Elucidating the Lithiation Process in Fe3-δO4 Nanoparticles by Correlating Magnetic and Structural Properties.

Due to their high potential energy storage, magnetite (Fe3O4) nanoparticles have become appealing as anode materials in lithium-ion batteries. However, the details of the lithiation process are still not completely understood. Here, we investigate chemical lithiation in 70 nm cubic-shaped magnetite nanoparticles with varying degrees of lithiation, x = 0, 0.5, 1, and 1.5. The induced changes in the structural and magnetic properties were investigated using X-ray techniques along with electron microscopy and magnetic measurements. The results indicate that a structural transformation from spinel to rock salt phase occurs above a critical limit for the lithium concentration (xc), which is determined to be between 0.5< xc ≤ 1 for Fe3-δO4. Diffraction and magnetization measurements clearly show the formation of the antiferromagnetic LiFeO2 phase. Upon lithiation, magnetization measurements reveal an exchange bias in the hysteresis loops with an asymmetry, which can be attributed to the formation of mosaic-like LiFeO2 subdomains. The combined characterization techniques enabled us to unambiguously identify the phases and their distributions involved in the lithiation process. Correlating magnetic and structural properties opens the path to increasing the understanding of the processes involved in a variety of nonmagnetic applications of magnetic materials.

Modular Drug-Loaded Nanocapsules with Metal Dome Layers as a Platform for Obtaining Synergistic Therapeutic Biological Activities.

Multifunctional drug-loaded polymer-metal nanocapsules have attracted increasing attention in drug delivery due to their multifunctional potential endowed by drug activity and response to physicochemical stimuli. Current chemical synthesis methods of polymer/metal capsules require specific optimization of the different components to produce particles with precise properties, being particularly complex for Janus structures combining polymers and ferromagnetic and highly reactive metals. With the aim to generate tunable synergistic nanotherapeutic actuation with enhanced drug effects, here we demonstrate a versatile hybrid chemical/physical fabrication strategy to incorporate different functional metals with tailored magnetic, optical, or chemical properties on solid drug-loaded polymer nanoparticles. As archetypical examples, we present poly(lactic-co-glycolic acid) (PLGA) nanoparticles (diameters 100-150 nm) loaded with paclitaxel, indocyanine green, or erythromycin that are half-capped by either Fe, Au, or Cu layers, respectively, with application in three biomedical models. The Fe coating on paclitaxel-loaded nanocapsules permitted efficient magnetic enhancement of the cancer spheroid assembly, with 40% reduction of the cross-section area after 24 h, as well as a higher paclitaxel effect. In addition, the Fe-PLGA nanocapsules enabled external contactless manipulation of multicellular cancer spheroids with a speed of 150 µm/s. The Au-coated and indocyanine green-loaded nanocapsules demonstrated theranostic potential and enhanced anticancer activity in vitro and in vivo due to noninvasive fluorescence imaging with long penetration near-infrared (NIR) light and simultaneous photothermal-photodynamic actuation, showing a 3.5-fold reduction in the tumor volume growth with only 5 min of NIR illumination. Finally, the Cu-coated erythromycin-loaded nanocapsules exhibited enhanced antibacterial activity with a 2.5-fold reduction in the MIC50 concentration with respect to the free or encapsulated drug. Altogether, this technology can extend a nearly unlimited combination of metals, polymers, and drugs, thus enabling the integration of magnetic, optical, and electrochemical properties in drug-loaded nanoparticles to externally control and improve a wide range of biomedical applications.

Efficient Tumor Eradication at Ultralow Drug Concentration via Externally Controlled and Boosted Metallic Iron Magnetoplasmonic Nanocapsules.

With the aim to locally enhance the efficacy of cancer nanotherapies, here we present metal iron based magnetoplasmonic drug-loaded nanocapsules (MAPSULES), merging powerful external magnetic concentration in the tumor and efficient photothermal actuation to locally boost the drug therapeutic action at ultralow drug concentrations. The MAPSULES are composed of paclitaxel-loaded polylactic-co-glycolic acid (PLGA) nanoparticles partially coated by a nanodome shape iron/silica semishell. The iron semishell has been designed to present a ferromagnetic vortex for incorporating a large quantity of ferromagnetic material while maintaining high colloidal stability. The large iron semishell provides very strong magnetic manipulation via magnetophoretic forces, enabling over 10-fold higher trapping efficiency in microfluidic channels than typical superparamagnetic iron oxide nanoparticles. Moreover, the iron semishell exhibits highly damped plasmonic behavior, yielding intense broadband absorbance in the near-infrared biological windows and photothermal efficiency similar to the best plasmonic nanoheaters. The in vivo therapeutic assays in a mouse xenograft tumor model show a high amplification of the therapeutic effects by combining magnetic concentration and photothermal actuation in the tumor, leading to a complete eradication of the tumors at ultralow nanoparticle and drug concentration (equivalent to only 1 mg/kg PLGA nanoparticles containing 8 µg/kg of paclitaxel, i.e., 100-500-fold lower than the therapeutic window of the free and PLGA encapsulated drug and 13-3000-fold lower than current nanotherapies combining paclitaxel and light actuation). These results highlight the strength of this externally controlled and amplified therapeutic approach, which could be applied to locally boost a wide variety of drugs for different diseases.

