synthesis of MRI contrast agents Research Papers (original) (raw)

Ce travail de thèse a été effectué au laboratoire de Reconnaissance Ionique et Chimie de Coordination du CEA Grenoble dirigé par Pascale Maldivi, que je remercie pour m'avoir accueilli au sein de son équipe. Je remercie Marinella Mazzanti qui a dirigé cette thèse, pour m'avoir suivi pendant ses trois ans, pour avoir toujours été disponible et pour m'avoir transmis son enthousiasme pour la chimie des lanthanides. Ce sujet a été pour moi l'occasion d'élargir mon horizon chimique grâce à l'opportunité qu'elle m'a offerte à travers ce sujet de thèse. Je voudrais remercier le professeur Jens Hasserodt et le docteur Loïc Charbonnière pour m'avoir fait l'honneur d'examiner ce mémoire en qualité de rapporteurs. Merci beaucoup pour le temps que vous avez pris pour lire et juger ce travail de thèse. Je remercie également le docteur Sarah Catoen et le professeur Fabrice Thomas pour l'intérêt qu'ils ont témoigné pour ce travail en acceptant de faire partie du jury de cette thèse. Je souhaite remercier tout particulièrement Pascal Fries, dont l'aide a été très précieuse au cours de ces trois ans, que ce soit pour les interprétations théoriques des résultats expérimentaux, pour les différentes expériences de relaxométrie ainsi que pour la relecture attentive du manuscrit. Je tiens à remercier Daniel Imbert pour les mesures de luminescence, ainsi que pour son aide pour la synthèse organique et les mesures de physico-chimie. Je tiens également à remercier Christelle Gâteau pour la synthèse des dérivés de la dpaa ainsi pour son aide et ses conseils pour la synthèse organique en général. En grand merci à Lydia Plassais qui m'a beaucoup aidé pour le développement des synthèses des ligands basés sur le 1,4,7 triazacyclononane. Je remercie Lother Helm pour m'avoir accueilli quelques jours au sein de son équipe à Lausanne et pour son aide pour les mesures de RMN de l' 17 O. Un grand merci également à Hugues Jacquard pour m'avoir aidé au laboratoire pendant ces dix jours. 3 Un grand merci à Colette Lebrun pour l'ensemble des spectres de masse, son aide précieuse et sa gentillesse au quotidien. Merci à Pierre-Alain Bayle pour toujours avoir pris le temps de m'aider pour les expériences de RMN, et pour m'avoir dépanné de nombreuses fois quand les spectromètres étaient capricieux ! Merci à Armelle Guillermo pour son aide et sa disponibilité pour les mesures de relaxométrie effectuées à 45 et 90 MHz. Je tiens également à remercier toutes les personnes qui ont collaboré sur le projet des nano billes : Samuel Jorice, Peter Cherns, Wai L. Ling, Olivier Raccurt et Olivier Poncelet. Je tiens également à remercier Michel De Waard et son équipe pour les expériences IRM réalisées sur les rats. Enfin je tiens à remercier Didier Gasparutto et Christine Saint Pierre pour leur travail sur le greffage des nucléosides. Merci également à Zohra pour sa disponibilité et pour l'efficacité dont elle fait preuve pour régler tous les soucis administratifs. Je tiens enfin à remercier l'ensemble des personnes du laboratoire, qui permettent que l'ambiance soit si agréable et qui rendent le travail au quotidien un peu plus facile.

