Magnet 10

19390041, 2019, 6, Downloaded from https://wires.onlinelibrary.wiley.com/doi/10.1002/wnan.1571 by University Of Oslo Central 340, Wiley Online Library on [01/11/2022].
See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Received: 1 November 2018 Revised: 29 April 2019 Accepted: 31 May 2019
DOI: 10.1002/wnan.1571
FOCUS ARTICLE
Use of magnetic fields and nanoparticles to trigger drug release

and improve tumor targeting
Jessica F. Liu | Bian Jang | David Issadore | Andrew Tsourkas
Department of Bioengineering, University of

Pennsylvania, Philadelphia, Pennsylvania
Abstract
Drug delivery strategies aim to maximize a drug's therapeutic index by increasing
Correspondence the concentration of drug at target sites while minimizing delivery to off-target tis-
Andrew Tsourkas, Department of
Bioengineering, University of Pennsylvania, sues. Because biological tissues are minimally responsive to magnetic fields, there
Philadelphia, PA 19104. has been a great deal of interest in using magnetic nanoparticles in combination
Email: atsourk@seas.upenn.edu
with applied magnetic fields to selectively control the accumulation and release of
Funding information drug in target tissues while minimizing the impact on surrounding tissue. In partic-
Brain and Behavior Research Foundation; ular, spatially variant magnetic fields have been used to encourage accumulation of
National Cancer Institute, Grant/Award
Number: R01 CA181429; National Institute
drug-loaded magnetic nanoparticles at target sites, while time-variant magnetic
of Biomedical Imaging and Bioengineering, fields have been used to induce drug release from thermally sensitive nanocarriers.
Grant/Award Number: R21 EB023989; In this review, we discuss nanoparticle formulations and approaches that have been
National Institute of Neurological Disorders
and Stroke, Grant/Award Number: T32 developed for magnetic targeting and/or magnetically induced drug release, as well
NS091006 as ongoing challenges in using magnetism for therapeutic applications.
This article is categorized under:

Diagnostic Tools > in vivo Nanodiagnostics and Imaging
Therapeutic Approaches and Drug Discovery > Emerging Technologies
Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic
Disease
KEYWORDS
drug delivery, magnetic, nanomaterials, nanoparticles, targeting
1 | INTRODUCTION
Effective drug delivery strategies must be able to achieve therapeutic drug concentrations in a particular region of interest,
such as a tumor, while minimizing delivery to off-target tissues (Bae & Park, 2011; R. Singh & Lillard, 2009). Delivery of
drug to nontarget tissues can result in a range of complications, ranging from mild discomfort to life threating side effects
(Kim, Lee, Lee, Park, & Lee, 2016). To solve this problem, nanoparticle-based drug delivery systems are being developed to
improve the therapeutic index of drugs. Various nanocarriers have been used to increase the preferential accumulation of drug
in tumors and impart control over drug biodistribution and release. These include polymer-drug conjugates (Duro-Castano,
Movellan, & Vicent, 2015), dendrimers (A. K. Sharma et al., 2017), nanogels (Wu & Wang, 2016), metal nanoparticles
(H. Sharma, Mishra, Talegaonkar, & Vaidya, 2015), mesoporous silica nanoparticles (Y. Li, Li, et al., 2017), virus-like parti-
cles (Rohovie, Nagasawa, & Swartz, 2017), lipid nanoparticles (Hörmann & Zimmer, 2016), and polymeric nanoparticles
(Merino, Martín, Kostarelos, Prato, & Vázquez, 2015). Accumulation of the nanocarrier in the region of interest is achieved
by direct injection (Cheng, Tietjen, Saucier-Sawyer, & Saltzman, 2015), passive targeting (enhanced permeability and
WIREs Nanomed Nanobiotechnol. 2019;11:e1571. wires.wiley.com/nanomed © 2019 Wiley Periodicals, Inc. 1 of 18

