Nanoparticles use magnetoelectricity to target and eradicate cancer cells.

This study presents the first in vivo and in vitro evidence of an externally controlled, predictive, MRI-based nanotheranostic agent capable of cancer cell specific targeting and killing via irreversible electroporation (IRE) in solid tumors. The rectangular-prism-shaped magnetoelectric nanoparticle is a smart nanoparticle that produces a local electric field in response to an externally applied magnetic field. When externally activated, MENPs are preferentially attracted to the highly conductive cancer cell membranes, which occurs in cancer cells because of dysregulated ion flux across their membranes. In a pancreatic adenocarcinoma murine model, MENPs activated by external magnetic fields during magnetic resonance imaging (MRI) resulted in a mean three-fold tumor volume reduction (62.3% vs 188.7%; P < .001) from a single treatment. In a longitudinal confirmatory study, 35% of mice treated with activated MENPs achieved a durable complete response for 14 weeks after one treatment. The degree of tumor volume reduction correlated with a decrease in MRI T 2 * relaxation time ( r = .351; P = .039) which suggests that MENPs have a potential to serve as a predictive nanotheranostic agent at time of treatment. There were no discernable toxicities associated with MENPs at any timepoint or on histopathological analysis of major organs. MENPs are a noninvasive alternative modality for the treatment of cancer. Summary: We investigated the theranostic capabilities of magnetoelectric nanoparticles (MENPs) combined with MRI via a murine model of pancreatic adenocarcinoma. MENPs leverage the magnetoelectric effect to convert an applied magnetic field into local electric fields, which can induce irreversible electroporation of tumor cell membranes when activated by MRI. Additionally, MENPs modulate MRI relaxivity, which can be used to predict the degree of tumor ablation. Through a pilot study (n=21) and a confirmatory study (n=27), we demonstrated that, ≥300 µg of MRI-activated MENPs significantly reduced tumor volumes, averaging a three-fold decrease as compared to controls. Furthermore, there was a direct correlation between the reduction in tumor T 2 relaxation times and tumor volume reduction, highlighting the predictive prognostic value of MENPs. Six of 17 mice in the confirmatory study's experimental arms achieved a durable complete response, showcasing the potential for durable treatment outcomes. Importantly, the administration of MENPs was not associated with any evident toxicities. This study presents the first in vivo evidence of an externally controlled, MRI-based, theranostic agent that effectively targets and treats solid tumors via irreversible electroporation while sparing normal tissues, offering a new and promising approach to cancer therapy.

Controlling action potentials with magnetoelectric nanoparticles.

Non-invasive or minutely invasive and wireless brain stimulation that can target any region of the brain is an open problem in engineering and neuroscience with serious implications for the treatment of numerous neurological diseases. Despite significant recent progress in advancing new methods of neuromodulation, none has successfully replicated the efficacy of traditional wired stimulation and improved on its downsides without introducing new complications. Due to the capability to convert magnetic fields into local electric fields, MagnetoElectric NanoParticle (MENP) neuromodulation is a recently proposed framework based on new materials that can locally sensitize neurons to specific, low-strength alternating current (AC) magnetic fields (50Hz 1.7 kOe field). However, the current research into this neuromodulation concept is at a very early stage, and the theoretically feasible game-changing advantages remain to be proven experimentally. To break this stalemate phase, this study leveraged understanding of the non-linear properties of MENPs and the nanoparticles' field interaction with the cellular microenvironment. Particularly, the applied magnetic field's strength and frequency were tailored to the M - H hysteresis loop of the nanoparticles. Furthermore, rectangular prisms instead of the more traditional "spherical" nanoparticle shapes were used to: (i) maximize the magnetoelectric effect and (ii) improve the nanoparticle-cell-membrane surface interface. Neuromodulation performance was evaluated in a series of exploratory in vitro experiments on 2446 rat hippocampus neurons. Linear mixed effect models were used to ensure the independence of samples by accounting for fixed adjacency effects in synchronized firing. Neural activity was measured over repeated 4-min segments, containing 90 s of baseline measurements, 90 s of stimulation measurements, and 60 s of post stimulation measurements. 87.5 % of stimulation attempts produced statistically significant (P < 0.05) changes in neural activity, with 58.3 % producing large changes (P < 0.01). In negative controls using either zero or 1.7 kOe-strength field without nanoparticles, no experiments produced significant changes in neural activity (P > 0.05 and P > 0.15 respectively). Furthermore, an exploratory analysis of a direct current (DC) magnetic field indicated that the DC field could be used with MENPs to inhibit neuron activity (P < 0.01). These experiments demonstrated the potential for magnetoelectric neuromodulation to offer a near one-to-one functionality match with conventional electrode stimulation without requiring surgical intervention or genetic modification to achieve success, instead relying on physical properties of these nanoparticles as "On/Off" control mechanisms. ONE-SENTENCE SUMMARY: This in vitro neural cell culture study explores how to exploit the non-linear and anisotropic properties of magnetoelectric nanoparticles for wireless neuromodulation, the importance of magnetic field strength and frequency matching for optimization, and demonstrates, for the first time, that magnetoelectric neuromodulation can inhibit neural responses.

