Alternating Magnetic Field Exposure Research Articles

Abstract 395: An alternating magnetic field suppresses tumor growth

Abstract Application of physical forces, ranging from ultrasound to electric field, is recommended in various clinical practice guidelines, including those for bone fracture or cancer treatment. However, mechanistic information for such treatments has been poorly provided, due to the lack of comprehensive study model. Here, we show an alternating magnetic field (AMF) per se exhibits direct anti-cancer effect through enhancing oxidative phosphorylation (OXPOHS) and thus metabolic reprograming. Proliferation of human glioblastoma cells (U87 and LN229), but not normal human astrocytes (NHA), was inhibited upon exposure to AMF within the narrow frequency range. Extracellular acidification rate was decreased while oxygen consumption was increased. These data indicated that AMF induced metabolic reprograming. This was accompanied by increased reactive oxygen species (ROS) production. Mouse models grafted with human glioblastoma cells showed that AMF exposure, 30 minutes per day for two weeks, suppressed the tumor growth and prolonged the overall survival. Our results suggest that the AMF exposure may be a simple strategy to inhibit cancer cell growth by utilizing oxidative stress via metabolic reprograming. Citation Format: Masanari Umemura, Taisuke Akimoto, Rafikul Islam, Kazuhito Kishi, Akane Nagasako, Rina Nakakaji, Takashi Yamaguchi, Yuto Mizuno, Soichiro Ishikawa, Tetsuya Yamamoto, Yoshihiro Ishikawa. An alternating magnetic field suppresses tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 395.

Bifunctional TRPV1 Targeted Magnetothermal Switch to Attenuate Osteoarthritis Progression

Transient receptor potential vanilloid family member 1 (TRPV1) has been revealed as a therapeutic target of osteoarthritis (OA), the most common deteriorating whole joint disease, by impeding macrophagic inflammation and chondrocytes ferroptosis. However, the clinical application for capsaicin as the TRPV1 agonist is largely limited by its chronic toxicity. To address this issue, we developed a bifunctional controllable magnetothermal switch targeting TRPV1 for the alleviation of OA progression by coupling of magnetic nanoparticles (MNPs) to TRPV1 monoclonal antibodies (MNPs-TRPV1). Under the alternating magnetic field (AMF) stimulation, MNPs-TRPV1 locally dissipated heat, which was sufficient to trigger the opening and activation of TRPV1, and effectively impeded macrophagic inflammation and chondrocyte ferroptosis. This magnetothermal modulation of TRPV1 simultaneously attenuated synovitis and cartilage degeneration in mice incurred by destabilization of medial meniscus surgery, indicating the delayed OA progression. Furthermore, MNPs-TRPV1 with AMF exposure remarkably reduced knee pain sensitivity, alleviated the crippled gait, and improved spontaneous ambulatory activity performance in the mice OA model. Overall, this work provides a potential pathogenesis-based precise OA therapy with temporally and spatially magnetothermal modulation of TRPV1 in a controllable manner.

Abstract CT170: Initial safety and feasibility results from a first-in-human clinical trial evaluating a novel magnetic hyperthermia approach for the treatment of metastatic solid tumors

