Hybrid core-shell nanoparticles for cell-specific magnetic separation and photothermal heating.

Hyperthermia, as the process of heating a malignant site above 42 °C to trigger cell death, has emerged as an effective and selective cancer therapy strategy. Various modalities of hyperthermia have been proposed, among which magnetic and photothermal hyperthermia are known to benefit from the use of nanomaterials. In this context, we introduce herein a hybrid colloidal nanostructure comprising plasmonic gold nanorods (AuNRs) covered by a silica shell, onto which iron oxide nanoparticles (IONPs) are subsequently grown. The resulting hybrid nanostructures are responsive to both external magnetic fields and near-infrared irradiation. As a result, they can be applied for the targeted magnetic separation of selected cell populations - upon targeting by antibody functionalization - as well as for photothermal heating. Through this combined functionality, the therapeutic effect of photothermal heating can be enhanced. We demonstrate both the fabrication of the hybrid system and its application for targeted photothermal hyperthermia of human glioblastoma cells.

Magnetic Anisotropy of Individual Nanomagnets Embedded in Biological Systems Determined by Axi-asymmetric X-ray Transmission Microscopy.

Over the past few years, the use of nanomagnets in biomedical applications has increased. Among others, magnetic nanostructures can be used as diagnostic and therapeutic agents in cardiovascular diseases, to locally destroy cancer cells, to deliver drugs at specific positions, and to guide (and track) stem cells to damaged body locations in regenerative medicine and tissue engineering. All these applications rely on the magnetic properties of the nanomagnets which are mostly determined by their magnetic anisotropy. Despite its importance, the magnetic anisotropy of the individual magnetic nanostructures is unknown. Currently available magnetic sensitive microscopic methods are either limited in spatial resolution or in magnetic field strength or, more relevant, do not allow one to measure magnetic signals of nanomagnets embedded in biological systems. Hence, the use of nanomagnets in biomedical applications must rely on mean values obtained after averaging samples containing thousands of dissimilar entities. Here we present a hybrid experimental/theoretical method capable of working out the magnetic anisotropy constant and the magnetic easy axis of individual magnetic nanostructures embedded in biological systems. The method combines scanning transmission X-ray microscopy using an axi-asymmetric magnetic field with theoretical simulations based on the Stoner-Wohlfarth model. The validity of the method is demonstrated by determining the magnetic anisotropy constant and magnetic easy axis direction of 15 intracellular magnetite nanoparticles (50 nm in size) biosynthesized inside a magnetotactic bacterium.

Shaping Up Zn-Doped Magnetite Nanoparticles from Mono- and Bimetallic Oleates: The Impact of Zn Content, Fe Vacancies, and Morphology on Magnetic Hyperthermia Performance.

The currently existing magnetic hyperthermia treatments usually need to employ very large doses of magnetic nanoparticles (MNPs) and/or excessively high excitation conditions (H × f > 1010 A/m s) to reach the therapeutic temperature range that triggers cancer cell death. To make this anticancer therapy truly minimally invasive, it is crucial the development of improved chemical routes that give rise to monodisperse MNPs with high saturation magnetization and negligible dipolar interactions. Herein, we present an innovative chemical route to synthesize Zn-doped magnetite NPs based on the thermolysis of two kinds of organometallic precursors: (i) a mixture of two monometallic oleates (FeOl + ZnOl), and (ii) a bimetallic iron-zinc oleate (Fe3-y Zn y Ol). These approaches have allowed tailoring the size (10-50 nm), morphology (spherical, cubic, and cuboctahedral), and zinc content (Zn x Fe3-x O4, 0.05 < x < 0.25) of MNPs with high saturation magnetization (≥90 Am2/kg at RT). The oxidation state and the local symmetry of Zn2+ and Fe2+/3+ cations have been investigated by means of X-ray absorption near-edge structure (XANES) spectroscopy, while the Fe center distribution and vacancies within the ferrite lattice have been examined in detail through Mössbauer spectroscopy, which has led to an accurate determination of the stoichiometry in each sample. To achieve good biocompatibility and colloidal stability in physiological conditions, the Zn x Fe3-x O4 NPs have been coated with high-molecular-weight poly(ethylene glycol) (PEG). The magnetothermal efficiency of Zn x Fe3-x O4@PEG samples has been systematically analyzed in terms of composition, size, and morphology, making use of the latest-generation AC magnetometer that is able to reach 90 mT. The heating capacity of Zn0.06Fe2.9 4O4 cuboctahedrons of 25 nm reaches a maximum value of 3652 W/g (at 40 kA/m and 605 kHz), but most importantly, they reach a highly satisfactory value (600 W/g) under strict safety excitation conditions (at 36 kA/m and 125 kHz). Additionally, the excellent heating power of the system is kept identical both immobilized in agar and in the cellular environment, proving the great potential and reliability of this platform for magnetic hyperthermia therapies.