Modeling the effect of magnetoelectric nanoparticles on neuronal electrical activity: An analog circuit approach.

This paper introduces a physical neuron model that incorporates magnetoelectric nanoparticles (MENPs) as an essential electrical circuit component to wirelessly control local neural activity. Availability of such a model is important as MENPs, due to their magnetoelectric effect, can wirelessly and noninvasively modulate neural activity, which, in turn, has implications for both finding cures for neurological diseases and creating a wireless noninvasive high-resolution brain-machine interface. When placed on a neuronal membrane, MENPs act as magnetic-field-controlled finite-size electric dipoles that generate local electric fields across the membrane in response to magnetic fields, thus allowing to controllably activate local ion channels and locally initiate an action potential. Herein, the neuronal electrical characteristic description is based on ion channel activation and inhibition mechanisms. A MENP-based memristive Hodgkin-Huxley circuit model is extracted by combining the Hodgkin-Huxley model and an equivalent circuit model for a single MENP. In this model, each MENP becomes an integral part of the neuron, thus enabling wireless local control of the neuron's electric circuit itself. Furthermore, the model is expanded to include multiple MENPs to describe collective effects in neural systems.

Nanomedicine and nanobiotechnology applications of magnetoelectric nanoparticles.

Unlike any other nanoparticles known to date, magnetoelectric nanoparticles (MENPs) can generate relatively strong electric fields locally via the application of magnetic fields and, vice versa, have their magnetization change in response to an electric field from the microenvironment. Hence, MENPs can serve as a wireless two-way interface between man-made devices and physiological systems at the molecular level. With the recent development of room-temperature biocompatible MENPs, a number of novel potential medical applications have emerged. These applications include wireless brain stimulation and mapping/recording of neural activity in real-time, targeted delivery across the blood-brain barrier (BBB), tissue regeneration, high-specificity cancer cures, molecular-level rapid diagnostics, and others. Several independent in vivo studies, using mice and nonhuman primates models, demonstrated the capability to deliver MENPs in the brain across the BBB via intravenous injection or, alternatively, bypassing the BBB via intranasal inhalation of the nanoparticles. Wireless deep brain stimulation with MENPs was demonstrated both in vitro and in vivo in different rodents models by several independent groups. High-specificity cancer treatment methods as well as tissue regeneration approaches with MENPs were proposed and demonstrated in in vitro models. A number of in vitro and in vivo studies were dedicated to understand the underlying mechanisms of MENPs-based high-specificity targeted drug delivery via application of d.c. and a.c. magnetic fields. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Where do we stand now regarding treatment of psychiatric and neurodegenerative disorders? Considerations in using magnetoelectric nanoparticles as an innovative approach.

