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Trabajo presentado a la 4th Spanish Conference on Biomedical Applications of Nanomaterials (SBAN), celebrada online del 2 al 4 de junio de 2021.

Resumen del trabajo presentado a la 1st Spanish Conference on Biomedical Applications of Nanomaterials (SBAN), celebrada en Madrid del 7 al 8 de junio de 2018., A crucial step for in vivo applications of nanoparticles in general and magnetic carriers in particular is to avoid the retention by the Reticuloendothelial System (RES). Without this requisite, the expectable benefits from nanoparticles in in vivo medical applications (controlled targeted delivery, reduced toxicity, early diagnosis, enhanced imaging sensitivity) will be severely limited. In vitro experiments with macrophage cell cultures (Schöttler, et al. Nat. Nanotechnol. 2016, 11, 372) have shown that an adequate polyethylenglycol (PEG) coating can prevent the macrophages uptake. In this manuscript, we show this effect in vivo using multicore iron oxide nanoparticles, opening the way for efficient targeted delivery of these type of magnetic nanocarriers in the future. The dense PEG coating is realized by Michael reaction of PEG acrylate chains on poly(4-vinylpyridine) nanoparticles embedding the iron oxide cores. Two important findings come along with the low RES retention: 1) a clear MRI contrast in kidneys is obtained for the first time with iron oxide nanoparticles; 2) the nanoparticles are excreted by the urinary system. The conclusions are supported by four independent biodistribution techniques: gamma-imaging, gamma-counting, MRI (Fig 1) and TEM histology. Moreover, the manuscript describes a new procedure for a direct radiolabeling of iron oxide nanoparticles through incorporation in the crystal lattice of 111In3+ ions.

Ferrimagnetic iron oxide nanoparticles (magnetite or maghemite) have been the subject of an intense research, not only for fundamental research but also for their potentiality in a widespread number of practical applications. Most of these studies were focused on nanoparticles with spherical morphology but recently there is an emerging interest on anisometric nanoparticles. This review is focused on the synthesis routes for the production of uniform anisometric magnetite/maghemite nanoparticles with different morphologies like cubes, rods, disks, flowers and many others, such as hollow spheres, worms, stars or tetrapods. We critically analyzed those procedures, detected the key parameters governing the production of these nanoparticles with particular emphasis in the role of the ligands in the final nanoparticle morphology. The main structural and magnetic features as well as the nanotoxicity as a function of the nanoparticle morphology are also described. Finally, the impact of each morphology on the different biomedical applications (hyperthermia, magnetic resonance imaging and drug delivery) are analysed in detail. We would like to dedicate this work to Professor Carlos J. Serna, Instituto de Ciencia de Materiales de Madrid, ICMM/CSIC, for his outstanding contribution in the field of monodispersed colloids and iron oxide nanoparticles. We would like to express our gratitude for all these years of support and inspiration on the occasion of his retirement.

Oral presentation given at the International Magnetics Conference (INTERMAG Europe 2017), held in Dublin (Ireland) on April 24-28th, 2017., The number of biomedical applications using colloidal magnetic iron oxide nanoparticles has been increasing exponentially over the past few years [1]. Several approaches exist to obtain single-core and multi-core particles but the production of particles with good control of the number of magnetic cores per particle, and the degree of polydispersity of both, particle and core sizes is still a difficult task [2-5]. In addition, the magnetic properties of the nanoparticles may change significantly depending on their aggregation degree (and further agglomeration), which depends to a large extent on the synthesis method [6]. The complexity of the problem of understanding the different magnetic properties of single-core and multi-core nanoparticles underlies the importance of reliable synthesis methods able to reproduce nanoparticle size, shape and structural homogeneity. Here, we present different synthesis strategies in organic, polyol and aqueous media for colloidal single-core and multi-core iron oxide nanoparticles for biomedical applications (Fig. 1). We explore the factors determining the monodispersity in terms of size and shape and the core assembly, and discuss their implication on the resulting structural, colloidal and magnetic properties. We will show that reliable and reproducible analysis methods are also needed to characterize the different magnetic particle systems [7]. For example, in order to compare size parameters precisely determined from different methods and models, it is crucial to establish standardized analysis methods and models to extract reliable parameters from the data, which are necessary both for defining magnetic nanoparticle systems and for quality control during the synthesis of magnetic nanoparticles. Many parameters of the synthesis procedure may have a strong effect on the particles obtained, including temperature, reaction time, reagent concentrations, and stirring conditions. This is one of the reasons why scaling-up of some of these synthesis routes is extremely complicated. Indeed, one of the difficulties that particle synthesis faces is batch-to batch reproducibility. Other important difficulty is the fundamental and pressing need to develop more sustainable protocols, using less toxic reagents in a more efficacious manner.

