Magnetoelectric Nanoparticles Research Articles

Nanoparticles use magnetoelectricity to target and eradicate cancer cells.

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.

Magnetoelectrics for Implantable Bioelectronics: Progress to Date.

ConspectusThe coupling of magnetic and electric properties manifested in magnetoelectric (ME) materials has unlocked numerous possibilities for advancing technologies like energy harvesting, memory devices, and medical technologies. Due to this unique coupling, the magnetic properties of these materials can be tuned by an electric field; conversely, their electric polarization can be manipulated through a magnetic field.Over the past seven years, our lab work has focused on leveraging these materials to engineer implantable bioelectronics for various neuromodulation applications. One of the main challenges for bioelectronics is to design miniaturized solutions that can be delivered with minimally invasive procedures and yet can receive sufficient power to directly stimulate tissue or power electronics to perform functions like communication and sensing.Magnetoelectric coupling in ME materials is strongest when the driving field matches a mechanical resonant mode. However, miniaturized ME transducers typically have resonance frequencies >100 kHz, which is too high for direct neuromodulation as neurons only respond to low frequencies (typically <1 kHz). We discuss two approaches that have been proposed to overcome this frequency mismatch: operating off-resonance and rectification. The off-resonance approach is most common for magnetoelectric nanoparticles (MENPs) that typically have resonance frequencies in the gigahertz range. In vivo experiments on rat models have shown that MENPs could induce changes in neural activity upon excitation with <200 Hz magnetic fields. However, the neural response has latencies of several seconds due to the weak coupling in the off-resonance regime.To stimulate neural responses with millisecond precision, we developed methods to rectify the ME response so that we could drive the materials at their resonant frequency but still produce the slowly varying voltages needed for direct neural stimulation. The first version of the stimulator combined a ME transducer and analog electronics for rectification. To create even smaller solutions, we introduced the first magnetoelectric metamaterial (MNM) that exhibits self-rectification. Both designs have effectively induced neural modulation in rat models with less than 5 ms latency.Based on our experience with in vivo testing of the rectified ME stimulators, we found it challenging to deliver the precisely controlled therapy required for clinical applications, given the ME transducer's sensitivity to the external transmitter alignment. To overcome this challenge, we developed the ME-BIT (MagnetoElectric BioImplanT), a digitally programmable stimulator that receives wireless power and data through the ME link.We further expanded the utility of this technology to neuromodulation applications that require high stimulation thresholds by introducing the DOT (Digitally programmable Overbrain Therapeutic). The DOT has voltage compliance up to 14.5 V. We have demonstrated the efficacy of these designs through various in vivo studies for applications like peripheral nerve stimulation and epidural cortical stimulation.To further improve these systems to be adaptive and enable a network of coordinated devices, we developed a bidirectional communication system to transmit data to and from the implant. To enable even greater miniaturization, we developed a way to use the same ME transducer for wireless power and data communication by developing the first ME backscatter communication protocol.

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 summaryThis 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.

Equivalent Circuit Model of Magnetoelectric Composite Nanoparticles

This study presents an analysis of magnetoelectric nanoparticles (MENPs) through the development of equivalent circuits to predict the frequency-dependent magnetoelectric coefficient, with a focus on the widely utilized CoFe2O4@BaTiO3 core–shell configuration. This approach involves –derivation of phenomenological expressions that capture the dynamic behavior of MENPs under varying magnetic and electric fields. By integrating piezoelectric and magnetostrictive constitutive equations, along with consideration of dynamic effects and bio-load conjugation, a magneto-elasto-electric effect equivalent circuit has been constructed. This circuit model not only facilitates the investigation of longitudinal data in cube-shaped MENPs but also offers insights into fundamental biological processes. The versatility of this model is shown through translation to other core–shell nanoparticles, composite structures, and multiferroic nanostructures. This analysis provides quantitative predictions of the magnetoelectric coefficients, enhancing general understanding of MENP characteristics across a broad frequency range. Furthermore, the study highlights the framework for future refinement to incorporate intrinsic composition-specific resonances, such as ferromagnetic and ferroelectric resonances, to further significantly improve the nanoparticles’ performance. Overall, this work lays the groundwork for future technology to intelligently and wirelessly control biological processes using MENPs, thus paving a way for innovative biomedical applications. This quantitative approach may facilitate further interdisciplinary research and contribute to advancement of magnetoelectric materials and their applications.