Almost 1000 million people have recently been diagnosed with a mental health or substance disorder (Ritchie & Roser, 2018). Psychiatric disorders, and their treatment, represent a big burden to the society worldwide, causing about 8 million deaths per year (Walker et al., 2015). Daily progress in science enables continuous advances in methods to treat patients; however, the brain remains to be the most unknown and complex organ of the body. There is a growing demand for innovative approaches to treat psychiatric as well as neurodegenerative disorders, disorders with unknown curability, and treatments mostly designed to slow disease progression. Based on that need and the peculiarity of the central nervous system, in the present review, we highlight the handicaps of the existing approaches as well as discuss the potential of the recently introduced magnetoelectric nanoparticles (MENPs) to become a game-changing tool in future applications for the treatment of brain alterations. Unlike other stimulation approaches, MENPs have the potential to enable a wirelessly controlled stimulation at a single-neuron level without requiring genetic modification of the neural tissue and no toxicity has yet been reported. Their potential as a new tool for targeting the brain is discussed. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease Therapeutic Approaches and Drug Discovery > Neurological Disease.

In Vivo Wireless Brain Stimulation via Non-invasive and Targeted Delivery of Magnetoelectric Nanoparticles.

Wireless and precise stimulation of deep brain structures could have important applications to study intact brain circuits and treat neurological disorders. Herein, we report that magnetoelectric nanoparticles (MENs) can be guided to a targeted brain region to stimulate brain activity with a magnetic field. We demonstrated the nanoparticles' capability to reliably evoke fast neuronal responses in cortical slices ex vivo. After fluorescently labeled MENs were intravenously injected and delivered to a targeted brain region by applying a magnetic field gradient, a magnetic field of low intensity (350-450 Oe) applied to the mouse head reliably evoked cortical activities, as revealed by two-photon and mesoscopic imaging of calcium signals and by an increased number of c-Fos expressing cells after stimulation. Neither brain delivery of MENs nor the magnetic stimulation caused significant increases in astrocytes and microglia. Thus, MENs could enable a non-invasive and contactless deep brain stimulation without the need of genetic manipulation.

Size-dependent intranasal administration of magnetoelectric nanoparticles for targeted brain localization.

The brain is a massive network of neurons which are interconnected through chemical and electrical field oscillations. It is hard to overestimate the significance of the ability to control chemical and physical properties of the network at both the collective and single-cell levels. Most psychiatric and neurodegenerative diseases are typically characterized by certain aberrations of these oscillations. Recently, magnetoelectric nanoparticles (MENs) have been introduced to achieve the desired control. MENs effectively enable wirelessly controlled nanoelectrodes deep in the brain. Although MENs have been shown to cross the blood-brain barrier via intravenous (IV) administration, achieving adequate efficacy of the delivery remains an open question. Herein, through in vivo studies on a mouse model, we demonstrate at least a 4-fold improved efficacy of the targeted delivery of MENs across BBB via intranasal administration compared to an equivalent IV administration.

Colossal Magnetoelectric Effect in Core-Shell Magnetoelectric Nanoparticles.

Magnetoelectric coefficient values of above 5 and 2 V cm-1 Oe-1 in 20 nm CoFe2O4-BaTiO3 and NiFe2O4-BaTiO3 core-shell magnetoelectric nanoparticles were demonstrated. These colossal values, compared to 0.1 V cm-1 Oe-1 commonly reported for the 0-3 system, are attributed to (i) the heterostructural lattice-matched interface between the magnetostrictive core and the piezoelectric shell, confirmed through transmission electron microscopy, and (ii) in situ scanning tunneling microscopy nanoprobe-based ME characterization. The nanoprobe technique allows measurements of the ME effect at a single-nanoparticle level which avoids the charge leakage problem of traditional powder form measurements. The difference in the frequency dependence of the ME value between the two material systems is owed to the Ni-ferrite cores becoming superparamagnetic in the near-dc frequency range. The availability of novel nanostructures with colossal ME values promises to unlock many new applications ranging from energy-efficient information processing to nanomedicine and brain-machine interfaces.

