Preparation of Selenium-Based Drug-Modified Polymeric Ligand-Functionalised Fe3O4 Nanoparticles as Multimodal Drug Carrier and Magnetic Hyperthermia Inductor.

In recent years, much effort has been invested into developing multifunctional drug delivery systems to overcome the drawbacks of conventional carriers. Magnetic nanoparticles are not generally used as carriers but can be functionalised with several different biomolecules and their size can be tailored to present a hyperthermia response, allowing for the design of multifunctional systems which can be active in therapies. In this work, we have designed a drug carrier nanosystem based on Fe3O4 nanoparticles with large heating power and 4-amino-2-pentylselenoquinazoline as an attached drug that exhibits oxidative properties and high selectivity against a variety of cancer malignant cells. For this propose, two samples composed of homogeneous Fe3O4 nanoparticles (NPs) with different sizes, shapes, and magnetic properties have been synthesised and characterised. The surface modification of the prepared Fe3O4 nanoparticles has been developed using copolymers composed of poly(ethylene-alt-maleic anhydride), dodecylamine, polyethylene glycol and the drug 4-amino-2-pentylselenoquinazoline. The obtained nanosystems were properly characterised. Their in vitro efficacy in colon cancer cells and as magnetic hyperthermia inductors was analysed, thereby leaving the door open for their potential application as multimodal agents.

Fe3O4-SiO2 Mesoporous Core/Shell Nanoparticles for Magnetic Field-Induced Ibuprofen-Controlled Release.

Hybrid magnetic nanoparticles made up of an iron oxide, Fe3O4, core and a mesoporous SiO2 shell with high magnetization and a large surface area were proposed as an efficient drug delivery platform. The core/shell structure was synthesized by two seed-mediated growth steps combining solvothermal and sol-gel approaches and using organic molecules as a porous scaffolding template. The system presents a mean particle diameter of 30(5) nm (9 nm magnetic core diameter and 10 nm silica shell thickness) with superparamagnetic behavior, saturation magnetization of 32 emu/g, and a significant AC magnetic-field-induced heating response (SAR = 63 W/gFe3O4, measured at an amplitude of 400 Oe and a frequency of 307 kHz). Using ibuprofen as a model drug, the specific surface area (231 m2/g) of the porous structure exhibits a high molecule loading capacity (10 wt %), and controlled drug release efficiency (67%) can be achieved using the external AC magnetic field for short time periods (5 min), showing faster and higher drug desorption compared to that of similar stimulus-responsive iron oxide-based nanocarriers. In addition, it is demonstrated that the magnetic field-induced drug release shows higher efficiency compared to that of the sustained release at fixed temperatures (47 and 53% for 37 and 42 °C, respectively), considering that the maximum temperature reached during the exposure to the magnetic field is well below (31 °C). Therefore, it can be hypothesized that short periods of exposure to the oscillating field induce much greater heating within the nanoparticles than in the external solution.

Iron Oxide Nanorings and Nanotubes for Magnetic Hyperthermia: The Problem of Intraparticle Interactions.

Magnetic interactions can play an important role in the heating efficiency of magnetic nanoparticles. Although most of the time interparticle magnetic interactions are a dominant source, in specific cases such as multigranular nanostructures intraparticle interactions are also relevant and their effect is significant. In this work, we have prepared two different multigranular magnetic nanostructures of iron oxide, nanorings (NRs) and nanotubes (NTs), with a similar thickness but different lengths (55 nm for NRs and 470 nm for NTs). In this way, we find that the NTs present stronger intraparticle interactions than the NRs. Magnetometry and transverse susceptibility measurements show that the NTs possess a higher effective anisotropy and saturation magnetization. Despite this, the AC hysteresis loops obtained for the NRs (0-400 Oe, 300 kHz) are more squared, therefore giving rise to a higher heating efficiency (maximum specific absorption rate, SARmax = 110 W/g for the NRs and 80 W/g for the NTs at 400 Oe and 300 kHz). These results indicate that the weaker intraparticle interactions in the case of the NRs are in favor of magnetic hyperthermia in comparison with the NTs.

Exploring the potential of the dynamic hysteresis loops via high field, high frequency and temperature adjustable AC magnetometer for magnetic hyperthermia characterization.

