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

François Lux, Vu Long Tran, Eloïse Thomas, Sandrine Dufort, Fabien Rossetti, Matteo Martini, Charles Truillet, Tristan Doussineau, Guillaume Bort, Franck Denat, Frédéric Boschetti, Goran Angelovski, Alexandre Detappe, Yannick Crémillieux, Nathalie Mignet, Bich-Thuy Doan, Benoit Larrat, Sébastien Meriaux, Emmanuel Barbier, Stéphane Roux, Peter Fries, Andreas Müller, Marie-Caline Abadjian, Carolyn Anderson, Emmanuelle Canet-Soulas, Penelope Bouziotis, Muriel Barberi-Heyob, Céline Frochot, Camille Verry, Jacques Balosso, Michael Evans, Jacqueline Sidi-Boumedine, Marc Janier, Karl Butterworth, Stephen McMahon, Kevin Prise, Marie-Thérèse Aloy, Dominique Ardail, Claire Rodriguez-Lafrasse, Erika Porcel, Sandrine Lacombe, Ross Berbeco, Awatef Allouch, Jean-Luc Perfettini, Cyrus Chargari, Eric Deutsch, Géraldine Le Duc, Olivier Tillement, François Lux, Vu Long Tran, Eloïse Thomas, Sandrine Dufort, Fabien Rossetti, Matteo Martini, Charles Truillet, Tristan Doussineau, Guillaume Bort, Franck Denat, Frédéric Boschetti, Goran Angelovski, Alexandre Detappe, Yannick Crémillieux, Nathalie Mignet, Bich-Thuy Doan, Benoit Larrat, Sébastien Meriaux, Emmanuel Barbier, Stéphane Roux, Peter Fries, Andreas Müller, Marie-Caline Abadjian, Carolyn Anderson, Emmanuelle Canet-Soulas, Penelope Bouziotis, Muriel Barberi-Heyob, Céline Frochot, Camille Verry, Jacques Balosso, Michael Evans, Jacqueline Sidi-Boumedine, Marc Janier, Karl Butterworth, Stephen McMahon, Kevin Prise, Marie-Thérèse Aloy, Dominique Ardail, Claire Rodriguez-Lafrasse, Erika Porcel, Sandrine Lacombe, Ross Berbeco, Awatef Allouch, Jean-Luc Perfettini, Cyrus Chargari, Eric Deutsch, Géraldine Le Duc, Olivier Tillement

Abstract

AGuIX® 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.

Conflict of interest statement

CONFLICT OF INTEREST: FL and OT have to disclose the patent WO2011/135101. GLD and OT have to disclose the patent WO2009/053644. These patents protect the AGuIX® NPs described in this publication. SD, GLD, TD, FL and OT are employees from NH TherAguix that is developing the AGuIX NPs and possess shares of this company.