Advances in Brain Stimulation, Nanomedicine and the Use of Magnetoelectric Nanoparticles: Dopaminergic Alterations and Their Role in Neurodegeneration and Drug Addiction.

Recent advancements in brain stimulation and nanomedicine have ushered in a new era of therapeutic interventions for psychiatric and neurodegenerative disorders. This review explores the cutting-edge innovations in brain stimulation techniques, including their applications in alleviating symptoms of main neurodegenerative disorders and addiction. Deep Brain Stimulation (DBS) is an FDA-approved treatment for specific neurodegenerative disorders, including Parkinson's Disease (PD), and is currently under evaluation for other conditions, such as Alzheimer's Disease. This technique has facilitated significant advancements in understanding brain electrical circuitry by enabling targeted brain stimulation and providing insights into neural network function and dysfunction. In reviewing DBS studies, this review places particular emphasis on the underlying main neurotransmitter modifications and their specific brain area location, particularly focusing on the dopaminergic system, which plays a critical role in these conditions. Furthermore, this review delves into the groundbreaking developments in nanomedicine, highlighting how nanotechnology can be utilized to target aberrant signaling in neurodegenerative diseases, with a specific focus on the dopaminergic system. The discussion extends to emerging technologies such as magnetoelectric nanoparticles (MENPs), which represent a novel intersection between nanoformulation and brain stimulation approaches. These innovative technologies offer promising avenues for enhancing the precision and effectiveness of treatments by enabling the non-invasive, targeted delivery of therapeutic agents as well as on-site, on-demand stimulation. By integrating insights from recent research and technological advances, this review aims to provide a comprehensive understanding of how brain stimulation and nanomedicine can be synergistically applied to address complex neuropsychiatric and neurodegenerative disorders, paving the way for future therapeutic strategies.

Ferroelectricity‐Induced Surface Ferromagnetism in Core–Shell Magnetoelectric Nanoparticles

Magnetoelectric nanoparticles (NPs) present an important class of nanomaterials with a wide interest in piezocatalytic and biomedical applications. Herein, the results of magnetoelectric and magnetization measurements performed on core–shell NPs having magnetic core (MnFe2O4, MFO) and ferroelectric shell (Ba0.85Ca0.15Ti0.5Zr0.5O3, BCZT) synthesized by the microwave hydrothermal method are reported. Magnetic results are compared with the measurements on reference MFO NPs prepared under identical conditions. Detailed SQUID magnetometer measurements of the magnetization hysteresis loops M(H) down to 2 K reveal the existence of a clear exchange bias effect in pure MFO NPs attributed to the coexistence of ferromagnetic and antiferromagnetic short‐range interactions. When the magnetic core is covered by the thin ferroelectric BCZT shell, it is observed that 1) the shell suppresses the apparent bias effect and 2) induces an “extra” ferromagnetic magnetization at T &lt; 20 K. The results indicate that this “extra” ferromagnetism has a 2D character and it is most likely related to the interface interactions between the MFO core and BCZT shell. Ferroelectric properties and strong magnetoelectric effect in core–shell NPs are revealed via piezoresponse force microscopy under magnetic field. The mechanisms of the observed effects are discussed.