Abstract A novel approach for cancer therapy was developed, comprising of magnetic multicore iron oxide nanoparticles (SaNPs) and alternating magnetic field (AMF) application. SaNPs are administered IV to the patient and accumulate in tumors through the enhanced permeability and retention (EPR) effect. The patient then undergoes regional AMF application (300kHz) that is converted to thermal energy, inducing sub-ablative hyperthermic cancer cell death. Based on extensive pre-clinical testing, treatment was proven safe and biocompatible in animal models without any associated toxicities. Efficacy studies in a murine metastatic cancer model, demonstrated the ability to reduce the number and size of metastatic lesions. Methods: A First-in-Human open label dose escalation study was designed to evaluate the feasibility and safety of treatment in patients (n=18) with advanced metastatic solid tumors. A secondary objective was to evaluate initial efficacy signs. Eligibility criteria included patients with a life expectancy of at least 30 days with measurable disease according to RECIST 1.1. The patients underwent toxicity analysis and MRI scans without contrast media before (baseline), after treatment, and at the end of the follow-up period of 1 month. Vital signs were monitored before, during, and after treatment. Measurements included ECG, oral and body surface temperatures, blood pressure, heart rate, and oxygen saturation. Results: 3 patients were enrolled in the first cohort that received a single SaNP injection of 10% (first dose level) without AMF. No systemic toxicity was observed. 7 patients were then enrolled and SaNP was administered at the same dose followed by AMF irradiation (first dose level of 40%) of the torso area, conducted for two intervals of 5 min. each. SaNP administration procedures were successful in all cases whereas, 3 patients succeeded to complete the full treatment in accordance to the study protocol. During AMF exposure, the patients were covered with a cooling blanket and temperatures were monitored using fiber-optic sensors. There were no significant temperature deviations beside one patient, where a rise in oral temperature was noted due to the presence of dental implants which heated up. In all patients there were no significant differences in any of the vital signs post-injection nor before or after AMF except for one patient, for whom increased heart rate was observed during irradiation, returning to baseline thereafter. No treatment-related abnormal clinical pathology or urinalysis results were identified. Some fluctuations were observed, attributed to the disease stage. Although tumor response was not expected at the first dose levels, MRI and CT results for one patient showed a reduction in a breast tumor and in another patient, stable disease was reported. Conclusion: SaNP administration either alone or followed by AMF application was not associated with any significant adverse reactions, and no clinical or humoral toxicity was observed at initial doses of 10% SaNP and 40% AMF. Citation Format: Sarah Kraus, Cheri Tal, Boaz Shalev, Moshe Eltanani, Pazit Rukenstein, Shir Arbib, Michal Eck, Raz Khandadash, Shaul Atar, Arnoldo Cyjon, Ofer Shalev. Initial safety and feasibility results from a first-in-human clinical trial evaluating a novel magnetic hyperthermia approach for the treatment of metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT170.

Application of biocompatible and ultrastable superparamagnetic iron(III) oxide nanoparticles doped with magnesium for efficient magnetic fluid hyperthermia in lung cancer cells.

Magnetic fluid hyperthermia (MFH) is a promising therapeutic strategy that targets malignant tissues by heating to 40-43 °C using magnetic nanoparticles (MNPs) subjected to an alternating magnetic field (AMF). In this study, novel magnetic iron(III) oxide nanoparticles doped with magnesium (Mg0.1-γ-Fe2O3(mPEG-silane)0.5) were synthesized, and their structural, chemical, and magnetic properties were analyzed using the following techniques: Fourier-transform infrared spectroscopy, Raman spectroscopy, vibrating magnetometer analysis, powder X-ray diffraction, inductively coupled plasma mass spectrometry, scanning electron microscopy, high-resolution transmission electron microscopy, and energy-dispersive X-ray spectroscopy. The as-synthesized MNPs were used as water ferrofluids for MFH under an AMF in two calorimetric setups, namely phantom and lung cancer cell (A549) models. The as-synthesized MNPs were hexagonal or rhombohedral shaped, with an average size of 27 nm. They showed a typical soft ferromagnetic behavior based on the hysteresis profile, with a magnetic saturation of 70 emu g-1 and remnant magnetization of 1.6 emu g-1. In phantom studies, the ferrofluid (3.0 mg mL-1) exposed to an AMF (18.3 kA m-1, 110.1 kHz) heated up extremely quickly, reaching more than 90 °C in the first 10 min of magnetization. In cell studies, the ferrofluid (0.25 mg mL-1) under an AMF (16.7 kA m-1, 110.1 kHz) showed a slight increase in temperature within the first 12 min, reaching a peak of ca. 43-45 °C, which was stable up to the end of the AMF exposure (45 min). Under these conditions, a pronounced cytotoxic effect on the lung cancer cells was observed (viability ca. 15-20%). No such deleterious effects were observed when the cells were treated with MNPs only without an AMF. Specific absorption rate (SAR) measurements were performed using three mathematical approaches, namely the initial slope method, the corrected slope method, and the Box-Lucas method, which ranged from ca. 429 to 596 W g-1 for phantom and cell studies. Iron(III) oxide MNPs doped with magnesium were found to be candidates for MFH in lung cancer treatments.

