Technobiology s Enabler: The Magnetoelectric Nanoparticle

Technobiology’s Enabler: The MagnetoelectricNanoparticle

Sakhrat Khizroev

Center for Personalized Nanomedicine, Florida International University, Miami, Florida 33199

Correspondence: [email protected]

To enable patient- and disease-specific diagnostic and treatment at the intracellular level inreal time, it is imperative to engineer a perfect way to locally stimulate selected individualneurons, navigate and dispense a cargo of biomolecules into damaged cells or image siteswith relatively high efficacy and with adequate spatial and temporal resolutions. Significantprogress has been made using biotechnology; especially with the development of bioinfor-matics, there are endless molecular databases to identify biomolecules to target almost anydisease-specific biomarker. Conversely, the technobiology approach that exploits advancedengineering to control underlying molecular mechanisms to recover biosystem’s energystates at the molecular level as well as at the level of the entire network of cells (i.e., theinternet of the human body) is still in its early research stage. The recently developed mag-netoelectric nanoparticles (MENPs) provide a tool to enable the unique capabilities of tech-nobiology. Using exemplary studies that could potentially lead to future pinpoint treatmentand prevention of cancer, neurodegenerative diseases, and HIV, this article discusses howMENPs could become a vital enabling tool of technobiology.

The rapidly growing interdisciplinary field ofnanomedicine promises unprecedented pa-

tient- and disease-specific high-precision med-ical diagnostic and treatment. To underscore thesignificance of its potential impact, with the rap-id growth of genetic engineering, nanomedicinecan become the ultimate enabling tool to unlockall the great potential of highly personalizedprecision medicine. Significant progress has al-ready been achieved using biotechnology. Espe-cially with the development of bioinformatics,today there are endless computational resourcesand molecular databases to help identify bio-molecules that could target almost any specificbiomarker. Conversely, the recently emerged

technobiology approach that exploits advancedengineering combined with physics, chemistry,and computer science to monitor and controlthe intracellular and intercellular biology in realtime is still in its very early stage of research. Thetechnobiology approach could potentially en-able a high-efficacy external control of intrinsicmolecular processes that underlie a disease pa-thology and gene variability at the single-mole-cule level as well as at the level of entire massivenetwork of trillions of interconnected cells ofthe human body also known as the internetof the human body. Communication betweenall the cells in this internet follows a set of lawsthat eventually define the state of human health.

Editors: Valentin A. Pavlov and Kevin J. TraceyAdditional Perspectives on Bioelectronic Medicine available at www.perspectivesinmedicine.org

Copyright © 2019 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a034207Cite this article as Cold Spring Harb Perspect Med 2019;9:a034207

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This set of laws remains to be understood;technobiology is the pathway to gaining andthen applying the required knowledge. In otherwords, technobiology aims to exploit the physicsof the molecular-level interactions as well as todecipher the science of the complex internet ofthe human body with the goal to engineer bettermedicines and make personalized medicine areality.

The biological processes that underlie med-ical diagnostic, treatment, and disease pathogen-esis at the molecular level are inherently drivenby intrinsic electric fields. For example, the brainis one biological system the understanding ofwhich could be substantially improved if theelectric fields deep in the brain could be mappedin real time. The neural activity in the centraland peripheral neural systems is determined bycomplex electric circuits and subcircuits thathave not been decoded yet. Despite the signifi-cant progress in neuroscience over the last fewdecades, we still know very little about the brain.Most of the modern therapies related to neuro-degenerative diseases or brain tumors are notdeveloped at this fundamental level and thusare substantially limited in their capabilities. Inaddition, the holy-grail task of reverse engineer-ing the brain would also significantly benefitfrom the ability to map the intrinsic electricfields in real time. Another familiar examplerelates to the field of cellular oncology. Normaland cancer cells of one type under equivalentconditions have distinctly different electric pro-perties, for example, reflected in different valuesof the membrane potential, the dielectric break-down voltage, the electroporation threshold en-ergy, the surface charge, or another parameterthat could be used for unique cellular identifica-tion and control and eventually high-specificitytherapy. One more application of a translationalimpact could result from using local electricfields to control lineage reprogramming ofsomatic cells into specific cell types such asvital dopaminergic neurons and others. Last,but not least, in general, the promising and rap-idly growing discipline of nanoparticle-basedtargeted drug delivery indispensably relies on achemical bond between the nanoparticle carrierand the drug(s); in turn, this bond, regardless of

its origin, is always electric-field driven andtherefore could be externally controlled provid-ed there is the right technobiology to accomplishthis feat. In this regard, for example, using nano-particles for externally controlled gene transfec-tion could unlock many new life-saving applica-tions.

