11 research outputs found

    Development and evaluation of low-dose rate radioactive gold nanoparticles for application in nanobrachytherapy

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    Depuis les dix derniĂšres annĂ©es, l’innovation des traitements d’oncologie a fait une utilisation croissante de la nanotechnologie. De nouveaux traitements Ă  base de nanoparticules (NPs) sont notamment rendus au stade de l’essai clinique. PossĂ©dant des caractĂ©ristiques physico-chimiques particuliĂšres, les NPs peuvent ĂȘtre utilisĂ©es afin de bonifier l’effet thĂ©rapeutique des traitements actuels. Par exemple, l’amĂ©lioration de la curiethĂ©rapie (c.-Ă -d. radiothĂ©rapie interne) nĂ©cessite le dĂ©veloppement de nouvelles procĂ©dures permettant de diminuer la taille des implants, et ce, tout en augmentant l’homogĂ©nĂ©itĂ© de la dose dĂ©posĂ©e dans les tumeurs. Des Ă©tudes thĂ©oriques et expĂ©rimentales ont dĂ©montrĂ© que l’injection de NPs d’or Ă  proximitĂ© des implants traditionnels de curiethĂ©rapie de faible dĂ©bit de dose (par ex. 125I, 103Pd) permettrait d’augmenter significativement leur efficacitĂ© thĂ©rapeutique. L'interaction entre l’or et les photons Ă©mis par les implants de curiethĂ©rapie (c.-Ă -d. l’effet de radiosensibilisation) gĂ©nĂšre des rayonnements divers (photoĂ©lectrons, Ă©lectrons Auger, rayons X caractĂ©ristiques) qui augmentent significativement la dose administrĂ©e. Dans le cadre de cette thĂšse, l’approche proposĂ©e Ă©tait de dĂ©velopper des NPs d’or radioactives comme nouveau traitement de curiethĂ©rapie contre le cancer de la prostate. L’aspect novateur et unique Ă©tait de synthĂ©tiser une particule coeurcoquille (Pd@Au) en utilisant l’isotope actuellement employĂ© en curiethĂ©rapie de la prostate: le palladium-103 (103Pd, 20 keV). Dans ce cas-ci, la prĂ©sence d’atomes d’or permet de produire l’effet de radiosensibilisation et d’augmenter la dose dĂ©posĂ©e. La preuve de concept a Ă©tĂ© dĂ©montrĂ©e par la synthĂšse et la caractĂ©risation des NPs 103Pd@Au-PEG NPs. Ensuite, une Ă©tude longitudinale in vivo impliquant l’injection des NPs dans un modĂšle xĂ©nogreffe de tumeurs de la prostate chez la souris a Ă©tĂ© effectuĂ©e. L’efficacitĂ© thĂ©rapeutique induite par les NPs a Ă©tĂ© dĂ©montrĂ©e par le retard de la croissance tumorale des souris injectĂ©es par rapport aux souris non injectĂ©es (contrĂŽles). Enfin, une Ă©tude de cartographie de la dose gĂ©nĂ©rĂ©e par les NPs Ă  l’échelle cellulaire et tumorale a permis de comprendre davantage les mĂ©canismes thĂ©rapeutiques liĂ©s aux NPs radioactives. En rĂ©sumĂ©, l’ensemble des travaux prĂ©sentĂ©s dans cette thĂšse font office de prĂ©curseurs relativement au domaine de la nanocuriethĂ©rapie, et pourraient ouvrir la voie Ă  une nouvelle gĂ©nĂ©ration de NPs pour la radiothĂ©rapie.The last decade saw the emergence of new innovative oncology treatments based on nanotechnology. New treatments using nanoparticles (NPs) are now translated to clinical trials. NPs possess unique physical and chemical properties that can be advantageously used to improve the therapeutic effect of current treatments. For instance, therapeutic efficiency enhancement related to internal radiotherapy (i.e., brachytherapy), requires the development of new procedures leading to a decrease of the implant size, while increasing the dose homogeneity and distribution in tumors. Several theoretical and experimental studies based on low-dose brachytherapy seeds (e.g., 125I and 103Pd) combined with gold nanoparticles (Au NPs) showed very promising results in terms of dose enhancement. Gold is a radiosensitizer that enhances the efficiency of radiotherapy by increasing the energy deposition in the surrounding tissues. Dose enhancement is caused by the photoelectric products (photoelectrons, Auger electrons, characteristic X-rays) that are generated after the irradiation of Au NPs. In this thesis, the proposed approach was to develop radioactive Au NPs as a new brachytherapy treatment for prostate cancer. The unique and innovative aspect of this strategy was to synthesize core-shell NPs based on the radioisotope palladium-103 (103Pd, 20 keV), which is currently used in low-dose rate prostate cancer brachytherapy. In this concept, the administrated dose is increased via the radiosensitization effect that is generated through the interactions of low-energy photons with the gold atoms. The proof-ofconcept of this approach was first demonstrated by the synthesis and characterization of the core-shell NPs (103Pd@Au-PEG NPs). Then, a longitudinal in vivo study following the injection of NPs in a prostate cancer xenograft murine model was performed. The therapeutic efficiency was confirmed by the tumor growth delay of the treated group as compared to the control group (untreated). Finally, a mapping study of the dose distribution generated by the NPs at the cellular and tumor levels provided new insights about the therapeutic mechanisms related to radioactive NPs. In summary, the studies presented in this thesis are precursors works in the field of nanobrachytherapy, and could pave the way for a new generation of NPs for radiotherapy

