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

Bifunctional Agents for MRI, PET and Fluorescence Imaging and Study of Nanoparticles Formed from Water Oxidation Catalysts /

The work is divided into four parts : (1) MRI contrast agents are designed to enhance T₁ relaxivity by coupling them to dendrimers, the precise structure of which can be controlled through synthesis. Cyclen is used as a starting scaffold for the synthesis of bifunctional Gd-DOTA and Gd- DOTMA analogues. One unique side chain on the macrocycle contains an azide moiety that can be clicked to an alkyne- containing core, making a first-generation dendrimer with the potential to improve MRI efficiency. (2) PET tracers are designed to specifically coordinate ⁶⁴Cu, a positron source, while containing clickable side arms. A functionalized cross-bridge tetraazamacrocycle with two identical azide-bearing side arms can be clicked to alkynyl amino acid, which provides several advantages with respect to applications. (3) Using the results of part 1, MRI-fluorescence imaging agents are constructed. Preliminary tests determine their efficiency as bimodal agents. (4) My contributions to a separate project to investigate the fate of water oxidation catalysts under acidic conditions are described. We have synthesized and characterized four novel bifunctional MRI imaging agents to date. Preliminary studies show successful clicking of these complexes to form dendrimers. We are also currently synthesizing and optimizing a unique bifunctional PET tracer. Future work includes, but is not limited to, optimization of syntheses, full characterization of the bifunctional PET tracer, theoretical calculations of expected T₁ relaxivities of bifunctional MRI contrast agents, imaging cells in tissue-like matrices for MRI- fluorescence agents, and designing more robust water oxidation catalyst

Bifunctional chelates optimized for molecular MRI.

Important requirements for exogenous dyes or contrast agents in magnetic resonance imaging (MRI) include an effective concentration of paramagnetic or superparamagnetic ions at the target to be imaged. We report the concise synthesis and characterization of several new enantiopure bifunctional derivatives of (α(1)R,α(4)R,α(7)R,α(10)R)-α(1),α(4),α(7),α(10)-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTMA) (and their 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) analogues as controls) that can be covalently attached to a contrast agent delivery system using either click or peptide coupling chemistry. Gd complexes of these derivatives can be attached to delivery systems while maintaining optimal water residence time for increased molecular imaging sensitivity. Long chain biotin (LC-biotin) derivatives of the Eu(III) and Gd(III) chelates associated with avidin are used to demonstrate higher efficiencies. Variable-temperature relaxometry, (17)O NMR, and nuclear magnetic resonance dispersion (NMRD) spectroscopy used on the complexes and biotin-avidin adducts measure the influence of water residence time and rotational correlation time on constrained and unconstrained systems. The Gd(III)-DOTMA derivative has a shorter water residence time than the Gd(III)-DOTA derivative. Compared to the constrained Gd(III)-DOTA derivatives, the rotationally constrained Gd(III)-DOTMA derivative has ∼40% higher relaxivity at 37 °C, which could increase its sensitivity as an MRI agent as well as reduce the dose of the targeting agent

Bifunctional Chelates Optimized for Molecular MRI

Important requirements for exogenous dyes or contrast agents in magnetic resonance imaging (MRI) include an effective concentration of paramagnetic or superparamagnetic ions at the target to be imaged. We report the concise synthesis and characterization of several new enantiopure bifunctional derivatives of (α¹<i>R</i>,α⁴<i>R</i>,α⁷<i>R</i>,α¹⁰<i>R</i>)-α¹,α⁴,α⁷,α¹⁰-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTMA) (and their 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) analogues as controls) that can be covalently attached to a contrast agent delivery system using either click or peptide coupling chemistry. Gd complexes of these derivatives can be attached to delivery systems while maintaining optimal water residence time for increased molecular imaging sensitivity. Long chain biotin (LC-biotin) derivatives of the Eu­(III) and Gd­(III) chelates associated with avidin are used to demonstrate higher efficiencies. Variable-temperature relaxometry, ¹⁷O NMR, and nuclear magnetic resonance dispersion (NMRD) spectroscopy used on the complexes and biotin–avidin adducts measure the influence of water residence time and rotational correlation time on constrained and unconstrained systems. The Gd­(III)-DOTMA derivative has a shorter water residence time than the Gd­(III)-DOTA derivative. Compared to the constrained Gd­(III)-DOTA derivatives, the rotationally constrained Gd­(III)-DOTMA derivative has ∼40% higher relaxivity at 37 °C, which could increase its sensitivity as an MRI agent as well as reduce the dose of the targeting agent

