Coupling the magnetic and heat dissipative properties of Fe₃O₄ particles to enable applications in catalysis, drug delivery, tissue destruction and remote biological interfacing

Abstract

As interest in nanomaterials continues to grow, and the scope of their applications widens, one subset of materials has set itself apart: magnetic nanoparticles (MNPs). Two unique properties of MNPs, their ability to move under the influence of an external magnetic field, and their propensity to dissipate heat upon exposure to an alternating, radio-frequency signal have enabled widespread applications in catalysis, drug delivery, tissue destruction and remote biological interfacing. Many of the uses rely either on the movement or the heating, though this review focuses on cutting edge research from recent years that has begun to develop applications that couple these two properties unique to MNPs. The more these properties are coupled, the more we can achieve a greater complexity of function with a reduced complexity of form.

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1. Introduction

Recent nanoparticle research has unveiled widespread applications ranging from catalysis,¹ environmental remediation,² sensors,³ semiconductors,⁴ antibacterial agents,⁵ and protective coatings,⁶ among others. Many of these nanoparticle applications rely on their small size^7,8 and high surface area to volume ratio.⁸ In addition to their morphological profiles, Fe₃O₄ nanoparticles specifically offer interesting magnetic properties⁹ that enable heating¹⁰ and movement by an external magnetic field.¹¹ Coupled with their limited toxicological impact,¹² these additional properties have facilitated biomedical applications¹³ including thermal treatment of malignant tumors,^8,14 drug delivery¹⁵ and even remote neural stimulation.¹⁶ Herein are introduced the magnetic¹⁷ and remotely triggered heat dissipative properties¹⁸ of Fe₃O₄ nanoparticles, their functionalized analogues,¹⁹ and similar materials.²⁰ A review follows of the applications in catalysis, drug delivery, tissue destruction, and remote biological interfacing that are enabled by a coupling of these two properties unique to MNPs.

1.1 Magnetic nature and manipulation

The magnetic moments of domains within ferrimagnetic and ferromagnetic materials will align with an applied magnetic field. Below a certain size, roughly 20 nanometers for Fe₃O₄ nanoparticles, a material will contain only a single domain, with a large magnetic moment (Fig. 1). Below this size range, these materials are referred to as superparamagnetic.²¹ At sufficiently high temperatures (blocking temperature, T_B), thermal energy is enough to rotate the particles, corresponding to a net loss of magnetization in the absence of an external magnetic field. Without remaining magnetized once out of the influence of an external field, the particles are more capable of maintaining colloidal stability, reducing agglomeration in reaction media or biological systems.

Fig. 1 Magnetic moments of ferromagnetic and superparamagnetic material with and without the influence of an applied magnetic field.

Once under the influence of a magnetic field, Fe₃O₄, or other magnetic nanoparticles, can be easily manipulated. Those searching for an easily recyclable catalyst can place an external magnet to the side of their reaction flask, or simply let their bare or functionalized magnetic particles adsorb to the stir bar. In biological applications, particles can be targeted to a specific location by direction via a magnetic field.

1.2 Remotely triggered heat dissipation

Coupling of remote electromagnetic signals to heat dissipation by nanoparticles has been achieved in several ways. In certain systems, nanoparticle electron density will oscillate in concert with electromagnetic radiation, often in the visible light range, due to the changing dipole that it induces on the particle.²² Such systems are referred to as plasmonic nanoparticles, and plasmon frequency can be tuned by altering particle size, geometry, or composition. While thoroughly covered elsewhere,²³ and not the focus of this review, this phenomenon observed in a broader range of nanoparticle systems serves as a good introduction to a similar coupling of external electromagnetic signals but specifically with magnetic nanoparticles for the dissipation of heat.

If an alternating magnetic field is able to re-orient the magnetic moment of MNPs, heat is dissipated into the surrounding environment. This re-orientation can occur by three main pathways: Brownian loss, Néel loss, hysteretic loss, or more likely, a combination of all three (Fig. 2).²⁴

Fig. 2 Remotely triggered heat dissipation.

