Gadolinium-based nanoparticles for theranostic MRI-radiosensitization

International audienceA rapid development of gadolinium-based nanoparticles is observed due to their attractive properties as MRI-positive contrast agents. Indeed, they display high relaxivity, adapted biodistribution and passive uptake in the tumor thanks to enhanced permeability and retention effect. In addition to these imaging properties, it has been recently shown that they can act as effective radiosensitizers under different types of irradiation (radiotherapy, neutron therapy or hadron therapy). These new therapeutic modalities pave the way to therapy guided by imaging and to personalized medicine

In vivo biodistribution and biological impact of injected carbon nanotubes using magnetic resonance techniques

International audienceSingle-walled carbon nanotubes (SWCNT) hold promise for applications as contrast agents and target delivery carriers in the field of nanomedicine. When administered in vivo, their biodistribution and pharmacological profile needs to be fully characterized. The tissue distribution of carbon nanotubes and their potential impact on metabolism depend on their shape, coating, and metallic impurities. Because standard radiolabeled or fluorescentlylabeled pharmaceuticals are not well suited for long-term in vivo follow-up of carbon nanotubes, alternative methods are required

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

Contrast Media Research 2019 “Ettore Majorana” Foundation and International Centre for Scientific Culture, Erice, Sicily, Italy, November 10–15, 2019 Conveners

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Implantable theranostic device for in vivo real-time NMR evaluation of drug impact in brain tumors

Abstract The evaluation of the efficacy of a drug is a fundamental step in the development of new treatments or in personalized therapeutic strategies and patient management. Ideally, this evaluation should be rapid, possibly in real time, easy to perform and reliable. In addition, it should be associated with as few adverse effects as possible for the patient. In this study, we present a device designed to meet these goals for assessing therapeutic response. This theranostic device is based on the use of magnetic resonance imaging and spectroscopy for the diagnostic aspect and on the application of the convection-enhanced delivery technique for the therapeutic aspect. The miniaturized device is implantable and can be used in vivo in a target tissue. In this study, the device was applied to rodent glioma models with local administration of choline kinase inhibitor and acquisition of magnetic resonance images and spectra at 7 Tesla. The variations in the concentration of key metabolites measured by the device during the administration of the molecules demonstrate the relevance of the approach and the potential of the device

Minimally invasive implantable NMR microcoils for in vivo metabolic profiling of microliter volumes

International audienceIntroductionThe use of implanted NMR microcoils still remains a relatively unexploited research area, without emerging or significant biomedical applications. The limitations inherent to implanted NMR coils derive obviously from the relatively weak detection sensitivity of NMR, hindering great challenges for nano-volume analyses. In addition, the necessity to preserve tissue during microprobe implantation imposes severe constraints on the geometry and structure of the NMR microcoil. In this study, we present in vitro and in vivo results obtained with innovative and minimally invasive microcoils.MethodsAn example of implantable NMR microprobe is shown in Figure 1. This filar-type architecture is based on the use of twisted copper microwires (diameter of 150 μm). The twisted wires are inserted inside a polyamide tubing (outer diameter of 380 μm). A biocompatible glue is used to seal the polyamide tube, while tuning and matching capacitors are connected to the two sides of the wire. For in vivo experiments, cannulae were stereotaxically positionned the day before the insertion of the NMR microcoils in the brain of male wistar rats. Experiments were performed at 7 T and 17.2 T. NMR spectra were acquired using a PRESS sequence. 3D MRI acquisitions were performed using a ZTE (zero echo time) sequence.Results/DiscussionThe quality factor of the loaded coils was ranging between 100 and 120. The full width at half maximum of water peak were measured to 6 Hz. In vivo results are illustrated in Figure 2 with a PRESS NMR spectrum obtained in the rat brain with a twisted microcoil (a volume coil was used for selective excitation). In this particular example of water-suppressed acquisition (240 averages, 10-minutes acquisition) at 7 Tesla, main peaks of brain metabolites (NAA, glu, gln, pCr, Cr, etc) can be easily identified and quantified. The ZTE MRI image (right side of Figure 1) shows the sensitive detection zone of the microprobe (volume evaluated to 500 nL) extending to about 200 μm away from the wire.ConclusionsThe MRS/MRI results obtained in vitro and in vivo illustrate the relevance of the microcoil design with respect to spectral resolution, detection sensitivity, spatial selectivity and limited invasiveness. Foreseen applications include the investigation of metabolism in microliter volumes in physiological conditions and in diseases with metabolic dysfunctions (tumoral environement, neurodegenerative pathologies, etc)

EPR-mediated tumor targeting using ultrasmall-hybrid nanoparticles: From animal to human with theranostic AGuIX nanoparticles

International audienceInterest of tumor targeting through EPR effect is still controversial due to intrinsic low targeting efficacy and rare translation to human cancers. Moreover, due to different reasons, it has generally been described for relatively large nanoparticles (NPs) (hydrodynamic diameter > 10 nm). In this review EPR effect will be discussed for ultrasmall NPs using the example of the AGuIX® NP (Activation and Guiding of Irradiation by X-ray) recently translated in clinic. AGuIX® NP is a 4 ± 2 nm hydrodynamic diameter polysiloxane based NP. Since AGuIX® NP biodistribution is monitored by magnetic resonance imaging (MRI) and its activation is triggered by irradiation upon X-rays, this NP is well adapted for a theranostic approach of radiotherapy cancer treatment. Here we show that AGuIX® NP is particularly well suited to benefit from EPR-mediated tumor targeting thanks to an ultrasmall size and efficacy under irradiation at small dose. Indeed, intravenously-injected AGuIX® NP into rodent cancer models passively reached the tumor and revealed no toxicity, favoured by renal clearance. Moreover, translation of AGuIX® NP accumulation and retention into humans carrying brain metastases was validated during a first-in-man phase Ib trial taking advantage of easy biodistribution monitoring by MRI

Aerosol administration of theranostic nanoparticles : from imaging to therapy

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Morphological and quantitative evaluation of emphysema in chronic obstructive pulmonary disease patients: A comparative study of MRI with CT

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Online Quantification of Lactate Concentration in Microdialysate During Cerebral Activation Using 1H-MRS and Sensitive NMR Microcoil

The dynamic in vivo profiling of lactate is of uppermost importance in both neuroenergetics and neuroprotection fields, considering its central suspected role as a metabolic and signaling molecule. For this purpose, we implemented proton magnetic resonance spectroscopy (1 H-MRS) directly on brain microdialysate to monitor online the fluctuation of lactate contents during neuronal stimulation. Brain activation was obtained by right whisker stimulation of rats, which leads to the activation of the left barrel cortex area in which the microdialysis probe was implanted. The experimental protocol relies on the use of dedicated and sensitive home-made NMR microcoil able to perform lactate NMR profiling at submillimolar concentration. The MRS measurements of extracellular lactate concentration were performed inside a pre-clinical MRI scanner allowing simultaneous visualization of the correct location of the microprobe by MRI and detection of metabolites contained in the microdialysis by MRS. A 40% increase in lactate concentration was measured during whisker stimulation in the corresponding barrel cortex. This combination of microdialysis with online MRS/MRI provides a new approach to follow in vivo lactate fluctuations, and can be further implemented in physio-pathological conditions to get new insights on the role of lactate in brain metabolism and signaling