Bismuth selenide nanostructured clusters as optical coherence tomography contrast agents: beyond gold-based particles

Optical coherence tomography (OCT) is an imaging technique currently used in clinical practice to obtain optical biopsies of different biological tissues in a minimally invasive way. Among the contrast agents proposed to increase the efficacy of this imaging method, gold nanoshells (GNSs) are the best performing ones. However, their preparation is generally time-consuming, and they are intrinsically costly to produce. Herein, we propose a more affordable alternative to these contrast agents: Bi2Se3 nanostructured clusters with a desert rose-like morphology prepared via a microwave-assisted method. The structures are prepared in a matter of minutes, feature strong near-infrared extinction properties, and are biocompatible. They also boast a photon-to-heat conversion efficiency of close to 50%, making them good candidates as photothermal therapy agents. In vitro studies evidence the prowess of Bi2Se3 clusters as OCT contrast agents and prove that their performance is comparable to that of GNSsJ.Y. acknowledges the support from the China Scholarship Council (CSC file no. 201704910867). R.M. acknowledges the support of the European Commission through the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Grant agreement no. 797945 (LANTERNS). This work was supported by the Spanish Ministry of Economy and Competitiveness under projects MAT2017-83111R, MAT2017-85617-R, and PID2019- 106211RB-I00, by the Instituto de Salud Carlos III (PI16/ 00812), by the Comunidad Autonoma de Madrid (B2017/ ́ BMD-3867 RENIM-CM), and cofinanced by the European Structural and Investment Fun

Eosin Y-functionalized upconverting nanoparticles: nanophotosensitizers and deep tissue bioimaging agents for simultaneous therapeutic and diagnostic applications

Functionalized upconverting nanoparticles (UCNPs) are promising theragnostic nanomaterials for simultaneous therapeutic and diagnostic purposes. We present two types of non-toxic eosin Y (EY) nanoconjugates derived from UCNPs as novel nanophotosensitizers (nano-PS) and deep-tissue bioimaging agents employing light at 800 nm. This excitation wavelength ensures minimum cell damage, since the absorption of water is negligible, and increases tissue penetration, enhancing the specificity of the photodynamic treatment (PDT). These UCNPs are uniquely qualified to fulfil three important roles: as nanocarriers, as energy-transfer materials, and as contrast agents. First, the UCNPs enable the transport of EY across the cell membrane of living HeLa cells that would not be possible otherwise. This cellular internalization facilitates the use of such EY-functionalized UCNPs as nano-PS and allows the generation of reactive oxygen species (ROS) under 800 nm light inside the cell. This becomes possible due to the upconversion and energy transfer processes within the UCNPs, circumventing the excitation of EY by green light, which is incompatible with deep tissue applications. Moreover, the functionalized UCNPs present deep tissue NIR-II fluorescence under 808 nm excitation, thus demonstrating their potential as bioimaging agents in the NIR-II biological windo

Adjustable near-infrared fluorescence lifetime emission of biocompatible rare-earth-doped nanoparticles for in vivo multiplexing

Rare-earth-doped inorganic nanocrystals are an important class of nanoparticles for bioimaging applications due to the facility of providing them with tailored emissions in the visible and near-infrared regions of the electromagnetic spectrum. Recently it has become of interest to engineer the dopant composition of these materials in order to enable multiplexed lifetime imaging for autofluorescence-free in vivo bioimaging. Herein we report a simple approach to obtain different fluorescence lifetimes for the Yb3+emission (2F5/2 → 2F7/2) in Nd3+, Yb3+, Tm3+ co-doped NaGdF4 nanoparticles by only changing their crystal size while keeping their hydrodynamic diameter constant. This allowed straightforward transformation of infrared images in the time domain into lifetime maps. The particles were then deployed as in vivo contrast agents for near-infrared imaging in a mouse demonstrating their multiplexing capabilityThis work was financed by the Spanish Ministerio de Ciencia e Inovación under projects PID2019-106211RB-I00 and PID2020-118878RB-I00, by the Instituto de Salud Carlos III (PI19/00565), by the Comunidad Autónoma de Madrid (CAM) S2017/ BMD3867 RENIM-CM grant and co-financed by the European structural and investment fund. Additional funding was provided by the European Union Horizon 2020 FETOpen project NanoTBTech (801305), the CAM young investigator project SI3/PJI/2021-00211 the Fundación para la Investigación Biomédica del Hospital Universitario Ramón y Cajal project IMP21_A4 (2021/0427), and also by COST action CA17140. R. M. acknowledges the support of the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Grant Agreement No. 797945 (LANTERNS). J.Y. acknowledges the support from the China Scholarship Council (CSC File No.201704910867