Néel loss proceeds via rotation of the particle's magnetic moment, independent of the particle. Brownian relaxation, on the other hand, proceeds via rotation of the particle itself, rather than simply its magnetic moment. Teasing apart the contributions to heat dissipations due to Néel relaxation vs. Brownian relaxation can be difficult,²⁵ which is why from a practical, applications standpoint, many researchers concern themselves only with an aggregate view of heat dissipation, rather than simply the effect of individual modes.²⁶ In larger, multi-domain particles, hysteretic loss involves the realignment of domains, which, after full oscillation of the field, generates a magnetic hysteresis loop. Each of these modes proceeds with the loss of energy, as heat, into the surrounding environment.

2. Catalysis

In the field of catalysis, practitioners continuously struggle with choosing the nature of the catalyst for use in a given transformation. Homogeneous catalysts often provide superior performance, but are notoriously difficult to separate from the reaction mixture. On the other hand, a heterogeneous catalyst is typically easy to recover, but generally offers inferior catalytic performance. As an intermediate, nanoparticles have long been touted as bridging the gaps between homogeneous and heterogeneous catalysis, by providing the ease of recovery of the later with the catalytic performance of the former. The small size of nanoparticles relative to bulk material means more accessible active sites as well as better distribution within the reaction media, and they often provide surface deformities that lend themselves as sites for catalysis. Unfortunately, with smaller and smaller particle sizes providing catalytic properties more and a more akin to a homogeneous catalyst, the recovery of the particles also begins to more closely resemble that of a homogeneous catalyst, often requiring centrifugation or ultrafiltration.

The use of magnetic nanoparticles greatly reduces the difficulty of retrieving and recycling these nanoscale catalysts; simple application of an external magnet (or internal stir bar), pulls the particles out of solution, so the supernatant can be decanted away. Typical schemes for MNP catalysis call on the particle only as a vehicle for magnetic retrieval, relying on some supported pseudohomogeneous species as the active catalytic center. By this strategy, numerous metal binding ligands²⁷ and organocatalysts²⁸ have been anchored either to the particle directly,²⁹ or to a silica³⁰ or polymer³¹ coating (Fig. 3).

Fig. 3 Common strategies for magnetic nanoparticle catalysis. A magnetic particle with an optional silica or polymer coating, to which an organocatalyst (A) or metal binding ligand (B) has been anchored. Also commonly used are (C) iron oxide nanoparticles decorated with another catalytically active particle, (D) mixed metal ferrite particles, (E) bare iron oxide nanoparticles, (F) bare reduced iron nanoparticles, (G) core–shell iron/iron oxide nanoparticles and (H) core–shell iron/iron oxide nanoparticles decorated with nanoparticles of another catalytically active metal. While monometallic systems are simplest, the potential reaction scope can be increased by incorporation of other metals or organocatalysts.

Given the tremendous synthetic effort involved in creating such a nanoparticle-tethered catalyst, an emerging trend is to use simpler particles to achieve the desired catalytic effect. Serving as examples of a slightly simpler catalyst system, metal-decorated, core/shell iron/iron oxide nanoparticles prepared in two steps can be used for click reactions,³² cyclopropanations,³³ Suzuki couplings,³⁴ and transfer hydrogenations³⁵ where the decorating metal is copper, copper, palladium or ruthenium, respectively.

Simpler still is the use of mono-metallic reduced iron nanoparticles, which have been used for Grignard type reactions,³⁶ hydrogenations³⁷ and dehydrogenation of ammonia borane.³⁸ Given the propensity for iron to oxidize, such particles are extremely air and moisture sensitive, which has led some researchers to attempt to protect them with various surface coatings. An attractive protecting option is simply a thin iron oxide shell, enough to prevent further oxidation, but not too much to hinder the reducing potential of the zero valent core. Such core/shell iron/iron oxide nanoparticles have been used for hydrogenation reactions, and do not lose their activity nearly as rapidly as their fully reduced analogues when exposed to air or moisture.³⁹