Bifunctional Chelates Optimized for Molecular MRI

Important requirements for exogenous dyes or contrast agents in magnetic resonance imaging (MRI) include an effective concentration of paramagnetic or superparamagnetic ions at the target to be imaged. We report the concise synthesis and characterization of several new enantiopure bifunctional derivatives of (α¹<i>R</i>,α⁴<i>R</i>,α⁷<i>R</i>,α¹⁰<i>R</i>)-α¹,α⁴,α⁷,α¹⁰-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTMA) (and their 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) analogues as controls) that can be covalently attached to a contrast agent delivery system using either click or peptide coupling chemistry. Gd complexes of these derivatives can be attached to delivery systems while maintaining optimal water residence time for increased molecular imaging sensitivity. Long chain biotin (LC-biotin) derivatives of the Eu­(III) and Gd­(III) chelates associated with avidin are used to demonstrate higher efficiencies. Variable-temperature relaxometry, ¹⁷O NMR, and nuclear magnetic resonance dispersion (NMRD) spectroscopy used on the complexes and biotin–avidin adducts measure the influence of water residence time and rotational correlation time on constrained and unconstrained systems. The Gd­(III)-DOTMA derivative has a shorter water residence time than the Gd­(III)-DOTA derivative. Compared to the constrained Gd­(III)-DOTA derivatives, the rotationally constrained Gd­(III)-DOTMA derivative has ∼40% higher relaxivity at 37 °C, which could increase its sensitivity as an MRI agent as well as reduce the dose of the targeting agent

Evolution of Iridium-Based Molecular Catalysts during Water Oxidation with Ceric Ammonium Nitrate

Organometallic iridium complexes have been reported as water oxidation catalysts (WOCs) in the presence of ceric ammonium nitrate (CAN). One challenge for all WOCs regardless of the metal used is stability. Here we provide evidence for extensive modification of many Ir-based WOCs even after exposure to only 5 or 15 equiv of Ce(IV) (whereas typically 100–10000 equiv are employed during WOC testing). We also show formation of Ir-rich nanoparticles (likely IrO_<i>x</i>) even in the first 20 min of reaction, associated with a Ce matrix. A combination of UV–vis and NMR spectroscopy, scanning transmission electron microscopy, and powder X-ray diffraction is used. Even simple IrCl₃ is an excellent catalyst. Our results point to the pitfalls of studying Ir WOCs using CAN

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

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

Bifunctional Chelates Optimized for Molecular MRI

Important requirements for exogenous dyes or contrast agents in magnetic resonance imaging (MRI) include an effective concentration of paramagnetic or superparamagnetic ions at the target to be imaged. We report the concise synthesis and characterization of several new enantiopure bifunctional derivatives of (α¹<i>R</i>,α⁴<i>R</i>,α⁷<i>R</i>,α¹⁰<i>R</i>)-α¹,α⁴,α⁷,α¹⁰-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTMA) (and their 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) analogues as controls) that can be covalently attached to a contrast agent delivery system using either click or peptide coupling chemistry. Gd complexes of these derivatives can be attached to delivery systems while maintaining optimal water residence time for increased molecular imaging sensitivity. Long chain biotin (LC-biotin) derivatives of the Eu­(III) and Gd­(III) chelates associated with avidin are used to demonstrate higher efficiencies. Variable-temperature relaxometry, ¹⁷O NMR, and nuclear magnetic resonance dispersion (NMRD) spectroscopy used on the complexes and biotin–avidin adducts measure the influence of water residence time and rotational correlation time on constrained and unconstrained systems. The Gd­(III)-DOTMA derivative has a shorter water residence time than the Gd­(III)-DOTA derivative. Compared to the constrained Gd­(III)-DOTA derivatives, the rotationally constrained Gd­(III)-DOTMA derivative has ∼40% higher relaxivity at 37 °C, which could increase its sensitivity as an MRI agent as well as reduce the dose of the targeting agent