With this said, the quest for an approach toexploit these molecular- and network-level elec-tric field–driven interactions to enable externallycontrolled therapy must not be surprising. Un-fortunately, achieving a local control of intrinsicelectric fields remotely has long been a formida-ble task. The reason is the fact that remote elec-tric fields cannot be used for a direct cellular levelcontrol of local electric properties without caus-ing and/or experiencing a major interferencewith/from the rest of the electric micro- andmacroenvironments of the human body. Forexample, that is the reason why the current ver-sion of deep-brain stimulation (DBS) requiresestablishment of direct physical contacts/wiresto neurons. That is the reason why DBS can beused only with an inadequately small numberof electrodes and thus cannot provide a single-neuron control. Obviously, a goal of attachingover 80 billion wires to the brain would be out ofthe question. In contrast, magnetic fields do notface this challenge. We do have the ubiquitousdiagnostic tool of magnetic resonance imaging(MRI) (Fox and Raichle 2007). Even relativelyhigh magnetic fields (on the order of 3 Tesla)only insignificantly interfere with the patient’sphysiological system and thus have been desig-nated as safe by the Food and Drug Administra-tion (FDA). However, despite the excellentstructural imaging capabilities of MRI, undernormal circumstances, magnetic fields can bare-ly couple to local electric fields and thus cannotprovide sufficiently rich information associatedwith intrinsic biological processes, in addition tothe temporal resolution ofMRI on the order of 1msec, is not sufficient for imaging in real time. Insummary, discovering a novel approach for pro-viding high-efficacy external control of localelectric fields in intrinsic physiological microen-vironments is vital for enabling technobiology.

One solution to this problem would be touse the recently introduced (in medicine) class

S. Khizroev

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of multiferroic nanostructures known as mag-netoelectric nanoparticles (MENPs). Unlike anyother materials and nanostructures, MENPshave unique properties that allow them to com-bine the wireless control capability of magneticfields and the intricate access to intrinsic molec-ular-level information by local electric fields.

MAGNETOELECTRICNANOPARTICLES ANDTHEIR MIGHTY CAPABILITIES

In general, the use of nanoparticles is consideredan essential enabling tool of personalized nano-medicine because of their unique and diversesize- and shape-dependent properties. Thereare many different types of nanoparticle sys-tems. To name a few, they rely on using thermal-ly responsive polymers, electromagnetically oracoustically activated materials, liposomes, elec-trochemical processes, or other mechanisms todeliver and release the drug or enhance an imagecontrast (Derfus et al. 2007). However, it is onlythe MENPs that can unlock all the aforemen-tioned technobiology capabilities. They can dothis because of the presence of the magnetoelec-tric (ME) effect.

Distinction between Magnetoelectric andTraditional Magnetic Nanoparticles

MENPs must not be confused with traditionalmagnetic nanoparticles (MNPs), which, likeMENPs, do have a field-dependent magneticmoment but, unlike MENPs, do not displayany ME effect. Although the ME effect has beenknown for many decades, only recently have welearned to synthesize materials with a nonzeroME effect at room temperature and above. Thereare many types of MENPs. They differ mostlydepending on the material composition. Thecoreshell ME nanoparticles represent the mostwidely used type of MENPs. These coreshellnanostructures belong to type I multiferroicsand are made of two ferroic components, theferromagnetic (or ferrimagnetic or antiferro-magnetic) core and the ferroelectric shell, re-spectively, as shown in Figure 1A. TheME effectis the result of a strain-induced lattice matchbetween the two components. Owing to this

lattice match, the magnetostrictive effect of themagnetic core is intrinsically coupled (throughstrain) to the piezoelectric effect of the ferro-electric shell. A transmission electron micro-scopy (TEM) image of 30-nm CoFe2O4–BaTiO3,made of the magnetostrictive ferrimagneticspinel core CoFe2O4 and the piezoelectric pe-rovskite shell BaTiO3, is shown in Figure 1B.The size can be controlled in a range from 10to over 100 nm through temperature conditions,while the magnetic component is fabricatedthrough a hydrothermal method (Guduru andKhizroev 2014; Stewart et al. 2018). This proce-dure results in MENPs that can be resuspendedin aqueous solutions because of the presenceof carboxyl groups. The carboxyl functionalgroups are used for drug/dye conjugation. Thesestructures have been shown not to cause anytoxicity when used in adequate doses and par-ticularly when coated with some lipid moleculessuch as glycerol mono-oleate (GMO) (Nair et al.2013; Kaushik et al. 2016; Rodzinski et al. 2016).It is noteworthy that the M-H hysteresis loopof these nanostructures does not follow a hys-teresis-free dependence typical of superpara-magnetic MNPs, as shown in Figure 1C (Islamet al. 2008; Nair et al. 2013). This fact could beexplained by an effectively increased anisotropyof the ferrimagnetic core caused by the addition-al strain-induced interaction with the piezoelec-tric component.

