Longitudinal mouse-PET imaging: a reliable method for estimating binding parameters without a reference region or blood sampling

International audienceLongitudinal mouse PET imaging is becoming increasingly popular due to the large number of transgenic and disease models available but faces challenges. These challenges are related to the small size of the mouse brain and the limited spatial resolution of microPET scanners, along with the small blood volume making arterial blood sampling challenging and impossible for longitudinal studies. The ability to extract an input function directly from the image would be useful for quantification in longitudinal small animal studies where there is no true reference region available such as TSPO imaging.METHODS:Using dynamic, whole-body 18F-DPA-714 PET scans (60 min) in a mouse model of hippocampal sclerosis, we applied a factor analysis (FA) approach to extract an image-derived input function (IDIF). This mouse-specific IDIF was then used for 4D-resolution recovery and denoising (4D-RRD) that outputs a dynamic image with better spatial resolution and noise properties, and a map of the total volume of distribution (VT) was obtained using a basis function approach in a total of 9 mice with 4 longitudinal PET scans each. We also calculated percent injected dose (%ID) with and without 4D-RRD. The VT and %ID parameters were compared to quantified ex vivo autoradiography using regional correlations of the specific binding from autoradiography against VT and %ID parameters.RESULTS:The peaks of the IDIFs were strongly correlated with the injected dose (Pearson R = 0.79). The regional correlations between the %ID estimates and autoradiography were R = 0.53 without 4D-RRD and 0.72 with 4D-RRD over all mice and scans. The regional correlations between the VT estimates and autoradiography were R = 0.66 without 4D-RRD and 0.79 with application of 4D-RRD over all mice and scans.CONCLUSION:We present a FA approach for IDIF extraction which is robust, reproducible and can be used in quantification methods for resolution recovery, denoising and parameter estimation. We demonstrated that the proposed quantification method yields parameter estimates closer to ex vivo measurements than semi-quantitative methods such as %ID and is immune to tracer binding in tissue unlike reference tissue methods. This approach allows for accurate quantification in longitudinal PET studies in mice while avoiding repeated blood sampling

Adaptability and reproducibility of a memory disruption rTMS protocol in the PharmaCog IMI European project

Transcranial magnetic stimulation (TMS) can interfere with cognitive processes, such as transiently impairing memory. As part of a multi-center European project, we investigated the adaptability and reproducibility of a previously published TMS memory interfering protocol in two centers using EEG or fMRI scenarios. Participants were invited to attend three experimental sessions on different days, with sham repetitive TMS (rTMS) applied on day 1 and real rTMS on days 2 and 3. Sixty-eight healthy young men were included. On each experimental day, volunteers were instructed to remember visual pictures while receiving neuronavigated rTMS trains (20 Hz, 900 ms) during picture encoding at the left dorsolateral prefrontal cortex (L-DLPFC) and the vertex. Mixed ANOVA model analyses were performed. rTMS to the L-DLPFC significantly disrupted recognition memory on experimental day 2. No differences were found between centers or between fMRI and EEG recordings. Subjects with lower baseline memory performances were more susceptible to TMS disruption. No stability of TMS-induced memory interference could be demonstrated on day 3. Our data suggests that adapted cognitive rTMS protocols can be implemented in multi-center studies incorporating standardized experimental procedures. However, our center and modality effects analyses lacked sufficient statistical power, hence highlighting the need to conduct further studies with larger samples. In addition, inter and intra-subject variability in response to TMS might limit its application in crossover or longitudinal studies

AGuIX® from bench to bedside-Transfer of an ultrasmall theranostic gadolinium-based nanoparticle to clinical medicine

International audienceAGuIX® are sub-5 nm nanoparticles made of a polysiloxane matrix and gadolinium chelates. This nanoparticle has been recently accepted in clinical trials in association with radiotherapy. This review will summarize the principal preclinical results that have led to first in man administration. No evidence of toxicity has been observed during regulatory toxicity tests on two animal species (rodents and monkeys). Biodistributions on different animal models have shown passive uptake in tumours due to enhanced permeability and retention effect combined with renal elimination of the nanoparticles after intravenous administration. High radiosensitizing effect has been observed with different types of irradiations in vitro and in vivo on a large number of cancer types (brain, lung, melanoma, head and neck…). The review concludes with the second generation of AGuIX nanoparticles and the first preliminary results on human

AGuIX® nanoprobes for theranostic applications : study of radiolabelling and photodynamic therapy (PDT) emitter