Direct Evidence of a Graded Magnetic Interface in Bimagnetic Core/Shell Nanoparticles Using Electron Magnetic Circular Dichroism (EMCD).

Interfaces play a crucial role in composite magnetic materials and particularly in bimagnetic core/shell nanoparticles. However, resolving the microscopic magnetic structure of these nanoparticles is rather complex. Here, we investigate the local magnetization of antiferromagnetic/ferrimagnetic FeO/Fe3O4 core/shell nanocubes by electron magnetic circular dichroism (EMCD). The electron energy-loss spectroscopy (EELS) compositional analysis of the samples shows the presence of an oxidation gradient at the interface between the FeO core and the Fe3O4 shell. The EMCD measurements show that the nanoparticles are composed of four different zones with distinct magnetic moment in a concentric, onion-type, structure. These magnetic areas correlate spatially with the oxidation and composition gradient with the magnetic moment being largest at the surface and decreasing toward the core. The results show that the combination of EELS compositional mapping and EMCD can provide very valuable information on the inner magnetic structure and its correlation to the microstructure of magnetic nanoparticles.

Reproducibility and Scalability of Magnetic Nanoheater Synthesis.

The application of magnetic nanoparticles requires large amounts of materials of reproducible quality. This work explores the scaled-up synthesis of multi-core iron oxide nanoparticles through the use of thermal decomposition in organic media and kilograms of reagents. To this end, we check the effect of extending the high temperature step from minutes to hours. To address the intrinsic variability of the colloidal crystallization nucleation process, the experiments were repeated and analyzed statistically. Due to the simultaneity of the nuclei growth and agglomeration steps, the nanostructure of the samples produced was a combination of single- and multi-core nanoparticles. The main characteristics of the materials obtained, as well as the reaction yields, were analyzed and compared. As a general rule, yield, particle size, and reproducibility increase when the time at high temperature is prolonged. The samples obtained were ranked in terms of the reproducibility of different structural, colloidal, and magnetic features. The capability of the obtained materials to act as nanoheaters in magnetic hyperthermia was assessed, showing a strong dependence on the crystallite size (calculated by X-ray diffraction), reflecting the nanoparticle volume with a coherent magnetization reversal.

Precise Size Control of the Growth of Fe3O4 Nanocubes over a Wide Size Range Using a Rationally Designed One-Pot Synthesis.

The physicochemical properties of spinel oxide magnetic nanoparticles depend critically on both their size and shape. In particular, spinel oxide nanocrystals with cubic morphology have shown superior properties in comparison to their spherical counterparts in a variety of fields, like, for example, biomedicine. Therefore, having an accurate control over the nanoparticle shape and size, while preserving the crystallinity, becomes crucial for many applications. However, despite the increasing interest in spinel oxide nanocubes there are relatively few studies on this morphology due to the difficulty to synthesize perfectly defined cubic nanostructures, especially below 20 nm. Here we present a rationally designed synthesis pathway based on the thermal decomposition of iron(III) acetylacetonate to obtain high quality nanocubes over a wide range of sizes. This pathway enables the synthesis of monodisperse Fe3O4 nanocubes with edge length in the 9-80 nm range, with excellent cubic morphology and high crystallinity by only minor adjustments in the synthesis parameters. The accurate size control provides evidence that even 1-2 nm size variations can be critical in determining the functional properties, for example, for improved nuclear magnetic resonance T2 contrast or enhanced magnetic hyperthermia. The rationale behind the changes introduced in the synthesis procedure (e.g., the use of three solvents or adding Na-oleate) is carefully discussed. The versatility of this synthesis route is demonstrated by expanding its capability to grow other spinel oxides such as Co-ferrites, Mn-ferrites, and Mn3O4 of different sizes. The simplicity and adaptability of this synthesis scheme may ease the development of complex oxide nanocubes for a wide variety of applications.

