3D imaging of theranostic nanoparticles in mice organs by means of x-ray phase contrast tomography

Theranostics is an innovative research field that aims to develop high target specificity cancer treatments by administering small metal-based nanoparticles (NPs). This new generation of compounds exhibits diagnostic and therapeutic properties due to the high atomic number of their metal component. In the framework of a combined research program on low dose X-ray imaging and theranostic NPs, X-ray Phase Contrast Tomography (XPCT) was performed at ESRF using a 3 \u3bcm pixel optical system on two samples: a mouse brain bearing melanoma metastases injected with gadolinium NPs and, a mouse liver injected with gold NPs. XPCT is a non-destructive technique suitable to achieve the 3D reconstruction of a specimen and, widely used at micro-scale to detect abnormalities of the vessels, which are associated to the tumor growth or to the development of neurodegenerative diseases. Moreover, XPCT represents a promising and complementary tool to study the biodistribution of theranostic NPs in biological materials, thanks to the strong contrast with respect to soft tissues that metal-based NPs provide in radiological images. This work is relied on an original imaging approach based on the evaluation of the contrast differences between the images acquired below and above K-edge energies, as a proof of the certain localization of NPs. We will present different methods aiming to enhance the localization of NPs and a 3D map of their distribution in large volume of tissues

Theranostics in Boron neutron capture therapy

Boron neutron capture therapy (BNCT) has the potential to specifically destroy tumor cells without damaging the tissues infiltrated by the tumor. BNCT is a binary treatment method based on the combination of two agents that have no effect when applied individually:10B and thermal neutrons. Exclusively, the combination of both produces an effect, whose extent depends on the amount of10B in the tumor but also on the organs at risk. It is not yet possible to determine the10B concentration in a specific tissue using non-invasive methods. At present, it is only possible to measure the10B concentration in blood and to estimate the boron concentration in tissues based on the assumption that there is a fixed uptake of10B from the blood into tissues. On this imprecise assumption, BNCT can hardly be developed further. A therapeutic approach, combining the boron carrier for therapeutic purposes with an imaging tool, might allow us to determine the10B concentration in a specific tissue using a non-invasive method. This review provides an overview of the current clinical protocols and preclinical experiments and results on how innovative drug development for boron delivery systems can also incorporate concurrent imaging. The last section focuses on the importance of proteomics for further optimization of BNCT, a highly precise and personalized therapeutic approach

Zwitterion functionalized gold nanoclusters for multimodal near infrared fluorescence and photoacoustic imaging

Gold nanoclusters (Au NCs) are an emerging type of theranostic agents combining therapeutic and imaging features with reduced toxicity. Au NCs stabilized by a zwitterion ligand with a fine control of the metal core size and the ligand coverage were synthesized by wet chemistry. Intense fluorescence signal is reported for the highest ligand coverage, whereas photoacoustic signal is stronger for the largest metal core. The best Au NC candidate with an average molecular weight of 17 kDa could be detected with high sensitivity on a 2D-near-infrared imaging instrument (limit of detection (LOD) = 2.3 μM μM ) and by photoacoustic imaging. In vitro and in vivo experiments demonstrate an efficient cell uptake in U87 cell lines, a fast renal clearance (t 1/2α t1/2α = 6.5 ± 1.3 min), and a good correlation between near infrared fluorescence and photoacoustic measurements to follow the early uptake of Au NCs in liver

Cancer-selective, single agent chemoradiosensitising gold nanoparticles

Two nanometre gold nanoparticles (AuNPs), bearing sugar moieties and/or thiol-polyethylene glycol-amine (PEG-amine), were synthesised and evaluated for their in vitro toxicity and ability to radiosensitise cells with 220 kV and 6 MV X-rays, using four cell lines representing normal and cancerous skin and breast tissues. Acute 3 h exposure of cells to AuNPs, bearing PEG-amine only or a 50:50 ratio of alpha-galactose derivative and PEG-amine resulted in selective uptake and toxicity towards cancer cells at unprecedentedly low nanomolar concentrations. Chemotoxicity was prevented by co-administration of N-acetyl cysteine antioxidant, or partially prevented by the caspase inhibitor Z-VAD-FMK. In addition to their intrinsic cancer-selective chemotoxicity, these AuNPs acted as radiosensitisers in combination with 220 kV or 6 MV X-rays. The ability of AuNPs bearing simple ligands to act as cancer-selective chemoradiosensitisers at low concentrations is a novel discovery that holds great promise in developing low-cost cancer nanotherapeutics