BBB-penetrating magnetoelectric nanoparticles with sustainable Gel formulation for enhanced chemotherapy and reduced postoperative glioma recurrence

Overcoming blood–brain barrier (BBB), reducing drug resistance and inhibiting postoperative recurrence are the huge challenges of glioma treatment. Herein, a magnetoelectric nanoparticle, applying CoFe2O4 as magnetic core, BaTiO3 as piezoelectric shell and polyethylene glycol-connected I6P8 peptide as surface coating (CBPI), was used for glioma-targeted treatment. This nanoparticle could down-regulate tight junction proteins of BBB via magnetoelectric effect, synergized with I6P8 peptide, to achieve the enhanced BBB permeability and glioma targeting. Under magnetic field activation, this nanoparticle, after doxorubicin loading to formulate CBPID, could accomplish magnetoelectricity and pH-responsive drug release, and generate mild reactive oxygen species to sensitize the chemotherapy through c-Jun N-terminal kinase phosphorylation pathway. Importantly, CBPID facilitated intraoperative cavity administration with magnetic immobilization after easy doping to Surgiflo filler, benefiting the repeated magnetoelectric-activated therapy to inhibit glioma postoperative recurrence. Moreover, CBPID could be mostly excreted through feces after intravenous injection, which did not cause obvious blood and organ abnormalities and even improved the behavioral abnormalities caused by glioma.

A novel MRI-based tumor-targeting theragnostic agent: Magnetoelectric nanoparticles in an in vivo murine KRAS/P53 pancreatic flank tumor model.

3075 Background: Magnetoelectric nanoparticles (MENPs) are a novel material with a magnetoelectric (ME) property that allows for conversion of an external magnetic field to a local electric field (EF) that can be exploited to generate a Coulomb force to target and electroporate the relatively non-polarized tumor cell walls. We hypothesized that their local EF and superparamagnetic cores can be exploited as an MRI-based anti-cancer theragnostic agent for solid tumors. Methods: 35 immunocompetent C57BL/6 mice were inoculated with KPC961 pancreatic adenocarcinoma cells in their flank. The 27 mice with the largest tumors at 4 weeks were randomized into 5 cohorts based on treatment: 300 µg of MENP (300; n=6), 600 µg of MENP (600; n=6), 300 µg of low-ME coefficient MENP (LM; n=5), 300 µg of MENP without M1 MRI (NM; MRI field control, n=5), and normal saline (NS; MENP causal effect control; n=5). The 300, 600, LM, and NS cohorts had T2 MRI maps (M0) on a 7T MRI. NM had T2 weighted MRIs at M0. All mice had a neodymium magnet placed over their tumors for 12 hours after tail vein injections (300 µl for all mice) for targeting. The 300, 600, LM, and NS cohorts then underwent MRI mapping (M1) after magnet removal (No M1 MRI for NM). MRI mapping was repeated 5 days after (M2). NM had a T2 weighted MRIs at M2. M1 and M2 data were used to assess relaxation time (contrast effect) and tumor volume from M0, respectively. Student t and ANOVA tests were used to compare differences for tumor volume and relaxation time data and one-sided Fisher’s exact test was used for complete response (CR) data. Results: The median M0 tumor volume was 109.6 mm3 for all mice, and there were no differences between any cohort ( p = 0.978; Table). The 300 and 600 MENP cohorts demonstrated a 102.7% reduction in volume (M2/M0; 56.7% vs. 159.4% for NS and NM controls, p = &lt;0.001) and a 7.2% T2 negative contrast effect (M1/M0; 94.2% vs. 101.3% for NS, p = 0.046) compared to controls. Six mice in 300, 600, and LM (2 each) achieved a clinical CR (between 1 to 2 weeks after M1) vs. none in the NS and NM control cohorts ( p = 0.0418), without any recurrences until end of study (6 weeks after M2). Conclusions: This is the first report demonstrating the theragnostic effects of MENPs having both T2 contrast and locally ablative therapy properties as an in vivo tumor targeting agent. These results confirm prior pilot study and point towards irreversible electroporation as the likely mechanism of action (MOA) since the antitumor effect is not seen within the NM cohort. Additional studies characterizing the MOA, dose-response relationships, and immunomodulatory effects are needed to better understand their full clinical potential.[Table: see text]

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.