Design strategies for shape-controlled magnetic iron oxide nanoparticles.

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.

Atomic-Scale Determination of Cation Inversion in Spinel-Based Oxide Nanoparticles.

The atomic structure of nanoparticles can be easily determined by transmission electron microscopy. However, obtaining atomic-resolution chemical information about the individual atomic columns is a rather challenging endeavor. Here, crystalline monodispersed spinel Fe3O4/Mn3O4 core-shell nanoparticles have been thoroughly characterized in a high-resolution scanning transmission electron microscope. Electron energy-loss spectroscopy (EELS) measurements performed with atomic resolution allow the direct mapping of the Mn2+/Mn3+ ions in the shell and the Fe2+/Fe3+ in the core structure. This enables a precise understanding of the core-shell interface and of the cation distribution in the crystalline lattice of the nanoparticles. Considering how the different oxidation states of transition metals are reflected in EELS, two methods of performing a local evaluation of the cation inversion in spinel lattices are introduced. Both methods allow the determination of the inversion parameter in the iron oxide core and manganese oxide shell, as well as detecting spatial variations in this parameter, with atomic resolution. X-ray absorption measurements on the whole sample confirm the presence of cation inversion. These results present a significant advance toward a better correlation of the structural and functional properties of nanostructured spinel oxides.

Combining X-Ray Whole Powder Pattern Modeling, Rietveld and Pair Distribution Function Analyses as a Novel Bulk Approach to Study Interfaces in Heteronanostructures: Oxidation Front in FeO/Fe3 O4 Core/Shell Nanoparticles as a Case Study.

Understanding the microstructure in heterostructured nanoparticles is crucial to harnessing their properties. Although microscopy is ideal for this purpose, it allows for the analysis of only a few nanoparticles. Thus, there is a need for structural methods that take the whole sample into account. Here, a novel bulk-approach based on the combined analysis of synchrotron X-ray powder diffraction with whole powder pattern modeling, Rietveld and pair distribution function is presented. The microstructural temporal evolution of FeO/Fe3 O4 core/shell nanocubes is studied at different time intervals. The results indicate that a two-phase approach (FeO and Fe3 O4 ) is not sufficient to successfully fit the data and two additional interface phases (FeO and Fe3 O4 ) are needed to obtain satisfactory fits, i.e., an onion-type structure. The analysis shows that the Fe3 O4 phases grow to some extent (≈1 nm) at the expense of the FeO core. Moreover, the FeO core progressively changes its stoichiometry to accommodate more oxygen. The temporal evolution of the parameters indicates that the structure of the FeO/Fe3 O4 nanocubes is rather stable, although the exact interface structure slightly evolves with time. This approach paves the way for average studies of interfaces in different kinds of heterostructured nanoparticles, particularly in cases where spectroscopic methods have some limitations.

Unravelling the Elusive Antiferromagnetic Order in Wurtzite and Zinc Blende CoO Polymorph Nanoparticles.

Although cubic rock salt-CoO has been extensively studied, the magnetic properties of the main nanoscale CoO polymorphs (hexagonal wurtzite and cubic zinc blende structures) are rather poorly understood. Here, a detailed magnetic and neutron diffraction study on zinc blende and wurtzite CoO nanoparticles is presented. The zinc blende-CoO phase is antiferromagnetic with a 3rd type structure in a face-centered cubic lattice and a Néel temperature of TN (zinc-blende) ≈225 K. Wurtzite-CoO also presents an antiferromagnetic order, TN (wurtzite) ≈109 K, although much more complex, with a 2nd type order along the c-axis but an incommensurate order along the y-axis. Importantly, the overall magnetic properties are overwhelmed by the uncompensated spins, which confer the system a ferromagnetic-like behavior even at room temperature.

Origin of the large dispersion of magnetic properties in nanostructured oxides: Fe(x)O/Fe3O4 nanoparticles as a case study.

The intimate relationship between stoichiometry and physicochemical properties in transition-metal oxides makes them appealing as tunable materials. These features become exacerbated when dealing with nanostructures. However, due to the complexity of nanoscale materials, establishing a distinct relationship between structure-morphology and functionalities is often complicated. In this regard, in the FexO/Fe3O4 system a largely unexplained broad dispersion of magnetic properties has been observed. Here we show, thanks to a comprehensive multi-technique approach, a clear correlation between the magneto-structural properties in large (45 nm) and small (9 nm) FexO/Fe3O4 core/shell nanoparticles that can explain the spread of magnetic behaviors. The results reveal that while the FexO core in the large nanoparticles is antiferromagnetic and has bulk-like stoichiometry and unit-cell parameters, the FexO core in the small particles is highly non-stoichiometric and strained, displaying no significant antiferromagnetism. These results highlight the importance of ample characterization to fully understand the properties of nanostructured metal oxides.