Technobiology's Enabler: The Magnetoelectric Nanoparticle.

To enable patient- and disease-specific diagnostic and treatment at the intracellular level in real time, it is imperative to engineer a perfect way to locally stimulate selected individual neurons, navigate and dispense a cargo of biomolecules into damaged cells or image sites with relatively high efficacy and with adequate spatial and temporal resolutions. Significant progress has been made using biotechnology; especially with the development of bioinformatics, there are endless molecular databases to identify biomolecules to target almost any disease-specific biomarker. Conversely, the technobiology approach that exploits advanced engineering to control underlying molecular mechanisms to recover biosystem's energy states at the molecular level as well as at the level of the entire network of cells (i.e., the internet of the human body) is still in its early research stage. The recently developed magnetoelectric nanoparticles (MENPs) provide a tool to enable the unique capabilities of technobiology. Using exemplary studies that could potentially lead to future pinpoint treatment and prevention of cancer, neurodegenerative diseases, and HIV, this article discusses how MENPs could become a vital enabling tool of technobiology.

One-step fabrication of size-controllable nicotine containing core-shell structures.

We report a one-step synthesis of nicotine-containing nanoparticles by using a size-controllable nanofiltration technique. Nanostructures with polydimethylsiloxane (PDMS) were prepared as a biocompatible well-type polymeric carrier containing a hydrophobic and highly viscous nicotine drug through a novel spontaneous emulsification solvent diffusion method. This approach could be used for efficient dispersion of nicotine in biological systems. Our present results, together with size controllability, pave a way to new types of functional material structures for novel transdermal pharmaceuticals that contain nicotine/cotinine in nanosized structures.

Shape transformation and self-alignment of Fe-based nanoparticles.

New types of functional material structures will emerge if the shape and properties are controlled in three-dimensional nanodevices. Possible applications of these would be nanoelectronics and medical systems. Magnetic nanoparticles (MNPs) are especially important in electronics such as magnetic storage, sensors, and spintronics. Also, in those that are used as magnetic resonance imaging contrasts, and tissue specific therapeutic agents, as well as in the labeling and sorting of cells, drug delivery, separation of biochemical products, and in other medical applications. Most of these applications require MNPs to be chemically stable, uniform in size, and controllable in terms of their magnetic properties and shape. In this paper three new functions of iron (Fe)-based nanoparticles are reported: shape transformation, oxidation prevention, and self-alignment. The shape of the Fe nanoparticles could be controlled by changing their oxidation states and properties by using a nanocarbon coating. Full field X-ray microscopy using synchrotron radiation revealed controllable magnetic properties of MNPs at the L3 edge which depended on the oxidation states. Then, inkjet printing was successfully performed to deposit a uniform layer of MNPs by the size.

Magnetoelectric nanoparticles for delivery of antitumor peptides into glioblastoma cells by magnetic fields.

AIM: We studied externally controlled anticancer effects of binding tumor growth inhibiting synthetic peptides to magnetoelectric nanoparticles (MENs) on treatment of glioblastomas. METHODS: Hydrothermally synthesized 30-nm MENs had the core-shell composition of CoFe2O4@BaTiO3. Molecules of growth hormone-releasing hormone antagonist of the MIA class (MIA690) were chemically bound to MENs. In vitro experiments utilized human glioblastoma cells (U-87MG) and human brain microvascular endothelial cells. RESULTS: The studies demonstrated externally controlled high-efficacy binding of MIA690 to MENs, targeted specificity to glioblastoma cells and on-demand release of the peptide by application of d.c. and a.c. magnetic fields, respectively. CONCLUSION: The results support the use of MENs as an effective drug delivery carrier for growth hormone-releasing hormone antagonists in the treatment of human glioblastomas.

