M. Puerto Morales

Controlled synthesis of uniform magnetite nanocrystals with high-quality properties for biomedical applications

Uniform iron oxide magnetic nanoparticles, with sizes in the range 9–22 nm, have been synthesized by thermal decomposition of an iron oleate complex in 1-octadecene, controlling reaction parameters related to the nucleation and growth processes. After transferring to water through a ligand substitution process, nanoparticles display very good magnetic and magneto-thermal properties. The relationship between these properties and the size and size distribution of the particles is discussed. The colloidal stability of the nanoparticles dispersed in common biological buffers has also been studied.

Efficient and safe internalization of magnetic iron oxide nanoparticles: two fundamental requirements for biomedical applications.

UNLABELLED We have performed a series of in vitro tests proposed for the reliable assessment of safety associated with nanoparticles-cell interaction. A thorough analysis of toxicity of three different coating iron oxide nanoparticles on HeLa cells has been carried out including, methyl thiazol tetrazolium bromide (MTT) and Trypan blue exclusion tests, cell morphology observation by optical and Scanning Electron Microscopy (SEM), study of cytoskeletal components, analysis of cell cycle and the presence of reactive oxygen species (ROS). We have quantified magnetic nanoparticle internalization, determined possible indirect cell damages and related it to the nanoparticle coating. The results confirm a very low toxicity of the analyzed iron oxide nanoparticles into HeLa cells by multiple assays and pave the way for a more successful cancer diagnostic and treatment without secondary effects. FROM THE CLINICAL EDITOR In this paper, three different iron oxide nanoparticles are studied and compared from the standpoint of safety and toxicity in HeLa cells, demonstrating low toxicity for each preparation, and paving the way to potential future clinical applications.

Ultrasmall Iron Oxide Nanoparticles for Biomedical Applications: Improving the Colloidal and Magnetic Properties

A considerable increase in the saturation magnetization, M(s) (40%), and initial susceptibility of ultrasmall (<5 nm) iron oxide nanoparticles prepared by laser pyrolysis was obtained through an optimized acid treatment. Moreover, a significant enhancement in the colloidal properties, such as smaller aggregate sizes in aqueous media and increased surface charge densities, was found after this chemical protocol. The results are consistent with a reduction in nanoparticle surface disorder induced by a dissolution-recrystallization mechanism.

Liver and brain imaging through dimercaptosuccinic acid-coated iron oxide nanoparticles

BACKGROUND & AIM Uptake, cytotoxicity and interaction of improved superparamagnetic iron oxide nanoparticles were studied in cells, tissues and organs after single and multiple exposures. MATERIAL & METHOD We prepared dimercaptosuccinic acid-coated iron oxide nanoparticles by thermal decomposition in organic medium, resulting in aqueous suspensions with a small hydrodynamic size (< 100 nm), high saturation magnetization and susceptibility, high nuclear magnetic resonance contrast and low cytotoxicity. RESULTS In vitro and in vivo behavior showed that these nanoparticles are efficient carriers for drug delivery to the liver and brain that can be combined with MRI detection.

Deferiprone and idebenone rescue frataxin depletion phenotypes in a Drosophila model of Friedreich's ataxia.

Friedreichs ataxia (FRDA), the most common inherited ataxia, is a neurodegenerative disease caused by a reduction in the levels of the mitochondrial protein frataxin, the function of which remains a controversial matter. Several therapeutic approaches are being developed to increase frataxin expression and reduce the intramitochondrial iron aggregates and oxidative damage found in this disease. In this study, we tested separately the response of a Drosophila RNAi model of FRDA (Llorens et al., 2007) to treatment with the iron chelator deferiprone (DFP) and the antioxidant idebenone (IDE), which are both in clinical trials. The FRDA flies have a shortened life span and impaired motor coordination, and these phenotypes are more pronounced in oxidative stress conditions. In addition, under hyperoxia, the activity of the mitochondrial enzyme aconitase is strongly reduced in the FRDA flies. This study reports that DFP and IDE improve the life span and motor ability of frataxin-depleted flies. We show that DFP eliminates the excess of labile iron in the mitochondria and thus prevents the toxicity induced by iron accumulation. IDE treatment rescues aconitase activity in hyperoxic conditions. These results validate the use of our Drosophila model of FRDA to screen for therapeutic molecules to treat this disease.