The endocytic penetration mechanism of iron oxide magnetic nanoparticles with positively charged cover: a morphological approach.

In this study we present a morphological approach in observing the interaction of cationic magnetic nanoparticles with A-549 cells (human lung adenocarcinoma). Under our experimental conditions, nanoparticles easily penetrated cells and were observed in vivo, using bright light microscopy. In fixed cells, nanoparticles remained inside cells, showing quantity and distribution patterns similar to those in unfixed cells. The presence of nanoparticles did not affect cell viability or the morphologic parameters assessed. We determined the potential internalization mechanism of nanoparticles into cells using endocytosis inhibitors. The results suggest that nanoparticles used in this study penetrate A-549 cells mainly through a macropinocytosis process.

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.

The influence of surface functionalization on the enhanced internalization of magnetic nanoparticles in cancer cells.

The internalization and biocompatibility of iron oxide nanoparticles surface functionalized with four differently charged carbohydrates have been tested in the human cervical carcinoma cell line (HeLa). Neutral, positive, and negative iron oxide nanoparticles were obtained by coating with dextran, aminodextran, heparin, and dimercaptosuccinic acid, resulting in colloidal suspensions stable at pH 7 with similar aggregate size. No intracellular uptake was detected in cells incubated with neutral charged nanoparticles, while negative particles showed different behaviour depending on the nature of the coating. Thus, dimercaptosuccinic-coated nanoparticles showed low cellular uptake with non-toxic effects, while heparin-coated particles showed cellular uptake only at high nanoparticle concentrations and induced abnormal mitotic spindle configurations. Finally, cationic magnetic nanoparticles show excellent properties for possible in vivo biomedical applications such as cell tracking by magnetic resonance imaging (MRI) and cancer treatment by hyperthermia: (i) they enter into cells with high effectiveness, and are localized in endosomes; (ii) they can be easily detected inside cells by optical microscopy, (iii) they are retained for relatively long periods of time, and (iv) they do not induce any cytotoxicity.

Effect of nanoparticle and aggregate size on the relaxometric properties of MR contrast agents based on high quality magnetite nanoparticles.

Colloidal dispersions of monodispersed and high-crystalline magnetite nanoparticles have been used to establish a relationship between magnetic properties and magnetic resonance (MR) relaxometric parameters in vitro. Magnetite nanoparticles with diameters between 4 and 14 nm were synthesized by thermal decomposition of Fe(acac)3 in different organic solvents and transformed to hydrophilic by changing oleic acid for dimercaptosuccinic acid (DMSA). A final treatment in alkaline water was critical to make the suspension stable at pH 7 with xi-potential values of -45 mV and hydrodynamic sizes as low as 50 nm. Samples showed superparamagnetic behavior at room temperature, which is an important parameter for biomedical applications. Susceptibility increased with both particle and aggregate size, and for particles larger than 9 nm, the aggregate size was the key factor controlling the susceptibility. Relaxivity values followed the same trend as the suspension susceptibilities, indicating that the aggregate size is an important factor above a certain particle size governing the proton relaxation times. The highest relaxivity value, r2=317 s(-1) mM(-1), much higher than those for commercial contrast agents with similar hydrodynamic size, was obtained for a suspension consisting of 9 nm particles and 70 nm of hydrodynamic size, and it was assigned to the higher particle crystallinity in comparison to particles prepared by coprecipitation. Therefore, it can be concluded that in addition to the sample crystallinity, both particle size and aggregate size should be considered in order to explain the magnetic and relaxivity values of a suspension.

A new method for the aqueous functionalization of superparamagnetic Fe2O3 nanoparticles.

A new methodology for the synthesis of hydrophilic iron oxide nanoparticles has been developed. This new method is based on the direct chemical modification of the nanoparticles' surfactant molecules. Using this methodology both USPIO (ultrasmall super paramagnetic iron oxide) (hydrodynamic size smaller than 50 nm) and SPIO (super paramagnetic iron oxide) (hydrodynamic size bigger than 50 nm) were obtained. In addition, we also show that it is possible to further functionalize the hydrophilic nanoparticles via covalent chemistry in water. The magnetic properties of these nanoparticles were also studied, showing their potential as MRI contrast agents.

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.