    Les nanoparticules de silice mésoporeuses comme sondes pour l'imagerie biomédicale - purification, études in vitro et in vivo

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    Les nanoparticules de silice mĂ©soporeuses (MSNs) sont utilisĂ©es de plus en plus pour des applications d’imagerie mĂ©dicale et d’élution de mĂ©dicament. Bien qu’elles ne soient pas encore approuvĂ©es pour la clinique, ces produits font actuellement l’objet de plusieurs Ă©tudes prĂ©cliniques. En particulier, notre groupe de recherche a dĂ©montrĂ© que les nanoparticules de silice poreuses marquĂ©es d’élĂ©ments paramagnĂ©tiques sont des agents de contraste efficaces en imagerie par rĂ©sonance magnĂ©tique (IRM). La porositĂ© ouverte de ces produits offre des pistes intĂ©ressantes pour des applications de livraison de mĂ©dicament sous imagerie mĂ©dicale. Ce projet de maĂźtrise porte plus particuliĂšrement sur la prĂ©paration des particules de silice mĂ©soporeuses marquĂ©es d’élĂ©ments paramagnĂ©tiques, en vue d’applications en imagerie cellulaire, et en imagerie vasculaire. Dans un premier temps, la possibilitĂ© de marquer des particules de silice au moyen d’un Ă©lĂ©ment paramagnĂ©tique (Mn) a Ă©tĂ© dĂ©montrĂ©e. Ces produits ont fait l’objet d’une Ă©tude de caractĂ©risation physico-chimique, et d’une Ă©tude de marquage cellulaire. Il a Ă©tĂ© dĂ©montrĂ© que les nanoparticules Mn-MSNs internalisĂ©es dans des cellules leucĂ©miques de souris sont visibles en IRM. Or, avant traitement des cellules, tout comme pour la prĂ©paration d’une suspension de MSNs pour une injection intravasculaire, il est nĂ©cessaire de purifier les nanoparticules de la prĂ©sence d’ions mĂ©talliques potentiellement toxiques (Gd3+, Mn2+, utilisĂ©s pour le marquage des nanoparticules et la visibilitĂ© en IRM). Afin de faciliter la purification des nanoparticules par une technique rapide, une mĂ©thode de chromatographie par exclusion stĂ©rique a Ă©tĂ© dĂ©veloppĂ©e, optimisĂ©e et appliquĂ©e Ă  une procĂ©dure de marquage de MSNs au moyen d’ions paramagnĂ©tiques (Gd3+) et radioactifs (64Cu2+). Le dĂ©veloppement de cette technique a Ă©tĂ© essentiel pour purifier les MSNs, qui ont ensuite Ă©tĂ© injectĂ©es dans des souris, et visualisĂ©es en IRM et en tomographie par Ă©mission de positons (TEP). Ces Ă©tudes ont permis de mesurer la biodistribution des particules de MSNs sur 48 h. Ce projet a Ă©galement permis de dĂ©montrer que les biodistribution dynamiques sous TEP permettront de mieux comprendre la biodistribution, la rĂ©tention aux organes, et l’excrĂ©tion des nanoparticules de MSNs dĂ©veloppĂ©es comme potentiel agent de vectorisation de mĂ©dicaments.Mesoporous silica nanoparticles (MSNs) are increasingly used in medical imaging and drug delivery applications. They are still not approved for the clinic; however, these products have been used in several preclinical studies, and are being evaluated for clinical trials. Our group demonstrated that MSNs labeled with paramagnetic elements are efficient as contrast agents for magnetic resonance imaging (MRI). The open porosity of these products leads to interesting applications for drug delivery under medical imaging. This master’s degree project has focused on the preparation of MSNs labeled with paramagnetic elements, for applications in cellular imaging, and vascular imaging. First, MSNs labeled with paramagnetic element (Mn) were used to label and to visualize cells in MRI. These products were subjected to a physico-chemical characterization study, and a cellular labelling study. It was demonstrated that Mn-MSNs nanoparticles internalized in leukaemia mouse cells are visible using MRI. However, before cells treatment, just like for the preparation of MSNs suspension for intravascular injection, it is necessary to purify nanoparticles from the potentially toxic paramagnetic metal ions (Gd3+, Mn2+). To facilitate and accelerate the purification time, a size exclusion chromatography method was developed, optimized and applied to MSNs labelled with paramagnetic (Gd3+) and radioactive (64Cu2+) ions. The development of this technique was essential to purify MSNs from both Gd3+ and 64Cu2+, which were then injected in mice, and visualized with MRI and positron emission tomography (PET). These studies have made it possible to measure the biodistribution of MSN over 48 h in the mouse model. PET dynamic biodistributions studies allow a better understanding of biodistribution, organ retention, and excretion of MSNs nanoparticles developed as potential drug vectors