Like the traditional MNPs, MENPs can beused for image-guided navigation through or-gans via application of external magnetic fieldgradients and be image guided with MRI orthe recently emerged magnetic particle imaging(MPI) (Senyei et al. 1978; McBain et al. 2008).Using MNPs as contrast-enhancing agentsin MRI has been well established for decades.Superparamagnetic iron oxide nanoparticles(SPIONs) and gadolinium nanoparticles aresome of the most common MRI contrast-en-hancement agents today. As for the applicationof MNPs for targeted drug delivery, it has alsobeen known for decades. Indeed, anyMNPs canbe wirelessly guided by magnetic field gradients;the rate of delivery is defined by the externalmagnetic field source and not limited by thecirculatory system and other internal processes.

The Magnetoelectric Nanoparticle

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For comparison, many conventional biology-driven approaches (e.g., based on the exocytosisof the drug with an intracellular vesicle) arestrongly dependent on the internal microenvi-ronment and thus often fail to adequately regu-late cellular phenomena (Batrakova et al. 2011).For instance, as it is related to drug deliveryacross the blood–brain barrier (BBB), MNP-based delivery provides a unique way to transferdrugs sufficiently fast for the drug-loadednanoparticles to avoid being engulfed by thereticuloendothelial system (RES) (Saiyed et al.2010). Unfortunately, like most conventionalapproaches, this delivery also suffers from un-certainty of the drug release when the nanopar-ticles reach the target site(s). Another problemwith MNPs is the difficulty to efficiently coupletheir magnetic properties to intrinsic electric-field-driven processes to enable superior diag-nostic and treatment. Again, revealing andcontrolling the intrinsic interaction with themicro- and macroenvironments is vital for en-abling personalized diagnostic and recovery orregeneration of all the normal functions. Hence,this review focuses on understanding how thenew type of nanoparticles (i.e., MENPs) couldbe exploited to overcome the stumbling road-block of external control in nanomedicine.

Unlike MNPs, owing to the presence of theME effect, MENPs display an entirely new set ofunique and important functions. These func-tions arise from the fact that theME effect allowsto strongly couple local intrinsic electric fields atthe intracellular level with magnetic fields toenable a wireless control of cellular processesin any organ (e.g., neural activity deep in thebrain, intracellular penetration specifically intocancer cells, and release of RNAs or other bio-molecules into specific cells of any specific organof the body). As described below in more detail,these functions allow for simultaneous imaging,local stimulation, targeted drug delivery, andfield-controlled release on demand with a nano-scale 3D precision in real time.

The ME effect, for example, present in sometype I multiferroics because of a relatively strongstrain-related coupling between the ferroelectricand ferromagnetic components, can be ex-plained thermodynamically according to the

Landau theory of multiferroics for the second-order free energy expansion, G (Landau 1937):

G(E,H) ¼ �aijEiHj, (1)

where Ei and Hj stand for the ith and jth com-ponents of the electric and magnetic fields, re-spectively, and αij represents the ME coefficienttensor. For simplicity, this expression includesonly the cross-term, which depends on bothfields.

As a result, in this order of approximation,the induced electric polarization (dipole mo-ment per unit volume), Pi, depends on the ap-plied magnetic field according to this linear ex-pression:

DPi ¼ �dG=dEi ¼ aijHi: (2)

For example, given α of 100 mV cm−1 Oe−1

(Corral-Flores et al. 2010), a relatively smallmagnetic field on the order of 100 Oe (0.01 T)would generate a local electric field on the orderof 10 V/cm, which could be used to stimulatethe neural network locally.

