Alain Roch

Magnetic iron oxide nanoparticles: synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications.

1. Introduction 20642. Synthesis of Magnetic Nanoparticles 20662.1. Classical Synthesis by Coprecipitation 20662.2. Reactions in Constrained Environments 20682.3. Hydrothermal and High-TemperatureReactions20692.4. Sol-Gel Reactions 20702.5. Polyol Methods 20712.6. Flow Injection Syntheses 20712.7. Electrochemical Methods 20712.8. Aerosol/Vapor Methods 20712.9. Sonolysis 20723. Stabilization of Magnetic Particles 20723.1. Monomeric Stabilizers 20723.1.1. Carboxylates 20733.1.2. Phosphates 20733.2. Inorganic Materials 20733.2.1. Silica 20733.2.2. Gold 20743.3. Polymer Stabilizers 20743.3.1. Dextran 20743.3.2. Polyethylene Glycol (PEG) 20753.3.3. Polyvinyl Alcohol (PVA) 20753.3.4. Alginate 20753.3.5. Chitosan 20753.3.6. Other Polymers 20753.4. Other Strategies for Stabilization 20764. Methods of Vectorization of the Particles 20765. Structural and Physicochemical Characterization 20785.1. Size, Polydispersity, Shape, and SurfaceCharacterization20795.2. Structure of Ferro- or FerrimagneticNanoparticles20805.2.1. Ferro- and Ferrimagnetic Nanoparticles 20805.3. Use of Nanoparticles as Contrast Agents forMRI20825.3.1. High Anisotropy Model 20845.3.2. Small Crystal and Low Anisotropy EnergyLimit20855.3.3. Practical Interests of Magnetic NuclearRelaxation for the Characterization ofSuperparamagnetic Colloid20855.3.4. Relaxation of Agglomerated Systems 20856. Applications 20866.1. MRI: Cellular Labeling, Molecular Imaging(Inflammation, Apoptose, etc.)20866.2.

Theory of proton relaxation induced by superparamagnetic particles

Evaluating and understanding the performances of magnetic colloids as contrast agents for MRI requires a theory describing their magnetic interactions with water protons. The field dependence of the proton longitudinal relaxation rate (nuclear magnetic relaxation dispersion profiles) in aqueous colloidal suspensions of superparamagnetic particles is based on the so-called Curie relaxation, which essentially accounts for the high field part of the NMRD profiles (B0>0.02 T). The low-field part of the NMRD profiles can only be explained by the crystal’s internal anisotropy energy, a concept which clarifies the important difference between superpara- and paramagnetic compounds: the anisotropy energy modifies both the electronic precession frequencies and the thermodynamic probability of occupation of the crystal magnetic states. Our theory clearly explains why a low-field dispersion exists for suspensions of small size crystals, and why it does not for large crystals’ suspensions. This important effect is due...

Magnetic resonance relaxation properties of superparamagnetic particles.

Nanometric crystals of maghemite are known to exhibit superparamagnetism. Because of the significance of their magnetic moment, maghemite nanoparticles are exceptional contrast agents and are used for magnetic resonance imaging (of the liver, spleen, lymph nodes), for magnetic resonance angiography and for molecular and cellular imaging. The relaxivity of these agents depends on their size, saturation magnetization and magnetic field and also on their degree of clustering. There are different types of maghemite particles whose relaxation characteristics are suited to a specific MRI application. The relaxation induced by maghemite particles is caused by the diffusion of water protons in the inhomogeneous field surrounding the particles. This is well described by a theoretical model that takes magnetite crystal anisotropy and Néel relaxation into account. Another type of superparamagnetic compound is ferritin, the iron-storing protein: it contains a superparamagnetic ferrihydrite core. Even if the resulting magnetic moment of ferritin is far smaller than for magnetite nanoparticles, its massive presence in different organs darkens T(2)-weighted MR images, allowing the noninvasive estimation of iron content, thanks to MRI. The relaxation induced by ferritin in aqueous solutions has been demonstrated to be caused by the exchange of protons between bulk water protons and the surface of the ferrihydrite crystal. However, in vivo, the relaxation properties of ferritin are still unexplained, probably because of protein clustering.