Abstract 490: Significant anti-proliferative effects of targeted magnetoelectric nanoparticles as potential theragnostic tools

Abstract Although current electroporation therapies have been demonstrated to be effective not only in ablating tumor tissue, but also in eliciting an anti-tumor immune response, they are limited in their application due to the strong risk factors associated with the high voltages required. Current methods of interacting with the body’s electrical currents are limited to traditional electrodes, which cause damage to surrounding tissue upon insertion, and require high voltages to create responses at the cellular level. Recent efforts at non-invasive interaction with the body’s electric fields have led to the fabrication of magnetoelectric nanoparticles (MENPs), a novel technology which has the ability to convert harmless magnetic fields into strong local electric fields, all while maintaining a diameter of ~70nm. These particles have been demonstrated to trigger neuronal firing under magnetic stimulation both in vitro and in vivo, and have been able to release chemotherapeutic agents on command in vitro and in vivo. This demonstrates the ability for MENPs to wirelessly generate electric fields within the body on demand with high temporal and spatial resolution. This suggests the potential for non-invasive electroporation therapy which could be triggered by external magnetic fields. Given the particles are themselves magnetic, this could show potential as a theragnostic tool as their magnetic properties suggest they may act simultaneously as an MRI contrast and an ablative therapy. To explore this possibility, we fabricated MENPs consisting of a magnetostrictive CoFe2O4 spinel core coupled with a piezoelectric BaTiO3 perovskite shell. These particles were then PEGylated to reduce agglomeration which is typical of magnetic nanoparticles. 50ul of a 1mg/ml PEG-MENP dispersion was deposited into a cell culture of SKOV-3 ovarian cancer cells. These cells were then stimulated by 120 10ms pulses of a 2kOe magnetic field over the course of 30 minutes. An cell-titre glo ATP assay was performed to indicate viability 24 hours after treatment. Treatment wells were compared to controls of no intervention, magnetic stimulation with no particles, and particles with no stimulation. The combination of particles and magnetic stimulation was the only group which showed significant decreases in viability, with a 32% reduction in viability. Particles on their own showed no effect on cell viability, neither did magnetic-only stimulation. This preliminary investigation into the use of MENPs as a non-invasive cancer treatment has shown some potential. The ability to wirelessly activate the particles provides an inherent targeting mechanism not found in traditional chemotherapeutics, while the nanometer diameter provides a non-invasive method to generate strong electric fields within the body. Citation Format: Max Shotbolt, Elric Zhang, Emily Zhu, Wael El-Rifai, John Bryant, Ping Liang, Sakhrat Khizroev. Significant anti-proliferative effects of targeted magnetoelectric nanoparticles as potential theragnostic tools [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 490.

The Study of Core–Shell Cobalt Ferrite–Barium Titanate Magnetoelectric Nanoparticles in Targeting and Optimized Drug Delivery: An Overview

This review provides a comprehensive understanding of magnetoelectric (ME) nanocomposite, cobalt ferrite–barium titanate (CFO–BTO) as a potential candidate for targeting specific cells. The synthesized core–shell material uses strain-mediated coupling between magnetostrictive and piezoelectric material. CFO–BTO has the competitive advantage of a high ME coefficient and is biocompatible. The shape and size play a pivotal role in passive drug delivery due to the enhanced permeability and retention effect at tumor sites. Surfactants can also enhance drug absorption and influence the interaction with nanoparticle composite. A comparison between external magnetic field–frequency parameters to navigate the ME nanoparticle and trigger release of the drug at site is also reviewed. Coating the nanoparticles with a layer of surfactant can reduce the threshold external magnetic field for navigation and triggering of drug particle release, making the prospect viable for clinical studies.

Multiscale Modeling of Magnetoelectric Nanoparticles for the Analysis of Spatially Selective Neural Stimulation.