AIM: The Specific Absorption Rate (SAR) is the key parameter to optimize the effectiveness of magnetic nanoparticles in magnetic hyperthermia. AC magnetometry arises as a powerful technique to quantify the SAR by computing the hysteresis loops' area. However, currently available devices produce quite limited magnetic field intensities, below 45mT, which are often insufficient to obtain major hysteresis loops and so a more complete and understandable magneticcharacterization. This limitation leads to a lack of information concerning some basic properties, like the maximum attainable (SAR) as a function of particles' size and excitation frequencies, or the role of the mechanical rotation in liquid samples. METHODS: To fill this gap, we have developed a versatile high field AC magnetometer, capable of working at a wide range of magnetic hyperthermia frequencies (100 kHz - 1MHz) and up to field intensities of 90mT. Additionally, our device incorporates a variable temperature system for continuous measurements between 220 and 380 K. We have optimized the geometrical properties of the induction coil that maximize the generated magnetic field intensity. RESULTS: To illustrate the potency of our device, we present and model a series of measurements performed in liquid and frozen solutions of magnetic particles with sizes ranging from 16 to 29 nm. CONCLUSION: We show that AC magnetometry becomes a very reliable technique to determine the effective anisotropy constant of single domains, to study the impact of the mechanical orientation in the SAR and to choose the optimal excitation parameters to maximize heating production under human safety limits.

Unlocking the Potential of Magnetotactic Bacteria as Magnetic Hyperthermia Agents.

Magnetotactic bacteria are aquatic microorganisms that internally biomineralize chains of magnetic nanoparticles (called magnetosomes) and use them as a compass. Here it is shown that magnetotactic bacteria of the strain Magnetospirillum gryphiswaldense present high potential as magnetic hyperthermia agents for cancer treatment. Their heating efficiency or specific absorption rate is determined using both calorimetric and AC magnetometry methods at different magnetic field amplitudes and frequencies. In addition, the effect of the alignment of the bacteria in the direction of the field during the hyperthermia experiments is also investigated. The experimental results demonstrate that the biological structure of the magnetosome chain of magnetotactic bacteria is perfect to enhance the hyperthermia efficiency. Furthermore, fluorescence and electron microscopy images show that these bacteria can be internalized by human lung carcinoma cells A549, and cytotoxicity studies reveal that they do not affect the viability or growth of the cancer cells. A preliminary in vitro hyperthermia study, working on clinical conditions, reveals that cancer cell proliferation is strongly affected by the hyperthermia treatment, making these bacteria promising candidates for biomedical applications.

Mn-Doping level dependence on the magnetic response of MnxFe3-xO4 ferrite nanoparticles.

Manganese/iron ferrite nanoparticles with different Mn2+/3+ doping grades have been prepared by a thermal decomposition optimized approach so as to ascertain the doping effect on magnetic properties and, especially, on the magnetic hyperthermia response. The oxidation state and interstitial position of Mn in the spinel structure is found to be critical. The particle size effect has also been studied by growing one of the prepared samples (from 10 to 15 nm in diameter) by a seed mediated growth mechanism. After analyzing the main structural and chemical parameters such as the Mn/Fe rate, crystalline structure, particle diameter, shape and organic coating, some Mn doping induced changes have been observed, such as the insertion of Mn2+ cations yielded more anisotropic shapes. Magnetic characterization, carried out by DC magnetometry (M(H), M(T)) and electron magnetic resonance (EMR) techniques, has shown interesting differences between samples with varying compositions. Lower Mn doping levels lead to larger saturation magnetization values, while an increase of the Mn content causes the decrease of the effective magnetic anisotropy constant at low T. The homogeneous magnetic response under applied magnetic fields, together with the great effect of nanoparticle size and shape in such a response, has been confirmed by the EMR analysis. Finally, a detailed magnetic hyperthermia analysis has demonstrated the large influence of NP size and shape on the magnetic hyperthermia response. The optimized Mn0.13Fe2.87O4_G sample with a diameter of 15 nm and slightly truncated octahedral shape is presented as an interesting candidate for future magnetic hyperthermia mediated biomedical treatments.

RGD-Functionalized Fe3O4 nanoparticles for magnetic hyperthermia.