As an alternative to the reducing power provided by zero-valent particles, oxidized iron nanoparticles, both Fe₂O₃ and Fe₃O₄, demonstrate a potential for various oxidation reactions,⁴⁰ cross dehydrogative couplings,⁴¹ and aldehyde–alkyne–amine couplings (A³).⁴² Despite these interesting examples of catalysis with iron oxide nanoparticles, the catalytic scope of iron remains quite limited. In order to retain the simple ferrite scaffold, but expand the catalytic scope, some researchers have turned toward MFe₂O₄ (where M = Cu,⁴³ Ni,⁴⁴ Co⁴⁵ or others⁴⁶). The copper substituted analogues can catalyze some of the same reactions as the iron system (A³ couplings,⁴⁷ cross-dehydrogenative couplings⁴⁸) while also catalyzing reactions that iron cannot, such as click reactions,⁴⁹ hydrosilylations,⁵⁰ as well as C–C,⁵¹ C–O,⁵² C–N,⁵³ C–S,⁵⁴ and C–Se⁵⁵ cross coupling reactions.

All of the above mentioned examples are but a handful of the reactions demonstrated with MNP catalysts. The expansion of the field over the past 10 years, and the broad collection of reaction examples showcase the ease and efficiency of MNP recovery and recycling by movement under a magnetic field. Until this year, however, no examples took advantage of MNPs' unique ability to dissipate heat upon exposure to remote radio-frequency signals. While long used in other fields, the Chaudret group was the first to demonstrate hysteretic power loss used in catalysis.⁵⁶ Using Co/Ru coated iron nanoparticles, they successfully afforded Fischer–Tropsch chemistry upon remote heating. This important proof of concept will likely pave the way for further studies that combine the movement of magnetic particles for easy recovery with the ability for remote heating to enable catalysis.

3. Drug delivery

Targeted drug delivery typically relies on a biomarker specific to the site of interest conjugated to a therapeutic agent. As a transformative technology, MNPs are re-writing the rules for both targeting and release for drug⁵⁷ or gene⁵⁸ delivery applications.⁵⁹ Their small size enables passage through certain biological gateways, like the blood brain barrier (BBB). Their directed movement under an external magnetic field enables easy and precise targeting, and some researchers have even taken advantage of their ability to dissipate heat by remote radio-frequency stimulation in order to affect a thermal response leading to drug release (Fig. 4).

Fig. 4 Magnetic targeting and remotely triggered thermal drug release.

Although proposed as a tool for drug delivery as early as the 1970s,⁶⁰ this type of drug carrier drew only modest attention and research effort until recently.⁶¹ Targeting not based on recognition of certain biochemical tags, but instead on physical manipulation under an external magnetic field opened new therapeutic avenues. Directing particles to near-dermal targets proved relatively easy, simply by placing a magnet at the surface of the skin. In order to enable drug delivery at deeper tissue targets, Yellen et al. demonstrated the viability of internal magnetic implants to guide the movement of MNPs.⁶² Introduction of magnetic particles or liposomes⁶³ can be as easy as intravenous administration.

Once circulating in the blood, the particles can be directed to target locations under the guidance of an applied magnetic field. Several groups have even demonstrated that such nanoparticles can be forced to cross various biological gateways, such as the BBB.⁶⁴ The Yang group, in efforts toward nanoparticle targeting through the BBB, injected into the carotid artery polyethyleneimine-modified MNPs, which demonstrated high cell association and low cytoxicity in in vitro studies.⁶⁵ Coupled with magnetic targeting, the group demonstrated a 30-fold increase in tumor entrapment of the particles, compared to the control with no magnetic targeting. In an effort to increase passage through the BBB, Liu et al. coupled magnetic targeting with focused ultrasound. Taking advantage of the nanoparticles' proven ability to act as contrast agents,⁶⁶ the group used MRI to verify the increased passage in vivo.⁶⁷ Aside from secondary signals, such as ultrasound, researchers can also turn toward changing the nature of the magnetic field to increase mobility. Toward this end, the Dobson group adopted an oscillating magnetic array to afford a lateral motion component.⁶⁸

