Some of the old and unrealizable dreams of biomedicine have become possible thanks to the appearance of novel advanced materials such as luminescent nanothermometers, nanoparticles capable of ...providing a contactless thermal reading through their light emission properties. Luminescent nanothermometers have already been demonstrated to be capable of in vivo subcutaneous punctual thermal reading but their real application as diagnosis tools still requires demonstrating their actual capacity for the acquisition of in vivo, time‐resolved subcutaneous thermal images. The transfer from 1D to 2D subcutaneous thermal sensing is blocked in the last years mainly due to the lack of high sensitivity luminescent nanothermometers operating in the infrared biological windows. This work demonstrates how core/shell engineering, in combination with selective rare earth doping, can be used to develop supersensitive infrared luminescent nanothermometers. Erbium, thulium, and ytterbium core–shell LaF3 nanoparticles, operating within the biological windows, provide thermal sensitivities as large as 5% °C−1. This “record” sensitivity has allowed for the final acquisition of subcutaneous thermal videos of a living animal. Subsequent analysis of thermal videos allows for an unequivocal determination of intrinsic properties of subcutaneous tissues, opening the venue to the development of novel thermal imaging‐based diagnosis tools.
The Er‐Yb@Yb‐Tm NPs are introduced as highly sensitive nanothermometers operating in the second and third biological windows. Their superior thermal sensitivity makes possible the acquisition of in vivo subcutaneous thermal videos at the small animal level. The results here presented may lead to a new era of biomedicine founded on thermal imaging based diagnosis.
Advanced diagnostic procedures are required to satisfy the continuously increasing demands of modern biomedicine while also addressing the need for cost reduction in public health systems. The ...development of infrared luminescence-based techniques for in vivo imaging as reliable alternatives to traditional imaging enables applications with simpler and more cost-effective apparatus. To further improve the information provided by in vivo luminescence images, the design and fabrication of enhanced infrared-luminescent contrast agents is required. In this work, we demonstrate how simple dopant engineering can lead to infrared-emitting rare-earth-doped nanoparticles with tunable (0.1-1.5 ms) and medium-independent luminescence lifetimes. The combination of these tunable nanostructures with time-gated infrared imaging and time domain analysis is employed to obtain multiplexed in vivo images that are used for complex biodistribution studies.
The development of technologies capable of early tumor detection is unquestionably demanded by physicians, as early diagnosis is key to achieve more efficient and less invasive treatments with ...improved outcomes. At the preclinical level, nanotechnology has already provided innovative solutions for tumor imaging and therapy, but it has failed to provide real early tumor diagnosis. In this work, an infrared nanothermometry‐based approach toward early melanoma detection, based on the changes produced in the thermal relaxation dynamics of tissues as the tumor develops, is introduced. In vivo experiments demonstrate that detection of incipient tumors from their very onset is possible through monitoring changes in their thermal relaxation dynamics using Ag2S infrared luminescent nanothermometers. For a total tumor development time of 14 days, luminescence nanothermometry allows tumor detection 6 days before its presence is evident by visual inspection. Simultaneous study of the tumoral vasculature reveals that the premature variation in the thermal relaxation dynamics is a consequence of the interplay between tumor angiogenesis and necrosis during the different tumor development stages.
Early tumor detection becomes possible by transient thermometry using infrared emitting Ag2S nanocrystals as noncontact intratumoral nanothermometers. The drastic changes of vascularization taking place at the early stages of tumor development lie at the heart of this diagnosis approach.
The emergence of luminescence nanothermometry in bio and nanomedicine has enabled achievements outside the reach of conventional techniques. For instance, it has provided real‐time monitoring of in ...vivo thermal therapies of tumors, a mandatory requirement for these techniques to work safely and efficiently. However, the reliability of intratumoral thermal readings is currently in question due to the presence of artefacts caused by the inhomogeneous optical properties of biological tissues. This work demonstrates how it is possible to avoid, under specific conditions, these artefacts and reach precise and reliable in vivo intratumoral thermal feedback during in vivo photothermal treatments. The method proposed is based on the use of luminescent nanoparticles capable of multiparametric thermal sensing. The results demonstrate how the convergence of the different thermal readouts becomes a solid indicator of their reliability. It is shown how this new approach makes possible precise (thermal uncertainties below 1 °C) intratumoral thermal feed‐back, while simple, efficient, and minimally invasive in vivo thermal treatments of surface tumors is carried out. Results included in this work provide an ingenious route toward the consolidation of luminescence nanothermometry as a convincing technique for high sensitivity preclinical thermal sensing, while also constituting a step toward improved photothermal therapies.
A new approach allowing reliable in vivo intratumoral thermal reading is described. It is based on the use of Ag2S luminescent nanothermometers capable of multiparametric thermal sensing. Rationale selection of their operation spectral range is also required to avoid tissue induced distortions. The simultaneous ability of Ag2S nanoparticles for heating enables efficient photothermal treatment of tumors with accurate and reliable thermal feedback.
Luminescence thermometry has substantially progressed in the last decade, rapidly approaching the performance of concurrent technologies. Performance is usually assessed through the relative thermal ...sensitivity, Sr, and temperature uncertainty, δT. Until now, the state‐of‐the‐art values at ambient conditions do not exceed maximum Sr of 12.5% K−1 and minimum δT of 0.1 K. Although these numbers are satisfactory for most applications, they are insufficient for fields that require lower thermal uncertainties, such as biomedicine. This has motivated the development of materials with an improved thermal response, many of them responding to the temperature through distinct photophysical properties. This paper demonstrates how the performance of multiparametric luminescent thermometers can be further improved by simply applying new analysis routes. The synergy between multiparametric readouts and multiple linear regression makes possible a tenfold improvement in Sr and δT, reaching a world record of 50% K−1 and 0.05 K, respectively. This is achieved without requiring the development of new materials or upgrading the detection system as illustrated by using the green fluorescent protein and Ag2S nanoparticles. These results open a new era in biomedicine thanks to the development of new diagnosis tools based on the detection of super‐small temperature fluctuations in living specimens.
