AGuIX radiosensitizing nanoparticles: from molecular events to clinical applications

Abstract : AGuIX (Activation and Guidance by Irradiation X) is a non-toxic gadolinium-based nanoparticle (GBN) (due to gadolinium entrapped in DOTA) developed by the Lyon University. It accumulates in the tumor through the enhanced permeability and retention (EPR) effect and clears rapidly through the kidneys due to its small size (sub-5nm). Furthermore, AGuIX demonstrates good performance as a contrast agent for MRI. We performed a proof of concept on head and neck squamous cell carcinoma (HNSCC), metastatic melanoma and chondrosarcoma tumors, known for their low survival rates, demonstrating the radiosensitizing efficacy of the AGuIX nanoparticles in cellular (2D and 3D cultures) and preclinical models. GBNs enter HNSCC cancer cells by passive diffusion and macropinocytosis (Rima et al, 2013), localize in cytoplasm, as free particle or entrapped in lysosomes, in close vicinity to the mitochondria. Gadolinium combined with irradiation can produce a large variety of secondary emissions such as secondary, Auger, and Compton electrons leading to the production of reactive oxygen species (ROS) that trigger an intra‐mitochondrial stress (ROS production, transmembrane potential decrease, mtDNA deletion) and nuclear DNA damage leading to cell death. Relative biological efficiency (RBE) in cancer cells is quite comparable to that observed in response to carbon ions, suggesting the existence of common mechanisms through the amplification of the local dose (Miladi et al. Al., Nanomedicine 2015, Wozny et al., submitted). The efficacy of AGuIX has also been demonstrated in orthotopic xenograft models of HNSCC and metastatic melanoma (Miladi et al., 2015, Kotb et al., Theranostics 2016); the experiments are ongoing for chondrosarcoma. Regulatory toxicity studies were conducted in rats and monkeys and a first clinical study was initiated in patients with multiple brain metastases (clinicaltrial.gov). This presentation will summarize our current results with AGuIX nanoparticles used in radiobiology and imaging as well as their first clinical applications. Supported by LabEx PRIMES (ANR-11-LABX-0063)
Type de document :
Communication dans un congrès
63rd annual international meeting of Radiation Reaserach Society, Oct 2017, Cancun, Mexico. 2017
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https://hal.archives-ouvertes.fr/hal-01610963
Contributeur : Béatrice Rayet <>
Soumis le : jeudi 5 octobre 2017 - 11:35:07
Dernière modification le : jeudi 19 avril 2018 - 14:34:08

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  • HAL Id : hal-01610963, version 1

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Claire Rodriguez-Lafrasse, Marie-Thérèse Aloy, Jacqueline Sidi Boumedine, Shady Kotb, Lucie Sancey, et al.. AGuIX radiosensitizing nanoparticles: from molecular events to clinical applications. 63rd annual international meeting of Radiation Reaserach Society, Oct 2017, Cancun, Mexico. 2017. 〈hal-01610963〉

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