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CORDIS - EU research results



Reporting period: 2019-05-01 to 2021-04-30

Imaging techniques used in the clinic include magnetic resonance imaging, computed tomography, and positron emission tomography. They require cumbersome and expensive setups, and some of them employ dangerous ionizing radiation. Fluorescence imaging (FI) is instead a non-invasive, inexpensive imaging technique that uses lower-energy radiation. It also boasts fast acquisition times, enabling real-time monitoring of biological processes within tissues of interests. As appealing as FI might sound, its application in the clinical context is a far reality. To obtain an image via FI, a contrast agent is required that accumulates at the site of interest and emit light when illuminated with light of proper energy. In this vein, luminescent nanoparticles are arguably the most promising candidates. Indeed, being thousand of times smaller than a single cell, they can target malignant tissues that are below the minimum size detectable with other diagnostic tools, hence allowing for treatments to be initiated early on. To be used in FI, luminescent nanoparticles should absorb and emit photons in the near-infrared (NIR) spectral range (750-1800 nm), because biological tissues are less impervious to light in this range (Figure 1). Unfortunately, there is a lack of nanoparticles that absorb and emit NIR photons efficiently enough to make FI a credible alternative to the above-mentioned imaging techniques. The development of FI contrast agents in the form of NIR luminescent nanoparticles with superior performance is therefore an urgent matter and of immense projected impact on future society, contributing at least on two fronts to its prosperity:

- reduction of direct and indirect costs sustained by the health system - stemming from the timely detection of diseases and use of less expensive equipment;
- increased well-being of the patients - thanks to the minimal discomfort sustained by the patient during the imaging process and the increased life expectancy guaranteed by early-stage detection of diseases such as cancer.

With LANTERNS (Lanthanide Ion Doping of Ternary Quantum Dots) I will tackle the major bottleneck of FI: the lack of luminescent contrast agents with bright NIR emission.
This project aims to combine the advantageous optical properties of semiconductor nanocrystals (aka, quantum dots) and those of NIR-emitting lanthanide ions, which are respectively strong light absorption and emission of photons in a narrow, biologically convenient spectral range. Quantum dots of copper indium sulfide (CuInS2) will be doped with ions of neodymium, erbium, ytterbium and holmium, all displaying NIR emission. CuInS2 is the chosen semiconductor material since it absorbs photons up to 830 nm (well into the NIR). After absorbing this optical energy, CuInS2 is expected to transfer it to the doped lanthanide, ultimately leading to emission of photons of longer wavelength (sensitized emission; Figure 2). Modification of the surface chemistry of the lanthanide-doped quantum dots will ensure water dispersibility, lack of cytotoxicity, and the capability to target tissues (e.g. solid tumors), overall guaranteeing their applicability as FI contrast agents.


1. Semiconductor-based nanocrystals were identified as the most promising contrast agents for FI and other optical diagnostic approaches (e.g. optical coherence tomography).
2. Methods to increase the brightness (the product of absorption and emission efficiencies) of available luminescent semiconductor nanocrystals were identified. Novel, efficient semiconductor nanocrystals were designed.
3. Although during the action a paradigm shift occurred - redirecting the effort towards undoped semiconductor nanocrystals - an in-depth literature survey allowed defining the guidelines to prepare the initially targeted class of materials: lanthanide-doped semiconductor nanocrystals.
The two initial months were dedicated to setting the chemistry laboratory where synthesis procedures will be conducted. During this time of limited scientific hands-on work, I spent my time researching literature and concluding the writing of manuscripts from my time as PhD and postdoc. I later started synthesizing metal complexes of copper, indium and lanthanides intended as precursors for the preparation of undoped and lanthanide-doped CuInS2 quantum dots. As per the researcher plan, I started testing the possibility to prepare undoped nanocrystals. However, the different reactivity featured by copper and indium precursors led to the rapid formation of copper sulfide (CuS) nanocrystals. I decided to profit from an apparent drawback, optimizing the synthesis and surface properties of CuS nanocrystals and fine-tuning their optical properties to make them the first reported negative contrast agents for optical coherence tomography.
During my 1.5-month secondment in Portugal, I perfected the synthesis of lanthanide complexes. The optical and magnetic properties of these complexes will be investigated in-depth in the near future.
Around this time, reports on the preparation of lanthanide-doped semiconductor nanocrystals appeared, and they started to highlight the need for specific conditions to be met to effectively incorporate lanthanide ions in a semiconductor nanocrystal. Thus, it became clear that CuInS2 was not the ideal material to dope lanthanide ions.
After 2 months of illness (COVID) I started writing three review papers as a product of my literature research on lanthanide ions and semiconductor nanocrystals for fluorescence imaging.
In the last section of the action, further experiments were conducted to incorporate lanthanide ions in semiconductor nanocrystals using strategies devised after the extensive literature survey of the previous months. Unfortunately, none of the strategies was successful and more trials are ongoing. Aside from these attempts, I have been working on the preparation of Ag2S- and AgInSe2-based semiconductor nanocrystals with NIR emission capable of acting as FI contrast agents. A green method that makes use of coffee extract has also been developed for the synthesis of Ag2S nanocrystals, which is expected to increase the appeal of luminescent nanoparticles due to their maximised environment-friendliness.
With the work performed in the context of this action, the following milestones have been achieved:

1 - Discovery of the first negative/dark contrast agents for optical coherence tomography (CuS nanocrystals).
2 - AgInSe2 nanocrystals were used for the first time as NIR-emitting contrast agents for FI imaging capable of marking the vasculature in animal models.
3 - An innovative green synthesis method that make use of coffee extract was developed for the preparation of Ag2S-based nanocrystals. In the same context, an approach to increase the emission intensity of these nanocrystals was identified, which is currently being applied to other FI contrast agents to boost their optical performance.
4 - I authored an authoritative review manuscript where the guidelines for the preparation of lanthanide-doped semiconductor nanocrystals are outlined. This paper is expected to provide solid foundations for the future development of this class of materials.

The results of this action will propel the research in the field of FI contrast agents with NIR absorption and emission, with the wider societal implications mentioned above that come with bringing FI one step closer to its use in the clinic.
Near-infrared penetration