In-situ particles reorientation during magnetic hyperthermia application: Shape matters twice

Promising advances in nanomedicine such as magnetic hyperthermia rely on a precise control of the nanoparticle performance in the cellular environment. This constitutes a huge research challenge due to difficulties for achieving a remote control within the human body. Here we report on the significant double role of the shape of ellipsoidal magnetic nanoparticles (nanorods) subjected to an external AC magnetic field: first, the heat release is increased due to the additional shape anisotropy; second, the rods dynamically reorientate in the orthogonal direction to the AC field direction. Importantly, the heating performance and the directional orientation occur in synergy and can be easily controlled by changing the AC field treatment duration, thus opening the pathway to combined hyperthermic/ mechanical nanoactuators for biomedicine. Preliminary studies demonstrate the high accumulation of nanorods into HeLa cells whereas viability analysis supports their low toxicity and the absence of apoptotic or necrotic cell death after 24 or 48 h of incubationThis work was partially supported by the EC FP-7 grant “NanoMag” (grant agreement no. 604448), the Spanish Ministry of Economy and Competitiveness (MAT2013-47078-C2-2-P, MAT2014-52069-R, MAT2013-47395-C4-3-R, MAT2015- 67557-C2-1-P-MICINN, CONSOLIDER CSD2007-00041, CTQ2013-48767-C3-3-R), and Gobierno de la Comunidad de Madrid (NANOFRONTMAG, S2013/MIT-2850). D.S. acknowledges financial support from Xunta de Galicia (I2C Postdoctoral Plan). A.T. thanks UAM for a predoctoral contrac

Cell Membrane-Coated Magnetic Nanocubes with a Homotypic Targeting Ability Increase Intracellular Temperature due to ROS Scavenging and Act as a Versatile Theranostic System for Glioblastoma Multiforme

In this study, hybrid nanocubes composed of magnetite (Fe3O4) and manganese dioxide (MnO2), coated with U-251 MG cell-derived membranes (CM-NCubes) are synthesized. The CM-NCubes demonstrate a concentration-dependent oxygen generation (up to 15%), and, for the first time in the literature, an intracellular increase of temperature (6 °C) due to the exothermic scavenging reaction of hydrogen peroxide (H2O2) is showed. Internalization studies demonstrate that the CM-NCubes are internalized much faster and at a higher extent by the homotypic U-251 MG cell line compared to other cerebral cell lines. The ability of the CM-NCubes to cross an in vitro model of the blood-brain barrier is also assessed. The CM-NCubes show the ability to respond to a static magnet and to accumulate in cells even under flowing conditions. Moreover, it is demonstrated that 500 µg mL−1 of sorafenib-loaded or unloaded CM-NCubes are able to induce cell death by apoptosis in U-251 MG spheroids that are used as a tumor model, after their exposure to an alternating magnetic field (AMF). Finally, it is shown that the combination of sorafenib and AMF induces a higher enzymatic activity of caspase 3 and caspase 9, probably due to an increment in reactive oxygen species by means of hyperthermia.C.T. and F.T. contributed equally to this work. This project received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant Agreement No. 709613, SLaMM). The authors would like to kindly thank Dr. Satoshi Arai, Dr. Young-Tae Chang, and Dr. Madoka Suzuki for providing the intracellular temperature sensor used for analyzing the temperature increment during the exothermic reaction between the CM-NCubes and hydrogen peroxide. SGIker technical services (UPV/EHU) are gratefully acknowledged for XRD and XPS support. The authors would like finally to acknowledge also the contribution of the COST Action MyWAVE CA17115 and the COST Action EURELAX CA15209

Cell Behavioral Changes after the Application of Magneto-Mechanical Activation to Normal and Cancer Cells

In vitro cell exposure to nanoparticles, depending on the applied concentration, can help in the development of theranostic tools to better detect and treat human diseases. Recent studies have attempted to understand and exploit the impact of magnetic field-actuated internalized magnetic nanoparticles (MNPs) on the behavior of cancer cells. In this work, the viability rate of MNP’s-manipulated cancerous (MCF-7, MDA-MB-231) and non-cancerous (MCF-10A) cells was investigated in three different types of low-frequency magnetic fields: static, pulsed, and rotating field mode. In the non-cancerous cell line, the cell viability decreased mostly in cells with internalized MNPs and those treated with the pulsed field mode. In both cancer cell lines, the pulsed field mode was again the optimum magnetic field, which together with internalized MNPs caused a large decrease in cells’ viability (50–55% and 70% in MCF-7 and MDA-MB-231, respectively) while the static and rotating field modes maintained the viability at high levels. Finally, F-actin staining was used to observe the changes in the cytoskeleton and DAPI staining was performed to reveal the apoptotic alterations in cells’ nuclei before and after magneto-mechanical activation. Subsequently, reduced cell viability led to a loss of actin stress fibers and apoptotic nuclear changes in cancer cells subjected to MNPs triggered by a pulsed magnetic field