Reciprocally, the induced magnetizationchange of the nanoparticle depends on the localelectric field according to the linear expressionderived from (1):

DMi ¼ �dG=dHi ¼ aijEi: (3)

In this case, the ME coefficient is known asthe converse ME effect coefficient. Although,according to the convention, the designationletter, α, remains the same, it is reasonable touse different units (i.e., G cm V−1 instead ofmV cm−1 Oe−1) to make the connection be-tween fields obvious. For example, given the val-ue for α of 0.1 G cm V−1 (Jia et al. 2006; Choand Priya 2011; Zhang et al. 2014), a local elec-tric field caused by an action potential at theneuronal membrane of 1 V/cm would inducethe nanoparticles’magnetization change on theorder of 1 emu/cc if the nanoparticle is inthe vicinity of the membrane. Assuming theMENP’s saturation magnetization is on the or-der of 10 emu/cc (Betal et al. 2015), the relativechange of themagnetization on the order of 10%would be quite significant for providing a high-



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contrast image of an electric-field profile. There-fore, if MENPs are used instead of traditionalMNPs (e.g., SPIONs or gadolinium nanoparti-cles) (Nielson and Thomsen 2012) to enhancethe image contrast of MRI or, better yet, MPI(Panagiotopoulos et al. 2015), they could pro-vide an image not only containing structuralinformation but also reflecting local intrinsicelectric fields. In turn, because the local electricfields are intrinsically linked to neural activity,MENPs-based magnetic imaging can shed lighton understanding the brain.

This paper gives an overview of recent stud-ies on using MENPs as a technobiology enablerto provide another dimension to the fieldsof targeted drug delivery, DBS, neuroimaging,and functionalized diagnostics that could triggerleapfrog advances in the state of treatment ofneurological diseases, cancer, HIV, and otherdevastating diseases in the near future.

Wireless Stimulation of Central andPeripheral Nervous Systems at a Single-Neuron Level

The significance of the capability of MENPs toprovide wireless stimulation of selective regionsdeep in the brain locally at the subneuronal levelor vagus nerve stimulation is hard to overesti-mate (Carreno and Frazer 2017). Such a capa-bility can open a pathway to ultimate treatmentof disabilities related to motor and sensory im-pairments and curing patients suffering fromParkinson’s disease (PD) and any other devas-tating neurodegenerative disease. Both the cen-tral and peripheral nervous systems (CNS andPNS) are driven by electric signals and thus canbe represented as electric circuits. A neurode-generative disease is a result of one or severalof electric subcircuits having a defect or beingcompletely broken. Such damaged subcircuitscould be repaired by local stimulation throughMENPs. It is noteworthy that electric-field-triggered stimulation is the basis for most cur-rent stimulation approaches such as variousforms of invasive direct-contact DBS andlow-efficacy transcranial magnetic stimulation(TMS) techniques (Fregni and Pascual-Leone2007; Kringelbach et al. 2007). However, all

these approaches are severely limited in theircapabilities. DBS needs to establish direct phys-ical contacts to the neural network and thus islimited by a finite number of implants. TMSonly indirectly interacts with the electric circuit-ry and thus has very low efficacy and poor spa-tial resolution. In contrast, wirelessly controlledMENP-based stimulation can be done locallyand therefore could be made entirely noninva-sive (or only minutely invasive) while achievingunprecedented high efficacy. The idea of usingMENPs for wireless stimulation to recover thecommunication between neurons in patientswith PD was discussed in a paper by Yue et al.(2012). Supporting experimental results of an invivo study on mice were presented in a paper byGuduru et al. (2015). These studies for the firsttime demonstrated that wireless stimulationwith MENPs was indeed feasible. In their invivo experiments, they administrated a relativelysmall dose of the nanoparticles into the blood-stream intravenously, through an injection ofapproximately 100 µg of MENPs in the tail ofa mouse. Then they pulled the nanoparticlesinto the brain across the BBB via applicationof a magnetic field gradient of approximately3000 Oe/cm. They confirmed the resulting sig-nificantly increased concentration of the nano-particles in the brain through atomic and mag-netic force microscopy (AFM andMFM) as wellas through scanning electronmicroscopy (SEM)imaging of brain slices post euthanasia. Wire-lessly controlled stimulation was demonstratedby measuring electroencephalography (EEG)signals from EEG implants in correlation withan applied ac magnetic field of 100 Oe strengthat a frequency in a range up to 100 Hz. Theconcept of MENPs-based wirelessly controlledstimulation is shown in Figure 2.