Relaxation Induced by Ferritin and Ferritin-Like Magnetic Particles: The Role of Proton Exchange

Proton T1 and T2 in solutions of ferritin and fercayl (a ferritin‐like iron‐dextran particle) solutions were measured, over a wide range of various parameters (Bo, temperature, interecho‐time and pH). The window of the previously referred linear dependence of 1/T2 on the static field was increased, up to 500 MHz, and the independence of T2 on the echo time was confirmed. Correlation times were extracted from T1 nuclear magnetic relaxation dispersion profiles. In the pH range studied, no strong variation of the relaxivities of ferritin solutions was noticed. Fercayl, which, unlike ferritin, remains stable under large pH variations, is characterized by strongly pH‐dependent relaxation rates. This feature is interpreted as due to the effect of proton exchange in the water relaxation process. Outer sphere theory, which ignores proton binding, is shown to be unable to describe the relaxation of ferritin and ferritin‐like particles solutions, first because it predicts a quadratic rate dependence on Bo, but also because it severely underestimates the relaxation rate. Explaining relaxation induced by ferritin and ferritin‐like particle solutions will likely require a model that accounts for proton binding. Magn Reson Med 43:237–243, 2000.

Dy-DTPA derivatives as relaxation agents for very high field MRI: The beneficial effect of slow water exchange on the transverse relaxivities

Proton longitudinal and transverse relaxivities of Dy(DTPA)2− and Dy‐DTPA bisamide derivatives (Dy(DTPA‐BA): Dy‐DTPA bisamide, Dy(DTPA‐BEA): Dy‐DTPA bisethylamide, Dy(DTPA‐BnBA): Dy‐DTPA bis‐n‐butylamide, and Dy(DTPA‐BBMA): Dy‐DTPA bisbismethylamide) were analyzed between 0.47 T and 18.8 T. Curie longitudinal relaxation was clearly observed at magnetic fields larger than 2.4 T, but the longitudinal relaxivities are limited by the fast rotation of the complexes. Rotational correlation times were separately assessed by deuterium relaxometry of the diamagnetic deuterated lanthanum analogs. Transverse relaxivity, which depends on the square of the magnetic field and on the residence time of the coordinated water molecule (τM), was more than 7.5 times larger at 18.8 T and 310 K for Dy(DTPA‐BA) and Dy(DTPA‐BEA) as compared to Dy(DTPA)2−. This difference is mainly related to the slower water exchange of the bisamide complexes, as confirmed by the values of τM measured by oxygen‐17 relaxometry. Such Dy‐complexes, characterized by relatively long τM values (τ M 310 larger than 100 ns but smaller than 1 μs), thus appear to be useful as negative T2 (or transverse) contrast agents for high‐field imaging. This was demonstrated by the spin‐echo images of phantoms obtained at 4.7 T on samples containing Dy(DTPA)2− and Dy(DTPA‐BEA). Magn Reson Med 47:1121–1130, 2002.

Uniform mesoporous silica coated iron oxide nanoparticles as a highly efficient, nontoxic MRI T2 contrast agent with tunable proton relaxivities

Monodisperse mesoporous silica (mSiO(2) ) coated superparamagnetic iron oxide (Fe(3) O(4) @mSiO(2) ) nanoparticles (NPs) have been developed as a potential magnetic resonance imaging (MRI) T(2) contrast agent. To evaluate the effect of surface coating on MRI contrast efficiency, we examined the proton relaxivities of Fe(3) O(4) @mSiO(2) NPs with different coating thicknesses. It was found that the mSiO(2) coating has a significant impact on the efficiency of Fe(3) O(4) NPs for MRI contrast enhancement. The efficiency increases with the thickness of mSiO(2) coating and is much higher than that of the commercial contrast agents. Nuclear magnetic resonance (NMR) relaxometry of Fe(3) O(4) @mSiO(2) further revealed that mSiO(2) coating is partially permeable to water molecules and therefore induces the decrease of longitudinal relaxivity, r(1) . Biocompatibility evaluation of various sized (ca. 35-95 nm) Fe(3) O(4) @mSiO(2) NPs was tested on OC-k3 cells and the result showed that these particles have no negative impact on cell viability. The enhanced MRI efficiency of Fe(3) O(4) @mSiO(2) highlights these core-shell particles as highly efficient T(2) contrast agents with high biocompatibility.

