Gorka Salas

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.

Long term biotransformation and toxicity of dimercaptosuccinic acid-coated magnetic nanoparticles support their use in biomedical applications

Although iron oxide magnetic nanoparticles (MNP) have been proposed for numerous biomedical applications, little is known about their biotransformation and long-term toxicity in the body. Dimercaptosuccinic acid (DMSA)-coated magnetic nanoparticles have been proven efficient for in vivo drug delivery, but these results must nonetheless be sustained by comprehensive studies of long-term distribution, degradation and toxicity. We studied DMSA-coated magnetic nanoparticle effects in vitro on NCTC 1469 non-parenchymal hepatocytes, and analyzed their biodistribution and biotransformation in vivo in C57BL/6 mice. Our results indicate that DMSA-coated magnetic nanoparticles have little effect on cell viability, oxidative stress, cell cycle or apoptosis on NCTC 1469 cells in vitro. In vivo distribution and transformation were studied by alternating current magnetic susceptibility measurements, a technique that permits distinction of MNP from other iron species. Our results show that DMSA-coated MNP accumulate in spleen, liver and lung tissues for extended periods of time, in which nanoparticles undergo a process of conversion from superparamagnetic iron oxide nanoparticles to other non-superparamagnetic iron forms, with no significant signs of toxicity. This work provides the first evidence of DMSA-coated magnetite nanoparticle biotransformation in vivo.

Short-chain PEG molecules strongly bound to magnetic nanoparticle for MRI long circulating agents

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 (>10nm) holds promise for biomedical applications.

Relationship between physico-chemical properties of magnetic fluids and their heating capacity

Abstract The final goal in magnetic hyperthermia research is to use nanoparticles in the form of a colloidal suspension injected into human beings for a therapeutic application. Therefore the challenge is not only to develop magnetic nanoparticles with good heating capacities, but also with good colloidal properties, long blood circulation time and with grafted ligands able to facilitate their specific internalisation in tumour cells. Significant advances have been achieved optimising the properties of the magnetic nanoparticles, showing extremely large specific absorption rate values that will contribute to a reduction in the concentration of the magnetic fluid that needs to be administered. In this review we show the effect of different characteristics of the magnetic particles, such as size, size distribution and shape, and the colloidal properties of their aqueous suspensions, such as hydrodynamic size and surface modification, on the heating capacity of the magnetic colloids.

Multiparametric Toxicity Evaluation of SPIONs by High Content Screening Technique: Identification of Biocompatible Multifunctional Nanoparticles for Nanomedicine

Superparamagnetic iron oxide nanoparticles (SPION) have shown potential as multifunctional nanoparticles for theranostic applications. The assessment of toxicity and biocompatibility of the tailored product is, therefore, paramount to deliver commercially sound theranostic tools. In this study, a systematic approach to testing the cytotoxicity of three differently coated SPIONs derived from two synthesis methods (co-precipitation in water and thermal decomposition), with different coatings, and surface charges has been carried out. Toxicity and biocompatibility were investigated by automated high content screening of two breast cancer cell lines (MCF7, and BT474) and healthy (MCF10A) control exposed to incremental doses of the SPIONs up to 24 h in vitro. In the case of iron oxide coated with aminodextran (ADNH), this elicited pronounced effects on the permeability of BT474 with reflected evidence on the cell count reduction and lysosomal mass when compared to the aminopropylsilane (ASi), dimercaptosuccininc acid (DMSA/OD10) coated particles. More subtle effect was observed in the cell count of MCF7 cell line at the highest concentration of ADNH coated nanoparticle. Therefore, from the three cell lines used in this study it is possible to evince subtleness in the cell-specific cytotoxicity response.

Safety assessment of chronic oral exposure to iron oxide nanoparticles.

Iron oxide nanoparticles with engineered physical and biochemical properties are finding a rapidly increasing number of biomedical applications. However, a wide variety of safety concerns, especially those related to oral exposure, still need to be addressed for iron oxide nanoparticles in order to reach clinical practice. Here, we report on the effects of chronic oral exposure to low doses of γ-Fe2O3 nanoparticles in growing chickens. Animal observation, weight, and diet intake reveal no adverse signs, symptoms, or mortality. No nanoparticle accumulation was observed in liver, spleen, and duodenum, with feces as the main excretion route. Liver iron level and duodenal villi morphology reflect the bioavailability of the iron released from the partial transformation of γ-Fe2O3 nanoparticles in the acid gastric environment. Duodenal gene expression studies related to the absorption of iron from γ-Fe2O3 nanoparticles indicate the enhancement of a ferric over ferrous pathway supporting the role of mucins. Our findings reveal that oral administration of iron oxide nanoparticles is a safe route for drug delivery at low nanoparticle doses.

Synthesis of Inorganic Nanoparticles

Abstract Inorganic nanoparticles with tailored optical, electronic, chemical, colloidal and magnetic properties can be synthesized by different methods that allow the control of the nanoparticle size and shape. Current methods for nanoparticle synthesis and surface modification match the requirements for biomedical applications. However, there is still room for improvements in terms of narrower size distributions, improved crystallinity and homogeneity in chemical composition, which will strongly affect the nanoparticle properties. Also, the challenge remains of developing cleaner, less contaminating synthetic routes preserving good colloidal properties.

Inducing glassy magnetism in Co-ferrite nanoparticles through crystalline nanostructure

This work reports on the study of three samples of 8 nm Co-ferrite particles prepared by standard methods based on the thermal decomposition of metal–organic precursors. Although all samples are single phase according to conventional techniques of structural and chemical characterization, they show strongly sample-dependent magnetic properties ranging from bulk-like ferrimagnetism to glassy magnetic behaviour. We show that the presence of crystallite domains associated with crystallographic defects throughout the particles leads to highly-frustrated ferrimagnetic cores that are responsible for the glassy phenomenology, while only samples almost free of structural imperfections show bulk-like magnetic properties. These results suggest the key role of the crystal quality in the large variability of magnetic properties previously reported for Co-ferrite nanoparticles. Besides, achieving control of the amount of structural defects in monodisperse, stoichiometric Co-ferrite nanoparticles can be an additional nano-structuring procedure to tailor their final magnetic properties.