It is important to note that to improvethe control and maximize the efficacy of theMENPs-based wireless stimulation, it makessense to have nanoparticles be positioned onthe neuronal membrane surface, right whereaction potentials start. As a reminder, a typicalvalue of the membrane potential at rest is ap-proximately −70 mV. Increasing the membranepotential by approximately +15 mV triggers fir-ing of an action potential. The exact value of the

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electric field required to achieve this thresholddepends on the neuron type and on the specificlocation on the membrane surface. MENPs onthe membrane should be able to locally generatean electric field strong enough to overcome thepotential threshold to fire action potentials. Us-ing a back-of-the-envelope-type estimation, as-suming an applied magnetic field of 1000 Oe,an MENP with an α of 100 mV cm−1 Oe−1

would generate an electric field of 100 V/cm(104 V/m). Generating such a field across themembrane would be sufficient to trigger firingof an action potential by a single nanoparticle(Ye and Steiger 2015). Furthermore, when actedcollectively and under application of periodicsignals corresponding to periodic rhythms ofbrain waves, MENPs could easily provide high-efficacy stimulation.

Learning from the recent development ofDBS and TMS, with MENPs, application of amagnetic field as a near-dc (10 to 100 Hz) trainof relatively sharp 100 Oe pulses with a pulsewidth ranging from 10 to 100 μsec would pro-vide an ideal local stimulation. Although pro-viding a relatively low-frequency periodic trainof narrow pulses could very efficiently stimulatethe neural network locally, such a relatively sus-

tained stimulation process involving a collectionof coherent action potentials would be limitedonly to several applications (e.g., to treat depres-sion, PD, and a few other neurodegenerativediseases). Ideally, to perfectly simulate/recoverany operation of the neural network (e.g., forrecovering movement of limbs and repairingsenses, etc.), it is necessary to trigger individualaction potentials through any channel in anydifferent region in the neural system at anytime instance on demand. With MENPs, suchhigh-precision control could be accomplishedthrough implementation of advanced electro-magnetic theory and signal processing.

Hence, further increasing theME coefficientis critical. The ME coefficient can be signifi-cantly increased through improving materialsproperties. There are claims of the coefficientvalue above 1 V cm−1 Oe−1 (Palneedi et al.2016). Further, the ME coefficient can be in-creased through a dc field biasing (Islam et al.2008). In addition, it is noteworthy that the MEeffect strongly depends on the frequency (Popovet al. 2008; Cho and Priya 2011; Liu et al. 2012).In fact, it could be substantially increased(by orders of magnitude) at a frequency corre-sponding to a natural resonance, whether the

acmagnetic

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Bloodstream

Figure 2. Illustration of a wireless electric stimulation with magnetoelectric nanoparticles (MENPs) via appli-cation of ac magnetic fields.



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resonance is the result of mechanical vibrations,ferromagnetic precession, or a combinationof the two or not (Yu et al. 2008). Ideally, thehighest resonance would take place when bothphases, magnetic and electric components,respectively, resonate at the same frequency (Po-pov et al. 2014). However, most of these reso-nances in such small nanostructures typicallyoccur in a GHz range (e.g., from below 5 toover 10 GHz). At the same time, it is knownthat electromagnetic waves in this frequencyrange strongly attenuate in this frequencyrange because of the absorption bywater (Chan-dra et al. 2014; Ziskin et al. 2018). Hopefully,integration of extremely sensitive nanotechnol-ogies with advanced signal processing and an-tenna technologies might be able to address thechallenge.

Last but not least, it is noteworthy that post-treatment MENPs can be removed from thebrain the same way they were brought in (i.e.,through application ofmagnetic field gradients).During the removal process, the gradient direc-tions should be reversed so that the nanoparti-cles are pulled back to the bloodstream. Indepen-dently, nanoparticles can be cleared from thebrain naturally. Indeed, it has been shown onanimal models that the nanoparticles areexcreted within a 2-month period dependingon their size (Hadjikhani et al. 2017). Finally, itis likely that some type of biodegradableMENPs,possibly based on carbon nanostructures, will bedeveloped in the future (Pridgen et al. 2007).

Externally Controlled Targeted Drug Deliveryand Release across the Blood–Brain Barrier

Probably, one of the most important propertiesof MENPs is not only their ability to deliver atherapeutic load across the BBB with a very highefficacy but also their ability to release the loadin any place at any time on demand. As dis-cussed above, like any other nanoparticles,MENPs can be used to deliver drugs across theBBB (Lockman et al. 2002; Guduru et al. 2015).However, for the delivered drug to be bioac-tive, it is important to release it off the carriernanoparticles when they reach the target site(Veronese and Pasut 2005). Although there are