Selecting green fluorescent protein and Ag2S nanocrystals as illustrative multiparametric thermographic phosphors, this work demonstrates that the synergy between multiparametric readouts and multiple linear regression makes possible a tenfold improvement in the performance of luminescent thermometers reaching a world record in the relative thermal sensitivity (Sr = 50% K−1) and an impressive temperature uncertainty of 0.05 K.
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 given.
The continuous development of nanotechnology has resulted in the actual possibility of the design and synthesis of nanostructured materials with pre-tailored functionabilities. Nanostructures capable ...of simultaneous heating and local thermal sensing are in strong demand as they would constitute a revolutionary solution to several challenging problems in bio-medicine, including the achievement of real time control during photothermal therapies. Several approaches have been demonstrated to achieve simultaneous heating and thermal sensing at the nanoscale. Some of them lack of sufficient thermal sensitivity and others require complicated synthesis procedures for heterostructure fabrication. In this study, we demonstrate how single core/shell dielectric nanoparticles with a highly Nd(3+) ion doped shell and an Yb(3+),Er(3+) codoped core are capable of simultaneous thermal sensing and heating under an 808 nm single beam excitation. The spatial separation between the heating shell and sensing core provides remarkable values of the heating efficiency and thermal sensitivity, enabling their application in single beam-controlled heating experiments in both aqueous and tissue environments.
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Malignant melanoma accounts for about 1% of all skin malignant tumors and represents the most aggressive and lethal form of skin cancer. Clinically, there exist different therapeutic ...options for melanoma treatment, such as surgery, chemotherapy, radiotherapy, photodynamic therapy and immunotherapy. However, serious adverse effects usually arise, and survival rates are still low because a high number of patients present relapses within 6–9 months after therapy.
AS1411 is a G-quadruplex (G4) aptamer capable of tumor-specific recognition, since it binds to nucleolin, a multi-functional protein expressed in many different types of cancer cells. In this work, we present a novel drug delivery system composed of AS1411 and indocyanine green (ICG) to track its accumulation in tumoral cells in a melanoma mouse model. Using a simple supramolecular strategy, we conjugated the complex AS1411-ICG with C8 ligand, an acridine orange derivative with potential anticancer ligand. Then, we performed in vitro cytotoxicity experiments using the B16 mouse melanoma cell line, and in vivo experiments using a B16 mouse melanoma model to study biodistribution and histological changes. The circular dichroism (CD) data suggest that C8 does not affect the parallel G4 topology of AS1411-ICG, whereas it increases its thermal stability. Incubation of B16 melanoma cells with the AS1411-ICG complex associated with C8 increases the cytotoxicity compared with AS1411-ICG alone.
From the in vivo studies, we conclude that both AS1411-ICG and AS1411-ICG-C8 presented the potential to accumulate preferentially in tumor tissues. Moreover, these compounds seem to be efficiently removed from the mice's bodies through kidney clearance.
In summary, these results suggest that these complexes derived from AS1411 aptamer could act as a delivery system of ligands with antitumoral activity for in vivo melanoma therapy.
Ag
S nanoparticles (NPs) emerge as a unique system that simultaneously features in vivo near-infrared (NIR) imaging, remote heating, and low toxicity thermal sensing. In this work, their capabilities ...are extended into the fields of optical coherence tomography (OCT), as contrast agents, and NIR probes in both ex vivo and in vivo experiments in eyeballs. The new dual property for ocular imaging is obtained by the preparation of Ag
S NPs ensembles with a biocompatible amphiphilic block copolymer. Rather than a classical ligand exchange, where surface traps may arise due to incomplete replacement of surface sites, the use of this polymer provides a protective extra layer that preserves the photoluminescence properties of the NPs, and the procedure allows for the controlled preparation of submicrometric scattering centers. The resulting NPs ensembles show extraordinary colloidal stability with time and biocompatibility, enhancing the contrast in OCT with simultaneous NIR imaging in the second biological window.
Fast and precise localization of ischemic tissues in the myocardium after an acute infarct is required by clinicians as the first step toward accurate and efficient treatment. Nowadays, diagnosis of ...a heart attack at early times is based on biochemical blood analysis (detection of cardiac enzymes) or by ultrasound‐assisted imaging. Alternative approaches are investigated to overcome the limitations of these classical techniques (time‐consuming procedures or low spatial resolution). As occurs in many other fields of biomedicine, cardiological preclinical imaging can also benefit from the fast development of nanotechnology. Indeed, bio‐functionalized near‐infrared‐emitting nanoparticles are herein used for in vivo imaging of the heart after an acute myocardial infarct. Taking advantage of the superior acquisition speed of near‐infrared fluorescence imaging, and of the efficient selective targeting of the near‐infrared‐emitting nanoparticles, in vivo images of the infarcted heart are obtained only a few minutes after the acute infarction event. This work opens an avenue toward cost‐effective, fast, and accurate in vivo imaging of the ischemic myocardium after an acute infarct.
Angiotensine II‐functionalized Ag2S nanodots enable rapid in vivo NIR‐II imaging of damage to the myocardium after a heart attack in mice. Less than 10 min after their intravenous injection, specific images are obtained and can be distinguished from control cases (non‐targeted nanoparticles and healthy mice).
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