    Rapid, one-pot procedure to synthesise 103Pd:Pd@Au nanoparticles en route for radiosensitisation and radiotherapeutic applications

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    The radioisotope palladium (103Pd), encapsulated in millimetre-size seed implants, is widely used in prostate cancer brachytherapy. Gold nanoparticles (Au NPs) distributed in the vicinity of 103Pd radioactive implants, strongly enhance the therapeutic dose of radioactive implants (radiosensitisation effect). A new strategy under development to replace millimetre-size implants, consist in injecting radioactive NPs in the affected tissues. The development of 103Pd@Au NPs distributed in the diseased tissue, could increase the uniformity of treatment (compared with massive seeds), while enhancing the radiotherapeutic dose to the cancer cells (through Au-mediated radiosensitisation effect). To achieve this goal, it is necessary to develop a rapid, efficient, one-pot and easy-to-automatise procedure, allowing the synthesis of coreshell Pd@Au NPs. The novel synthesis route proposed here enables the production of Pd@Au NPs in not more than 4h, in aqueous media, with minimal manipulations, and relying on biocompatible and non-toxic molecules. This rapid multi-step process consists of the preparation of ultra-small Pd NPs by chemical reduction of an aqueous solution of H2PdCl4 supplemented with ascorbic acid (AA) as reducing agent and 2, 3-meso-dimercaptosuccinic acid (DMSA) as a capping agent. Pd conversion yields close to 87% were found, indicating the efficiency of the reaction process. Then Pd NPs were used as seeds for the growth of a gold shell (Pd@Au), followed by grafting with polyethylene glycol (PEG) to ensure colloidal stability. Pd@Au-PEG (TEM: 20.2 ± 12.1 nm) formed very stable colloids in saline solution as well as in cell culture medium. The physico-chemical properties of the particles were characterised by FTIR, XPS, and UV-vis. spectroscopies. The viability of PC3 human prostate cancer cells was not affected after a 24-h incubation cycle with Pd@Au-PEG NPs to concentrations up to 4.22 mM Au. Finally, suspensions of Pd@Au-PEG NPs measured in computed tomography (CT) are found to attenuate X-rays more efficiently than commercial Au NPs CT contrast media. A proof-of-concept was performed to demonstrate the possibility synthesise radioactive 103Pd:Pd@Au-PEG NPs. This study reveals the possibility to synthesise Pd@Au NPs rapidly (including radioactive 103Pd:Pd@Au-PEG NPs), and following a methodology that respects all the strict requirements underlying the production of NPs for radiotherapeutic use (rapidity, reaction yield, colloidal stability, NPs concentration, purification)