approaches in which they formulate or func-tionalize nanoparticles to allow for triggeringdrug release by thermal activation, applicationof magnetic fields, electromagnetic, or acousticwaves through a change in intracellular pH orintracellular enzymes, in most cases, the releasemechanism cannot be controlledwith adequate-ly high efficacy (Torchilin 2005; Arruebo et al.2007). To ensure the drug gets released at thetarget site, the conjugation strength between thedrug and the nanoparticles is often kept relative-ly weak. As a result, most of the drug is prema-turely released off the nanoparticles in the plas-ma or interstitial space, not at the intendedtarget site (Zhang et al. 2010). In contrast, withMENPs, the conjugation strength, defined byelectric fields between the drug and the nano-particles, can be wirelessly controlled via appli-cation of dc and ac magnetic fields. In the paperby Nair et al. (2013), they showed that owing totheME effect, application of an acmagnetic fieldis equivalent to shaking the drug off the nano-particles. Therefore, the conjugation strengthbetween the drug and the nanoparticles can bemade adequately strong to ensure no drug isreleased before the nanoparticles reach the tar-get site. Only after the nanoparticles with thedrug are pulled across the BBB and reach thetarget site in the brain, an ac magnetic fieldcan be applied to trigger the desired high-effica-cy release. The concept of the ac magnetic field–controlled drug release is shown in Figure 3. Intheir study, they used an in vitro BBB model toshow that this MENPs concept could be used todeliver and release the well-known antiretroviraltherapy AZTTP to eliminate HIV-1 virus hid-den deep in the brain. They used a dc magneticfield gradient of approximately 3000 Oe/cmto pull the drug-loaded nanoparticles acrossthe BBB. Then, when the loaded nanoparticlesreached the brain, they applied a 100 Oe acmag-netic field at a frequency of 100 Hz to trigger thedrug release.

High-Specificity Intracellular Targeted DrugDelivery

Again, one of the most important properties ofMENPs is the capability they provide to control

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local electric fields wirelessly via application ofmagnetic fields. It is well known that differentcells, particularly theirmembranes, could be dis-tinguished through their electric properties suchas membrane potential, dielectric permittivity,conductivity, and others. For example, themem-brane potentials of cancer cells can be quite dif-ferent from those of their normal counterparts(Yang and Brackenbury 2013). The membranepotential defines the energy required to breakthrough the membrane for entering the cell.That is the reason there is a well-establishedhigh-specificity process, called electroporation,used to deliver biomolecules specifically intocancer cells, without affecting the surroundingnormal cells of the same type (Prausnitz et al.1993). One challenge with this approach is theneed to apply relatively high electric fields, onthe order of 1000 V/cm, to electroporate cancercells.When applied to a relatively large region inthe body, with a characteristic size on the orderof a few millimeters, such high fields can bedamaging also to surrounding normal tissues.In contrast, if MENPs are used to induce elec-troporation, the high fields are applied only ina local nanoscale region around the nanopar-

ticles. Thus, the MENP-triggered electropora-tion, known as nanoelectroporation, does notproduce any field-sensitive side effects. TheMENPs-triggered nanoelectroporation was forthe first time used to deliver the well-knownmitotic inhibitor paclitaxel into ovarian cancercells while sparing the surrounding normalovarian cells. Such experiments were conductedboth in vitro and in vivo (Guduru et al. 2013;Rodzinski et al. 2016). The high specificity of thiseffect was explained by the substantial differencein the membrane potential between the two celltypes. The membrane potentials of ovarian can-cer and normal cells are on the order of −5 and−50 mV, respectively. In other words, the fieldrequired to “break into” the normal cells needsto be higher by a factor of ten compared to thatfor the cancer cells. The underlying physics ofthe nanoelectroporation was discussed in thepaper by Stimphil et al. (2017). To directly mea-sure the tissue specificity of this approach anddetect the presence of MENPs with a nanoscaleprecision, the mode of SEM known as the en-ergy-dispersive spectroscopy (EDS) was used(Rodzinski et al. 2016). The EDS-SEM imagingcombines the advantages of the elemental com-

ac field is “On”

Figure 3. Illustration of steps using magnetoelectric nanoparticles (MENPs) to deliver drugs across the blood–brain barrier (BBB): (1) Intravenous (IV) injection of drug-loaded nanoparticles, (2) the drug-loadedMENPs arepulled across the BBB via application of a dc magnetic field gradient (on the order of 3000 Oe/cm), (3) when,optionally through image guiding, MENPs can be localized at the intended site, a relatively weak ac magneticfield, with a strength of 100 Oe at a frequency of 100 Hz, is applied to release the drug.