Figures

Figure 1.
Figure 1.
(A) Schematic representation of AGuIX® NPs (gadolinium atoms in green are chelated in DOTAGA ligands grafted to polysiloxane matrix). (B) Hydrodynamic diameter (~3 nm) distribution of AGuIX NPs as obtained by dynamic light scattering. (C) ESI-MS measurements on AGuIX nanoparticles. A mass around 10 kDa is obtained for the particle. Inset is obtained after using deconvolution with a multiplicative correlation algorithm. (D) Zeta potential vs pH for AGuIX NPs. Adapted from.NPs, nanoparticles.
Figure 2.
Figure 2.
(A) Laser-induced breakdown spectroscopy analysis (Gd and Na) after i.v. administration (8 µmol) in mice. (B) MRI first pass kinetics of AGuIX NPs in a male monkey after iv injection of AGuIX NPs. Adapted from. , NPs, nanoparticles.
Figure 3.
Figure 3.
Accumulation of AGuIX NPs in tumours of the CNS. (A) MRI and gadolinium quantification at different time points after administration of AGuIX NPs in 9L-gliosarcoma-bearing rats. (B) MR axial image of the brain before and after intravenous administration of AGuIX NPs in U87MG tumour bearing mice. (C) T1 weighted image of the brain of a B16F10 tumour-bearing mouse after administration of AGuIX NPs. Adapted from,, and. CNS, central nervous system; NPs, nanoparticles.
Figure 4.
Figure 4.
(A) T1 weighted MRI of a pancreatic tumour bearing mouse after i.v. administration of AGuIX NPs. Yellow arrows indicate tumour localization. (B) T1 weighted image of hepatic colorectal cancer metastasis after i.v. administration of molecular agent (Gd-DOTA) and AGuIX NPs. Comparison of contrast-to-noise ratio and signal-to-noise ratio for Gd-DOTA and AGuIX NPs in tumour. (C) In vivo SPECT imaging in the paw of a swarm rat chondrosarcoma orthotopic model after i.v. administration of radiolabelled 111In AGuIX NPs. (D) Ultrashort echo-time MRI axial slices of a lung tumour bearing mouse before and after i.v. administration of AGuIX NPs. (E) PET/CT imaging of a 4T1 tumour bearing mice after i.v. administration of radiolabelled 64Cu AGuIX NPs. Adapted from,–. i.v., intravenous; NPs, nanoparticles; SPECT, single photon emission computed tomography.
Figure 5.
Figure 5.
(A) Optical images of a head and neck SQ20B tumour bearing mouse after intratumoral administration of Cy 5.5 labelled AGuIX NPs. (B) Micro-PET images and biodistribution of HepG2 tumour bearing mice after intraperitoneal administration of radiolabelled 64Cu AGuIX NPs. Animals were sacrificed 9 h, 21 h and 40 h after intraperitoneal administration of the NPs and radioactivity was quantified. (C) MRI and 3D optical images at different time points after administration via the airways of AGuIX NPs labelled by Cy 5.5 in orthotopic NSCLC tumour bearing mice. Adapted from.– 3D, three-dimensional; PET, positron emission tomography.
Figure 6.
Figure 6.
Comparison of lymphadenography with AGuIX NPs and Gd-DOTA. Scale bars: 9.5 mm. Copyright from.NPs,
Figure 7.
Figure 7.
(A) Schematic formation of electron showers and reactive oxygen species obtained after irradiation. (B) Simulation of the deposited dose after irradiation at 2 Gy. Adapted from.
Figure 8.
Figure 8.
Survival of HeLa cells (A, B) or panc1 cells (C, D) after irradiation with 220 kV (A, C) or 6 MV (B, D) with or without AGuIX NPs at different doses. Adapted from and.
Figure 9.
Figure 9.
Survey of CHO (A), SQ20B (B), Cal33 (C) and FaDu (D) under irradiation by hadrons at different doses with or without AGuIX NPs. Adapted from and.
Figure 10.
Figure 10.
Radiosensitization on different preclinical models. (A) Survival curves obtained for 9LGS bearing rats. (B) Survival curves obtained for B16F10 brain metastases bearing mice and irradiation at 7 Gy. (C) Survival curves obtained for capan-1 tumour bearing mice under preclinical (220 kV) irradiation. (D) Survival curves obtained for capan-1 tumour bearing mice under clinical (6 MV) irradiation. (E) Relative tumour progression after intratumoral administration of AGuIX NPs in A375 tumour bearing mice. (F) Relative tumour evolution after intratumoral administration of AGuIX NPs in SQ20B tumour bearing mice. (G) Survival follow-up in a rat xenograft model of chondrosarcoma (SWARM). (H) Survival curve obtained for H358-luc tumour bearing mice after administration of AGuIX NPs by the airways. (I)18F-FDG PET quantitative evaluation before and after irradiation of hepatocellular carcinoma HepG2 tumour bearing mice. Adapted from,–.18F-18-fludeoxyglucose.
Figure 11.
Figure 11.
In vitroand in vivo experiments related to Bi@AGuIX NPs. (A) Qualitative visualization of γH2AX and 53BP1 foci in vitro irradiation of A549 adenocarcinoma cells under 6 MV irradiation. (B) Quantitative measurement of the number of γH2AX and 53BP1 foci per cell after irradiation. (C) Clonogenic assay after irradiation of A549 cells under irradiation at different doses with or without Bi@AGuIX NPs. (D) Biodistribution of Bi@AGuIX NPs after iv. administration in A549 tumour bearing mice evaluated by quantification of Gd and Bi by ICP/MS after sacrifice of the animals at different time points. (E) Evaluation of the tumour growth after treatment for A549 tumour bearing mice. (F) Survival curves obtained after the treatment A549 tumour bearing mice for the different groups. Adapted from.
Figure 12.
Figure 12.
(A) Optical fibre insertion monitored by T2 weighted MRI. (B) Survival curves obtained after illumination for control and PS@AGuIX NPs-treated groups.(C) Survival curves obtained after illumination for control, non-responder and responder groups. (D) Relative growth of the tumour diameters for the different animals and determination of non-responder and responder groups. (E) Relative levels of metabolites measured by MRS 1 day after treatment. (F) Relative levels of metabolites measured by MRS two days after treatment. (G) Relative levels of metabolites measured by MRS 3 days after treatment. Adapted from.MRS, magnetic resonance spectroscopy; NPs, nanoparticles.
Figure 13.
Figure 13.
Illustration of 3D MR imaging of the NanoRAD clinical trial obtained 2 h after i.v. administration of AGuIX NPs. Brain metastases (issued from melanoma, non-small cell lung cancer NSCLC, colon cancer and breast cancer) are targeted by AGuIX NPs while no enhancement of the signal is observed in healthy tissues. NPs, nanoparticles.
Figure 14.
Figure 14.
Protocol of the NanoCOL Phase Ib clinical trial.

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Source: PubMed

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