Large scale production of biocompatible magnetite nanocrystals with high saturation magnetization values through green aqueous synthesis

In this work, a straightforward aqueous synthesis for mass production (up to 20 g) of uniform and crystalline magnetite nanoparticles with core sizes between 20 and 30 nm, which are the optimum nanoparticle core sizes for hyperthermia applications, is proposed. Magnetic and heating properties have been analyzed showing very high saturation magnetization and magnetic heating values. To stabilize the naked magnetite nanocrystals at physiological pH and increase their circulation time in blood, they have been covalently coated with carboxymethyl dextran, a biocompatible polymer. The influence of this superficial modification on the magnetic and heating properties has been studied showing that these biocompatible magnetic nanocrystals maintain high saturation magnetization values, good colloidal stability and hyperthermia properties in the presence of the polymeric external layer. These particles, suitably functionalized, could be used to selectively kill cancer cells under a moderate alternating magnetic field (44 mT and 70 kHz).

Fast synthesis and bioconjugation of (68) Ga core-doped extremely small iron oxide nanoparticles for PET/MR imaging.

Combination of complementary imaging techniques, like hybrid PET/MRI, allows protocols to be developed that exploit the best features of both. In order to get the best of these combinations the use of dual probes is highly desirable. On this sense the combination of biocompatible iron oxide nanoparticles and 68Ga isotope is a powerful development for the new generation of hybrid systems and multimodality approaches. Our objective was the synthesis and application of a chelator-free 68Ga-iron oxide nanotracer with improved stability, radiolabeling yield and in vivo performance in dual PET/MRI. We carried out the core doping of iron oxide nanoparticles, without the use of any chelator, by a microwave-driven protocol. The synthesis allowed the production of extremely small (2.5 nm) 68Ga core-doped iron oxide nanoparticles. The microwave approach allowed an extremely fast synthesis with a 90% radiolabeling yield and T1 contrast in MRI. With the same microwave approach the nano-radiotracer was functionalized in a fast and efficient way. We finally evaluated these dual targeting nanoparticles in an angiogenesis murine model by PET/MR imaging. Copyright

In-situ particles reorientation during magnetic hyperthermia application: Shape matters twice

Promising advances in nanomedicine such as magnetic hyperthermia rely on a precise control of the nanoparticle performance in the cellular environment. This constitutes a huge research challenge due to difficulties for achieving a remote control within the human body. Here we report on the significant double role of the shape of ellipsoidal magnetic nanoparticles (nanorods) subjected to an external AC magnetic field: first, the heat release is increased due to the additional shape anisotropy; second, the rods dynamically reorientate in the orthogonal direction to the AC field direction. Importantly, the heating performance and the directional orientation occur in synergy and can be easily controlled by changing the AC field treatment duration, thus opening the pathway to combined hyperthermic/mechanical nanoactuators for biomedicine. Preliminary studies demonstrate the high accumulation of nanorods into HeLa cells whereas viability analysis supports their low toxicity and the absence of apoptotic or necrotic cell death after 24 or 48 h of incubation.

FeCo magnetic nanoneedles obtained by Co-coating haematite

Uniform FeCo magnetic nanoneedles of ?nm in width and axial ratio have been obtained by Co-coating haematite and subsequent hydrogen reduction in two steps. By this method, FeCo needle-like nanoparticles were obtained with Co contents up to 10% evenly distributed inside the particles. Higher Co contents up to 30% were incorporated by coating the Co-doped magnetite nanoneedles. No segregation of a secondary phase was observed in any case and the morphology of the particles was preserved without adding any extra element. Structural changes during the reduction process have been followed by several techniques. Although protected by an oxide layer, the final metal nanoparticles behave as single crystals, but they are composed of sub-crystals with the same crystallographic orientation and a mean diameter that decreases as the Co content increases. We found the highest reported saturation magnetization values for samples of similar size (180?emu?g?1). The evolution of the coercivity with the cobalt modification could arise from the changes of the microstructure and the contributions of shape and crystalline anisotropies. Time dependence magnetization measurements showed the thermal activation to be related to the presence of crystallographic sub-units within the nanoneedles.

One-Step Fast Synthesis of Nanoparticles for MRI: Coating Chemistry as the Key Variable Determining Positive or Negative Contrast

Iron oxide nanomaterial is a typical example of a magnetic resonance imaging probe for negative contrast. It has also been shown how this nanomaterial can be synthesized for positive contrast by modification of the composition and size of the core. However, the role of the organic coating in the relaxometric properties is largely unexplored. Here, maghemite nanoparticles with either excellent positive or very good negative contrast performance are obtained by modifying coating thickness while the core is kept unchanged. Different nanoparticles with tailored features as contrast agent according to the coating layer thickness have been obtained in a single-step microwave-driven synthesis by heating at different temperatures. A comprehensive analysis is conducted of how the composition and structure of the coating affects the final magnetic, relaxometric, and imaging performance. These results show how the organic coating plays a fundamental role in the intrinsic relaxometric parameters of iron oxide-based contrast media.