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positional analysis on par with that by massspectroscopy and the high spatial resolution bySEM (Hadjikhani et al. 2017). The concept ofMENP-triggered nanoelectroporation used todeliver drugs specifically into cancer cells viaapplication of a 100 Oe dc magnetic field isshown in Figure 4. To ensure the required spe-cificity, it is important to keep the dc field be-tween the nanoelectroporation thresholds forthe cancer and normal cells, respectively. Afterthe loaded nanoparticles were delivered into thecancer cells, a relatively weak ac magnetic field,with a strength of 30 Oe at a frequency of 100Hz, was applied to release the drug on demand.

It is noteworthy that because of the funda-mental nature of the approach,MENPs could beused for intracellular delivery of any biomole-cules, including nucleic acids for enabling genet-ic engineering or certain antitumor peptides fortreatment of glioblastomas, as described in thepaper by Stewart et al. (2018).

HIGH-CONTRAST FUNCTIONALIZEDIMAGING AND HIGH-SPECIFICITYBIOMOLECULAR DIAGNOSTICS

According to the principle of reciprocity, ifMENPs can be used to “write” information (orstimulate locally), then the same nanoparticlesshould be able to “read back” (or record) theinformation because of local cellular or neuralactivity (Khizroev et al. 1997). Just applied to thebrain alone, the importance of the capability torecord the neural activity with the subneuronal

spatial resolution at an adequately high tempo-ral resolution with the goal to monitor the brainin real time is hard to overestimate (Fox andRaichle 2007; Marblestone et al. 2013). Such acapability would not only revolutionize the largearea of diagnostics of neurodegenerative dis-eases but would also pave the way to fundamen-tal understanding and reverse engineering thebrain (Koch and Reid 2012).

There are already a number of technologiesavailable for functionalized brain imaging, in-cluding (1) EEG (Coenen 1995), (2) functional-ized MRI (fMRI), and diffusion MRI (dMRI)also known as diffusion tensor imaging (DTI),or a combination of these two (DfMRI) (Yassaet al. 2010), (3) positron emission tomography(Grafton et al. 1992), (4) magnetoencephalogra-phy (MEG) (de Pasquale et al. 2010), (5) neuro-nal optogenetics (Toettcher et al. 2010), and (6)molecular recording (Zamft et al. 2012). How-ever, all these approaches are strongly limited intheir capabilities because of inadequate spatialand temporal resolutions. In other words, todate, there is no viable way to map local electricfields caused by neural activity deep in the brain.

Again, owing to their ME effect, MENPsallow to fill in this gap. Particularly, MENPsallow to take advantage of both the magneticfield’s capability to penetrate through the brainwithout a significant interference with the com-plex electric circuitry of the brain and theelectric field’s capability to couple to neural ac-tivity locally with the subneuronal resolution.Therefore, if MENPs are integrated with a mag-

H = Hth H = 0H = 0

Figure 4. Illustration of steps of the concept of the field-controlled MENP-based nanoelectroporation to deliverdrugs specifically into cancer cells. (1) Drug-loaded MENPs are administrated into the cellular microenviron-ment of interest; (2) a dc magnetic field above the threshold value for the particular cancer cell line is applied toinduce the process of nanoelectroporation; and (3) the magnetic field is turned off to trap the drug-loadednanoparticles inside the cancer cells.

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netic imaging approach, they could be usedto map electric fields in the brain. For example,if MENPs are used instead of the traditionalMNPs (e.g., SPIONS, as image contrast en-hancement agents), they will not only enhancethe contrast caused by the structural image butalso will provide additional information causedby the local electric activity. However, to beable to record neural activity in real time, it isimportant to have a sufficiently high temporalresolution, arguably, in the microsecond range.Unfortunately, MRI cannot achieve such reso-lution. Its resolution is limited by the nuclearspin relaxation time to the hundreds of millisec-onds range. Therefore, in the study by Guduruet al. (2018), they propose to couple the advan-tageous properties of MENPs with the recentlydeveloped approach of MPI (Gleich andWeize-necker 2005; Goodwill et al. 2009; Weizeneckeret al. 2009). The MPI’s temporal resolution islimited by the ferromagnetic resonance of thenanoparticles, which in turn is defined by themagnetic anisotropy and can be in the nanosec-ond range. As an illustration, numerically sim-ulated MPI images taken with traditional MNPsand equivalent MENPs at three consecutivetime instances from the same brain region underequivalent conditions are shown in Figure 5. Asa result of the ME effect, MENPs can detect

some time-dependent process, which cannotbe detected by MNPs. For example, this processcould result from some kind of neuroinflamma-tion dynamic, which would be characteristic of adisease progression.

