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This study developed an approach for the synthesis of magnetic nanoparticles coated with three different polyethylene glycol (PEG)-derived molecules. The influence of the coating on different properties of the nanoparticles was studied. Magnetite nanoparticles (7 and 12 nm in diameter) were obtained via thermal decomposition of a coordination complex as an iron precursor to ensure nanoparticle homogeneity in size and shape. Particles were first coated with meso-2,3-dimercaptosuccinic acid by a ligand exchange process to remove oleic acid, followed by modification with three distinct short-chain PEG polymers, which were covalently bound to the nanoparticle surface via 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride activation of the carboxylic acids. In all cases, colloidal suspensions had hydrodynamic sizes <100 nm and low surface charge, demonstrating the effect of PEG coating on the aggregation properties and steric stabilization of the magnetic nanoparticles. The internalization and biocompatibility of these materials in the HeLa human cervical carcinoma cell line were tested. Cells preincubated with PEG-coated iron nanoparticles were visualized outside the cells, and their biocompatibility at high Fe concentrations was demonstrated using a standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Finally, relaxivity parameters (r1 and r2) were used to evaluate the efficiency of suspensions as magnetic resonance imaging contrast agents; the r2 value was similar to that for Resovist and up to four times higher than that for Sinerem, probably due to the larger nanoparticle size. The time of residence in blood of the nanoparticles measured from the relaxivity values, and the Fe content in blood was doubled for rats and rabbits due to the PEG on the nanoparticle surface. The results suggest that this PEGylation strategy for large magnetic nanoparticles (>10 nm) holds promise for biomedical applications., Depto. de Química Física, Fac. de Ciencias Químicas, TRUE, pub

Development of nanosized materials to enhance the image contrast between the normal and diseased tissue and/or to indicate the status of organ functions or blood flow is essential in nuclear magnetic resonance imaging (MRI). Here we describe a contrast agent based on a new iron oxide design (superparamagnetic iron oxide clusters embedded in antiferromagnetic iron oxide porous nanorods). We show as a proof-of-concept that aqueous colloidal suspensions containing these particles show enhanced-proton relaxivities (i.e., enhanced MRI contrast capabilities). A remarkable feature of this new design is that large scale production is possible since aqueous-based routes are used, and porosity and iron oxide superparamagnetic clusters are directly developed from a single phase. We have also proved with the help of a simple model that the physical basis behind the increase in relaxivities lies on both the increase of dipolar field (interactions within iron oxide clusters) and the decrease of proton-cluster distance (porosity favors the close contact between protons and clusters). Finally, a list of possible steps to follow to enhance capabilities of this contrast agent is also included (partial coating with noble metals to add extra sensing capacity and chemical functionality, to increase the amount of doping while simultaneously carrying out cytotoxicity studies, or to find conditions to further decrease the size of the nanorods and to enhance their stability)., Depto. de Química Física, Fac. de Ciencias Químicas, TRUE, pub

The new and unique possibilities that nanomaterials offer have greatly impacted biomedicine, from the treatment and diagnosis of diseases, to the specific and optimized delivery of therapeutic agents. Technological advances in the synthesis, characterization, standardization, and therapeutic performance of nanoparticles have enabled the approval of several nanomedicines and novel applications. Discoveries continue to rise exponentially in all disease areas, from cancer to neurodegenerative diseases. In Spain, there is a substantial net of researchers involved in the development of nanodiagnostics and nanomedicines. In this review, we summarize the state of the art of nanotechnology, focusing on nanoparticles, for the treatment of diseases in Spain (2017–2022), and give a perspective on the future trends and direction that nanomedicine research is taking.

Normalized calculation for SAR values and magnetization relative to the (Fe + Mn) content of the ferrite; FT-IR spectra for S2 and NF NPs, high-resolution XPS spectra and table with the peak position of the Mn 3s orbital for S1, S2, and NF NPs, table with the Mössbauer parameters derived from the spectra recorded at 5 and 270 K, respectively, for the samples under study, and table with AC data fitted to the Arrhenius model; and heating curves of temperature increase as a function of time for the four samples at different frequencies (100 kHz up to 300 kHz) and 16 kA/m.