    High sensitivity detection of nanoparticles permeation through polymer membranes: A physico-chemical and nuclear imaging measurement approach

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    Diffusion cells are devices made of donor and acceptor compartments (DC and AC), separated by a membrane. They are widely used in pharmaceutical, cosmetic, toxicology, and protective equipment tests (e.g., gloves) to measure the kinetics of permeants (molecules and nanoparticles) across biological membranes as the skin. However, rarely is the concentration of permeants in the AC measured in continuous or in real-time, and this limitation leads to significant discrepancies in the calculations of kinetic parameters that define the permeation mechanisms. In this study, a diffusion cell compatible with positron emission tomography was used to measure the permeation kinetics of nanoparticles across glove membranes. The technology allows for the measurement of nanoparticle concentration in real-time in the two compartments (DC and AC) and at a detection sensitivity several orders of magnitude higher compared with conventional spectroscopies, thus allowing a much more precise extraction of kinetic parameters. Ultra-small (<10 nm) gold nanoparticles were used as a model nanoparticle contaminant. They were radiolabeled, and their diffusion kinetics was measured in continuous through latex and nitrile polymer membranes. Permeation profiles were recorded at sub-nanomolar sensitivity and in real-time, thus allowing the high precision extraction of kinetic permeation parameters. The technology, methodology, and data extraction process developed in this work could be applied to measure in real-time the kinetics of diffusion of a whole range of potentially toxic molecules and nanoparticles across polymer membranes, including glove membranes

    A diffusion cell adapted to nuclear imaging instruments for the measurement of molecular release and pharmacokinetics across membranes

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    Diffusion cells are routinely used in pharmacology to measure the permeation of pharmaceutical compounds and contaminants across membranes (biological or synthetic). They can also be used to study drug release from excipients. The device is made of a donor (DC) and an acceptor (AC) compartment, separated by a membrane. Usually, permeation of molecules across membranes is measured by sampling from the AC at different time points. However, this process disturbs the equilibrium of the cell. Furthermore, analytical techniques used in association with diffusion cells sometimes lack either accuracy, sensitivity, or both. This work reports on the development of nuclear imaging – compatible diffusion cells. The cell is made of a polymer transparent to high-energy photons typically detected in positron emission tomography (PET). It was tested in a finite-dose set-up experiment with a pre-clinical PET system. Porous cellulose membranes (3.5, 25 and 300 kDa), a common excipient in pharmacology, as well as for dialysis membranes, were used as test membranes. The radioisotope 89Zr chelated with deferoxamine B (DFO; 0.65 kDa), was used as an imaging probe (7–10 MBq; 0.2–0.3 nMol 89Zr-DFO). In medicine, DFO is also commonly used for iron removal treatments and pharmacological formulations often require the association of this molecule with cellulose. Permeation profiles were obtained by measuring the radioactivity in the DC and AC for up to 2 weeks. The kinetic profiles were used to extract lag time, influx, and diffusion coefficients of DFO across porous cellulose membranes. A sensitivity threshold of 0.005 MBq, or 3.4 fmol of 89Zr-DFO, was revealed. The lag time to permeation (τ) measured in the AC compartment, was found to be 1.33, 0.5, and 0.19 h with 3.5, 25, and 300 kDa membranes, respectively. Diffusion coefficients of 3.65 × 10−6, 8.33 × 10−6, and 4.74 × 10−5 cm2 h−1 where revealed, with maximal pseudo steady-state influx values (Jpss) of 6.55 × 10−6, 1.76 × 10−5, and 1.29 × 10−5 nmol cm−2 h−1. This study confirms the potential of the technology for monitoring molecular diffusion and release processes at low concentrations, high sensitivities, in real time and in a visual manner. © 2021 Elsevier B.V