Heat induction of iron oxide nanoparticles with rational artificial neural network design-based particle swarm optimization for magnetic cancer hyperthermia

This study presented the optimization of synthesis experimental conditions by examining the simultaneous effects of synthesis environment and precipitating agent type on the physiochemical, morphological, and magnetization characteristics of Fe3O4 nanoparticles (FeNPs). The experimental results implied that the effect of the synthesis environment outweighed that of the precipitating agent by enhancing the crystallinity and magnetization of FeNPs with smaller particle sizes. The hyperthermic performance of the optimal FeNPs was evaluated at different concentrations and different alternating magnetic fields (AMF). The promising candidate was 4 mg.mL−1 of FeNPs under the AMF exposure of 15 kA.m−1 and 320 kHz, according to the safe clinical criterion of H×f (product) < 5×109 A.m−1s−1, which produced desirable heat within the secure hyperthermia temperature range. Accordingly, the localized anticancer heat of optimal FeNPs was first examined using an artificial neural network (ANN) with three different ANN learning algorithms (namely BFGS Quasi-Newton (ANN-BFG), Levenberg–Marquardt, and Bayesian Regularization) to assess the highest performance accuracy. According to the results, the ANN-BFG model exhibited the best prediction performance with the smallest MSE and RMSE values. Thereafter, the particle swarm optimization (PSO) algorithm was successfully employed to amend the ANN-BFG speed rate. The hybrid ANN-PSO approach showed a remarkable potential mainly in predicting the effect of different influential parameters, including particle concentration, AMF product, and exposure time, on the localized temperature under hyperthermia conditions with excellent accuracy, convergence, and precise optimization according to the experimental or safe clinical hyperthermia setup.

Quantifying the relationship between biofilm reduction and thermal tissue damage on metal implants exposed to alternating magnetic fields

Aim Metal implant infections are a devastating problem due to the formation of biofilm which impairs the effectiveness of antibiotics and leads to surgical replacement as definitive treatment. Biofilm on metal implants can be reduced using heat generated by alternating magnetic fields (AMF). In this study, the relationship between implant surface biofilm reduction and surrounding tissue thermal damage during AMF exposure is investigated through numerical simulations. Methods Mathematical models of biofilm reduction with heat were created based on in vitro experiments. Simulations were performed to predict the spatial and temporal heating on the implant surface and surrounding tissue when exposed to AMF. Results The modeling results show that intermittent and slow heating can achieve biofilm reduction with a narrow zone of tissue damage around an implant of less than 3 mm. The results also emphasize that uniformity of implant heating is an extremely important factor impacting the effectiveness of biofilm reduction. For a knee implant, using a target temperature of 75 °C, an intermittent treatment strategy of 15 exposures (10 s to target temperature followed by cooldown) achieved a bacterial CFU reduction of 6-log10 across 25% of the implant surface with less than 3 mm of tissue damage. Alternatively, a single 60 s heating exposure to same temperature achieved a bacterial reduction of 6-log10 across 85% of the implant surface, but with 4 mm of tissue damage. Conclusion Overall, this study demonstrates that with uniform heating to temperatures above 70 °C, an implant surface can be largely reduced of biofilm, with only a few mm of surrounding tissue damage.

Hyperthermia-Induced In Situ Drug Amorphization by Superparamagnetic Nanoparticles in Oral Dosage Forms.

Superparamagnetic iron oxide nanoparticles (SPIONs) generate heat upon exposure to an alternating magnetic field (AMF), which has been studied for hyperthermia treatment and triggered drug release. This study introduces a novel application of magnetic hyperthermia to induce amorphization of a poorly aqueous soluble drug, celecoxib, in situ in tablets for oral administration. Poor aqueous solubility of many drug candidates is a major hurdle in oral drug development. A novel approach to overcome this challenge is in situ amorphization of crystalline drugs. This method facilitates amorphization by molecular dispersion of the drug in a polymeric network inside a tablet, circumventing the physical instability encountered during the manufacturing and storage of conventional amorphous solid dispersions. However, the current shortcomings of this approach include low drug loading, toxicity of excipients, and drug degradation. Here, doped SPIONs produced by flame spray pyrolysis are compacted with polyvinylpyrrolidone and celecoxib and exposed to an AMF in solid state. A design of experiments approach was used to investigate the effects of SPION composition (Zn0.5Fe2.5O4 and Mn0.5Fe2.5O4), doped SPION content (10–20 wt %), drug load (30–50 wt %), and duration of AMF (3–15 min) on the degree of drug amorphization. The degree of amorphization is strongly linked to the maximum tablet temperature achieved during the AMF exposure (r = 0.96), which depends on the SPION composition and content in the tablets. Complete amorphization is achieved with 20 wt % Mn0.5Fe2.5O4 and 30 wt % celecoxib in the tablets that reached the maximum temperature of 165.2 °C after 15 min of AMF exposure. Furthermore, manganese ferrite exhibits no toxicity in human intestinal Caco-2 cell lines. The resulting maximum solubility of in situ amorphized celecoxib is 5 times higher than that of crystalline celecoxib in biorelevant intestinal fluid. This demonstrates the promising capability of SPIONs as enabling excipients to magnetically induce amorphization in situ in oral dosage forms.