Synergistic Effect of Combined Treatment with Magnetic Hyperthermia and Magneto-Mechanical Stress of Breast Cancer Cells

With the development of nanotechnology, the emergence of new anti-tumor techniques using nanoparticles such as magnetic hyperthermia and magneto-mechanical activation have been the subject of much attention and study in recent years, as anticancer tools. Therefore, the purpose of the current in vitro study was to investigate the cumulative effect of a combination of these two techniques, using magnetic nanoparticles against breast cancer cells. After 24 h of incubation, human breast cancer (MCF-7) and non-cancerous (MCF-10A) cells with and without MNPs were treated (a) for 15 min with magnetic hyperthermia, (b) for 30 min with magneto-mechanical activation, and (c) by a successive treatment consisting of a 15-min magnetic hyperthermia cycle and 30 min of magneto-mechanical activation. The influence of treatments on cell survival and morphology was studied by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) assay and light microscopy. When applied, separately, magneto-mechanical and thermal (hyperthermia) treatment did not demonstrate strong reduction in cell viability. No morphological changes were observed in non-cancerous cells after treatments. On the other hand, the combination of magneto-mechanical and thermal treatment in the presence of MNPs had a synergistic effect on decreased cell viability, and apoptosis was demonstrated in the cancer cell line. Synergism is most evident in the cancer cell line, incubated for 120 h, while in the non-cancerous line after 120 h, an increase in proliferation is clearly observed. MCF-7 cells showed more rounded cell morphology, especially after 120 h of combined treatment

Synergistic Effect of Combined Treatment with Magnetic Hyperthermia and Magneto-Mechanical Stress of Breast Cancer Cells

With the development of nanotechnology, the emergence of new anti-tumor techniques using nanoparticles such as magnetic hyperthermia and magneto-mechanical activation have been the subject of much attention and study in recent years, as anticancer tools. Therefore, the purpose of the current in vitro study was to investigate the cumulative effect of a combination of these two techniques, using magnetic nanoparticles against breast cancer cells. After 24 h of incubation, human breast cancer (MCF-7) and non-cancerous (MCF-10A) cells with and without MNPs were treated (a) for 15 min with magnetic hyperthermia, (b) for 30 min with magneto-mechanical activation, and (c) by a successive treatment consisting of a 15-min magnetic hyperthermia cycle and 30 min of magneto-mechanical activation. The influence of treatments on cell survival and morphology was studied by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) assay and light microscopy. When applied, separately, magneto-mechanical and thermal (hyperthermia) treatment did not demonstrate strong reduction in cell viability. No morphological changes were observed in non-cancerous cells after treatments. On the other hand, the combination of magneto-mechanical and thermal treatment in the presence of MNPs had a synergistic effect on decreased cell viability, and apoptosis was demonstrated in the cancer cell line. Synergism is most evident in the cancer cell line, incubated for 120 h, while in the non-cancerous line after 120 h, an increase in proliferation is clearly observed. MCF-7 cells showed more rounded cell morphology, especially after 120 h of combined treatment

A methodology for the measurement of the specific absorption rate of magnetic scaffolds

Deep-seated tumors can be treated performing local interstitial hyperthermia treatment (HT), using thermoseeds exposed to a radiofrequency magnetic field. Several novel biocompatible magnetic nanostructured thermoseeds, defined magnetic scaffolds (MagS), are available to this aim. In the literature, the methodology adopted for the evaluation of the heating potential is lab specific, but also characterized by variable experimental conditions and different protocols. In this work, a perspective critical comment and analysis of the experimental protocols is provided. Then, a robust estimation methodology of the specific absorption rate (SAR) of MagS for the HT is provided, supported by numerical multiphysics simulations, an experimentally tested. The simulations highlight that overestimation in the SAR values can result from the sample misplacement. From the experimental analysis, it is found that the averaging of multiple temperature records is needed to reliably and effectively estimate the SAR of MagS for DST HT

