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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - NanoTBTech (Nanoparticles-based 2D thermal bioimaging technologies)

Teaser

Summary

NanoTBTech is a 36-month collaborative project supported by the European Union\'s Horizon 2020 FET Open programme (grant agreement No 801305). The NanoTBTech consortium includes the following partners: Universidade de Aveiro (Coordinator), Fundacion Para La Investigacion Biomedica Del Hospital Universitario Ramon Y Cajal (Universidad Autonoma de Madrid as a linked third party), Centre National de la Recherche Scientifique CNRS (SORBONNE UniversitÃ© as a linked third party), Agencia Estatal Consejo Superior de Investigaciones Cientificas (CSIC), Institut Za Nuklearne Nauke VINCA, Instytut Niskich Temperatur I Badan Strukturalnych Im. Wlodzimierza Trzebiatowskiego Polskiej Akademii Nauk, Universiteit Utrecht, Nanoimmunotech SL, and Biospace LAB.

The goal of NanoTBTech is to develop a new 2-D time-resolved temperature readout overcoming the conundrum represented by those biomedical imaging demands that cannot be handled with any thermometric method currently available. The overall objectives of the project are:
1) Design and fabrication of near infrared (NIR) emitting nanoparticles (NPs) and heater-thermometer nanostructures.
2) Understanding the parameters of the nanothermometers and heater-thermometer nanostructures crucial to reach objectives 3-5.
3) Optimization and in vitro/in vivo incorporation of luminescent, nontoxic, long-term biodegradable, long-circulating, tumour-targeted, and heating/sensing nanoplatforms.
4) Developing a new technology for in vitro and in vivo (small animal level) simultaneous luminescent 2D thermal imaging and optical microscopy imaging for localized controlled hyperthermia in cancer cells and tumour microenvironment.
5) Explore in vivo time-gated and 2D magnetic- or optical-gated thermal transient thermometry in murine models of liver metastasis.

While proof-of-concept thermal sensing using luminescent NPs has been already demonstrated by numerous groups worldwide (including NanoTBTech consortium members), remote 2D thermal imaging is a tremendous challenge implying: i) the fabrication of novel nanostructures with substantially improved thermal sensitivities in first (BW-I, 650-1000 nm) second (BW-II, 1000â€“1350 nm) and third (BW-III, 1550â€“1870 nm) biological windows, and embedding novel optical functionalities with tumour targeting properties and long-term biodegradation; and ii) the development of technological solutions and dedicated instruments, yet not commercially available.

To achieve these ambitious breakthroughs, nontoxic NIR emitting nanostructures, operating essentially beyond 1000 nm (where tissues become partially transparent) and combining nanothermometry and nanoheating, will be implemented and tested in vitro and in vivo. To monitor the emission thermal dependence (triggered by magnetic or optical heating sources) a dedicated new imaging platform will be developed leading to major advances in 2-D thermal bioimaging technologies, implementing novel diagnostic tools through two applications: in vitro and in vivo magnetic/optical hyperthermia and in vivo time-resolved thermal images for detection and dynamical monitoring of tumours. The new imaging platform involves the construction of distinct instruments for in vitro and in vivo applications.

Work performed

The work carried out during the first 12 months of the NanoTBTech project included i) the design and fabrication of several nanothermometers and heater-thermometer nanostructures; ii) its structural and optical characterization; iii) the use of models to validate currently reported luminescence thermometry approaches and to predict potential luminescent thermometers; and iv) the development of the initial steps of the functionalization/PEGylation of the particles. We also started the simultaneous implementation in vitro and in vivo (small animal level) of luminescent 2D thermal imaging and optical microscopy imaging for tumour detection and localized controlled hyperthermia in cancer cells and tumour microenvironment. The work performed is smoothly progressing toward the achievement of the project goals with no delays. All the planned deliverables have been submitted on time and the project has completed the milestone projected for this period. The risk plans were, thus, not activated.

Final results

Temperature measurements are crucial in countless technical developments, accounting for 80% of the sensor market throughout the world. The pitfalls of temperature readouts at the biomedical battleground are mostly represented by the currently achievable spatial resolution. To address key issues, such as intracellular temperature fluctuations and in vivo thermal transients, a technique able to go clearly below 1 Î¼m is highly and urgently needed, as the traditional contact-based sensors and near infrared (NIR) thermometers are not suitable for measurements at that tight spatial range. To overcome these limitations requires a non-contact thermometry approach granted with sub-micrometer resolution, also providing real-time high relative thermal sensitivity values.

NanoTBTech is an ambitious high risk/high gain project to supply a decisive breakthrough in non-invasive 2D luminescent thermal monitoring and imaging technology â€“ which proof of concept will be illustrated and demonstrated in two biomedical challenges: magnetically-or optically-induced local controlled hyperthermia and non-invasive, fast and deep-tissue tumour detection.

Our ambition is to demonstrate that the innovations developed in the frame of NanoTBtech will enable the development of a dedicated imaging platform with unprecedented performance leading to major advances in 2-D thermal imaging technologies. Moreover, the ability to develop an accurate method to glean intracellular temperatures and in vivo thermal transients (triggered by optical/magnetic external sources) will result on novel insight about cell pathology and physiology, heat transfer at the nanoscale, and non-invasive detection of subcutaneous anomalies, in turn, contributing to the development of novel theranostic tools.

NanoTBTech will completely change the landscape of real-time non-invasive imaging, providing a new kind of technology that will supply game-changing insights over physiological processes, perturbations or ongoing therapies, all of them featuring the common aspect of a biomedically-relevant thermal load to assess. The two-pronged applicability of NanoTBTech happens within two framed biomedical battlefronts, namely highly-modulated heat gradients induced at cellular level, and spreading-area determination of tumours and monitoring ongoing thermal therapies (exemplified by magnetically or optically-induced hyperthermia), are expected to ascend to a completely new level through the 2D thermal imaging developed thanks to NanoTBTech. Physicians at pre-clinical and clinical level will be freed of the inaccurate temperature readouts (typical from mid-infrared thermal cameras, currently used to measure temperatures, see Table 1 of ref. 1). The step forward that NanoTBTech is proposing makes feasible to know the inner temperature of the region of interest, not just the surface temperature. That will represent a deep transformation of the biomedical landscape, creating a new branch of sensing technology.

NanoTBTech will greatly facilitate active synergies between the different members of this strongly interacting consortium gathering 7 Europeâ€™s leading university teams and 2 industrial companies.