Closed‐Loop Temperature‐Controlled Magnetic Hyperthermia Therapy with Magnetic Guidance of Superparamagnetic Iron‐Oxide Nanoparticles

AbstractHyperthermia therapy eliminates cancer cells by heating them above physiological temperatures. Superparamagnetic iron oxide nanoparticles (SPIONs) are promising for targeted hyperthermia therapy because of their excellent heating efficiency, biocompatibility, and active magnetic navigation. When exposed to a high‐frequency alternating magnetic field (AMF), SPIONs dissipate heat to damage cancer cells. Accurate temperature control is crucial for safe and efficient hyperthermia therapy. A closed‐loop temperature controller to control the temperature and heating rate by adjusting AMF’s strength, thereby enabling controllable hyperthermia therapy. Under a low‐frequency rotating magnetic field (RMF), the SPIONs form chains which can be actively manipulated towards the target by adjusting RMF’s direction, followed by AMF exposure for hyperthermia therapy. The SPIONs are precisely manipulated in a microfluidic chip and rat brain vessels ex vivo, highlighting the potential for targeted position control. Last, in vitro, and in vivo hyperthermia treatments are performed on human prostate cancer cells (PC3) and a PC3 xenograft mouse model using the proposed temperature controller, with tracking errors under 0.5°C and significant reduction in cancer cell viability and tumor volume. The magnetic locomotion with RMF, and the controlled heating using AMF, show the feasibility of using SPIONs for targeted hyperthermia therapy.

Precise Regulation of Enzyme-Nanozyme Cascade Reaction Kinetics by Magnetic Actuation toward Efficient Tumor Therapy.

Spatiotemporal regulation of multi-enzyme catalysis with stimuli is crucial in nature to meet different metabolic requirements but presents a challenge in artificial cascade systems. Here, we report a strategy for precise and tunable modulation of enzyme-nanozyme cascade reaction kinetics by remote magnetic stimulation. As a proof of concept, glucose oxidase (GOx) was immobilized onto a ferrimagnetic vortex iron oxide nanoring (Fe3O4 NR) functionalized with poly(ethylene glycol) of different molecular weights to construct a series of Fe3O4 NR@GOx with nanometer linking distances. The activities of GOx and the Fe3O4 NR nanozyme in these systems were shown to be differentially stimulated by Fe3O4 NR-mediated local heat in response to an alternating magnetic field (AMF), leading to modulated cascade reaction kinetics in a distance-dependent manner. Compared to the free GOx and Fe3O4 NR mixture, Fe3O4 NR(D2)@GOx with an optimum linking distance of 1 nm exhibits a superior kinetic match between GOx and the Fe3O4 NR nanozyme and over a 400-fold higher cascade activity under AMF exposure. This enables remarkable intracellular reactive oxygen species production and significantly improved tumor inhibition of AMF-stimulated Fe3O4 NR(D2)@GOx in 4T1 tumor-bearing mice. The strategy reported here offers a straightforward new tool for fine-tuning multi-enzyme catalysis at the molecular level using magnetic stimuli and holds great promise for use in a variety of biotechnology and synthetic biology applications.

Micron-sized iron oxide particles for both MRI cell tracking and magnetic fluid hyperthermia treatment

Iron oxide particles (IOP) are commonly used for Cellular Magnetic Resonance Imaging (MRI) and in combination with several treatments, like Magnetic Fluid Hyperthermia (MFH), due to the rise in temperature they provoke under an Alternating Magnetic Field (AMF). Micrometric IOP have a high sensitivity of detection. Nevertheless, little is known about their internalization processes or their potential heat power. Two micrometric commercial IOP (from Bangs Laboratories and Chemicell) were characterized by Transmission Electron Microscopy (TEM) and their endocytic pathways into glioma cells were analyzed. Their Specific Absorption Rate (SAR) and cytotoxicity were evaluated using a commercial AMF inductor. T2-weighted imaging was used to monitor tumor growth in vivo after MFH treatment in mice. The two micron-sized IOP had similar structures and r2 relaxivities (100 mM−1 s−1) but involved different endocytic pathways. Only ScreenMAG particles generated a significant rise in temperature following AMF (SAR = 113 W g−1 Fe). After 1 h of AMF exposure, 60% of ScreenMAG-labeled cells died. Translated to a glioma model, 89% of mice responded to the treatment with smaller tumor volume 42 days post-implantation. Micrometric particles were investigated from their characterization to their intracellular internalization pathways and applied in one in vivo cancer treatment, i.e. MFH.

