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Thermometry and Photoacoustic-Imaging Outstanding Nanoprobes

Periodic Reporting for period 2 - TEMPTATION (Thermometry and Photoacoustic-Imaging Outstanding Nanoprobes)

Reporting period: 2018-12-01 to 2019-11-30

Nowadays, medical imaging has become a widely needed tool to effectively detect and fight a gamut of diseases, thus becoming a paramount factor to promote higher life expectancy and well-being worldwide. Optical imaging, and more specifically fluorescence imaging (hereafter FI), is a “younger relative” among the family of medical imaging modalities such as magnetic resonance imaging (MRI), positron emission tomography (PET), computed tomography (CT; based on X-rays) and ultrasound (US).

Dynamic (patho-) physiological processes can be feasibly tracked in real time by means of FI, unveiling key metabolic aspects still unknown. Second, and much closer to the clinical level, both such signal collection speed plus the absence of post-processing requirements after image acquisition make of FI the ideal intra-operative guide for surgical resection of tumor margins. Although modern surgical advancements have improved surgical oncology, adequate tumor visualization remains a limitation preventing total removal. Surgeons rely primarily on white light reflectance, which limits the differentiation between healthy issue and tumor and can lead to residual cancer cells inadvertently left behind at the resection border. FI also has the potential to distinguish different anatomic structures to reduce inadvertent injury to healthy tissue. For none of these two relevant applications above exists an actual alternative to FI.

Core-ingredient for credible fluorescence in vivo imaging: picking the right probe. At the forefront of the components ‘checklist to develop better FI procedural lies the selection of the probe (contrast agent). Unequivocally, the main physics-related drawback for in vivo implementation of this imaging method, as based on light propagation through optical dense media, is lacking enough sub-tissue penetration depth. To address as much as possible that shortcoming, a current top request for any FI probe worth considering is for it to absorb excitation light and to emit its signal within the near-infrared (NIR, 700-2000nm) spectral range. The sub-tissue deep penetration and higher optical contrast achieved by using NIR light of an appropriate wavelength justifies the choice of such radiation. Hence, three biological optical transparency windows (TWs) have been specifically recognized TWI: 700 nm to 950 nm; TW-II: 1000 nm to 1350 nm; TW-III: 1550 nm to 1700 nm). In these TWs, the light absorption and scattering by biological components is minimized making feasible, in the most favorable scenario, up to a few centimetres of penetration depth underneath the skin. The first two aspects make a strong case to markedly increase the optical penetration depth, also mitigating the light scattering that negatively affects optical contrast.

From the MATERIALS SCIENCE viewpoint, to get a completely new kinds of contrast agent (probe), valid for b fluorescence imaging (and secondarily photoacoustic) modalities, also featuring thermometry possibilities in some cases.

At the BIOMEDICAL side, implementation through animal models of the new probe in a couple of SPECIFIC applications in the mid-term future, such as (i) a biological study by real-time tracking of lipids metabolism, (ii) pre-clinical showcase of the imaging-guided tumor margin surgical resection.


1) VALIDATION of lanthanide-doped nanoparticles as NIR fluorescence nanoprobes (at least at ""small animal model"" range) which can be effectively modified to minimize the effect of ""water quenching"" over their brightness.

2) ENLARGING & DEEPING knowledge database about in vivo ""deep penetration"" biocompatible fluorescent probes: Ag2S NPs ---also with in situ thermometry capabilities

3) PRELIMINARY PROOF on its way about a different conceptual frame ruling the heat transport at nano-scale, compared with the well-known macrocopic laws"
Overview of the results; different approaches have been tested for luminescent nanoparticles (emitting in the near-infrared range) for biomedical applications, -especially imaging.

AXIS 1) Nneodymium-doped nanoparticles; RESULTS have conceptually connected the ""architecture implemented"" on the nanoparticle with the ""brightness achieved"".
In particular because for biomedical applications these contrast agents (i.e. nanoparticles in our case) are dispersed in AQUEOUS solutions. As water molecules are usually a source of quenching -in mundane words, a ""luminescence killer"", to quantitatively assess the protective shield effect impact of a undoped outer shell.

AXIS 2) RESULTS obtained with respect to the materials side of the project, ""heavy-metal free"" Ag2S semiconductor nanocrystals, featuring intense emission within TW-II. In particular, the luminescence thermometry performance, a ""non-invasive & real-time"" local monitoring of temperature, --as featured in TEMPTATION proposal--, is fully developed along this line.

AXIS 3) Study on heat at nanoscale, tracked by means of luminescence thermometry.
AT the aim of the original TEMPTATION proposal: ""heat delivery & transport (from contrast agents)"" matches the very conceptual core of photoacoustic imaging (PAI) -where excitation of contrast agents is made by way of light but
the output signal is a mechanical wave (such as ultrasounds) .



Peer-reviewed publications (high impact factor) connected with each one of the results´ lines above -in particular during the final period specifically covered by this report-:

1)----> ""Inert Shell Effect on the Quantum Yield of Neodymium-Doped Near-Infrared Nanoparticles: The Necessary Shield in an Aqueous Dispersion""
(2020) Nano Letters Vol. 20 Page 7648

2)----> Ag2S Nanoheaters with Multiparameter Sensing for Reliable Thermal Feedback during In Vivo Tumor Therapy
(2020) Advanced Functional Materials Vol. 30 Page 2002730

3) No publication yet, stages of this research line currently ongoing."
Under te umbrella of TEMPTATION our research walked a relevant step forward in quantification of the factors affecting the brightness of luminescent (particularly, neodymium doped) nanoparticles. That will help to rationally design advanced multilayered structures of Nd3+-doped NPs and credibly facilitate their real-life use as deep-tissue NIR probes.

Wider foreseeable impact, at a societal scale, should be considered in terms of better healthcare by way of more specific image-assisted procedural. hence, the research progress accomplish within 32-month TEMPTATION timeframe, decisively pushes FLUORESCENCE IMAGING to be fully translated into clinics in the very next future. (Achieving so by profiting from the paradigmatic assets of such modality: NON-INVASIVENESS & REAL TIME readout).
Mechanism influencing the QY