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.

Highly Reproducible Hyperthermia Response in Water, Agar, and Cellular Environment by Discretely PEGylated Magnetite Nanoparticles.

Local heat generation from magnetic nanoparticles (MNPs) exposed to alternating magnetic fields can revolutionize cancer treatment. However, the application of MNPs as anticancer agents is limited by serious drawbacks. Foremost among these are the fast uptake and biodegradation of MNPs by cells and the unpredictable magnetic behavior of the MNPs when they accumulate within or around cells and tissues. In fact, several studies have reported that the heating power of MNPs is severely reduced in the cellular environment, probably due to a combination of increased viscosity and strong NP agglomeration. Herein, we present an optimized protocol to coat magnetite (Fe3O4) NPs larger than 20 nm (FM-NPs) with high molecular weight PEG molecules that avoid collective coatings, prevent the formation of large clusters of NPs and keep constant their high heating performance in environments with very different ionic strengths and viscosities (distilled water, physiological solutions, agar and cell culture media). The great reproducibility and reliability of the heating capacity of this FM-NP@PEG system in such different environments has been confirmed by AC magnetometry and by more conventional calorimetric measurements. The explanation of this behavior has been shown to lie in preserving as much as possible the magnetic single domain-type behavior of nearly isolated NPs. In vitro endocytosis experiments in a colon cancer-derived cell line indicate that FM-NP@PEG formulations with PEGs of higher molecular weight (20 kDa) are more resistant to endocytosis than formulations with smaller PEGs (5 kDa), showing quite large uptake mean-life (τ > 5 h) in comparison with other NP systems. The in vitro magnetic hyperthermia was performed at 21 mT and 650 kHz during 1 h in a pre-endocytosis stage and complete cell death was achieved 48 h posthyperthermia. These optimal FM-NP@PEG formulations with high resistance to endocytosis and predictable magnetic response will aid the progress and accuracy of the emerging era of theranostics.

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.

Mechanical, Electrical and Magnetic Properties of Ferrogels with Embedded Iron Oxide Nanoparticles Obtained by Laser Target Evaporation: Focus on Multifunctional Biosensor Applications.

Hydrogels are biomimetic materials widely used in the area of biomedical engineering and biosensing. Ferrogels (FG) are magnetic composites capable of functioning as magnetic field sensitive transformers and field assisted drug deliverers. FG can be prepared by incorporating magnetic nanoparticles (MNPs) into chemically crosslinked hydrogels. The properties of biomimetic ferrogels for multifunctional biosensor applications can be set up by synthesis. The properties of these biomimetic ferrogels can be thoroughly controlled in a physical experiment environment which is much less demanding than biotests. Two series of ferrogels (soft and dense) based on polyacrylamide (PAAm) with different chemical network densities were synthesized by free-radical polymerization in aqueous solution with N,N'-methylene-diacrylamide as a cross-linker and maghemite Fe2O3 MNPs fabricated by laser target evaporation as a filler. Their mechanical, electrical and magnetic properties were comparatively analyzed. We developed a giant magnetoimpedance (MI) sensor prototype with multilayered FeNi-based sensitive elements deposited onto glass or polymer substrates adapted for FG studies. The MI measurements in the initial state and in the presence of FG with different concentrations of MNPs at a frequency range of 1-300 MHz allowed a precise characterization of the stray fields of the MNPs present in the FG. We proposed an electrodynamic model to describe the MI in multilayered film with a FG layer based on the solution of linearized Maxwell equations for the electromagnetic fields coupled with the Landau-Lifshitz equation for the magnetization dynamics.