Synthesis, characterization and in vitro analysis of superparamagnetic iron oxide nanoparticles for targeted hyperthermia therapy

Superparamagnetic iron oxide nanoparticles (SPIONs) are considered as promising magnetic nanoheating agents for diagnostic as well as therapeutic applications due to their biocompatibility and tunability of magnetic properties. These nanoheating agents are commonly synthesized by coprecipitation of two iron precursors, though applying less amount of these chemicals may minimize the toxicity risks for biomedical purposes. The aim of this study is to address this issue by considering the high oxidation vulnerability of ferrous ions to ferric ions to synthesize SPIONs via a single-iron precursor under four varied oxidative conditions. The obtained results implied that the properties of SPIONs can be modified by the variation in the oxidizing conditions. Thereby, the optimal sample was produced as the oxygen/nitrogen flow ratio adjusted to 50% in the synthesis environment. The induction heating efficiency of this optimal sample was investigated under the exposure of varied alternating magnetic field (AMF), which resulted in a remarkable specific absorption rate (SAR) of 168.96 W g−1 while maintaining the temperature medium within the secure hyperthermia range. The cytotoxic effect of the optimal SPIONs sample against human liver carcinoma (HepG2) cells was determined using MTT assay, leading to a considerable decrement in the cell viability. The incorporation of SPIONs under the AMF exposure is, therefore, considered as an effectual mechanism to the tumor intervention.

Iron nanoparticles augmented chemodynamic effect by alternative magnetic field for wound disinfection and healing

Utilizing the iron-carrying nanomaterials for Fenton chemistry mediation to catalyze decomposition of hydrogen peroxide and generate toxic hydroxyl radical (OH) has drawn much attention in antimicrobial therapy field. However, these nanomaterials are usually with unsatisfactory catalytic efficacy and lack of the capacity to modulate the catalytic activity, which may give the bacteria opportunity in developing resistance against the antibacterial treatment. Herein, we systematically investigated the influence of alternating magnetic field (AMF) on the catalytic activity and antibacterial efficiency of the amorphous iron nanoparticles (AIronNPs). With rapidly ionized and the AMF augmented chemodynamic effect, the AIronNPs can convert low concentration of H2O2 into more OH, the possible mechanism might be attributed to the accelerated ferrous iron ions releasing with AMF exposure. As a proof of concept, the AIronNPs and AMF synergetic antibacterial system have shown excellent broad-spectrum antimicrobial properties, 91.89% antibacterial efficiency is shown toward Escherichia coli and 92.65% toward Staphylococcus aureus. It also facilitated the formation of granulation tissue and accelerated wound healing on in vivo infected model, whereas AIronNPs alone have limited effect. We believe this work will broaden the thoughts for spatiotemporally manipulating the catalytic activity of nanomaterials and advance the development of magnetic nano-antibiotics in the antibacterial field.

Polycaprolactone-coated superparamagnetic iron oxide nanoparticles for in vitro magnetic hyperthermia therapy of cancer

Magnetic hyperthermia therapy of cancer is a promising alternative for the current chemotherapy and radiation options, due to its targeting capability and lower systemic toxicity. However, agglomeration vulnerability of the nano-heating agents in aqueous solutions, low control over the heat generation and dissipation at the target region, and eschewed clearance by the renal and reticuloendothelial systems remain as the main challenges for clinical translation of this approach. Here we report superparamagnetic iron oxide nanoparticles (SPIONs) were synthesized by using a single precursor, stabilized with a controlled micellar conformation, and coated with a thin polycaprolactone biopolymer shell to achieve enhanced cytocompatibility and thermosensitivity under external alternating magnetic field (AMF) of varied intensities. The in vitro investigations indicated a negligible influence of the polymer-coated SPIONs on cell viability of human liver cancer cells (HepG2) at a maximum concentration of 100 μg∙mL−1. However, the cell viability was reduced significantly to 40.1 ± 0.9% within the secure hyperthermia temperature range achieved by the heating effect of polymer-coated SPIONs in presence of AMF, depicting the on/off cytotoxicity phenomenon of polymer-coated SPIONs under AMF exposure. Therefore, the developed nanostructure presents a step-change as potential targeted nano-heating agents for new therapeutic options.

