Rocío Costo

Progress in the preparation of magnetic nanoparticles for applications in biomedicine

This review summarizes recent advances in synthesis routes for quickly and reliably making and functionalizing magnetic nanoparticles for applications in biomedicine. We put special emphasis on describing synthetic strategies that result in the production of nanosized materials with well-defined physical and crystallochemical characteristics as well as colloidal and magnetic properties. Rather than grouping the information according to the synthetic route, we have described methods to prepare water-dispersible equiaxial magnetic nanoparticles with sizes below about 10 nm, sizes between 10 and 30 nm and sizes around the monodomain–multidomain magnetic transition. We have also described some recent examples reporting the preparation of anisometric nanoparticles as well as methods to prepare magnetic nanosized materials other than iron oxide ferrites, for example Co and Mn ferrite, FePt and manganites. Finally, we have described examples of the preparation of multicomponent systems with purely inorganic or organic–inorganic characteristics.

Uniform and water stable magnetite nanoparticles with diameters around the monodomain–multidomain limit

A direct method for the preparation of uniform magnetite nanoparticles with sizes around 30?nm and stable in aqueous media at pH 7 has been developed. This method is based on the precipitation of an iron (II) salt (FeSO4) in the presence of a base (NaOH) and a mild oxidant (KNO3). Reaction rate seems to be controlled by the iron salt concentration and the presence of ethanol in the media. Thus lower iron concentration and a water/ethanol ratio equal to one lead to the formation of the smallest particles, 30?nm in diameter. Colloidal suspensions of these particles were directly obtained by simple ultrasonic treatment of the powders leading to very stable ferrofluids at pH 7. Sulphate anions present at the particle surface seem to be responsible for the colloidal stability, providing a biocompatible character to the suspensions. The structural, morphological and magnetic characterization of the nanoparticles is also described and suggests that the smallest particles have a diameter close to the limit between monodomain?multidomain magnetic structure, which could account for the high powder absorption of magnetic fields. According to this calorimetric experiments resulted in specific power absorption rates of ca 80?95?W?g?1, which are among the highest values reported in the literature and make these nanoparticles very interesting for hyperthermia.

Magnetic nanoparticles for power absorption: Optimizing size, shape and magnetic properties

We present a study on the magnetic properties of naked and silica-coated Fe{sub 3}O{sub 4} nanoparticles with sizes between 5 and 110 nm. Their efficiency as heating agents was assessed through specific power absorption (SPA) measurements as a function of particle size and shape. The results show a strong dependence of the SPA with the particle size, with a maximum around 30 nm, as expected for a Neel relaxation mechanism in single-domain particles. The SiO{sub 2} shell thickness was found to play an important role in the SPA mechanism by hindering the heat outflow, thus decreasing the heating efficiency. It is concluded that a compromise between good heating efficiency and surface functionality for biomedical purposes can be attained by making the SiO{sub 2} functional coating as thin as possible. - Graphical Abstract: The magnetic properties of Fe{sub 3}O{sub 4} nanoparticles from 5 to 110 nm are presented, and their efficiency as heating agents discussed as a function of particle size, shape and surface functionalization.

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.

Cytokine adsorption/release on uniform magnetic nanoparticles for localized drug delivery.

Attachment of cytokines to magnetic nanoparticles has been developed as a system for controlled local drug release in cancer therapy. We studied the adsorption/release of murine interferon gamma (IFN-gamma) on negatively charged magnetic nanoparticles prepared by three different methods, including coprecipitation, decomposition in organic media, and laser pyrolysis. To facilitate IFN-gamma adsorption, magnetic nanoparticles were surface modified by distinct molecules to achieve high negative charge at pH 7, maintaining small aggregate size and stability in biological media. We analyzed carboxylate-based coatings and studied the colloidal properties of the resulting dispersions. Finally, we incubated the magnetic dispersions with IFN-gamma and determined optimal conditions for protein adsorption onto the particles, as well as the release capacity at different pH and as a function of time. Particles prepared by decomposition in organic media and further modified with dimercaptosuccinic acid showed the most efficient adsorption/release capacity. IFN-gamma adsorbed on these nanoparticles would allow concentration of this protein or other biomolecules at specific sites for treatment of cancer or other diseases.

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.

Degradation of magnetic nanoparticles mimicking lysosomal conditions followed by AC susceptibility.