Conditions determining the morphology and nanoscale magnetism of Co nanoparticles: Experimental and numerical studies

Co-based nanostructures ranging from core/shell to hollow nanoparticles were prepared by varying the reaction time and the chemical environment during the thermal decomposition of Co2(CO)8. Both structural characterization and kinetic model simulation illustrate that the diffusivities of cobalt and oxygen determine the growth ratio and the final morphology of the nanoparticles. Exchange coupling between Co and Co-oxide in core/shell nanoparticles induced a shift of field-cooled hysteresis loops that is proportional to the shell thickness, as verified by numerical studies. The increasing nanocomplexity,when passing from core/shell to hollowparticles, also leads to the appearance of hysteresis above 300 K due to an enhancement of the surface anisotropy resulting from the additional spin-disordered surfaces

Conditions determining the morphology and nanoscale magnetism of Co nanoparticles: Experimental and numerical studies

Co-based nanostructures ranging from core/shell to hollow nanoparticles were prepared by varying the reaction time and the chemical environment during the thermal decomposition of Co2(CO)8. Both structural characterization and kinetic model simulation illustrate that the diffusivities of cobalt and oxygen determine the growth ratio and the final morphology of the nanoparticles. Exchange coupling between Co and Co-oxide in core/shell nanoparticles induced a shift of field-cooled hysteresis loops that is proportional to the shell thickness, as verified by numerical studies. The increasing nanocomplexity,when passing from core/shell to hollowparticles, also leads to the appearance of hysteresis above 300 K due to an enhancement of the surface anisotropy resulting from the additional spin-disordered surfaces

Multiplying Magnetic Hyperthermia Response by Nanoparticle Assembling

The oriented attachment of magnetic nanoparticles is recognized as an important pathway in the magnetic-hyperthermia cancer treatment roadmap, thus, understanding the physical origin of their enhanced heating properties is a crucial task for the development of optimized application schemes. Here, we present a detailed theoretical analysis of the hysteresis losses in dipolar-coupled magnetic nanoparticle assemblies as a function of both the geometry and length of the array, and of the orientation of the particles’ magnetic anisotropy. Our results suggest that the chain-like arrangement biomimicking magnetotactic bacteria has the superior heating performance, increasing more than 5 times in comparison with the randomly distributed system when aligned with the magnetic field. The size of the chains and the anisotropy of the particles can be correlated with the applied magnetic field in order to have optimum conditions for heat dissipation. Our experimental calorimetrical measurements performed in aqueous and agar gel suspensions of 44 nm magnetite nanoparticles at different densities, and oriented in a magnetic field, unambiguously demonstrate the important role of chain alignment on the heating efficiency. In low agar viscosity, similar to those of common biological media, the initial orientation of the chains plays a minor role in the enhanced heating capacity while at high agar viscosity, chains aligned along the applied magnetic field show the maximum heating. This knowledge opens new perspectives for improved handling of magnetic hyperthermia agents, an alternative to conventional cancer therapies

In-situ particles reorientation during magnetic hyperthermia application: Shape matters twice

Promising advances in nanomedicine such as magnetic hyperthermia rely on a precise control of the nanoparticle performance in the cellular environment. This constitutes a huge research challenge due to difficulties for achieving a remote control within the human body. Here we report on the significant double role of the shape of ellipsoidal magnetic nanoparticles (nanorods) subjected to an external AC magnetic field: first, the heat release is increased due to the additional shape anisotropy; second, the rods dynamically reorientate in the orthogonal direction to the AC field direction. Importantly, the heating performance and the directional orientation occur in synergy and can be easily controlled by changing the AC field treatment duration, thus opening the pathway to combined hyperthermic/mechanical nanoactuators for biomedicine. Preliminary studies demonstrate the high accumulation of nanorods into HeLa cells whereas viability analysis supports their low toxicity and the absence of apoptotic or necrotic cell death after 24 or 48 h of incubation.Ministerio de Economía, Comercio y Empresa (España)Comunidad de MadridEC FP-7 grant “NanoMag”Xunta de GaliciaUniversidad Autónoma de MadridDepto. de Química en Ciencias FarmacéuticasFac. de FarmaciaTRUEpu