The growing field of nanoscale neural stimulators offers a potential alternative to larger scale electrodes for brain stimulation. Nanoelectrodes made of magnetoelectric nanoparticles (MENPs) can provide an alternative to invasive electrodes for brain stimulation via magnetic-to-electric signal transduction. However, the magnetoelectric effect is a complex phenomenon and challenging to probe experimentally. Consequently, quantifying the stimulation voltage provided by MENPs is difficult, hindering precise regulation and control of neural stimulation and limiting their practical implementation as wireless nanoelectrodes. The work herein develops an approach to determine the stimulation voltage for MENPs in a finite element analysis (FEA) model. This model is informed by atomistic material properties from ab initio Density Functional Theory (DFT) calculations and supplemented by experimentally obtainable nanoscale parameters. This process overcomes the need for experimentally inaccessible characteristics for magnetoelectricity, and offers insights into the effect of the more manageable variables, such as the driving magnetic field. The model's voltage is compared to in vivo experimental data to assess its validity. With this, a predictable and controllable stimulation is simulated by MENPs, computationally substantiating their spatial selectivity. This work proposes a generalizable and accessible method for evaluating the stimulation capability of magnetoelectric nanostructures, facilitating their realization as wireless neural stimulators in the future.

Flexible, Biodegradable, and Wireless Magnetoelectric Paper for Simple In Situ Personalization of Bioelectric Implants.

Bioelectronic implants delivering electrical stimulation offer an attractive alternative to traditional pharmaceuticals in electrotherapy. However, achieving simple, rapid, and cost-effective personalization of these implants for customized treatment in unique clinical and physical scenarios presents a substantial challenge. This challenge is further compounded by the need to ensure safety and minimal invasiveness, requiring essential attributes such as flexibility, biocompatibility, lightness, biodegradability, and wireless stimulation capability. Here, a flexible, biodegradable bioelectronic paper with homogeneously distributed wireless stimulation functionality for simple personalization of bioelectronic implants is introduced. The bioelectronic paper synergistically combines i) lead-free magnetoelectric nanoparticles (MENs) that facilitate electrical stimulation in response to external magnetic field and ii) flexible and biodegradable nanofibers (NFs) that enable localization of MENs for high-selectivity stimulation, oxygen/nutrient permeation, cell orientation modulation, and biodegradation rate control. The effectiveness of wireless electrical stimulation in vitro through enhanced neuronal differentiation of neuron-like PC12 cells and the controllability of their microstructural orientation are shown. Also, scalability, design flexibility, and rapid customizability of the bioelectronic paper are shown by creating various 3D macrostructures using simple paper crafting techniques such as cutting and folding. This platform holds promise for simple and rapid personalization of temporary bioelectronic implants for minimally invasive wireless stimulation therapies.

Magnetic Properties of Magnetoelectric Nanoparticles With Varying Core–Shell Ratios and Their Effects on In Vitro Neuron Stimulation

Magnetic Properties of Magnetoelectric Nanoparticles With Varying Core–Shell Ratios and Their Effects on In Vitro Neuron Stimulation

Low-frequency magnetic fields potentiate plasma-modified magneto-electric nanoparticle drug loading for anticancer activity in vitro and in vivo

A multiferroic nanostructure of manganese ferrite barium-titanate called magneto-electric nanoparticles (MENs) was synthesized by a co-precipitation method. FTIR, Raman spectroscopy, TEM, and X-ray diffraction confirmed the presence of spinel core and perovskite shell phases with average crystallite sizes of 70–90 nm. Magnetic, optical, and magnetoelectrical properties of MENs were investigated using VSM, UV-Vis spectrophotometry, DLS, and EIS spectroscopy techniques. After pre-activation by low-pressure argon (Ar) plasma, the MENs were functionalized by a highly hydrophilic acrylic acid and Oxygen (AAc+O2) mixture to produce COOH and C=O-rich surfaces. The loading and release of doxorubicin hydrochloride (DOX) on MENs were investigated using UV-vis and fluorescence spectrophotometry under alternating low-frequency magnetic fields. Plasma treatment enabled drug-loading control by changing the particles’ roughness as physical adsorption and creating functional groups for chemical absorption. This led to reduced metabolic activity and cell adherences associated with elevated expression of pro-apoptotic genes (BCL-2, caspase 3) in 4T1 breast cancer cells in vitro exposed to alternating current magnetic field (ACMF) compared to MENs-DOX without field exposure. ACMF-potentiated anticancer effects of MENs were validated in vivo in tumor-bearing Balb/C mice. Altogether, our results suggest potentiated drug loading of MENs showing superior anticancer activity in vitro and in vivo when combined with ACMF.