To improve the selectivity of magnetic nanoparticles for tumor treatment by hyperthermia, Fe3O4 nanoparticles have been functionalized with a peptide of the type arginine-glycine-aspartate (RGD) following a "click" chemistry approach. The RGD peptide was linked onto the previously coated nanoparticles in order to target αvß3 integrin receptors over-expressed in angiogenic cancer cells. Different coatings have been analyzed to enhance the biocompatibility of magnetic nanoparticles. Monodispersed and homogeneous magnetite nanoparticles have been synthesized by the seed growth method and have been characterized using X-ray diffraction, thermogravimetric analysis, infrared spectroscopy, transmission electron microscopy and magnetic measurements. The magnetic hyperthermia efficiency of the nanoparticles has also been investigated and cytotoxicity assays have been perfomed for functionalized nanoparticles.

Tuning Sizes, Morphologies, and Magnetic Properties of Monocore Versus Multicore Iron Oxide Nanoparticles through the Controlled Addition of Water in the Polyol Synthesis.

The polyol route is a versatile and up-scalable method to produce large batches of iron oxide nanoparticles with well-defined structures and magnetic properties. Importance of parameters such as temperature and reaction time, heating profile, nature of the polyol solvent or organometallic precursors on nanostructure and properties has already been described in the literature. Yet, the crucial role of water in the forced hydrolysis pathway has never been reported, despite its mandatory presence for nanoparticle production. This communication investigates the influence of the water amount and temperature at which it is injected in the reflux system for either a pure polyol solvent system or a mixture with poly(hydroxy)amine. Distinct morphologies of nanoparticles were thereby obtained, from ultra-ultra-small smooth spheres down to 4 nm in diameter to larger ones up to 37 nm. Well-defined multicore assemblies with narrow grain size dispersity termed nanoflowers were also synthesized. A diverse and large library of samples was obtained by manipulating the nature of solvents and the amount of added water while keeping all other parameters constant. The different morphologies lead to magnetic nanoparticles suitable for important biomedical applications such as magnetic hyperthermia, magnetic resonance imaging (MRI) contrast agent, or both.

In Vivo Imaging of Local Gene Expression Induced by Magnetic Hyperthermia.

The present work aims to demonstrate that colloidal dispersions of magnetic iron oxide nanoparticles stabilized with dextran macromolecules placed in an alternating magnetic field can not only produce heat, but also that these particles could be used in vivo for local and noninvasive deposition of a thermal dose sufficient to trigger thermo-induced gene expression. Iron oxide nanoparticles were first characterized in vitro on a bio-inspired setup, and then they were assayed in vivo using a transgenic mouse strain expressing the luciferase reporter gene under transcriptional control of a thermosensitive promoter. Iron oxide nanoparticles dispersions were applied topically on the mouse skin or injected subcutaneously with Matrigel™ to generate so-called pseudotumors. Temperature was monitored continuously with a feedback loop to control the power of the magnetic field generator and to avoid overheating. Thermo-induced luciferase expression was followed by bioluminescence imaging 6 h after heating. We showed that dextran-coated magnetic iron oxide nanoparticle dispersions were able to induce in vivo mild hyperthermia compatible with thermo-induced gene expression in surrounding tissues and without impairing cell viability. These data open new therapeutic perspectives for using mild magnetic hyperthermia as noninvasive modulation of tumor microenvironment by local thermo-induced gene expression or drug release.

Enhanced magnetic anisotropy and heating efficiency in multi-functional manganese ferrite/graphene oxide nanostructures.

A promising nanocomposite material composed of MnFe2O4 (MFO) nanoparticles of ∼17 nm diameter deposited onto graphene oxide (GO) nanosheets was successfully synthesized using a modified co-precipitation method. X-ray diffraction, transmission electron microscopy, and selected area electron diffraction confirmed the quality of the synthesized samples. Fourier transform infrared measurements and analysis evidenced that the MFO nanoparticles were attached to the GO surface. Magnetic measurements and analysis using the modified Langevin model evidenced the superparamagnetic characteristic of both the bare MFO nanoparticles and the MFO-GO nanocomposite at room temperature, and an appreciable increase of the effective anisotropy for the MFO-GO sample. Magnetic hyperthermia experiments performed by both calorimetric and ac magnetometry methods indicated that relative to the bare MFO nanoparticles, the heating efficiency of the MFO-GO nanocomposite was similar at low ac fields (0-300 Oe) but became progressively larger with increasing ac fields (>300 Oe). This has been related to the higher effective anisotropy of the MFO-GO nanocomposite. In comparison with the bare MFO nanoparticles, a smaller reduction in the heating efficiency was observed in the MFO-GO composites when embedded in agar or when their concentration was increased, indicating that the GO helped minimize the physical rotation and aggregation of the MFO nanoparticles. These findings can be of practical importance in exploiting this type of nanocomposite for advanced hyperthermia. Magnetoimpedance-based biodetection studies also indicated that the MFO-GO nanocomposite could be used as a promising magnetic biomarker in biosensing applications.