An MRI-based classification scheme to predict passive access of 5 to 50-nm large nanoparticles to tumors

Nanoparticles are useful tools in oncology because of their capacity to passively accumulate in tumors in particular via the enhanced permeability and retention (EPR) effect. However, the importance and reliability of this effect remains controversial and quite often unpredictable. In this preclinical study, we used optical imaging to detect the accumulation of three types of fluorescent nanoparticles in eight different subcutaneous and orthotopic tumor models, and dynamic contrast-enhanced and vessel size index Magnetic Resonance Imaging (MRI) to measure the functional parameters of these tumors. The results demonstrate that the permeability and blood volume fraction determined by MRI are useful parameters for predicting the capacity of a tumor to accumulate nanoparticles. Translated to a clinical situation, this strategy could help anticipate the EPR effect of a particular tumor and thus its accessibility to nanomedicines

Combining metal nanoparticles and nanobodies to boost the biomedical imaging in neurodegenerative diseases

Introduction: In the study of neurodegenerative diseases, the possibility to follow the fate of specific cells or molecules within the whole body would be a milestone to better understand the complex evolution of disease mechanisms and to monitor the effects of therapies. The techniques available today do not allow the visualization of disease-relevant cells within the whole tridimensional biological context at high spatial resolution.Methods: Here we show the results from the first validation steps of a novel approach: by combining the conjugate nanobodies anti-glial fibrillary acidic protein (GFAP) and metal-nanoparticles (i.e. 2 nm gold NP) with X-ray phase contrast tomography (XPCT) we would be able to obtain a tridimensional visualization and identification of cells of interest together with the surrounding tissue and the vascular and neuronal networks.Results: By exploiting the X-ray attenuation properties of metal nanoparticles and the specific targeting capabilities of nanobodies, we could give XPCT the specificity it presently lacks, making it no longer a pure morphological but a molecular and targeted imaging technique. In our case, we synthesized and characterized Gold-NP/GFAP nanobody to target the astrocytes of mouse brain.Discussion: The results of the first tests presented in this paper have provided us with information on the feasibility of the approach, encouraging us to carry out further experiments in order to achieve the ultimate goal of setting up this new imaging technique

Ultrasmall gadolinium based nanoparticles for multimodal imaging

International audienceMedical diagnostic become more and more reliable by the combination of data issued from multiple assays. Each imaging technique display advantages and disadvantages (sensitivity, resolution…). In this context, new fused instruments have been developed that combine two imaging modalities (PET/MRI, PET/CT…). To accompany the development of these instruments, many multimodal contrast agents have been developed by the scientists, in particular in the field of nanotechnology. Our team has recently developed a new family (AGuIX) of ultrasmall nanoparticles (size < 5 nm) made of a polysiloxane network and surrounded by gadolinium chelates that can be used for multimodal imaging1 and therapy guided by imaging

AGuIX® nanoparticles for enhanced radiation therapy: Safety evaluation and major issues

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Elemental imaging using laser-induced breakdown spectroscopy: A new and promising approach for biological and medical applications

International audienceBiological tissues contain various metal and metalloid ions that play different roles in the structure and function of proteins and are therefore indispensable to several vital biochemical processes. In this review, we discuss the broad capability of laser-induced breakdown spectroscopy (LIBS) for in situ elemental profiling and mapping of metals in biological materials such as plant, animal and human specimens. These biological samples contain or accumulate metal species and metal-containing compounds that can be detected, quantified, and imaged. LIBS enables performing microanalysis, mapping and depth profiling of endogenous and exogenous elements contained in the tissues with a parts-per-million scale sensitivity and microscopic resolution. In addition, this technology generally requires minimal sample preparation. Moreover, its tabletop instrumentation is compatible with optical microscopy and most elements from the periodic table. Specifically, low- and high-atomic-number elements can be detected simultaneously. Recent advances in space-resolved LIBS are reviewed with various examples from vegetable, animal and human specimens. Overall, the performance offered by this new technology along with its ease of operation suggest innumerable applications in biology, such as for the preclinical evaluation of metal-based nanoparticles and in medicine, where it could broaden the horizons of medical diagnostics for all pathologies involving metals