Once effectively targeted, the bound or encapsulated drug can be delivered passively,⁶⁹ or by a stimulus provided from the target environment. The Wang group effectively used acid-sensitive, mesoporous magnetic colloidal nanocrystal clusters, which would selectively release the anti-cancer agent doxorubicin upon entering the lower pH environment of the targeted tumor.⁷⁰ Instead of pH, other biological cues have been investigated to trigger the release of cargo from MNP drug carriers. Toward this end, Lee et al. used mesoporous silica coated iron oxide nanoparticles with a cyclodextrin gatekeeper. Exposure to glutathione would cleave the cyclodextrin, enabling release of the targeted drug.⁷¹

Instead of relying on biological cues, many researchers are now turning toward the ability of MNPs to dissipate heat as a trigger for drug release, providing a dual function for the particles.⁷² Using a thermo-responsive poly(maleic anhydride-alt-1-ocatadecene) coating around a cluster of magnetic particles, and encapsulating a drug, Leal et al. were able to achieve controlled drug release triggered by the swelling of the polymer upon remotely activated hysteretic power loss.⁷³ Similarly reliant on macromolecular structural changes as a result of remote heating, Louguet et al. effectively dumped doxorubicin from its entrapment in brush-like structures at the surface of silica-coated magnetite nanoparticles.⁷⁴ In 2010, the Jin group demonstrated not just a one-time release of targeted drug, but instead, a thermoswitchable, on/off mode for on-demand delivery of multiple anti-cancer drugs.⁷⁵

Rather than a macromolecular temperature-dependent structural change enabling drug delivery, an alternative route entails the use of thermolabile linkages to release drugs to their target. The Pellegrino group applied this technique with dyes and drugs linked through a temperature-sensitive azo bond to surface functionalizations of iron oxide nanoparticles.⁷⁶ Upon heating, the azo-linkage cleaves, releasing the cargo.

In a slightly different mode for external radio-frequency actuation of drug release, the Karathanasis group tethered a chain of MNPs to a drug-containing liposome, which, upon field-induced movement of the nanoparticles would release the targeted drug.⁷⁷

Use of magnetic iron oxide nanoparticles for therapeutic purposes raises increased scrutiny of their pharmacokinetics and toxicity.⁷⁸ Early studies found no subacute toxic effects in rats or beagle dogs receiving a total of 3000 μmol Fe per kg.⁷⁹ A more recent study examining the toxicological effect of size, shape, saturation magnetization and thickness of polymer coating, identified the nature of the polymer coating as important in impacting cell viabilities.⁸⁰

4. Hyperthermia

Rather than use the MNP simply as a vehicle for drug delivery, researchers and even practitioners have for many years been using magnetic particles to target an area of therapeutic need while at the same time the MNPs serve themselves as the agents of therapeutic action. Remotely triggered hysteretic power loss enables the particles to dissipate enough heat to kill malignant tumor cells to which they have been targeted in a process known as magnetic hyperthermia.⁸¹ This technique has been established for years,⁸¹ is currently in clinical use⁸² and has been thoroughly reviewed elsewhere,⁸³ so the remainder of this brief section will highlight only a few examples from this year that incorporate a high degree of functionality.

Some of the newest trends in hyperthermia treatment couple the cell-destructive heating with other therapeutic methods. Toward this end, Corato et al. were able to load microsomes with a dual payload. The inside contained MNPs for hyperthermia treatment, while the lipid bilayer carried a photosensitizer capable of generating reactive oxygen species. The combined effect of the dual action liposomes were able to destroy tumor cells in vivo and in vitro.⁸⁴ Rather than relying on a second type of stimulation (light), as in the Corato et al. study, Kakwere et al.⁸⁵ combined technology for thermosensitive doxorubicin release similar to that described in the drug delivery section. In this system, they were able to afford both drug release and hyperthermia treatment triggered by an external alternating magnetic field where both actions were achieved with the same functionalized magnetic nanocubes.

5. Remotely controlled biological interface

Rather than take advantage of iron oxide nanoparticles' ability to dissipate heat through hysteresis for the destruction of tissue (hyperthermia), or to affect some change in the particle that enables it to release targeted cargo (drug delivery), recent work focuses on coupling remotely controlled nanoparticle actions toward directly interfacing with biological functions.