Abstract Background: A deeper knowledge on the effects of the degradation of magnetic nanoparticles on their magnetic properties is required to develop tools for the identification and quantification of magnetic nanoparticles in biological media by magnetic means. Methods: Citric acid and phosphonoacetic acid-coated magnetic nanoparticles have been degraded in a medium that mimics lysosomal conditions. Magnetic measurements and transmission electron microscopy have been used to follow up the degradation process. Results: Particle size is reduced significantly in 24 h at pH 4.5 and body temperature. These transformations affect the magnetic properties of the compounds. A reduction of the interparticle interactions is observed just 4 h after the beginning of the degradation process. A strong paramagnetic contribution coming from the degradation products appears with time. Conclusions: A model for the in vivo degradation of magnetic nanoparticles has been followed to gain insight on the changes of the magnetic properties of iron oxides during their degradation. The degradation kinetics is affected by the particle coating, in our case being the phosphonoacetic acid-coated particles degraded faster than the citric acid-coated ones.

Improving magnetic properties of ultrasmall magnetic nanoparticles by biocompatible coatings

This paper deals with the effect of a biocompatible surface coating layer on the magnetic properties of ultrasmall iron oxide nanoparticles. Particles were synthesized by laser pyrolysis and fully oxidized to maghemite by acid treatment. The surface of the magnetic nanoparticles was systematically coated with either phosphonate (phosphonoacetic acid or pamidronic acid) or carboxylate-based (carboxymethyl dextran) molecules and the binding to the nanoparticle surface was analyzed. Magnetic properties at low temperature show a decrease in coercivity and an increase in magnetization after the coating process. Hysteresis loop displacement after field cooling is significantly reduced by the coating, in particular, for particles coated with pamidronic acid, which show a 10% reduction of the displacement of the loop. We conclude that the chemical coordination of carboxylates and phosphonates reduces the surface disorder and enhances the magnetic properties of ultrasmall maghemite nanoparticles.

Time-course assessment of the aggregation and metabolization of magnetic nanoparticles

To successfully develop biomedical applications for magnetic nanoparticles, it is imperative that these nanoreagents maintain their magnetic properties in vivo and that their by-products are safely metabolized. When placed in biological milieu or internalized into cells, nanoparticle aggregation degree can increase which could affect magnetic properties and metabolization. To evaluate these aggregation effects, we synthesized citric acid-coated iron oxide nanoparticles whose magnetic susceptibility can be modified by aggregation in agar dilutions and dextran-layered counterparts that maintain their magnetic properties unchanged. Macrophage models were used for in vitro uptake and metabolization studies, as these cells control iron homeostasis in the organism. Electron microscopy and magnetic susceptibility studies revealed a cellular mechanism of nanoparticle degradation, in which a small fraction of the particles is rapidly degraded while the remaining ones maintain their size. Both nanoparticle types produced similar iron metabolic profiles but these profiles differed in each macrophage model. Thus, nanoparticles induced iron responses that depended on macrophage programming. In vivo studies showed that nanoparticles susceptible to changes in magnetic properties through aggregation effects had different behavior in lungs, liver and spleen. Liver ferritin levels increased in these animals showing that nanoparticles are degraded and their by-products incorporated into normal metabolic routes. These data show that nanoparticle iron metabolization depends on cell type and highlight the necessity to assess nanoparticle aggregation in complex biological systems to develop effective in vivo biomedical applications. STATEMENT OF SIGNIFICANCE Magnetic iron oxide nanoparticles have great potential for biomedical applications. It is however imperative that these nanoreagents preserve their magnetic properties once inoculated, and that their degradation products can be eliminated. When placed in a biological milieu nanoparticles can aggregate and this can affect their magnetic properties and their degradation. In this work, we showed that iron oxide nanoparticles trigger the iron metabolism in macrophages, the main cell type involved in iron homeostasis in the organism. We also show that aggregation can affect nanoparticle magnetic properties when inoculated in animal models. This work confirms iron oxide nanoparticle biocompatibility and highlights the necessity to assess in vivo nanoparticle aggregation to successfully develop biomedical applications.

Studies of the Colloidal Properties of Superparamagnetic Iron Oxide Nanoparticles Functionalized with Platinum Complexes in Aqueous and PBS Buffer Media

The authors would like to thank the Brazilian agencies National Council for Scientific and Technological Development (CNPq: Jovens Pesquisadores em Nanotecnologia grant number 550572/2012-0 and G. B. da Silva was recipient of Science without borders fellowship grant number 279444/2013-9), Brazilian Federal Agency for Support and Evaluation of Graduate Education (CAPES) and Rio de Janeiro Research Foundation (FAPERJ) for financial support. M. D. Vargas and C. M. Ronconi are recipients of CNPq research fellowships. We also thank the Multiuser Laboratory of Material Characterization (http://www.uff.br/lamate/). R. Costo and M. P. Morales would like to thank NANOMAG project (EC FP-7 grant agreement number 604448) for funding. X-ray diffraction, FTIR spectroscopy and thermogravimetric and chemical analysis were carried out in the support laboratories of Instituto de Ciencia de Materiales de Madrid (ICMM/CSIC).