    High-sensitivity permeation analysis of ultra-small nanoparticles across the skin by positron emission tomography (PET)

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    Ultrasmall nanoparticles (US-NPs; <20 nm in hydrodynamic size) are now included in a variety of pharmacological and cosmetic products, and new technologies are needed to detect at high sensitivity the passage of small doses of these products across biological barriers such as the skin. In this work, a diffusion cell adapted to positron emission tomography (PET), a highly sensitive imaging technology, was developed to measure the passage of gold NPs (AuNPs) in skin samples in continuous mode. US-AuNPs (3.2 nm diam.; TEM) were functionalized with deferoxamine (DFO) and radiolabeled with 89Zr(IV) (half-life: 3.3 days, matching the timeline of diffusion tests). The physicochemical properties of the functionalized US-AuNPs (US-AuNPs-PEG-DFO) were characterized by FTIR (DFO grafting; hydroxamate peaks: 1629.0 cm–1, 1569.0 cm–1), XPS (presence of the O═C–N C 1s peak of DFO at 287.49 eV), and TGA (organic mass fraction). The passage of US-AuNPs-PEG-DFO-89Zr(IV) in skin samples was measured by PET, and the diffusion parameters were extracted thereby. The signals of radioactive US-AuNPs-PEG-DFO-89Zr(IV) leaving the donor compartment, passing through the skin, and entering the acceptor compartment were detected in continuous at concentrations as low as 2.2 nM of Au. The high-sensitivity acquisitions performed in continuous allowed for the first time to extract the lag time to the start of permeation, the lag time to start of the steady state, the diffusion coefficients, and the influx data for AuNPs permeating into the skin. PET could represent a highly valuable tool for the development of nanoparticle-containing topical formulations of drugs and cosmetics

    Multidentate Block-Copolymer-Stabilized Ultrasmall Superparamagnetic Iron Oxide Nanoparticles with Enhanced Colloidal Stability for Magnetic Resonance Imaging

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    Ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) with diameters <5 nm hold great promise as <i>T</i><sub>1</sub>-positive contrast agents for in vivo magnetic resonance imaging. However, control of the surface chemistry of USPIOs to ensure individual colloidal USPIOs with a ligand monolayer and to impart biocompatibility and enhanced colloidal stability is essential for successful clinical applications. Herein, an effective and versatile strategy enabling the development of aqueous colloidal USPIOs stabilized with well-defined multidentate block copolymers (MDBCs) is reported. The multifunctional MDBCs are designed to consist of an anchoring block possessing pendant carboxylates as multidentate anchoring groups strongly bound to USPIO surfaces and a hydrophilic block having pendant hydrophilic oligo­(ethylene oxide) chains to confer water dispersibility and biocompatibility. The surface of USPIOs is saturated with multiple anchoring groups of MDBCs, thus exhibiting excellent long-term colloidal stability as well as enhanced colloidal stability at biologically relevant electrolyte, pH, and temperature conditions. Furthermore, relaxometric properties as well as in vitro and in vivo MR imaging results demonstrate that the MDBC-stabilized USPIO colloids hold great potential as an effective <i>T</i><sub>1</sub> contrast agent

    Intratumoral Injection of Low-Energy Photon-Emitting Gold Nanoparticles: A Microdosimetric Monte Carlo-Based Model