Localized and triggered release of oxaliplatin for the treatment of colorectal liver metastasis.

Purpose: The aim of this study was to develop and evaluate a liposome formulation that deliver oxaliplatin under magnetic field stimulus in high concentration to alleviate the off-target effects in a rat model of colorectal liver metastases (CRLM).Materials and Methods: Hybrid liposome-magnetic nanoparticles loaded with Cy5.5 dye and oxaliplatin (L-NIR- Fe3O4/OX) were synthesized by using thermal decomposition method. CRLM (CC-531) cell viability was assessed and rats orthotopically implanted with CC-531 cells were treated with L-NIR-Fe3O4/OX or by drug alone via different routes, up to 3 cycles of alternating magnetic field (AMF). Optical and MR imaging was performed to assess the targeted delivery. Biodistribution and histology was performed to determine the distribution of oxaliplatin.Results: L-NIR-Fe3O4/OX presented a significant increase of oxaliplatin release (~18%) and lower cell viability after AMF exposure (p<0.001). Optical imaging showed a significant release of oxaliplatin among mesenteric vein injected (MV) group of animals. MR imaging on MV injected animals showed R2* changes in the tumor regions at the same regions immediately after infusion compared to the surrounding liver (p<0.001). Biodistribution analysis showed significantly higher levels of oxaliplatin in liver tissues compared to lungs (p<0.001) and intestines (p<0.001) in the MV animals that received AMF after L-NIR- Fe3O4/OX administration. Large tumor necrotic zones and significant improvement in the survival rates were noted in the MV animals treated with AMF.Conclusion: AMF triggers site selective delivery of oxaliplatin at high concentrations and improves survival outcomes in colorectal liver metastasis tumor bearing rats.

Hyperbranched Polymer-Functionalized Magnetic Nanoparticle-Mediated Hyperthermia and Niclosamide Bimodal Therapy of Colorectal Cancer Cells.

Functionalized magnetic nanoparticles (MNPs) have attracted particular interest as potential drug delivery carriers as they offer dual advantage of delivering drugs to the target site complemented with magnetic hyperthermia-mediated therapy. Hyperbranched polymer-functionalized MNPs have the potential to perform a dual role of killing cancer cells by hyperthermia (by magnetite core) with apoptosis (by loaded niclosamide). These are formed by the co-precipitation of iron salts followed by aminocellulose grafting, branch growth, and PEGylation. NP formation was investigated by determining particle size, zeta potential, and microscopic (transmission electron microscopy, field-emission scanning electron microscopy, and atomic force microscopy) studies. Results showed that these nanocarriers were 107 ± 57 nm in size with a zeta potential of -18 mV and exist as NPs. Drug loading and encapsulation efficiency were calculated as 15.28 ± 2.72 and 76.41 ± 1.84%, respectively, using UV-vis spectroscopy. NPs were internalized into HCT116 cells as investigated using confocal microscopy and flow cytometry. Blank NPs at the dose of 200 μg/mL were found to be cytocompatible using hTERT cells and hemocompatible. The cell viability study suggested that niclosamide-loaded functionalized magnetic nanoparticles (NFMNPs) were more effective (7 times) than free niclosamide in killing colon cancer cells. Moreover, NFMNPs induced apoptosis in an immunofluorescence study of cleaved caspase-3. Exposure of NFMNPs to an alternating magnetic field (AMF) resulted in a slight increase in the rate of niclosamide release. AMF exposure drastically reduced cell viability due to dual effects of hyperthermia and niclosamide after treatment with NFMNPs. The potentiation of cell death due to dual effects of hyperthermia and niclosamide was further confirmed by Annexin-V/propidium iodide assay using flow cytometry. The results imply that niclosamide delivery through hyperbranched polymer-functionalized MNPs may serve as an effective strategy for the treatment of colorectal cancer.

