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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - PHELLINI (Plasmonic Heaters Linked to Lanthanide-Based Nanothermometers for Photodynamic Therapy in the Near-Infrared)

Teaser

Summary

Temperature is a key parameter for the metabolism of cells. Indeed, thereÂ´s a narrow thermal range in which cells can live and grow. Temperatures slightly above this range (5 to 10 degrees more) start affecting their proteins and may cause irreversible damage if the exposure to the increased temperature is long (typically above one hour). For even higher temperatures, irreversible damage can be caused even for shorter heating times. These facts are behind hyperthermia treatments that seek killing infected cells by increasing temperature.
Nanotechnology brings the possibility of triggering this type of treatments in well located areas through minimally invasive techniques. Specifically, light can be used to excite physical processes in several materials that would subsequently provoke a thermal increase, constituting a technique known as photothermal therapy. A key example of such materials is given by plasmonic nanoparticles. When these nanoparticles are excited at the wavelength of the plasmon resonance, they can transform a large part of the absorbed energy into heat, creating a hot spot. Accordingly, placing them inside the infected area it is possible to apply localized photothermal treatments. However, due to the complexity of biological environments the actual control on the achieved temperature is low, as the actual light power reaching the particles as well as their exact number and distribution cannot be accurately described. From the therapeutic point of view this constitutes a major limitation, since it means that the achieved temperature in the infected spot can be too low to have any therapeutic effect, or too high, damaging the surrounding areas.
The starting idea of this project is to combine plasmonic nanoparticles that can transform light into heat with thermometric nanoparticles, whose luminescence can be used to deduce the temperature on the spot where they are. The nanoplatforms proposed here could then become therapeutic agents for several diseases, as long as the infected area is within the area accessible by light. In order to maximize this area, we proposed to create particles that would have their functionalities fully working in the near-infrared range of the electromagnetic spectrum, matching the regions where biological tissues have the lowest light extinction coefficients.
This project mainly faces the challenge of creating different materials with optimized functionalities, linking them together and then, testing them in biological environments. This requires stablishing links between chemistry, physics and biology, which is a valuable input for the development of nanomedicine, a research field that can potentially benefit society in a reasonable short term. The competitiveness that this field of research provides to Europe is supported by the large number of companies and consortia that work in it (e.g. Midatech, a British company devoted to the therapeutic use of gold nanoparticles; Madrid-MIT M+Vision, a Spanish/USA bioimaging research consortium or Nanobiotix, a French company working with oxide nanoparticles for cancer treatment). Indeed, the Global Nanomedicine Market is estimated to witness a compound annual growth rate of 14% during the forecast period 2017-2022, according to BCC Research.

Work performed

This report covers the whole period of the project (two years). During this time, different approaches have been tested in each of the aspects that needed to be developed to prepare a heating/sensing nanoplatform.
The first main task was to investigate the possibilities in which luminescent materials in the near-infrared can be exploited to measure temperature. In order to do so, the lanthanide-doped family of materials was selected, since they allow good control on the luminescent properties. To get to a final answer on what material we could better apply for the specific application proposed here, it was necessary to test different crystals (fluoride-based) and combinations of lanthanide ions, which were synthesized either following a thermal decomposition approach at 315 oC or a hydrothermal route at 185 oC. Finally, we selected the hydrothermal approach as preferred synthesis method. Although the thermal decomposition route produces nanoparticles of higher quality in terms of homogeneity, those obtained through the hydrothermal protocol reach also the quality criteria (Figure 1) and the easiness of the protocol reduces the synthesis cost and time investment required to obtain the volume of material needed in the next stages of the project.
The choice of material required also a detailed spectroscopic study in order to find the best strategy to measure temperature both in terms of sensitivity and thermal resolution, two aspects that will later determine how accurate the calculated temperature is. We chose as thermometric method an intensity ratio technique based on the measurement of two different emission bands that are thermally linked.
Next we tested different types of gold nanoparticles to be used as heaters. The wavelength of the plasmon resonance is strongly dependent on the geometry of the material as it is its heating ability. Thus, we made a study on the link between the particle morphology and its heating efficiency using particles with different shapes (Figure 2), always having the plasmon resonance within the first biological window. After this study, we proceeded selecting gold nanostars as preferred heaters and addressed the next stage of the project: linking heaters and thermometers. Different approaches were tested, considering that the final product had to be stable enough to stand thermal changes and biological environments. The most successful and robust option obtained was based on the use of a third particle whose only functionality was to serve as scaffold to link heaters and thermometers.
The described construct was then taken to perform in vitro experiments, partially developed at the University of Manchester. These experiments were designed to understand first how the heating/sensing platforms interact with animal cells in terms of internalization and diffusion inside 3D cultivated cell models. Finally, we tested to what extent it is possible to kill the cells that had been exposed to the nanoparticles due to a thermal increase, while temperature was monitored.

Final results

While this is a proof-of-concept project, the results obtained indicate that monitored photothermal therapy is possible, and help understanding how to solve some of the limitations that photothermal therapy was suffering when the project started. The way to reach actual clinic use of novel techniques in medicine is long. Indeed, as most Global Nanomedicine Market studies point out, its growth is largely slowed down by the many steps needed in order to reach clinical use (steps that, of course, shouldnÂ´t be avoided). In our case, the prepared composites are in a very early stage, to the extent that more work in the materialÂ´s development field and in the sensing device development are needed even before thinking to move forward in the path that goes towards the actual clinical use. However, the results obtained represent a relevant step forward of the technique and show that it is worthy to continue devoting efforts in the proposed direction.