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- MRI, Contrast Agents, Luminescence of lanthanide ions, synthesis of MRI contrast agents

Superparamagnetic iron oxide nanoparticles (SPIONs, ~11-nm cores) were PEGylated without anchoring groups and studied as efficient MRI T 2 contrast agents (CAs). The ether group of PEG is efficiently and directly linked to the positively charged surface of SPIONs, and mediated through a dipole-cation covalent interaction. Anchor-free PEG-SPIONs exhibit a spin-spin relaxivity of 123 ± 6 mM −1 s −1 , which is higher than those of PEG-SPIONs anchored with intermediate biomolecules, iron oxide nanoworms, or Feridex. They do not induce a toxic response for Fe concentrations below 2.5 mM, as tested on four different cell lines with and without an external magnetic field. Magnetic resonance phantom imaging studies show that anchor-free PEG-SPIONs produce a significant contrast in the range of 0.1–0.4 [Fe] mM. Our findings reveal that the PEG molecules attached to the cores immobilize water molecules in large regions of ~85 nm, which would lead to blood half-life of a few tens of minutes. This piece of research represents a step forward in the development of next-generation CAs for nascent-stage cancer detection.

tBovine serum albumin (BSA) (Mn= 66.5 kD, size = 14 × 4 × 4 nm) is an attractive biological molecule forbiomedical applications because of its water-solubility and bio-compatibility. It can also bind manyultrasmall nanoparticles (NPs) as confirmed in this study. We synthesized polyethylene glycol diacid(PEGD) coated ultrasmall Gd2O3nanoparticles (PEGD-GNPs, the core davg= 2.0 nm), which were then con-jugated to BSA and cleaved-BSA (C-BSA) (i.e. BSA-PEGD-GNPs and C-BSA-PEGD-GNPs) through amidebonding. Large relaxivities were observed in both aqueous sample solutions (r1= 6.0 s−1mM−1andr2= 28.0 s−1mM−1for BSA-PEGD-GNPs and r1= 7.6 s−1mM−1and r2= 22.0 s−1mM−1for C-BSA-PEGD-GNPs). Three tesla T2magnetic resonance imaging (MRI) in a mouse after the injection of an aqueoussample solution of BSA-PEGD-GNPs into a mouse tail vein revealed significant negative contrast enhance-ments. Large relaxivities and in vivo MR images prove that BSA-PEGD-GNPs and C-BSA-PEGD-GNPs arepotential MRI contrast agents.

A hexadentate ligand built on an amine-bis(phenol) skeleton with an aminal, self-immolative moiety is presented. Synthesis of the ligand is convenient and relatively high yielded. Moreover, it enables synthesis of many derivatives, both in the amino-phenol and aminal fragment (various heterocycles). Once the final hexadentate ligand is synthesized via the Katritzky reaction, it becomes prone to hydrolysis. Bioactivation by beta-galactosidase cleaves the glycosylic bond and a spontaneous collapse of the aminal fragment occurs, thus leading to a pentadentate chelate. This bioactivation has been shown for pyrazole, 1,2,4 triazole and benzotriazole derivatives.

This review describes recent research efforts focused on increasing the specificity of contrast agents for magnetic
resonance imaging (MRI). Contrast agents play an indispensable role in MRI by enhancing the inherent contrast of
images; however, the non-specific nature of current clinical contrast agents limits their usefulness. This limitation
can be addressed by conjugating contrast agents or contrast-agent-loaded carriers—including polymers,
nanoparticles, dendrimers, and liposomes—to molecules that bind to biological sites of interest. An alternative
approach to conjugation is synthetically mimicking biological structures with metal complexes that are also contrast
agents. In this review, we describe the advantages and limitations of these two targeting strategies with respect to
translation from in vitro to in vivo imaging while focusing on advances from the last ten years.