Ab Initio Physics Considerations in the Design of Wireless and Non-Invasive Neural Recording Systems Using Magnetoelectric Nanoparticles

Ab Initio Physics Considerations in the Design of Wireless and Non-Invasive Neural Recording Systems Using Magnetoelectric Nanoparticles

Magnetoelectric nanoparticles shape modulates their electrical output.

Core-shell magnetoelectric nanoparticles (MENPs) have recently gained popularity thanks to their capability in inducing a local electric polarization upon an applied magnetic field and vice versa. This work estimates the magnetoelectrical behavior, in terms of magnetoelectric coupling coefficient (αME), via finite element analysis of MENPs with different shapes under either static (DC bias) and time-variant (AC bias) external magnetic fields. With this approach, the dependence of the magnetoelectrical performance on the MENPs geometrical features can be directly derived. Results show that MENPs with a more elongated morphology exhibits a superior αME if compared with spherical nanoparticles of similar volume, under both stimulation conditions analyzed. This response is due to the presence of a larger surface area at the interface between the magnetostrictive core and piezoelectric shell, and to the MENP geometrical orientation along the direction of the magnetic field. These findings pave a new way for the design of novel high-aspect ratio magnetic nanostructures with an improved magnetoelectric behaviour.

Novel Biocompatible Magnetoelectric MnFe2 O4 Core@BCZT Shell Nano-Hetero-Structures with Efficient Catalytic Performance.

Magnetoelectric (ME) small-scale robotic devices attract great interest from the scientific community due to their unique properties for biomedical applications. Here, novel ME nano hetero-structures based on the biocompatible magnetostrictive MnFe2 O4 (MFO) and ferroelectric Ba0.85 Ca0.15 Zr0.1 Ti0.9 O3 (BCZT) are developed solely via the hydrothermal method for the first time. An increase in the temperature and duration of the hydrothermal synthesis results in increasing the size, improving the purity, and inducing morphology changes of MFO nanoparticles (NPs). A successful formation of a thin epitaxial BCZT-shell with a 2-5nm thickness is confirmed on the MFO NPs(77 ± 14nm) preliminarily treated with oleic acid (OA) or polyvinylpyrrolidone (PVP), whereas no shell is revealed on the surface of pristine MFO NPs. High magnetization is revealed for the developed ME NPs based on PVP- and OA-functionalized MFO NPs (18.68 ± 0.13 and 20.74 ± 0.22 emug-1 , respectively). Moreover, ME NPs demonstrate 95% degradation of a model pollutant Rhodamine B within 2.5 h under an external AC magnetic field (150 mT, 100Hz). Thus, the developed biocompatible core-shell ME NPs of MFO and BCZT can be considered as a promising tool for non-invasive biomedical applications, environmental remediation, and hydrogen generation for renewable energy sources.

Abstract 819: Investigating the impacts of membrane potential on nano-electroporation efficacy