Antitumor magnetic hyperthermia induced by RGD-functionalized Fe3O4 nanoparticles, in an experimental model of colorectal liver metastases.

This work reports important advances in the study of magnetic nanoparticles (MNPs) related to their application in different research fields such as magnetic hyperthermia. Nanotherapy based on targeted nanoparticles could become an attractive alternative to conventional oncologic treatments as it allows a local heating in tumoral surroundings without damage to healthy tissue. RGD-peptide-conjugated MNPs have been designed to specifically target αVß3 receptor-expressing cancer cells, being bound the RGD peptides by "click chemistry" due to its selectivity and applicability. The thermal decomposition of iron metallo-organic precursors yield homogeneous Fe3O4 nanoparticles that have been properly functionalized with RGD peptides, and the preparation of magnetic fluids has been achieved. The nanoparticles were characterized by transmission electron microscopy (TEM), vibrating sample magnetometry (VSM), electron magnetic resonance (EMR) spectroscopy and magnetic hyperthermia. The nanoparticles present superparamagnetic behavior with very high magnetization values, which yield hyperthermia values above 500 W/g for magnetic fluids. These fluids have been administrated to rats, but instead of injecting MNP fluid directly into liver tumors, intravascular administration of MNPs in animals with induced colorectal tumors has been performed. Afterwards the animals were exposed to an alternating magnetic field in order to achieve hyperthermia. The evolution of an in vivo model has been described, resulting in a significant reduction in tumor viability.

Specific absorption rate dependence on temperature in magnetic field hyperthermia measured by dynamic hysteresis losses (ac magnetometry).

Magnetic nanoparticles (NPs) are intensively studied for their potential use for magnetic hyperthermia, a treatment that has passed a phase II clinical trial against severe brain cancer (glioblastoma) at the end of 2011. Their heating power, characterized by the 'specific absorption rate (SAR)', is often considered temperature independent in the literature, mainly because of the difficulties that arise from the measurement methodology. Using a dynamic magnetometer presented in a recent paper, we measure here the thermal dependence of SAR for superparamagnetic iron oxide (maghemite) NPs of four different size-ranges corresponding to mean diameters around 12 nm, 14 nm, 15 nm and 16 nm. The article reports a parametrical study extending from 10 to 60 °C in temperature, from 75 to 1031 kHz in frequency, and from 2 to 24 kA m(-1) in magnetic field strength. It was observed that SAR values of smaller NPs decrease with temperature whereas for the larger sample (16 nm) SAR values increase with temperature. The measured variation of SAR with temperature is frequency dependent. This behaviour is fully explained within the scope of linear response theory based on Néel and Brown relaxation processes, using independent magnetic measurements of the specific magnetization and the magnetic anisotropy constant. A good quantitative agreement between experimental values and theoretical values is confirmed in a tri-dimensional space that uses as coordinates the field strength, the frequency and the temperature.

Fe3O4 nanoparticles prepared by the seeded-growth route for hyperthermia: electron magnetic resonance as a key tool to evaluate size distribution in magnetic nanoparticles.

Monodispersed Fe3O4 nanoparticles have been synthesized by a thermal decomposition method based on the seeded-growth technique, achieving size tunable nanoparticles with high crystallinity and high saturation magnetization. EMR spectroscopy becomes a very efficient complementary tool to determine the fine details of size distributions of MNPs and even to estimate directly the size in a system composed of a given type of magnetic nanoparticles. The size and size dispersity affect directly the efficiency of MNPs for hyperthermia and EMR provides a direct evaluation of these characteristics almost exactly in the same preparation and with the same concentration as used in hyperthermia experiments. The correlation observed between the Specific Absorption Rate (SAR) and the effective gyromagnetic factor (geff) is extremely remarkable and renders a way to assess directly the heating capacity of a MNP system.