Bovine serum albumin (BSA) (Mn= 66.5 kD, size = 14 × 4 × 4 nm) is an attractive biological molecule forbiomedical applications because of its water-solubility and bio-compatibility. It can also bind manyultrasmall nanoparticles (NPs) as confirmed in this study. We synthesized polyethylene glycol diacid(PEGD) coated ultrasmall Gd2O3nanoparticles (PEGD-GNPs, the core davg= 2.0 nm), which were then con-jugated to BSA and cleaved-BSA (C-BSA) (i.e. BSA-PEGD-GNPs and C-BSA-PEGD-GNPs) through amidebonding. Large relaxivities were observed in both aqueous sample solutions (r1= 6.0 s−1mM−1andr2= 28.0 s−1mM−1for BSA-PEGD-GNPs and r1= 7.6 s−1mM−1and r2= 22.0 s−1mM−1for C-BSA-PEGD-GNPs). Three tesla T2magnetic resonance imaging (MRI) in a mouse after the injection of an aqueoussample solution of BSA-PEGD-GNPs into a mouse tail vein revealed significant negative contrast enhance-ments. Large relaxivities and in vivo MR images prove that BSA-PEGD-GNPs and C-BSA-PEGD-GNPs arepotential MRI contrast agents.

The gadolinium oxide (Gd2O3) nanoparticles are well-known potential candidates for a positive
magnetic resonance imaging (MRI) contrast agent owing to their large longitudinal water proton
relaxivity (r1) value with r2/r1 ratio close to one (r2 = transverse water proton relaxivity). In addition
they may be used to sense metal ions because their r1 and r2 values can be altered in the presence
of metal ions. This may allow us to study metabolic processes involving metal ions and to diagnose
disease related to abnormal concentrations of metal ions in the body in a non-invasive way. In this
study ultrasmall Gd2O3 nanoparticles were for the first time applied to non-specifically sense Zn2+
ions in aqueous solution. We explored this by measuring r1 and r2 values in the presence of Zn2+
ions in solution.

- by BADRUL ALAM BONY
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- synthesis of MRI contrast agents

Nonivasive diagnosis of cancer can be provided by molecular imaging using hybrid modality to obtain better sensitivity, specificity and depiction localization of the disease. In this study, we developed a new molecular imaging agent, radiogadolinium(III)-DOTA-PAMAM G3.0-trastuzumab in the form of 147Gd-DOTA-PAMAM G3.0-trastuzumab, that can be both target-specific radiopharmaceutical in SPECT as well as targeted contrast agent in MRI for the purpose of diagnosis of HER-2 positive breast cancer. 147Gd radionuclide emits γ-rays that can be used in SPECT modality, but because of technical constraint, 147Gd radionuclide was simulated by its radioisotope, 153Gd. Gd-DOTA complex has also been known as good MRI contrast agent. PAMAM G3.0 is useful to concentrate Gd-DOTA compelexes in large quantities, thus minimizing the number of trastuzumab molecules used. Trastuzumab is human monoclonal antibody that can spesifically interact with HER-2. Synthesis of radiogadolinium(III)-DOTA-PAMAM G3.0-trastuzumab was initiated by conjugating DOTA NHS ester ligand with PAMAM G3.0 dendrimer. The DOTA-PAMAM G3.0 produced was conjugated to trastuzumab molecule and labeled with 153Gd. Characterization DOTA-PAMAM G3.0-trastuzumab immunoconjugate was performed using HPLC system equipped with SEC. The formation of immunoconjugate was indicated by the shorter retention time (6.82 min) compared to that of trastuzumab (7.06 min). Radiochemical purity of radiogadolinium(III)-DOTA-PAMAM G3.0-trastuzumab was >99% after purification process by PD-10 desalting column. Radiogadolinium(III)-DOTA-PAMAM G3.0-trastuzumab compound was stable at room temperature and at 2–8 0C as indicated by its radiochemical purity 97.6 ± 0.5%–99.1 ± 0.5% after 144 h storage.