Printed Conformable Liquid Metal e‐Skin‐Enabled Spatiotemporally Controlled Bioelectromagnetics for Wireless Multisite Tumor Therapy

AbstractWith inherent flexibility, high electroconductivity, excellent thermal conductivity, easy printability and biosafety, gallium‐based functional liquid metals (LMs) have been increasingly evaluated for biomedical applications, especially as electronic skin (e‐skin). Extending these versatile materials to more challenging applications is a worthwhile pursuit. To realize precise and spatiotemporal multisite tumor treatment under an alternating magnetic field (AMF), an oxidized GaIn (O‐GaIn) mixture‐based e‐skin is developed and demonstrated to be printable. Compared with the commonly utilized non‐oxidized GaIn, O‐GaIn possesses outstanding adhesion to the skin surface and can be directly and quickly printed into various customized patterns. The LM e‐skin thus constructed as conformable bioelectrodes on tumor‐bearing mice exhibits evident feasibility for administrating non‐invasive wireless multisite tumor therapy under AMF exposure due to its favorable magnetothermal effects. These in vivo experiments reveal remarkable tumor growth inhibition and increased life span in mice, especially in the case of multilesion treatment. A favorable biomedical strategy based on O‐GaIn material for developing future non‐invasive and high‐performance cancer therapy, which is also promising for treating whole‐body diseases in the future, is provided.

Flower-like Mn-Doped Magnetic Nanoparticles Functionalized with αvβ3-Integrin-Ligand to Efficiently Induce Intracellular Heat after Alternating Magnetic Field Exposition, Triggering Glioma Cell Death.

Despite the potential of magnetic nanoparticles (NPs) to mediate intracellular hyperthermia when exposed to an alternating magnetic field (AMF), several studies indicate that the intracellular heating capacity of magnetic NPs depends on factors such as cytoplasm viscosity, nanoparticle aggregation within subcellular compartments, and dipolar interactions. In this work, we report the design and synthesis of monodispersed flowerlike superparamagnetic manganese iron oxide NPs with maximized SAR (specific absorption rate) and evaluate their efficacy as intracellular heaters in the human tumor-derived glioblastoma cell line U87MG. Three main strategies to tune the particle anisotropy of the core and the surface to reach the maximum heating efficiency were adopted: (1) varying the crystalline anisotropy by inserting a low amount of Mn2+ in the inverse spinel structure, (2) varying the NP shape to add an additional anisotropy source while keeping the superparamagnetic behavior, and (3) maximizing NP-cell affinity through conjugation with a biological targeting molecule to reach the NP concentration required to increase the temperature within the cell. We investigate possible effects produced by these improved NPs under the AMF (f = 96 kHz, H = 47 kA/m) exposure in the glioblastoma cell line U87MG by monitoring the expression of hsp70 gene and reactive oxygen species (ROS) production, as both effects have been described to be induced by increasing the intracellular temperature. The induced cell responses include cellular membrane permeabilization and rupture with concomitant high ROS appearance and hsp70 expression, followed by cell death. The responses were largely limited to cells that contained the NPs exposed to the AMF. Our results indicate that the developed strategies to optimize particle anisotropy in this work are a promising guidance to improve the heating efficiency of magnetic NPs in the human glioma cell line.

Spatial, Temporal, and Dose Control of Drug Delivery using Noninvasive Magnetic Stimulation.

Noninvasive stimuli-responsive drug delivery using magnetic fields in conjunction with superparamagnetic nanoparticles offers the potential for the spatial and temporal control of drug release. When hyperthermia is not desired and control of the dosage is required, it is necessary to design a platform in which local heating on the nanoscale releases the therapeutic cargo without the bulk heating of the surrounding medium. In this paper, we report a design using a stimuli-responsive nanoparticle platform to control the dosage of the cargo released by an alternating magnetic field (AMF) actuation. A core@shell structure with a superparamagnetic doped iron oxide (MnFe2O4@CoFe2O4) nanoparticle core in a mesoporous silica shell was synthesized. The core used here has a high saturation magnetization value and a high specific loss power for heat generation under an AMF. The mesoporous shell has a high cargo-carrying capacity. A thermoresponsive molecular-based gatekeeper containing an aliphatic azo group was modified on the core@shell nanoparticles to regulate the cargo release. The mesoporous structure of the silica shell remained intact after exposure to an AMF, showing that the release of cargo is due to the removal of the gatekeepers instead of the destruction of the structure. Most importantly, we demonstrated that the amount of cargo released could be adjusted by the AMF exposure time. By applying multiple sequential exposures of AMF, we were able to release the cargo step-wise and increase the total amount of released cargo. In vitro studies showed that the death of pancreatic cancer cells treated by drug-loaded nanoparticles was controlled by different lengths of AMF exposure time due to different amount of drugs released from the carriers. The strategy developed here holds great promise for achieving the dosage, temporal, and spatial control of therapeutics delivery without the risk of overheating the particles' surroundings.