Core-shell rare-earth-doped nanostructures in biomedicine

The current status of the use of core-shell rare-earth-doped nanoparticles in biomedical applications is reviewed in detail. The different core-shell rare-earth-doped nanoparticles developed so far are described and the most relevant examples of their application in imaging, sensing, and therapy are summarized. In addition, the advantages and disadvantages they present are discussed. Finally, a critical opinion of their potential application in real life biomedicine is givenThis work has been partially supported by the Ministerio de Economía y Competitividad de España (MINECO) (MAT2016-75362-C3-1-R), by the Instituto de Salud Carlos III (PI16/ 00812), by the Comunidad Autónoma de Madrid (B2017/ BMD-3867RENIM-CM), by the European Comission (NanoTBTech), and co-financed by European Structural and Investment Fund. This work has also been partially supported by COST action CM1403. L. L. P. thanks the Universidad Autónoma de Madrid for the “Formación de personal investi-gador (FPI-UAM)” program. P. R. S. thanks MINECO and the Fondo Social Europeo (FSE) for the “Promoción del talento y su Empleabilidad en I+D+i” statal program (BES-2014-069410). D. H. O. is grateful to the Instituto de Salud Carlos III for a Sara Borrell Fellowship (CD17/00210

Columnar liquid crystalline triphenylene-bis(dithiolene)nickel complexes. Soft photothermal materials

This work reports new soft photothermal materials based on liquid crystalline nickel bis(dithiolene) complexes bearing pentakis(dodecyloxy)triphenylene units in which the triphenylene core and the metal complex are linked through –(CH2)n– (n = 2, 4, 10) connectors. The mesomorphic properties of these materials can be modulated by the length of the linker. All the complexes, except the derivative with the longest linker, show columnar mesomorphism, characterized by polarized optical microscopy (POM), differential scanning calorimetry (DSC) and X-ray scattering studies. The structure of the mesophases contains segregated organic and inorganic columns supported respectively by π-stacking of the triphenylene discs and weak intermolecular nickel–sulfur interactions. The photothermal activity was studied on the complex with n = 2. Under laser irradiation with a power density of 0.098 W cm−2 for just over a minute an increase in temperature of ΔT = 50 °C was achieved. This produced the melting of the crystalline solid to give rise to the columnar mesophase, where, interestingly, the photothermal effect was enhanced. Quantum chemical calculations have also been performed to gain insight into the supramolecular self-assembled columnar structure at the molecular level, as well as into the photothermal behavior.This work was sponsored by the Ministerio de Ciencia e Innovación (PID2020-118547GB-I00/AEI/10.13039/501100011033). E. D. thanks MECD for a FPU grant. The authors thankfully acknowledge the computer resources at Tirant and Lusitania II and the Technical support provided by Universitat de València (FI-2022-2-005, QHS-2023-1-0010) and Cénits-COMPUTAEX (FI-2022-1-0009, FI-2022-3-0008). This research has made use of the high performance computing resources of the Castilla y León Supercomputing Center (SCAYLE, www.scayle.es), financed by the European Regional Development Fund (ERDF). This work was also supported by the Comunidad de Madrid and Universidad Autónoma de Madrid (SI3/PJI/2021-00211) and D.H.O is grateful for a Ramón y Cajal Fellowship Grant RYC2022-036732-I funded by MCIN/AEI/10.13039/501100011033 and by “ESF investing in your future”. This work was also financially supported by the Basque Government (project IT1458-22)

In vivo near-infrared imaging using ternary selenide semiconductor nanoparticles with an uncommon crystal structure