Erratum: Multiferroic coreshell magnetoelectric nanoparticles as NMR sensitive nanoprobes for cancer cell detection.

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

Biodistribution and clearance of magnetoelectric nanoparticles for nanomedical applications using energy dispersive spectroscopy.

AIM: The biodistribution and clearance of magnetoelectric nanoparticles (MENs) in a mouse model was studied through electron energy dispersive spectroscopy. MATERIALS & METHODS: This approach allows for detection of nanoparticles (NPs) in tissues with the spatial resolution of scanning electron microscopy, does not require any tissue-sensitive staining and is not limited to MENs. RESULTS: The size-dependent biodistribution of intravenously administrated MENs was measured in vital organs such as the kidneys, liver, spleen, lungs and brain at four different postinjection times including 1 day, 1 week, 4 and 8 weeks, respectively. CONCLUSION: The smallest NPs, 10-nm MENs, were cleared relatively rapidly and uniformly across the organs, while the clearance of the larger NPs, 100- and 600-nm MENs, was highly nonlinear with time and nonuniform across the organs.

Multiferroic coreshell magnetoelectric nanoparticles as NMR sensitive nanoprobes for cancer cell detection.

Magnetoelectric (ME) nanoparticles (MENs) intrinsically couple magnetic and electric fields. Using them as nuclear magnetic resonance (NMR) sensitive nanoprobes adds another dimension for NMR detection of biological cells based on the cell type and corresponding particle association with the cell. Based on ME property, for the first time we show that MENs can distinguish different cancer cells among themselves as well as from their normal counterparts. The core-shell nanoparticles are 30 nm in size and were not superparamagnetic. Due to presence of the ME effect, these nanoparticles can significantly enhance the electric field configuration on the cell membrane which serves as a signature characteristic depending on the cancer cell type and progression stage. This was clearly observed by a significant change in the NMR absorption spectra of cells incubated with MENs. In contrast, conventional cobalt ferrite magnetic nanoparticles (MNPs) did not show any change in the NMR absorption spectra. We conclude that different membrane properties of cells which result in distinct MEN organization and the minimization of electrical energy due to particle binding to the cells contribute to the NMR signal. The nanoprobe based NMR spectroscopy has the potential to enable rapid screening of cancers and impact next-generation cancer diagnostic exams.

Targeted and controlled anticancer drug delivery and release with magnetoelectric nanoparticles.

It is a challenge to eradicate tumor cells while sparing normal cells. We used magnetoelectric nanoparticles (MENs) to control drug delivery and release. The physics is due to electric-field interactions (i) between MENs and a drug and (ii) between drug-loaded MENs and cells. MENs distinguish cancer cells from normal cells through the membrane's electric properties; cancer cells have a significantly smaller threshold field to induce electroporation. In vitro and in vivo studies (nude mice with SKOV-3 xenografts) showed that (i) drug (paclitaxel (PTX)) could be attached to MENs (30-nm CoFe2O4@BaTiO3 nanostructures) through surface functionalization to avoid its premature release, (ii) drug-loaded MENs could be delivered into cancer cells via application of a d.c. field (~100 Oe), and (iii) the drug could be released off MENs on demand via application of an a.c. field (~50 Oe, 100 Hz). The cell lysate content was measured with scanning probe microscopy and spectrophotometry. MENs and control ferromagnetic and polymer nanoparticles conjugated with HER2-neu antibodies, all loaded with PTX were weekly administrated intravenously. Only the mice treated with PTX-loaded MENs (15/200 µg) in a field for three months were completely cured, as confirmed through infrared imaging and post-euthanasia histology studies via energy-dispersive spectroscopy and immunohistochemistry.

Magnetoelectric 'spin' on stimulating the brain.

