multifunctional capabilities. This means that the design of the NPs could incorporate different features like other contrast/imaging components (ESR5), coatings like PEG to control toxicological and pharmacological parameters (ESR2 and ESR5), delivery components for sustainable release of therapeutic payloads or functional linkages to other molecules for targeted delivery at specific sited like peptides targeted at CD11b (ESR4) or at cardiac stromal cells (ESR3). Primary application was of course the compatibility of PFC with 19F MRI and has been investigated by the ESRs 1-5. ESR15 worked on the design of a successful method to introduce a fluorinated probe into an antibody fragment and the consequent biological assays and imaging on neoplastic cells.
ESRs 10, 11, and 13 have worked on the development of multimodality probes for optical and MR imaging. Dual-modal imaging probes would be beneficial for both cell fluorescence imaging and in vivo 19F MRI with high sensitivity and deep penetration in tissue. 19F MRI contrast agents in the form on PFC nanoparticles and NEs will be formulated together with a near infrared fluorescent (NIRF) dye so that detailed information regarding deep tissues and cell localization can be obtained simultaneously. ESR11 initiated efforts on the development of a new fluorophore system for carbon monoxide (CO) sensing in vivo by incorporating NIR dyes in NPs. ESR13 analysed cytokine/chemokine markers of macrophage polarisation and tested different chemical materials to induce macrophage phenotypes.
Tracking fate and function of specific cell types by molecular imaging methods is of great importance for basic research and holds the potential to be clinically applied for initial diagnosis as well as the monitoring of subsequent pharmacological treatment. ESRs 6, 7, 8, 9, 12, 14 and 15 are working on the development of novel 19F MRI applications relevant for clinical translation. These include 19F MRI angiography of venous and arterial structures, myocardial perfusion (ESR 6), inflammation (immune cell trafficking (ESR 7), macrophages), and structural/functional cardiac imaging in ischemic heart disease, thromboembolism and chronic thromboembolic pulmonary hypertension (ESR 8). A further application will involve monitoring of DCs (ESR9) or cancer immunotherapy.
The ESRs 1 -5, 15 have focused on the synthesis, preparation, and characterization of nanomaterials that have multifunctional capabilities. This means that the design of the NPs could incorporate different features like other contrast/imaging components (ESR5), coatings like PEG to control toxicological and pharmacological parameters (ESR2 and ESR5), delivery components for sustainable release of therapeutic payloads or functional linkages to other molecules for targeted delivery at specific sited like peptides targeted at CD11b (ESR4) or at cardiac stromal cells (ESR3). Primary application was of course the compatibility of PFC with 19F MRI and has been investigated by the ESRs 1-5. ESR15 worked on the design of a successful method to introduce a fluorinated probe into an antibody fragment and the consequent biological assays and imaging on neoplastic cells.
ESRs 10, 11, and 13 have worked on the development of multimodality probes for optical and MR imaging. Dual-modal imaging probes would be beneficial for both cell fluorescence imaging and in vivo 19F MRI with high sensitivity and deep penetration in tissue. 19F MRI contrast agents in the form on PFC nanoparticles and NEs will be formulated together with a near infrared fluorescent (NIRF) dye so that detailed information regarding deep tissues and cell localization can be obtained simultaneously. ESR11 initiated efforts on the development of a new fluorophore system for carbon monoxide (CO) sensing in vivo by incorporating NIR dyes in NPs. ESR13 analysed cytokine/chemokine markers of macrophage polarisation and tested different chemical materials to induce macrophage phenotypes.
Tracking fate and function of specific cell types by molecular imaging methods is of great importance for basic research and holds the potential to be clinically applied for initial diagnosis as well as the monitoring of subsequent pharmacological treatment. ESRs 6, 7, 8, 9, 12, 14 and 15 are working on the development of novel 19F MRI applications relevant for clinical translation. These include 19F MRI angiography of venous and arterial structures, myocardial perfusion (ESR 6), inflammation (immune cell trafficking (ESR 7), macrophages), and structural/functional cardiac imaging in ischemic heart disease, thromboembolism and chronic thromboembolic pulmonary hypertension (ESR 8). A further application will involve monitoring of DCs (ESR9) or cancer immunotherapy.
Due to the COVID-19 related project delay we cannot report on progress beyond state of the art at this time. The expected results and potential impacts remain as described in the Description of Action of the Grant Agreement. This will be part of a next report.