Stimuli-responsive nanomaterials are very attractive for biomedical applications. They can be activated through external stimuli or by the physico-chemical conditions present in cells or tissues. Here, we describe the preparation of hybrid iron oxide-manganese oxide core-satellite shell nanostructures that change their contrast mode in magnetic resonance imaging (MRI) from T2 to T1, after being internalized by cells. This occurs by the dissolution of the MnO2 of the shell, preserving intact the iron oxide at the core. First, we study the seeded-growth synthesis of iron oxide-manganese oxide nanoparticles studying the effect of varying the core size of the magnetic seeds and the concentration of the surfactant. This allows tuning the size and shape of the final hybrid nanostructure. Then, we show that the shell can be removed by a redox reaction with glutathione, which is naturally present inside the cells at much higher concentrations than outside the cells. Finally, the dissolution of the MnO2 shell and the change in the contrast mode is confirmed in cell cultures. After this process, the iron oxide nanoparticles at the core remain intact and are still active as heating mediators when an alternating magnetic field is applied.

Four different manganese ferrite (MnxFe3–xO4) nanostructures (9 and 15 nm spheres (S1, S2), 18 nm nanoflowers (NFs), and 20 nm cubes (NC)) were prepared in this work through a thermal decomposition method by tuning the critical synthetic parameters. In all of the prepared materials, the cation composition of the ferrite phase was rather similar. The occurrence of a secondary phase of mangano-wüstite within MnxFe3–xO4 nanoparticles and its impact on the magnetic properties were studied in detail from static and dynamic magnetic measurements complemented with Mössbauer spectroscopy, X-ray diffraction, high-resolution transmission electron microscopy (HRTEM) analysis, and X-ray photoelectron spectroscopy (XPS). All of the computed data were consistent with a deterioration of the magnetic output as the reduced phase becomes progressively important, leading to a marked spin disorder and the reduction of either the effective magnetic size or the saturation magnetization. The heating efficiency was measured from 100 up to 300 kHz and from 8 up to 24 kA/m, the NF sample being the one displaying the highest specific absorption rate (SAR) under all tested conditions. These results agreed with the physicochemical and magnetic characterization of the particles, highlighting the interest of the detailed characterization of the particles to understand their heating properties relevant for biomedical applications and others such as catalysis.

©2021 by the authors. Licensee MDPI This work was supported by Fondo de Investigaciones Sanitarias, FIS [PI17/01489] and the Miguel Servet Program [CP11/00147 and CPII16/00056] from Instituto de Salud Carlos III (AAS); RTC-2015-3846-1 (AAS) and RTC-2016-4990-1 (AAS) from Spanish Ministerio de Economia y Competitividad (MINECO)/FEDER funds. GS gratefully acknowledges projects PID2019-106301RB-I00 from Spanish Ministry of Science, Innovation and Universities and NANOMAGCOST-CM, P2018/NMT-4321 from Madrid Regional Government. BCL acknowledges MINECO (FPI program fellowship) from Spain. GFC thanks the funding from Ministerio de Ciencia e Innovacion, Spain (Grant Number PID2019-110895RB-I00). This research has also been supported by a grant awarded to GFC and JBB by the Junta de Comunidades de Castilla-La Mancha, Spain (Grant Number SBPLY/19/180501/000211). GFC and JBB also thank funding from project supported by the James S. Mc. Donnell Foundation 21st Century Science Initiative in Mathematical and Complex Systems Approaches for Brain Cancer (USA) [Collaborative Award 220020560]., Iron oxide nanoparticles (IONPs) are suitable materials for contrast enhancement in magnetic resonance imaging (MRI). Their potential clinical applications range from diagnosis to therapy and follow-up treatments. However, a deeper understanding of the interaction between IONPs, culture media and cells is necessary for expanding the application of this technology to different types of cancer therapies. To achieve new insights of these interactions, a set of IONPs were prepared with the same inorganic core and five distinct coatings, to study their aggregation and interactions in different physiological media, as well as their cell labelling efficiency. Then, a second set of IONPs, with six different core sizes and the same coating, were used to study how the core size affects cell labelling and MRI in vitro. Here, IONPs suspended in biological media experience a partial removal of the coating and adhesion of molecules. The FBS concentration alters the labelling of all types of IONPs and hydrodynamic sizes & GE; 300 nm provide the greatest labelling using the centrifugation-mediated internalization (CMI). The best contrast for MRI results requires a core size range between 12-14 nm coated with dimercaptosuccinic acid (DMSA) producing R_2^* values of 393.7 s_(-1) and 428.3 s_(-1), respectively. These findings will help to bring IONPs as negative contrast agents into clinical settings., Ministerio de Economía y Competitividad (MINECO) / FEDER, Ministerio de Economía y Competitividad (MINECO), Ministerio de Ciencia e Innovación (MICINN), Comunidad de Madrid, Junta de Castilla-La Mancha, Depto. de Física de Materiales, Fac. de Ciencias Físicas, TRUE, pub