Anomalous nuclear magnetic relaxation of aqueous solutions of ferritin: an unprecedented first-order mechanism.

Ferritin, the iron‐storing protein, speeds up proton transverse magnetic relaxation in aqueous solutions. This T2 shortening is used in MRI to quantify iron in the brain and liver. Current theoretical models underestimate the relaxation enhancement by ferritin at imaging fields, and they do not predict the measured dependence of the rate enhancement on the magnetization of the particles. Here it is shown that a proton exchange dephasing model (PEDM) overcomes these limitations by allowing a first‐order relaxation mechanism. The PEDM considers proton exchange between bulk water and exchangeable protons located at the surface of the hydrated iron oxide nanometric core of the protein. Relaxation is shown to depend on the distribution of the frequency shifts of the adsorption sites; the observed properties agree with a Lorentzian distribution. Computer simulations utilizing recent Mössbauer spectroscopy data show that the distribution of these shifts is effectively Lorentzian. Magn Reson Med 48:959–964, 2002.

Proton magnetic relaxation in superparamagnetic aqueous colloids: a new tool for the investigation of ferrite crystal anisotropy

The effect of the anisotropy energy was evaluated experimentally and theoretically through the study of NMRD curves which represent the dependence of the water proton nuclear relaxation rate on the magnetic field. Evaluation of the NMRD curves of colloids made of ferrite doped with cobalt and magnetite shows that the existence of low field dispersion in the profiles indicates a low anisotropy energy. These experimental results are in agreement with the theory taking into account the Curie relaxation model and including the anisotropy energy in the Hamiltonian describing the magnetic interaction.

RELAXATION BY METAL-CONTAINING NANOSYSTEMS

Publisher Summary Super-paramagnetic (spm) crystals are used as contrast agents for Magnetic Resonance Imaging (MRI). Improving their efficiency requires a better knowledge of their physical and morphological properties that can be deduced from experimental and theoretical studies of proton relaxation in ferrofluids. Colloidal suspensions of super-paramagnetic nanocrystals are candidates for the development of new intelligent contrast agents, opening an early detection of several pathologies. This chapter reviews the parameters influencing the proton relaxation of a nanomagnet suspension. The chapter presents an analysis of NMRD profiles, which provide the relaxivity dependence with the external field, expressed in proton Larmor frequency units. Ferrofluid NMR studies can also be used in order to determine geometrical and physical properties of the super-paramagnetic crystals, like their specific magnetization or radius. They also give valuable information on the aggregation level and on anisotropy.

Nuclear magnetic relaxation dispersion of ferritin and ferritin-like magnetic particle solutions : A pH-effect study

The relaxation mechanism of water protons in the presence of ferritin is still being debated. In this work, the pH dependence of the relaxation induced by ferritin and Fercayl®, a ferritin‐like akaganeite particle, is studied through T1 and T2 nuclear magnetic relaxation dispersion (NMRD) profiles. To differing extents, the relaxation brought about by both systems is significantly affected by pH. A proton exchange time of 33 ns (at pH 6 and 37°C) is deduced from the fittings of Fercayl® T1 NMRD profiles. The linearity of the relationship between 1/T2 and the magnetic field B0 for ferritin and Fercayl® solutions is not altered by changes in pH. The parameters of this linearity strongly depend on pH for the latter, while remaining unchanged for the former. These results are interpreted in terms of an exchange between protons belonging to hydroxyl groups at the surface of the particle and bulk water protons. Magn Reson Med 46:476–481, 2001.