Early forays into coupling magnetic fields to biological responses relied on mechanical force,⁸⁶ such as a 2008 Hughes et al. study⁸⁷ that used MNPs targeted to the extracellular loop of the mechanosensitive potassium channel, TREK-1, to trigger a response. In an effort to put this technique to work for the purpose of controlled differentiation of human bone marrow stromal cells, Kanczler et al.⁸⁸ remotely activated the same TREK-1 ion channel that had been tagged with MNPs to affect differentiation in vitro and in vivo, offering exciting avenues for tissue repair. Gloria et al. affected similar osteogenic differentiation with fully biodegradable magnetic nanocomposites made from iron-doped hydroxyapatite coated with a poly(ε-caprolactone) matrix. Focusing efforts on a different machanosenstive cellular target, Hu et al.⁸⁹ also promoted osteogenic differentiation via MNP stimulation of platelet-derived growth factor receptor α and β (PDGFRα and β), which provided further downstream stimuli to promote smooth muscle formation. The group later included another mechanosensitive target, integrin α_νβ₃, in their continued efforts to control stem cell differentiation by external magnetic stimuli.⁹⁰ Using a magnetite–alginate nanocomposite material, Sapir et al.,⁹¹ were able control cellular organization towards vascularization efforts by similar magnetic stimulation. Validating this approach for MNP induced actions triggering cell differentiation for possible applications in tissue repair, the Xu group demonstrated that even after uptake of MNPs, the original functions of corneal endothelial cells remained unchanged.⁹²

The use of magnetic particle movement to induce a physiological response is not limited to pathways reliant on mechanosensitive receptors. Indeed, a 2007 report from Mannix et al.⁹³ demonstrated the viable use MNPs functionalized with monovalent ligands, which, when induced to agglomerate by magnetic attraction at cell surfaces, would trigger a response from the targeted cell surface receptor.

On a slightly larger scale, Lee et al.⁹⁴ were able to elicit a response from inner-ear hair cells that had been tagged with cubic MNPs. Under the control of an external magnetic field, the collection of MNPs could exert picoNewtons of force on the cells to which they were bound, enough to displace them on the scale of tens of nanometers, which in turn was enough to trigger ion influx into the cells, an important step in further downstream signaling.

Through either actuation of mechanosensitive cell surface receptors, ligand-receptor triggering by agglomeration of tagged nanoparticles on cell surfaces, or the exertion of force upon entire cells by a collection of magnetic particles, all of the previously mentioned examples of remotely controlled nanoparticles interfacing with biological systems rely on the ability of these particles to move under an external magnetic field.

An exciting new field of research relies instead on the ability of superparamagnetic nanoparticles to dissipate heat through hysterysis. As previously mentioned, this dissipation of heat has been used for hyperthermia and targeted drug delivery, but until recently, researchers had not coupled this heat dissipation directly to interfacing with biological systems. Just as motion actuated signal transduction by MNPs relies on mechanosensitive receptors, it follows that heat-actuated signal transduction relies on temperature sensitive receptors. Toward this end, several research teams have turned to the heat-sensitive capsaicin receptor TRPV1.

Huang et al.⁹⁵ first reported the activation of this TRPV1 receptor by MNPs in 2010. Their study targeted tagged ferrite nanoparticles to specific proteins on cells also expressing TRPV1. The particles, upon application of an alternating radio-frequency magnetic signal, provided highly localized heating capable of actuating the TRPV1 cation channel, and inducing action potentials in cultured neurons.

Adapting this technology to an in vivo study, the Friedman group adorned modified TRPV1 with an antibody-functionalized iron oxide nanoparticle.⁹⁶ Remote controlled heating of the nanoparticles activated the TRPV1 channel to allow the flux of calcium, thereby inducing a calcium sensitive promoter to stimulate production of insulin in mice.

Despite a 2012 study⁹⁷ suggesting that in cultures of primary neural cells, MNPs are mainly taken up in the microglia (an immune response thought to limit the use of this technology in in vivo neural studies), the Khizroev group in the same year conducted a computational study simulating the use of MNPs for non-invasive stimulation of Parkinson's disease patients in order to match neural activity with that of healthy individuals.⁹⁸

Given the difficulty of external brain stimulation, this approach carries a remarkable upside. Currently, deep brain stimulation is achieved through invasive, permanently implanted electrodes.⁹⁹ Alternative technologies rely on acoustic,¹⁰⁰ optical¹⁰¹ or electromagnetic induction,¹⁰² but these options are limited by the loss of signal through tissue, and thus for in vivo studies necessitate the use of a conduit to enable deep brain stimulation. The ability of radio-frequency alternating magnetic fields to penetrate tissue without absorbing/scattering the signal, allows MNPs to convert this energy to heat through hysteretic power loss, as previously discussed with hyperthermia applications.