AIM: The in vivo study on imprinting control region mice aims to show that magnetoelectric nanoparticles may directly couple the intrinsic neural activity-induced electric fields with external magnetic fields. METHODS: Approximately 10 µg of CoFe2O4-BaTiO3 30-nm nanoparticles have been intravenously administrated through a tail vein and forced to cross the blood-brain barrier via a d.c. field gradient of 3000 Oe/cm. A surgically attached two-channel electroencephalography headmount has directly measured the modulation of intrinsic electric waveforms by an external a.c. 100-Oe magnetic field in a frequency range of 0-20 Hz. RESULTS: The modulated signal has reached the strength comparable to that due the regular neural activity. CONCLUSION: The study opens a pathway to use multifunctional nanoparticles to control intrinsic fields deep in the brain.

Magneto-electric nanoparticles to enable field-controlled high-specificity drug delivery to eradicate ovarian cancer cells.

The nanotechnology capable of high-specificity targeted delivery of anti-neoplastic drugs would be a significant breakthrough in Cancer in general and Ovarian Cancer in particular. We addressed this challenge through a new physical concept that exploited (i) the difference in the membrane electric properties between the tumor and healthy cells and (ii) the capability of magneto-electric nanoparticles (MENs) to serve as nanosized converters of remote magnetic field energy into the MENs' intrinsic electric field energy. This capability allows to remotely control the membrane electric fields and consequently trigger high-specificity drug uptake through creation of localized nano-electroporation sites. In in-vitro studies on human ovarian carcinoma cell (SKOV-3) and healthy cell (HOMEC) lines, we applied a 30-Oe d.c. field to trigger high-specificity uptake of paclitaxel loaded on 30-nm CoFe2O4 @BaTiO3 MENs. The drug penetrated through the membrane and completely eradicated the tumor within 24 hours without affecting the normal cells.

Chemically engineered graphene-based 2D organic molecular magnet.

Carbon-based magnetic materials and structures of mesoscopic dimensions may offer unique opportunities for future nanomagnetoelectronic/spintronic devices. To achieve their potential, carbon nanosystems must have controllable magnetic properties. We demonstrate that nitrophenyl functionalized graphene can act as a room-temperature 2D magnet. We report a comprehensive study of low-temperature magnetotransport, vibrating sample magnetometry (VSM), and superconducting quantum interference (SQUID) measurements before and after radical functionalization. Following nitrophenyl (NP) functionalization, epitaxially grown graphene systems can become organic molecular magnets with ferromagnetic and antiferromagnetic ordering that persists at temperatures above 400 K. The field-dependent, surface magnetoelectric properties were studied using scanning probe microscopy (SPM) techniques. The results indicate that the NP-functionalization orientation and degree of coverage directly affect the magnetic properties of the graphene surface. In addition, graphene-based organic magnetic nanostructures were found to demonstrate a pronounced magneto-optical Kerr effect (MOKE). The results were consistent across different characterization techniques and indicate room-temperature magnetic ordering along preferred graphene orientations in the NP-functionalized samples. Chemically isolated graphene nanoribbons (CINs) were observed along the preferred functionality directions. These results pave the way for future magnetoelectronic/spintronic applications based on promising concepts such as current-induced magnetization switching, magnetoelectricity, half-metallicity, and quantum tunneling of magnetization.

Fabrication of dense non-circular nanomagnetic device arrays using self-limiting low-energy glow-discharge processing.

We describe a low-energy glow-discharge process using reactive ion etching system that enables non-circular device patterns, such as squares or hexagons, to be formed from a precursor array of uniform circular openings in polymethyl methacrylate, PMMA, defined by electron beam lithography. This technique is of a particular interest for bit-patterned magnetic recording medium fabrication, where close packed square magnetic bits may improve its recording performance. The process and results of generating close packed square patterns by self-limiting low-energy glow-discharge are investigated. Dense magnetic arrays formed by electrochemical deposition of nickel over self-limiting formed molds are demonstrated.