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H2020

MultimodalCellTrack Report Summary

Project ID: 705600
Funded under: H2020-EU.1.3.2.

Periodic Reporting for period 1 - MultimodalCellTrack (Multimodal preclinical imaging probes to evaluate the safety and efficacy of regenerative medicine therapies)

Reporting period: 2016-08-01 to 2018-07-31

Summary of the context and overall objectives of the project

This research focuses on developing nanomaterials that can aid in the non-invasive detection of stem cells/macrophage tracking towards the translation of regenerative medicine therapies to the clinic. Our inability to accurately monitor the biodistribution of transplanted cells is a major barrier to assess the safety and efficacy of cell-based regenerative medicine therapies. To assess safety, it is important to know if cells have engrafted into non-target organs so that possible adverse effects can be monitored over time. To assess efficacy, it is crucial to know what proportion of cells reach the target organ, for how long they persist, and whether they ameliorate injury. Various imaging technologies, including magnetic resonance imaging (MRI), bioluminescence imaging (BLI) and photoacoustic imaging can be used for monitoring the cellular biodistribution and assessing the effect of the cells on host organs and tissues. But no single technique provides high sensitivity, spatial and temporal resolution, and functional and anatomical imaging. It is therefore necessary to combine several imaging approaches. The main objective of this project (Multimodalcelltrack) is to tailor multimodal imaging probes to track stem cells with unprecedented spatial and temporal resolution in preclinical models which is important to evaluate the safety and efficacy of regenerative medicine therapies.
This work is highly relevant to the United Kingdom Regenerative Medicine Platform (UKRMP) on evaluating the safety and efficacy of regenerative medicine therapies, which is being pioneered at the University of Liverpool.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

"To achieve project’s goals, initially, we have optimized the synthesis of individual nanoparticles, i.e., silica coated gold nanorods having different aspect ratios, luminescent nanoparticles, and superparamagnetic iron oxide nanoparticles (SPIONs). These particles were tested for their characteristics including imaging potential and their effect on cells’ viability was evaluated. Later, polyelectrolyte multi-layered and multifunctional capsules were fabricated which were incorporating nanoparticle-based imaging probes as individual particles and also in combination in defined ratio inside single particle for bio-luminescence (luminescent nanoparticles), magnetic resonance (SPIONs), and multispectral optoacoustic tomography (MSOT; gold nanorods) having desired properties (sharp intense IR absorbance, high luminescence and magnetic susceptibility). Phantoms mimicking the biological tissues containing these multimodal capsules were tested by bioluminescence, MRI and MSOT. These probes retained their unique imaging characteristics after incorporation inside single entity (capsules). It was also possible to incorporate two types of gold nanorods having different dimensions (aspect ratios) inside single capsule which retained their characteristic IR absorbance properties and had potential applications in enhancing the sensitivity of detection of MSOT through engineering of an ideal spectrum (work in progress). These multimodal imaging probes were tested for their cellular uptake, accumulation, labelling efficiency and effects on cell phenotype using a range of in vitro assays in mouse bone marrow derived mesenchymal stem cells (mMSCs). The probes tailored by this approach showed significant potential for multimodal imaging when tested inside agar based phantoms and were non-toxic to the stem cells when phagocytosed with no alteration in cell phenotype. However, it was difficult to trace labelled cells in vivo because sensitivity of the detection limit for in vivo imaging and tracking depends on the amount of imaging material incorporated inside the capsules and during cell labelling the amount of imaging material taken up by the cells was below the detection limit of these imaging instruments. Therefore, for in vivo imaging and tracking the stem cells a bimodal imaging system MRI/BLI was used (genetically modified cells for producing bioluminescence signals upon stimulation labelled with superparamagnetic iron oxide nanoparticles) and it was possible to track stem cells in vivo and see the in vivo fate of the particles after cell death. Details can be found in our recent preprint (https://www.biorxiv.org/content/early/2018/07/20/366518.article-info) coupled with MR data (https://zenodo.org/record/1203991#.W1R51dJKjIU) which is submitted in Nanoscale Advances.
In addition, we have worked to optimize the synthesis of gold nanoparticles and their functionalization with peptide self-assembled monolayers (SAMS) which is helpful for their use in biological applications, such as cell tracking.
In collaborative projects we have provided silica coated gold nanorods: (1) to be initially tested in animal models (breast and pancreas) and later on in pancreatic cancer, and in the long run to look at metastatic foci (work with Chris Madsen, Sweden) (2) and to track gold nanorods labelled macrophages inside different body organs of mice by MSOT (work in the University of Liverpool).
Throughout the length of the project, the researcher has acquired extensive training in multidisciplinary fields, which included intense training in animal handling and surgical procedures (obtained personal licence from the British Home office), in vivo and in vitro imaging, and stem cell biology. This training is very useful to bridge the gap between research and the market and comes under the remit of the future objectives of the EU listed in the Horizon 2020 programme.
During the course of fellowship, the researcher was engaged in the in activities to share t"

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

This research focuses on developing nanomaterials that can aid in the non-invasive detection and tracking of stem cells in vivo which is an important step towards the translation of regenerative medicine therapies to the clinic. In addition, the in vivo fate of the imaging probes upon cell death was monitored longitudinally which is important parameter to evaluate the long term toxicity of the imaging probes. These findings are particularly important in the field of regenerative medicine therapies and oncology which can benefit from the in vivo tracking and monitoring the cells and see the fate of imaging probes once particle-labelled cells die. By means of long term imaging and tracking the cells there is possibility to understand their immunotherapeutic potential and might be beneficial in the field of drug development.

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