Synergistic effects of Radiofrequency Hyperthermia temperature rate with magnetic Graphene oxide nanoparticles drug targeting on CT26 colon cancer cell line

Introduction: Graphene oxide (GO) sheets are carbon-networking nanomaterials offering excellent potential for drug delivery platforms due to hydrophobic interactions and high drug-loading efficiency. Superparamagnetic iron oxide nanoparticles can be used in certain applications such as cell labeling, drug delivery, targeting, magnetic resonance imaging and hyperthermia. Due to the larger surface to volume ratio for unmodified iron oxide nanoparticles, they usually possess high surface energy leading to particle aggregation. The magnetic nanoparticles could induce heat energy in an alternating magnetic field (AMF). The absorption of radiofrequency energy by biological tissue results in higher tissue temperatures as a function of time, which eventually causes cell death due to hyperthermia. Mensuration of the temperatures inside the tumors and in normal tissues within AMF demonstrated that this treatment could induce tumor-specific hyperthermia. Materials and Methods: CT26 colon cancer cell line was cultured in vitro as a monolayer. The monolayer culture was treated with of 5-FU, 5-FU- MGO nanoparticles, and MGO nanoparticles for 24 hours. then the flasks were located at the centre of the RF coil where the alternative magnetic field strength had reached its maximum value (40 kA/m) and was exposed to the AMF (forward power, 70 W), for 12 min (43°C) without MGO nanoparticles and 4 min (43°C) with MGO nanoparticles. During the AMF exposure, the temperature increase was monitored using a T-type thermocouple (copperconstantan, 0.1 mm diameter) linked to a digital thermometer (Lutron thermometer TM-917, Taiwan) every 1 min for 15 min with ± 0.1°C accuracy. Results: Increase in the temperature was measured. The results revealed that the temperature increase of the culture depends on the nanoparticles concentrations. The results also indicated that the temperature of cells exposed to AMF (13.56 MHz) at a forward power of 70 W reached to 43°C after 12 min, whereas the combination of accumulated 50 μg/ml 5-FU- MGO nanoparticles and RF hyperthermia was 3 min and for 25 and 5 μg/ml, it was calculated as 4 and 9 min, respectively. The significant difference was observed between the 5-FU, 5- FU- MGO nanoparticles, and MGO nanoparticles in RF hyperthermia at power of 70 W (P < 0.05). This suggests that MGO nanoparticles act as effective thermal agents in AMF hyperthermia. Conclusion: On the basis of this study is According to the temperature-time curves at different intensities, the rate of temperature rise was very sharp during the first few minutes of AMF exposure; however, it then reached a near equilibrium because cell heat transfer parameters (conduction and convection) started to perform, The radiofrequency heats cells with a steep gradient pending the initial stage of exposure.

Remote acoustic sensing as a safety mechanism during exposure of metal implants to alternating magnetic fields.

Treatment of prosthetic joint infections often involves multiple surgeries and prolonged antibiotic administration, resulting in a significant burden to patients and the healthcare system. We are exploring a non-invasive method to eradicate biofilm on metal implants utilizing high-frequency alternating magnetic fields (AMF) which can achieve surface induction heating. Although proof-of-concept studies demonstrate the ability of AMF to eradicate biofilm in vitro, there is a legitimate safety concern related to the potential for thermal damage to surrounding tissues when considering heating implanted metal objects. The goal of this study was to explore the feasibility of detecting acoustic emissions associated with boiling at the interface between a metal implant and surrounding soft tissue as a wireless safety sensing mechanism. Acoustic emissions generated during in vitro and in vivo AMF exposures were captured with a hydrophone, and the relationship with surface temperature analyzed. The effect of AMF exposure power, surrounding media composition, implant location within the AMF transmitter, and implant geometry on acoustic detection during AMF therapy was also evaluated. Acoustic emissions were reliably identified in both tissue-mimicking phantom and mouse studies, and their onset coincided with the implant temperature reaching the boiling threshold. The viscosity of the surrounding medium did not impact the production of acoustic emissions; however, emissions were not present when the medium was oil due to the higher boiling point. Results of simulations and in vivo studies suggest that short-duration, high-power AMF exposures combined with acoustic sensing can be used to minimize the amount of thermal damage in surrounding tissues. These studies support the hypothesis that detection of boiling associated acoustic emissions at a metal/tissue interface could serve as a real-time, wireless safety indicator during AMF treatment of biofilm on metallic implants.