Poster presented at the 11th International Conference on the Scientific and Clinical Applications of Magnetic Carriers, held in Vancouver (BC, Canada) from May 31st to June 4th, 2016., Recent studies on the magnetic properties of ferrihydrite during the aging process to hematite have revealed an intermediate phase with pronounced ferrimagnetism [Michel et al., PNAS, 2010, 107, 2787]. This finding has encouraged the study of the magnetic properties of this new phase as it could be a promising alternative material for biomedical applications. We have prepared a series of samples following the same procedure as to obtain ferrimagnetic (aged) ferrihydrite. In this case, though, a varying amount of dextran was added in the synthesis in order to determine the variations of the relaxometric properties in a context of conceiving this material as an MRI contrast agent. A detailed characterization of the series has been performed by X-ray diffraction, Transmission Electron Microscopy (TEM), AC and DC magnetic measurements and in-solution 1H Nuclear Magnetic Resonance measurements. As suspected, the amount of dextran used during the ferrihydrite nanoparticle synthesis results in a departure of the magnetic properties from those of ferrimagnetic ferrihydrite. The ratios between the transverse and longitudinal relaxivities (r2/r1 ¿ 25) indicate the possible use of dextran coated ferrihydrite as a negative contrast agent but not as a positive one. The detailed magnetic characterization of the series provides more insights on the effect of the dextran amount on the mechanisms of particle growth. Our results explore the particle formation during the synthesis of ferrihydrite in the presence of different amounts of coating and its influence on modifying its magnetic properties.

Oral presentation given at the 7th International Conference on Nanomaterials - Research & Application (NANOCON 2015), held on October 14th-16th, 2015, Brno (Czech Republic)., Recent developments indicate that magnetic nanoparticles could help to improve clinical practice in the treatment of cancer, most probably in synergy with other conventional treatments [1]. There already exist methods to obtain magnetic nanoparticles with the appropriate properties to be used in diagnosis and therapy but these properties need to be optimized to avoid its alteration after intravenous injection, via interaction between the nanoparticles and the blood components, aggregation in lysosomes inside cells or accumulation in tissues [2]. In this work we will describe a number of proven synthesis routes for magnetic nanoparticles intended for their use in biomedical applications [3]. We will show the effect of different characteristics of the magnetic colloids, such as particle size and size distribution, colloidal properties of the aqueous suspensions, such as hydrodynamic size and surface modification, and magnetic properties on their MRI relaxivity and heating capacity. Finally, it will be shown that magnetic nanoparticles biodistribution following systemic administration and its transformation over time can be tracked by AC magnetic susceptibility measurements, which allow identifying and quantifying magnetic nanoparticles in tissues, differentiating them from other endogenous species such as the ferritin iron cores [4]., This work was partially supported by projects from the Spanish Ministry of Economy and Competitiveness (MAT2011-23641), EU-FP7 MULTIFUN project (246479), EU-FP7 NANOMAG (604448), and AXA Research Fund (L.G.).

Poster presented at the 10th International Conference on the Scientific and Clinical Applications of Magnetic Carriers that took place in Dresden (Germany) during June 10-14th, 2014., Several diseases are characterized by an excess of iron in the brain, liver, spleen or heart and magnetic resonance imaging (MRI) is a non-invasive novel alternative for the diagnosis and follow-up of these diseases It is generally accepted that ferrihydrite constitutes the crystal core of ferritin, the storage protein essential to cellular iron metabolism, however, the crystalline structure or the magnetic properties of ferrihydrite, crucial for the knowledge of its relaxometric properties, are still a controversial issue Generally, ferrihydrite has been described to be antiferromagnetic with superparamagnetic behaviour at room temperature Interestingly, recent studies on the magnetic properties of ferrihydrite during the aging process to hematite in the presence of citrates have revealed an intermediate phase with pronounced ferrimagnetism relative to the initial disordered ferrihydrite [Michel et al, PNAS, 2010, 107, 2787] We have prepared a series of samples obtained during the aging process of ferrihydrite to hematite to gain better understanding on the relaxometric properties of biomineralized ferrihydrites, as well as to explore the possibility of optimizing the ferrihydrite aging process to improve the relaxivity of the material for its use as a MRI contrast agent A detailed characterization of ferrihydrite during the aging process in the presence of citrates has been performed by X-ray diffraction, Transmission Electron Microscopy (TEM), AC and DC magnetic measurements and Nuclear Magnetic Resonance measurements An increase on the ferrihydrite nanoparticle average size and saturation magnetization has been found during the aging process The high ratios between the transverse and longitudinal relaxivities (r2/r1) indicate the possible use of ferrihydrite as a negative contrast agent The detailed magnetic characterization of the intermediate phases also shows some sort of spin-glass-like behaviour at low temperatures Our results provide new insights into the magnetic and relaxometric properties of intermediate phases of ferrihydrite during the aging process to hematite, although the unravelling the relationship with the crystalline structure of the nanoparticles is still a challenging goal.