Iron-platinum alloy nanoparticles (FePt NPs) are extremely promising candidates for the next generation of contrast agents for magnetic resonance (MR) diagnostic imaging and MR-guided interventions, including hyperthermic ablation of solid cancers. FePt has high Curie temperature, saturation magnetic moment, magneto-crystalline anisotropy, and chemical stability. We describe the synthesis and characterization of a family of biocompatible FePt NPs suitable for biomedical applications, showing and discussing that FePt NPs can exhibit low cytotoxicity. The importance of engineering the interface of strongly magnetic NPs using a coating allowing free aqueous permeation is demonstrated to be an essential parameter in the design of new generations of diagnostic and therapeutic MRI contrast agents. We report effective cell internalization of FePt NPs and demonstrate that they can be used for cellular imaging and in vivo MRI applications. This opens the way for several future applications of FePt NPs, including regenerative medicine and stem cell therapy in addition to enhanced MR diagnostic imaging.

- by Pascal Andre
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- Biomedical Engineering, Medical Imaging, Synthesis of nanoparticles, Biomaterials

We report the synthesis, characterization and application of highly water-soluble fluoresceinpolyethyleneimine
(PEI) coated gadolinium oxide (Gd2O3) nanoparticles to magnetic resonance
imaging (MRI) and cell labeling (CL). The average particle diameter and average hydrodynamic
diameter were estimated to be 3.92 and 7.5 nm, respectively. Fluorescein-PEI was prepared from
EDC/NHS coupling method. The surface coating was characterized by the FT-IR absorption
spectrum and the surface coating amount was estimated to be 22.42 wt% from a TGA analysis,
corresponding to 0.65 nm22 grafting density. The fluorescein-PEI coated gadolinium oxide
nanoparticles showed r1 and r2 of 6.76 and 20.27 s21mM21, respectively, and a strong fluorescence at
y527 nm. A pronounced positive contrast enhancement was clearly observed in 3 tesla T1 MR
images of a rat with a liver tumor after injection of an aqueous sample solution into a rat tail vein.
After treatment of DU145 cells with a sample solution, a strong fluorescence in confocal images was
also observed. These two results together confirm the excellent MRI-CL dual functionality of
fluorescein-PEI coated gadolinium oxide nanoparticles.

Gadolinium (Gd) is a unique and powerful element in chemistry and biomedicine which can be applied
simultaneously to magnetic resonance imaging (MRI), X-ray computed tomography (CT), and neutron
capture therapy for cancers. This multifunctionality can be maximized using gadolinium oxide (Gd2O3)
nanoparticles (GNPs) because of the large amount of Gd per GNP, making both diagnosis and therapy (i.e.,
theragnosis) for cancers possible using only GNPs. In this study, the T1 MRI and CT dual imaging capability
of GNPs is explored by synthesizing various iodine compound (IC) coated GNPs (IC-GNPs). All the
IC-GNP samples showed stronger X-ray absorption and larger longitudinal water proton relaxivities (r1 5
26–38 s21mM21 and r2/r151.4–1.9) than the respective commercial contrast agents. In vivo T1MRand CT
images of mice were also acquired, supporting that the GNP is a potential dual imaging agent.

- by Md. Wasi Ahmad
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- Magnetic Resonance Imaging, Imaging, Cytotoxicity, Surface Coatings

The water-soluble and biocompatible D-glucuronic acid coated Eu(OH)3 nanorods (average thickness
x average length=90×1183 nm) have been prepared in one-pot synthesis. The D-glucuronic
acid coated Eu(OH)3 nanorods showed a strong fluorescence at ∼600 nm with a narrow emission
band width. A cytotoxicity test by using DU145 cells showed that D-glucuronic acid coated Eu(OH)3
nanorods are not toxic up to 100 M, making them a promising candidate for biomedical applications
such as fluorescent imaging. The minimum Eu concentration needed for a conventional
confocal imaging was estimated to be ∼0.1 mM. Therefore, D-glucuronic acid coated Eu(OH)3
nanorods can be applied to fluorescent imaging. However, a very tiny magnetization of ∼1.2 emu/g
at room temperature and at an applied field of 5 tesla was observed. As a result, very small r1 and
r2 water proton relaxivities were estimated, implying that surface coated Eu(OH)3 nanorods are not
sufficient for MRI contrast agents.