Building upon the in vitro neural work of Huang et al.,⁹⁵ the Anikeeva group was the first to effectively couple this remote controlled heat signal with in vivo interfacing with deep brain tissue.¹⁰³ With the guidance of more recent studies¹⁰⁴ suggesting that decorated nanoparticles targeted for specific locations quickly loose their specificity in complex biological systems by adsorption of a masking protein ‘corona’, the Anikeeva group opted for non-targeted Fe₃O₄ nanoparticles injected directly into the brain region of interest. Prior to injection, they sensitized excitatory neurons to thermal stimuli by lentiviral delivery of TRPV1. Remaining intact and implanted on the time scale of months,¹⁰⁵ these MNPs were able to reliably evoke neural excitation long after injection, offering significant implications for minimally invasive chronic treatment.

In a similar in vivo study with CoFe₂O₄ nanoparticles injected intravenously outside the brain, but directed to cross the blood brain barrier under the influence of an external magnetic field, the Khizroev group, building on their 2012 computational work,⁹⁸ affected remote signal transduction in deep brain tissue.¹⁰⁶

6. Summary and outlook

Over the past 10 years, researchers have developed a broad range of applications that rely on either the magnetic movement of nanoparticles or their ability for remote heating. Just in the past few years more effort has been put into applications that use both of these properties in tandem—catalysts that heat remotely and can be recovered with a magnet, drug carriers that can be guided under a magnetic field and thermally induced to drop their cargo, agents for biological interfacing put in place with magnetic guidance and stimulating a response based on radio-wave signals. Future research will surely continue to couple these properties more, which will mean we will be able to achieve a greater complexity of function with a reduced complexity of form in a broad spectrum of applications.

Elaborate magnetic nanoparticles adorned with highly engineered catalysts have garnered significant attention over the past 15 years. More recently, researchers have begun to more heavily examine bare particles that participate both in catalysis and in magnetic separation. Researchers can tune activity by size, shape, or chemical composition of the particles. Because of their strong magnetic moments, Fe₃O₄ nanoparticles tend to be most common in biological applications, but where surface chemistries are key, as with applications in catalysis, Fe₂O₃ nanoparticles provide a useful alternative. The recent use of magnetic particles not only for their catalytic and magnetic separation characteristics, but also for their remote heating, will surely usher in a new era of nanocatalysis with simple yet highly functional particles.

In a similar development sequence as in the field of catalysis, researchers in drug delivery first identified magnetic movement as an important tool, and later began to achieve greater complexity of function by coupling this with the ability to heat under an external magnetic field as a means to trigger cargo release. Such heating of magnetic nanoparticles in biological systems for therapeutic action was a reasonable advance given the similarity to the already developed field of magnetic hyperthermia.

While destruction of malignant tissue by remote magnetic nanoparticle heating has been known for quite some time, researchers in the past 7 years have been able to perhaps more elegantly interface with biological processes via MNPs by several means. Early, and continued studies focused on motion actuated stimulation of mechanosensitive ion surface receptors such as TREK-1, integrin ανβ₃, or PDGFRα and β. Others demonstrated that force exerted on the cell scale rather than the receptor scale, could likewise result in signal transduction, as in the case of inner ear stimulation. Even in cases where magnetic movement of particles is necessary to elicit signal transduction, transduction need not proceed via a mechanosensitive mechanism, as was the case with magnetic agglomeration of ligand tagged particles to trigger specific ligand-sensitive receptors. Alternatively to motion mediated interfaces, recent techniques rely on heat activation of the thermo-sensitive ion channel, TRPV1.

Acknowledgements

The author thanks the National Science Foundation (SMA 1415189) and Colby College for financial support.

Notes and references

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