The implementation of in vivo fluorescence imaging as a reliable diagnostic imaging modality at the clinical level is still far from reality. Plenty of work remains ahead to provide medical practitioners with solid proof of the potential advantages of this imaging technique. To do so, one of the key objectives is to better the optical performance of dedicated contrast agents, thus improving the resolution and penetration depth achievable. This direction is followed here and the use of a novel AgInSe2 nanoparticle-based contrast agent (nanocapsule) is reported for fluorescence imaging. The use of an Ag2Se seeds-mediated synthesis method allows stabilizing an uncommon orthorhombic crystal structure, which endows the material with emission in the second biological window (1000–1400 nm), where deeper penetration in tissues is achieved. The nanocapsules, obtained via phospholipid-assisted encapsulation of the AgInSe2 nanoparticles, comply with the mandatory requisites for an imaging contrast agent—colloidal stability and negligible toxicity—and show superior brightness compared with widely used Ag2S nanoparticles. Imaging experiments point to the great potential of the novel AgInSe2-based nanocapsules for high-resolution, whole-body in vivo imaging. Their extended permanence time within blood vessels make them especially suitable for prolonged imaging of the cardiovascular systemJ.Y. acknowledges the support from the China Scholarship Council (CSC File No. 201704910867). R.M. acknowledges the support of the European Commission through the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Grant Agreement No. 797945 (LANTERNS). P.R. is grateful for a Juan de la Cierva – Incorporación scholarship (IJC2019-041915-I). This work was supported by the Ministerio de Ciencia e Innovación de España under projects MAT2016-75362-C3-1-R, MAT2017-83111R, and MAT2017-85617-R, by the Instituto de Salud Carlos III (PI16/00812), by the Comunidad Autónoma de Madrid (B2017/BMD3867/RENIM-CM, PID2019-106211RB-I00), and cofinanced by the European Structural and investment fund. Additional funding was provided by the European Union Horizon 2020 FETOpen project NanoTBTech (801305), the Fundación para la Investigación Biomédica del Hospital Universitario Ramón y Cajal project IMP18_38 (2018/0265), and also by COST action CA17140. E.X. is grateful for a Juan de la Cierva Formación scholarship (FJC2018-036734-I

Rare-earth-doped fluoride nanoparticles with engineered long luminescence lifetime for time-gated: In vivo optical imaging in the second biological window

Biomedicine is continuously demanding new luminescent materials to be used as optical probes for the acquisition of high resolution, high contrast and high penetration in vivo images. These materials, in combination with advanced techniques, could constitute the first step towards new diagnosis and therapy tools. In this work, we report on the synthesis of long lifetime rare-earth-doped fluoride nanoparticles by adopting different strategies: core/shell and dopant engineering. The here developed nanoparticles show intense infrared emission in the second biological window with a long luminescence lifetime close to 1 millisecond. These two properties make the here presented nanoparticles excellent candidates for time-gated infrared optical bioimaging. Indeed, their potential application as optical imaging contrast agents for autofluorescence-free in vivo small animal imaging has been demonstrated, allowing high contrast real-time tracking of gastrointestinal absorption of nanoparticles and transcranial imaging of intracerebrally injected nanoparticles in the murine brainThis work was supported in part by the grants from the Fundamental Research Funds for the Central Universities, China (HIT. BRETIV.201503 and AUGA5710052614) and the National Natural Science Foundation of China (51672061). We thank Dr Lina Wu at the Fourth Hospital of Harbin Medical University for her kind help with the MTT assay, and Dr Tymish Y. Ohulchanskyy at Shenzhen University for his kind help with the fluorescence lifetime measurement. The work was also supported by the Ministerio de Economia y Competitividad of Spain (grant MAT2016-75362-C3-1-R). Jie Hu acknowledges the scholarship from the China Scholarship Council (No. 201506650003). Dirk H. Ortgies is grateful to the Spanish Ministry of Economy and Competitiveness for a Juan de la Cierva scholarship (No. FJCI-2014-21101) and the Spanish Institute of Health (ISCIII) for a Sara Borell Fellowship (No. CD17/00210