Electrolito nanoestructurado útil para desalinización por osmosis directa. Procedimiento de obtención del electrolito y usos del mismo. El electrolito nanoestructurado basado en nanopartículas magnéticas de óxido de hierro magnético es fácilmente separable con un imán y comprende un ligando recubriendo la superficie unido fuertemente a la nanopartícula por un extremo y en el otro contiene un grupo funcional que proporciona alta presión osmótica para utilizarlo en procesos de potabilización de agua de mar o continental mediante osmosis directa. El electrolito es también reutilizable. La invención también se refiere al procedimiento de fabricación del electrolito y a su uso por ejemplo en procesos de desalinización., Consejo Superior de Investigaciones Científicas (España), Jayim Mayim, A1 Solicitud de patente con informe sobre el estado de la técnica

Paper presented at Latin American Workshop on Magnetism (LAW3M) that took place during 7-12th April 2013., There is an increasing need for magnetic nanoparticles for different applications that could be solved through high-performance techniques producing large quantities of nanoparticles, such as synthesis methods based on precipitation of Fe precursors in aqueous and organic media or aerosol pyrolysis. However, for real industrial applicability (kilogram-scale synthesis), especially in the case of biomedicine, it is necessary to overcome a series of difficulties such as surface disorder for the smallest nanoparticles, internal defects when growing large particles or the high tendency to aggregate in water that strongly affect their magnetic properties and finally their performance for a specific application [1]. Different approaches have been followed to optimize magnetic properties of iron oxide nanoparticles by controlling synthesis parameters. Thus, a considerable increase in the saturation magnetization, Ms (40%), and initial susceptibility of ultrasmall (

La presente invención está dirigida a nanopartículas magnéticas caracterizadas porque comprenden un núcleo de magnetita con bismuto en su superficie, presentan un tamaño comprendido entre 5 nm y 30 nm, incluidos ambos límites, y son de forma octaédrica, cristalinas y monodispersas. Estas nanopartículas presentan entre otras ventajas su elevada imanación de saturación y su opacidad a la hora de obtener imágenes de contraste. Asimismo, constituye otro objeto de la invención el método de obtención de esta nanopartículas, partiendo de una solución hidro-alcohólica. Adicionalmente, la presente invención engloba una suspensión acuosa y una composición farmacéutica que comprenden dichas nanopartículas, así como su uso en biomedicina, principalmente como agente de contraste para detectar flujo sanguíneo o tumores, o para prevenir y tratar tumores al potenciar los efectos del principio activo., Universidad de Extremadura, A1 Solicitud de patente con informe sobre el estado de la técnica

The EC BONSAI Project intends to develop multifunctional nanoparticles with tailored optical and/or magnetic properties for visualizing complex cellular structures (in tissues and organs), receptors, tumor cells and masses. In this framework, here we will report on recent advances on the preparation of luminescent silicon nanoparticles, magnetic iron oxide nanoparticles and Au nanorods for bio-imaging applications

In the present work, a new process for depositing nanoparticle layers onto glass has been developed by using one of the most interesting nanoparticle generation technologies at the moment, which is based on the pyrolysis induced by laser of vapours combined with CVD of the particles onto glass. Nanoparticles prepared by this method were deposited into a hot silica substrate obtaining new nanocomposites with unique properties. The coated glasses present new specific functionalities such as colour, and interesting magnetic and optical properties. Control of the thickness and the iron oxide phase, either magnetic or not, has been achieved by adjusting the experimental conditions. Thus, thickness is controlled by the glass and the precursor temperature, while the iron phase is controlled by the precursor temperature and the nature and the flow of the carrier gas. This process is inexpensive, adaptable to current glass production technologies and takes place at atmospheric pressure.