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    Gold nanoparticles (Au NPs) distributed in the vicinity of low-dose rate (LDR) brachytherapy seeds could multiply their efficacy thanks to the secondary emissions induced by the photoelectric effect. Injections of radioactive LDR gold nanoparticles (LDR Au NPs), instead of conventional millimeter-size radioactive seeds surrounded by Au NPs, could further enhance the dose by distributing the radioactivity more precisely and homogeneously in tumors. However, the potential of LDR Au NPs as an emerging strategy to treat cancer is strongly dependent on the macroscopic diffusion of the NPs in tumors, as well as on their microscopic internalization within the cells. Understanding the relationship between interstitial and intracellular distribution of NPs, and the outcomes of dose deposition in the cancer tissue is essential for considering future applications of radioactive Au NPs in oncology. Here, LDR Au NPs (<sup>103</sup>Pd:Pd@Au-PEG NPs) were injected in prostate cancer tumors. The particles were visualized at time-points by computed tomography imaging (<i>in vivo</i>), transmission electron microscopy (<i>ex vivo</i>), and optical microscopy (<i>ex vivo</i>). These data were used in a Monte Carlo-based dosimetric model to reveal the dose deposition produced by LDR Au NPs both at tumoral and cellular scales. <sup>103</sup>Pd:Pd@Au-PEG NPs injected in tumors produce a strong dose enhancement at the intracellular level. However, energy deposition is mainly confined around vesicles filled with NPs, and not necessarily close to the nuclei. This suggests that indirect damage caused by the production of reactive oxygen species might be the leading therapeutic mechanism of tumor growth control, over direct damage to the DNA

    Towards a Multifunctional Electrochemical Sensing and Niosome Generation Lab-on-Chip Platform Based on a Plug-and-Play Concept

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    In this paper, we present a new modular lab on a chip design for multimodal neurotransmitter (NT) sensing and niosome generation based on a plug-and-play concept. This architecture is a first step toward an automated platform for an automated modulation of neurotransmitter concentration to understand and/or treat neurodegenerative diseases. A modular approach has been adopted in order to handle measurement or drug delivery or both measurement and drug delivery simultaneously. The system is composed of three fully independent modules: three-channel peristaltic micropumping system, a three-channel potentiostat and a multi-unit microfluidic system composed of pseudo-Y and cross-shape channels containing a miniature electrode array. The system was wirelessly controlled by a computer interface. The system is compact, with all the microfluidic and sensing components packaged in a 5 cm × 4 cm × 4 cm box. Applied to serotonin, a linear calibration curve down to 0.125 mM, with a limit of detection of 31 ÎŒ M was collected at unfunctionalized electrodes. Added sensitivity and selectivity was achieved by incorporating functionalized electrodes for dopamine sensing. Electrode functionalization was achieved with gold nanoparticles and using DNA and o-phenylene diamine polymer. The as-configured platform is demonstrated as a central component toward an “intelligent” drug delivery system based on a feedback loop to monitor drug delivery

    Rapid Nucleation of Iron Oxide Nanoclusters in Aqueous Solution by Plasma Electrochemistry

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    Progresses in cold atmospheric plasma technologies have made possible the synthesis of nanoparticles in aqueous solutions using plasma electrochemistry principles. In this contribution, a reactor based on microhollow cathodes and operating at atmospheric pressure was developed to synthesize iron-based nanoclusters (nanoparticles). Argon plasma discharges are generated at the tip of the microhollow cathodes, which are placed near the surface of an aqueous solution containing iron salts (FeCl<sub>2</sub> and FeCl<sub>3</sub>) and surfactants (biocompatible dextran). Upon reaction at the plasma–liquid interface, reduction processes occur and lead to the nucleation of ultrasmall iron-based nanoclusters (IONCs). The purified IONCs were investigated by XPS and FTIR, which confirmed that the nucleated clusters contain a highly hydrated form of iron oxide, close to the stoichiometric constituents of α-FeOOH (goethite) or Fe<sub>5</sub>O<sub>3</sub>(OH)<sub>9</sub> (ferrihydrite). Relaxivity values of <i>r</i><sub>1</sub> = 0.40 mM<sup>–1</sup> s<sup>–1</sup> and <i>r</i><sub>2</sub>/<i>r</i><sub>1</sub> = 1.35 were measured (at 1.41 T); these are intermediate values between the relaxometric properties of superparamagnetic iron oxide nanoparticles used in medicine (USPIO) and those of ferritin, an endogenous contrast agent. Plasma-synthesized IONCs were injected into the mouse model and provided positive vascular signal enhancement in <i>T</i><sub>1</sub>-w. MRI for a period of 10–20 min. Indications of rapid and strong elimination through the urinary and gastrointestinal tracts were also found. This study is the first to report on the development of a compact reactor suitable for the synthesis of MRI iron-based contrast media solutions, on site and upon demand
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