Depuis une vingtaine d'années, la recherche dans le domaine des nanoobjets pour de l'imagerie et de la thérapie devient de plus en plus importante. En effet, les nanoparticules présentent de nombreux avantages par rapport aux composés moléculaires : leur temps de résidence dans le système sanguin est plus long ; la nanoparticule peut contenir une grande quantité de molécules actives ; les nanoparticules peuvent contenir plusieurs fonctionnalités grâce à leur multimodalité ; et elles peuvent s'accumuler dans les zones cibles grâce à un ciblage passif ou actif. Dans ce cadre, nous proposons une nouvelle structure hybride AGuIX® de taille inférieure à 5 nm, constituée d'une matrice de polysiloxane à la surface de laquelle sont greffés des complexes de gadolinium et des ligands libres. Ces nanoparticules ont été développées pour des applications en imagerie (IRM, scintigraphie, fluorescence) ainsi que des applications en thérapie (radiothérapie). Le but de la thèse consiste d'une part à maîtriser le mécanisme de synthèse, caractériser les nanoparticules par le développement de techniques originales et enfin à exploiter les propriétés multimodales de la nanoparticule afin de proposer plusieurs solutions en imagerie et en thérapie. Les tests biologiques montrent un fort potentiel des nanoparticules pour des applications biologiques. Dans un premier temps, les nanoparticules ont été couplées à des photosensibilisateurs afin d'induire un autre mode de thérapie : la PDT. Ce couplage a permis de travailler sur les mécanismes physiques opérant dans ce modèle. Afin de proposer une dualité en imagerie, les particules AGuIX® ont été marquées par différents isotopes radioactifs. Pour cela, la nanoparticule a été modifiée par l'ajout de ligands spécifiques complexant certains isotopes. Cette étude a abouti également sur le recherche d'un autre mode de thérapie possible avec les AGuIX® : la curie thérapieNanoparticles research has become one of the most promising way for biological applications. They present alternative solutions to the traditional diagnostic and therapeutic methods thanks to (i) their appropriate size and surface which can enhance circulation time in the blood, (ii) their large compartments able to contain considerable amounts of imaging or drugs agents, (iii) their multimodality which makes them potential multifunctional nanoplatforms for both diagnosis and therapy (theranostic), (iv) their capacity to target disease by their appropriate size and surface of by specific targeting moieties grafted on their surface. We propose a new sub-5 nanometer nanoparticles multimodal nanoparticle (called AGuIX®), composed of a polysiloxane network surrounded by gadolinium chelates and free chelates. They have previously demonstrated their efficiency for multimodal imaging and theranostic applications, especially MRI, scintigraphy and fluorescence imaging and radiotherapy. The aim of the thesis was to characterize the synthesis and the nanoparticles in order then to explore the multi-possibilities of therapy and imaging of these nanoparticles AGuIX®. Original characterizations technics were developed. The intrinsic measured properties of AGuIX® solutions fulfill the conditions for potential clinical applications, a wide series of biological tests have been performed. Then first, the coupling of the AGuIX® with another therapy method was explored: PDT effect with photosensitizers grafting on the surface of the nanoparticles. A good understanding of the mechanism was studied. The multimodality of imaging was tested by the labeling with radioactive elements on the surface of the nanoparticles. It was necessary to use a specific ligand in order to obtain high labeling yield. The coupling MRI/scintigraphy is one of the major field in order to have an imaging agent with high resolution and high sensitivity. This study was the opportunities to try to couple another therapy technic: brachytherap

La traite des êtres humains et le travail forcé

Bruxelles, Larcierinfo:eu-repo/semantics/publishe

Venom peptides: emergent biological tools for lung cancer imaging

National audienceMany cancers, including non-small cell lung cancer (NSCLC), are associated with disrupted mechanisms due to dysfunction and/or overexpression of numerous ion channels such as certain subtypes of sodium (NaV1.7) and potassium (KCa3.1) channels, ASICs (acid sensing ion channels) or nicotinic acetylcholine receptors (α7, α9/α10). In particular, the activation of these ion channels plays an important role in cancer cell aggressiveness and tumor invasion1, their overexpression seeming to be correlated with the appearance of metastases. Although imaging approaches (radiography, CTscan for computed tomography scanning, PET-scan for positron emission tomography) are commonly used in the anatomical characterization of NSCLC, some limitations require the development of new imaging probes more specific of overexpressed molecular targets lung adenocarcinomas2. Peptide toxins are known to act selectively and with high affinity on certain ion channels overexpressed in cancer cells. The development of new imaging agents for NSCLC will therefore involve exploiting the pharmacological properties of peptide toxins, and will focus on three research areas : (1) the chemical synthesis of these toxins enabling them to be labelled by "click" chemistry, using fluorescent or radioactive probes, (2) the functional validation of labelled toxins using electrophysiological techniques to ensure that their pharmacological properties are maintained, and (3) proof-of-concept through in vitro imaging of adenocarcinoma lines and in vivo imaging of xenografted mice to validate the specificity and quality of labelled toxins. Mambalgine, an ASIC-targeted toxin, was synthesized with and without fluorochrome. The overexpression of NaV1.7, α7 and α9 proteins in lung cancer cell lines was validated. In addition, their membrane expression was also validated by fluorescence microscopy, using the tagged toxins. These preliminary results are highly encouraging for designing the "labeled toxin/ion channel" pair as an imaging tool to detect NSCLC