Abstract Electroporation has been shown to be an effective method of intracellular drug delivery and tissue ablation, however it faces significant challenges not only in clinical application due to the risks associated with the necessity of high voltage electrodes, but also due to a lack of fundamental research into the electrical characteristics of cancer cells. In order to improve outcomes in the clinic when using irreversible electroporation(IRE), it will be crucial to create a deeper understanding of the mechanisms underlying electroporation, such as the impacts of resting membrane potential on IRE outcomes. Magnetoelectric-nanoparticles (MENPs)have proven their ability to generate electric fields when stimulated by an external magnetic field and thus may be an effective alternative to electrodes for in-vivo electroporation and electro-chemotherapy. The ability of MENPs to electroporate cells is limited by the strength of their magnetoelectric (ME)effect, as such it is important to optimize MENPs fabrication for future applications. Improving this technology will require a deeper understanding of the membrane potential and other electrical properties of cancer cells.We fabricated MENPs consisting of a magnetostrictive CoFe2O4 core coupled with a piezoelectric BaTiO3shell. SKOV-3 and HOMEC cells were seeded in culture plates and given a 50ul dose of particle suspension, and 10ul of propidium iodide(PI). The cell samples were then stimulated by a 10 minute exposure to an alternating magnetic field of 400Oe at 100Hz. Fluorescence-microscope images were taken at 5 minute intervals during, and for 10 minutes following, the magnetic stimulation. These images were processed in MATLAB to quantify total fluorescence, and thus PI uptake, over time for each cell culture-particle combination.MENPs coupled with magnetic field stimulation were able to cause PI uptake in both HOMEC and SKOV-3 cells, indicating electroporation had occurred. By adding PI at time intervals after stimulation, we were able to determine whether electroporation had been reversible or irreversible by showing dye uptake would stop soon after stimulation had ended in the case of reversible EP but not IRE. We found SKOV-3 to have been reversibly electroporated, and HOMEC to have undergone IRE. To understand these results we used Oxonol uptake in a flow cytometry measurement to estimate resting membrane potential (RMP). HOMEC cells were shown to have a RMP approximately 20mV smaller than SKOV-3, which corresponded to the occurrence of IRE in HOMEC compared to reversible electroporation in SKOV-3.These results demonstrate the efficacy of MENPs to electroporate mammalian cells in the presence of a magnetic field. They also indicate a link between RMP and reversibility of electroporation. Further research into the electrical properties of cancer cells will be needed to formulate a complete model of the interactions between the nanoparticles and mammalian cells. Citation Format: Max Shotbolt, Victoria Andre, Skye Conlan, Ping Liang, Sakhrat Khizroev. Investigating the impacts of membrane potential on nano-electroporation efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 819.

Wireless stimulation of the subthalamic nucleus with nanoparticles modulates key monoaminergic systems similar to contemporary deep brain stimulation

BackgroundDeep brain stimulation (DBS) is commonly used to alleviate motor symptoms in several movement disorders. However, the procedure is invasive, and the technology has remained largely stagnant since its inception decades ago. Recently, we have shown that wireless nanoelectrodes may offer an alternative approach to conventional DBS. However, this method is still in its infancy, and more research is required to characterize its potential before it can be considered as an alternative to conventional DBS. ObjectivesHerein, we aimed to investigate the effect of stimulation via magnetoelectric nanoelectrodes on primary neurotransmitter systems that have implications for DBS in movement disorders. MethodsMice were injected with either magnetoelectric nanoparticles (MENPs) or magnetostrictive nanoparticles (MSNPs, as a control) in the subthalamic nucleus (STN). Mice then underwent magnetic stimulation, and their motor behavior was assessed in the open field test. In addition, magnetic stimulation was applied before sacrifice and post-mortem brains were processed for immunohistochemistry (IHC) to assess the co-expression of c-Fos with either tyrosine hydroxylase (TH), tryptophan hydroxylase-2 (TPH2) or choline acetyltransferase (ChAT). ResultsStimulated animals covered longer distances in the open field test when compared to controls. Moreover, we found a significant increase in c-Fos expression in the motor cortex (MC) and paraventricular region of the thalamus (PV-thalamus) after magnetoelectric stimulation. Stimulated animals showed fewer TPH2/c-Fos double-labeled cells in the dorsal raphe nucleus (DRN), as well as TH/c-Fos double-labeled cells in the ventral tegmental area (VTA), but not in the substantia nigra pars compacta (SNc). There was no significant difference in the number of ChAT/ c-Fos double-labeled cells in the pedunculopontine nucleus (PPN). ConclusionsMagnetoelectric DBS in mice enables selective modulation of deep brain areas and animal behavior. The measured behavioral responses are associated with changes in relevant neurotransmitter systems. These changes are somewhat similar to those observed in conventional DBS, suggesting that magnetoelectric DBS might be a suitable alternative.