Magnetic nanoparticles (MNP) are employed as nanocarriers and in magnetic hyperthermia (MH) for the treatment of cancers. Herein, a smart drug delivery system composed of MNP functionalized with the cytotoxic drug gemcitabine (MNP-GEM) has been thoroughly evaluated. The linker employed is based on a disulfide bond and allows the controlled release of GEM under a highly reducing environment, which is frequently present in the cytoplasm of tumor cells. The stability, MH, and the interaction with plasma proteins of the nanoparticles are evaluated, highlighting their great potential for biological applications. Their cytotoxicity is assessed in three pancreatic cancer cell lines with different sensitivity to GEM, including the generation of reactive oxygen species (ROS), the effects on the cell cycle, and the mechanisms of cell death involved. Remarkably, the proposed nanocarrier is better internalized than unmodified nanoparticles, and it is particularly effective in PANC-1 cells, resistant to GEM, but not in non-tumoral keratinocytes. Additionally, its combination with MH produces a synergistic cytotoxic effect in all cancer cell lines tested. In conclusion, MNP-GEM presents a promising potential for treating pancreatic cancer, due to multiple parameters, such as reduced binding to plasma proteins, increased internalization, and synergistic activity when combined with MH., IMDEA Nanociencia, Comunidad de Madrid, Ministerio de Economía y Competitividad (España), Depto. de Bioquímica y Biología Molecular, Fac. de Ciencias Biológicas, TRUE, pub

[EN] Heat generation by pointlike structures is an appealing concept for its implications in nanotechnology and biomedicine. The way to pump energy that excites heat locally and the synthesis of nanostructures that absorb such energy are key issues in this endeavor. High-frequency alternating magnetic or near-infrared optical fields are used to induce heat in iron oxide nanoparticles, a combined solution that is being exploited in hyperthermia treatments. However, the temperature determination around a single iron oxide nanoparticle remains a challenge. We study the heat released from iron oxide nanostructures under near-infrared illumination on a one-by-one basis by optical tweezers. To measure the temperature, we follow the medium viscosity changes around the trapped particle as a function of the illuminating power, thus avoiding the use of thermal probes. Our results help interpret temperature, a statistical parameter, in the nanoscale and the concept of heat production by nanoparticles under thermal agitation.

[Hypothesis]: Superparamagnetic MnxFe3-xO4 nanoparticles are promising materials for applications in biomedicine and other fields. Small variations in the Mn/Fe ratio have a strong impact on the properties of the nanoparticles. Those variations may be caused by the synthesis itself and by common post-synthesis manipulations like surface modification., [Experiments]: Mn-ferrite nanoparticles have been prepared changing systematically the Mn/Fe ratio of the metal precursors and repeating each reaction three times. Nanoparticles were subjected to surface modification with two different and typical molecules to stabilize them in aqueous media. The discrepancy in the Mn/Fe ratios of the precursors with the ones measured after the synthesis and the surface modification have been studied, as well as its impact on the saturation magnetization, blocking temperature, contrast enhancement for magnetic resonance imaging, magnetic heating, and on the cytotoxicity., [Findings]: Mn is incorporated in the nanoparticles in a relatively lower amount than Fe and, as this report shows for the first time, both Mn and Fe ions leach out from the nanoparticles during the surface modification step. The blocking temperature decreases exponentially as the Mn/Fe ratio increases. The transverse and longitudinal relaxation times and the magnetic heating ability change appreciably even with small variations in the composition.