[EN] New doped inorganic nanocrystals (NC) consisting on iron oxide and other metal integrated into the structure have been synthesized in one-step by adapting the oxidant precipitation synthesis route for magnetite. Different metals have been chosen to confer extra and unique properties to the resulting magnetic hetero-nanostructure: Co and Gd for enhancing transversal and longitudinal relaxivities for magnetic resonance imaging and Bi and Au for achieving X-ray absorption for computed tomography imaging. Apart of that, gold optical properties are interesting for photothermal therapy and iron oxides for magnetic hyperthermia. All metals have been incorporated into the magnetite structure in different ways during the synthesis: by forming a solid solution, by modifying the surface of the NCs, or by co-crystallization with the magnetite. The nanostructure formed in each case depends on the ionic radius of the secondary metal ion and the solubility of its hydroxide that control the co-precipitation in the initial steps of the reaction. Magnetic properties and imaging capabilities of the hetero-nanostructures have been analyzed as a function of the element distribution. Due to the synergistic combination of the different element properties, these magnetic hetero-nanostructures have great potential for biomedical applications., Thanks to the general services from ICMM (X-ray, ICP) and URJC, in particular to Jesus Gonzalez for TEM images, and to the NAP group of Institute of Nanoscience of Aragon (INA), in particular to Laura Asín and Lucía Gutiérrez for the SAR measurement assistance. The work has been supported by the Spanish Ministerio de Ciencia, Innovación y Universidades under the following projects: Project MAT2017-88148-R and PIE-201760E007. STEM/EELS observations at Oak Ridge National Laboratory (ORNL) U.S. Department of Energy (DOE), Basic Energy Sciences (BES), Materials Sciences and Engineering Division and through the Center for Nanophase Materials Sciences (CNMS), which is sponsored by the Scientific User Facilities Division, DOE-BES. Research at UCM supported by MINECO-FEDER MAT2015-66888-C3-3-R. Thanks to SAF2016-79593-P project and to Nanobioapcluster of excellence supported by the Ministry of Economy and Competitiveness of Spanish Government through MAT2016-81955-REDT.

In vitro experiments have shown the great potential of magnetic nanocarriers for multimodal imaging diagnosis and non-invasive therapies. However, their extensive clinical application is still jeopardized by a fast retention in the reticuloendothelial system (RES). The other issue that restrains their potential performance is slow degradation and excretion, which increases their risks of toxicity. We report a promising case in which multicore iron oxide nanoparticles coated with a poly(4-vinylpyridine) polyethylene glycol copolymer show low RES retention and high urinary excretion, as confirmed by single photon emission computerized tomography (SPECT), gamma counting, magnetic resonance imaging (MRI) and electron microscopy (EM) biodistribution studies. These iron oxide-copolymer nanoparticles have a high PEG density in their coating which may be responsible for this effect. Moreover, they show a clear negative contrast in the MR imaging of the kidneys. These nanoparticles with an average hydrodynamic diameter of approximately 20 nm were nevertheless able to cross the glomerulus wall which has an effective pore size of approximately 6 nm. A transmission electron microscopy inspection of kidney tissue revealed the presence of iron containing nanoparticle clusters in proximal tubule cells. This therefore makes them exceptionally useful as magnetic nanocarriers and as new MRI contrast agents for the kidneys., Financial support by the Spanish Ministry of Science and Innovation (MAT2014-52069-R) (SAF2014-53413-R) (PC2015-1-05 (53-80)) is gratefully acknowledged.

We report results of CaCO3 crystallization experiments by counter diffusion in agar gel with two different solid contents (0.5 and 2 wt %) and two solute concentrations (0.1 M CaCl2, 0.1 M Na2CO3; 0.5 M CaCl2, 0.5 M Na2CO3). Solute concentration and hydrogel strength influence the characteristics of the gel–mineral composite formation. High reagent solution concentrations give rise to high supersaturation and high growth rates. When combined with a light gel, single crystal composites form; in a dense gel, the aggregates are mosaic crystal composites. Low reagent solution concentrations result in low supersaturation and low growth rates; when combined with a light gel, single crystal composites form; in a dense gel, the precipitate is a co-oriented polycrystal composite. Gel occlusion within the mineral increases with gel density. Gel distribution inside the mineral is homogeneous for high growth rates. For low growth rates, the gel accumulates locally in the precipitates. Light gels are pushed ahead by the growing crystals, and gel occlusion into the mineral is decreased; at low reagent solution concentrations, slightly more gel gets occluded. In conclusion, agar gel solid content determines the amount of gel occlusion and calcite orientation organization; reagent solution concentration influences the mode of gel distribution inside the mineral/gel composite aggregates., This research was partially funded by projects CGL2013-47988-C2-1-P and CGL2016-77138-C2-1-P (MECC-Spain). M.G. is supported by Deutsche Forschungsgemeinschaft, DFG Grant Gr 959/20-1,2.