Using the same underlying physics, MENPscould be used for early-stage diagnostic and/orrapid screening of diseases. For example, thepaper by Nagesetti et al. (2017) describes an invitro study in which they used MENPs togetherwith the nuclear magnetic resonance (NMR)spectroscopy to diagnose cancer. In their exper-iment, they mixed MENPs into different cellmedia for further NMR measurements. Thestudy showed not only that cancer cells havedistinctly different NMR spectra compared totheir normal counterparts but also that differ-ent cancer cell lines can be distinguished fromeach other through their signature NMR spec-tra. They compared several breast cancer,ovarian cancer, and brain tumor (glioblastoma)cell lines.

CONCLUSION

In summary, MENPs have proven as a formida-ble enabling tool, implementation of which canpave the way for many unprecedented technobi-ology capabilities in medicine. Technobiology’s

MNPs

MENPs

t0 t1 t2

Figure 5. Simulated magnetic particle imaging (MPI) images taken with traditional magnetic nanoparticles(MNPs) (top row) and equivalent magnetoelectric nanoparticles (MENPs) at three consecutive time instances,t0, t1, and t2, respectively. The computation was performed by Dr. Rakesh Guduru of Florida InternationalUniversity (FIU).



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capabilities are complementary to those of thetraditional approach of biotechnology. The dis-cussed research on MENPs during the last sev-eral years has been instrumental to shed light onthese capabilities in the fields of targeted drugdelivery, cancer, HIV/AIDS, neurodegenerativediseases, neuroimaging, diagnostic, and otherfields. In a layman’s perspective, these novel ca-pabilities can be summarized as a technologyplatform allowing for ultimate pinpoint treat-ment and prevention of any disease. WithMENPs, the human body can be wirelessly con-nected to a computer at the subcellular level sothat its fundamental electric circuitry can becontinuously monitored and repaired in realtime. In other words,MENPs allow us to directlysee and control the complex dynamics of electricfields that govern all the biological processes un-derlying any medical disease. Further, such acapability opens a pathway to understandingthe basic principles of the intra- and intercellu-lar communication within the human body,which in turn define the operation of the inter-net of the human body. In the future, the result-ing potential applications of technobiologywould not only revolutionize medicine butalso lead to leapfrog advances in science andtechnology. Reciprocally, it is likely that whatwe will learn from the human body at this tech-nobiology level will also improve our under-standing of the nature and change the way webuild our technologies.

ACKNOWLEDGMENTS

I dedicate this work to the memory of my friendand colleague Professor Robert Haddon of theUniversity of California–Riverside. His unyield-ing dedication to science and constantly push-ing the boundaries had always inspired me andwas instrumental in defining my vision to con-duct research at the intersection ofmedicine andnanotechnology. Special thanks go to all themembers of my team at Florida InternationalUniversity (FIU) with whom I have been privi-leged to work during the last several years (inalphabetical order): Dr. Rakesh Guduru, Dr. AliHadjikhani, Dr. Kevin Luongo, Dr. AbhignyanNagesetti, Brayan Navarette, Krystine Pimentel,

Dr. Alexandra Rodzinski, Dr. Tiffanie Stewart,Dr. Emmanuel Stimphil, Dr. Mark Stone, andPing Wang for conducting most of the experi-ments described in the paper. I am particularlyindebted to Dr. Rakesh Guduru, my first PhDGraduate Student in the field of technobiology.Without his multifaceted talent, dedication, andcontagious passion for engineering innovations,this work would not have been possible. I ac-knowledge vital collaborations with a multidis-ciplinary team of scientists at FIU and Neuro-science Centers of Florida Foundation (NSCFF).I am particularly grateful to my friend and col-league Professor Ping Liang of the University ofCalifornia–Riverside. His extraordinary visionfor research excellence, talent and passion forresearch have been instrumental in spearhead-ing this effort. I am grateful to Professor VishPrasad of the University of North Texas for hisinspiration and help to organize the first journaldedicated to this new field called Technobiology.Last but not least, I thank Professor James Tienof The University of Miami for coining the newterm of technobiology and his continuous sup-port of our research in this emerging field.I acknowledge partial financial support fromNational Science Foundation (NSF) awards#ECCS-1408063, ECCS-0939514, and IIP-1237818, National Institutes of Health (NIH)R21-MH101025-01 and R01-DA034547-01,and numerous other awards from Departmentof Defense (DoD) agencies and the NSCFF.

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October 5, 20182019; doi: 10.1101/cshperspect.a034207 originally published onlineCold Spring Harb Perspect Med

Sakhrat Khizroev Technobiology's Enabler: The Magnetoelectric Nanoparticle

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Technobiology s Enabler: The Magnetoelectric Nanoparticle