3D Optical Coherence Thermometry Using Polymeric Nanogels

In nanothermometry, the use of nanoparticles as thermal probes enables remote and minimally invasive sensing. In the biomedical context, nanothermometry has emerged as a powerful tool where traditional approaches, like infrared thermal sensing and contact thermometers, fall short. Despite the strides of this technology in preclinical settings, nanothermometry is not mature enough to be translated to the bedside. This is due to two major hurdles: the inability to perform 3D thermal imaging and the requirement for tools that are readily available in the clinics. This work simultaneously overcomes both limitations by proposing the technology of optical coherence thermometry (OCTh). This is achieved by combining thermoresponsive polymeric nanogels and optical coherence tomography (OCT)—a 3D imaging technology routinely used in clinical practice. The volume phase transition of the thermoresponsive nanogels causes marked changes in their refractive index, making them temperature-sensitive OCT contrast agents. The ability of OCTh to provide 3D thermal images is demonstrated in tissue phantoms subjected to photothermal processes, and its reliability is corroborated by comparing experimental results with numerical simulations. The results included in this work set credible foundations for the implementation of nanothermometry in the form of OCTh in clinical practiceThis work was financed by the Spanish Ministerio de Innovación y Ciencia under project NANONERV PID2019-106211RB-I00, NANOGRANZ PID2021-123318OB-I00, PID2020-118878RB-I00, RYC2021-032913-I, and TED2021-132317-I00B and under project COLUMNAS (PID2019- 110632RB-I00), by the Instituto de Salud Carlos III (PI19/00565), by the Comunidad Autónoma de Madrid (S2022/BMD-7403 RENIM-CM and SI3/PJI/2021-00211) and co-financed by the European structural and investment fund. Additional funding was provided by COST action CA17140, supported by COST (European Cooperation in Science and Technology) and the Fundación para la Investigación Biomédica del Hospital Universitario Ramón y Cajal (IMP21_A4 (2021/0427)

Mn5+ Lifetime-Based Thermal Imaging in the Optical Transparency Windows Through Skin-Mimicking Tissue Phantom

Lifetime-based luminescence thermometry has been shown to enable accurate deep-tissue monitoring of temperature changes – even at the in vivo level – in a minimally invasive way. However, major limiting factors to the performance of this approach are short lifetimes and poor brightness. These are characteristics, respectively, of semiconductor nanocrystals and lanthanide-doped nanoparticles, of which most luminescent nanothermometers are made. To address these limitations, the composition of luminescent nanothermometers co-doped with transition metal (Mn5+) and Er3+ ions are designed and optimized. The salient features of these nanothermometers are strong, near-infrared emission and long, temperature-dependent photoluminescence lifetime. The potential of these luminescent nanophosphors for thermal sensing is then showcased by monitoring a thermal gradient using a one-of-a-kind piece of equipment designed for lifetime-based luminescence thermometry measurements. The combination of the newly developed nanothermometers and the custom-made instrument allows for obtaining 2D thermal maps both in the absence and presence of tissue phantoms mimicking the optical properties of the skin. The results presented in this study thus provide credible foundations for the deployment of lifetime-based thermometry for accurate deep-tissue thermal mapping at the preclinical level

Temperature Dependence of Water Absorption in the Biological Windows and Its Impact on the Performance of Ag2S Luminescent Nanothermometers

The application of nanoparticles in the biological context generally requires their dispersion in aqueous media. In this sense, luminescent nanoparticles are an excellent choice for minimally invasive imaging and local temperature sensing (nanothermometry). For these applications, nanoparticles must operate in the physiological temperature range (25–50 °C) but also in the nearinfrared spectral range (750–1800 nm), which comprises the three biological windows of maximal tissue transparency to photons. In this range, water displays several absorption bands that can strongly affect the optical properties of the nanoparticles. Therefore, a full understanding of the temperature dependence of water absorption in biological windows is of paramount importance for applications based on these optical properties. Herein, the absorption spectrum of water in the biological windows over the 25–65 °C temperature range is systematically analyzed, and its temperature dependence considering the coexistence of two states of water is interpreted. Additionally, to illustrate the importance of state-of-the-art applications, the effects of the absorption of water on the emission spectrum of Ag2S nanoparticles, the most sensitive luminescent nanothermometers for in vivo applications to date, are presented. The spectral shape of the nanoparticles’ emission is drastically affected by the water absorption, impacting their thermometric performanceThis work was financed by the Spanish Ministerio de Ciencia e Innovación under project PID2019-106211RB-I00, by the Instituto de Salud Carlos III (PI19/00565), by the Comunidad Autónoma de Madrid (S2017/BMD3867 RENIM-CM) and co-financed by the European structural and investment fund. Additional funding was provided by the European Union Horizon 2020 FETOpen project NanoTBTech (801305), the Fundación para la Investigación Biomédica del Hospital Universitario Ramón y Cajal project IMP21_A4 (2021/0427), and by COST action CA17140. A.B. acknowledges funding support through the TALENTO 2019T1/IND14014 contract (Comunidad Autónoma de Madrid). F.E.M. and L.D.C. acknowledge the financial support received from the project Shape of Water (PTDC/NAN-PRO/3881/2020) through Portuguese fund