https://doi.org/10.1002/wnan.1571
19390041, 2019, 6, Downloaded from https://wires.onlinelibrary.wiley.com/doi/10.1002/wnan.1571 by University Of Oslo Central 340, Wiley Online Library on [01/11/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
2 of 18 LIU ET AL.
retention) (Maeda, 2015), or active targeting methods including ligand targeting (Srinivasarao, Galliford, & Low, 2015), pH-
dependent targeting (B. Chen et al., 2017), matrix metalloproteinases (Vandooren, Opdenakker, Loadman, & Edwards, 2016),
radiotherapy (Haume et al., 2016), magnetic targeting (Ulbrich et al., 2016), and pharmacological methods such as TNF-alpha
and VEGF inhibitors (Ojha et al., 2017). Drug release can then occur via leakage from the nanocarrier or as a result of nano-
particle degradation. Accelerated drug release can also be triggered using particles or linkages that are sensitive to the acidic
tumor microenvironment (Kanamala, Wilson, Yang, Palmer, & Wu, 2016), hypoxia (Thambi, Park, & Lee, 2016), light
(Linsley & Wu, 2017), ultrasound (Boissenot, Bordat, Fattal, & Tsapis, 2016), or temperature (Mura, Nicolas, & Couvreur,
2013; Sánchez-Moreno, de Vicente, Nardecchia, Marchal, & Boulaiz, 2018). Rapid/triggered drug release can lead to a tran-
sient spike in the local concentration of drug and result in improved therapeutic efficacy.
Strategies that rely on environmental and molecular signatures to enhance nanocarrier accumulation or to trigger drug
release are often limited by heterogeneity within the target tissue and lack of selectivity, due to the presence of similar signa-
tures in some nontarget tissues (Muro, 2012; Tredan, Galmarini, Patel, & Tannock, 2007; Vaupel, Kallinowski, & Okunieff,
1989). Meanwhile, exogenous strategies that rely on light or ultrasound energy have the potential to be absorbed by, and there-
fore damage, adjacent and intervening tissue. One way to avoid these challenges is to use a bio-orthogonal trigger, such as
magnetism. Biological tissue is nearly “transparent” to magnetic energy, and magnetic fields pass through tissue without being
significantly absorbed or distorted by body tissues. Magnetic nanoparticles introduced into the body can therefore allow for
high local energy delivery to the particles, compared to the surrounding tissue. As a result, magnetic fields and magnetically
responsive particles can be harnessed for therapy and drug delivery, particularly in cancer (C. Sun, Lee, & Zhang, 2008). Two
approaches are most common: (a) the use of magnetic particles to improve the accumulation of drugs in a desired region via
magnetic targeting (Alexiou et al., 2000; Shapiro et al., 2015) and (b) the use of magnetic fields to heat magnetic particles to
directly induce hyperthermia in or ablation of diseased tissues (Hedayatnasab, Abnisa, & Daud, 2017) and/or to trigger the
release of drugs from thermally sensitive carriers (Moros et al., 2019; Yoo, Jeong, Noh, Lee, & Cheon, 2013; Figure 1). As
there are already a number of very comprehensive reviews on hyperthermia and thermal tissue ablation (Chang et al., 2018;
Dewhirst, Lee, & Ashcraft, 2016; Périgo et al., 2015), these topics will not be discussed extensively here. Rather, we focus on
approaches that have been developed for magnetic targeting of drug-loaded magnetic nanocarriers as well as magnetically
induced drug release. We also discuss some of the challenges of using magnetism for therapeutic applications.
2 | MAGNET I C NA N OP A R T I C L E S
Magnetic drug delivery strategies rely on transferring externally applied magnetic energy to magnetic particles that have been
introduced into the body (Sensenig, Sapir, MacDonald, Cohen, & Polyak, 2012). One of the most commonly used magnetic
particle for drug delivery is superparamagnetic iron oxide nanoparticles (SPIONs). Unlike ferromagnetic materials, in which
materials are permanently magnetized, paramagnetic materials are magnetized only when placed into an applied field. When
FIGURE 1 Magnetic fields and

nanoparticles are used to improve drug
delivery, particularly in cancer. Time-
variant magnetic fields can induce
drug release from temperature-
sensitive drug carriers via magnetic
heating (left). Space-variant magnetic
fields can improve drug accumulation
in target tissues via magnetic drug
targeting (right)
LIU ET AL. 3 of 18
the magnetic field is removed, the moments revert to a random orientation (Tipler, 1999). If the size and number of domains
in a magnetic material is sufficiently small, generally less than 150 nm, these nanoparticles are considered to be super-
paramagnetic and exhibit significantly higher magnetic susceptibility than paramagnets (Andrews, Lipson, & Nann, 2019;
Roch, Muller, & Gillis, 1999).
The use of magnetic nanoparticles for imaging, hyperthermia/thermal ablation, and magnetic targeting applications are all
linked to the response of SPIONs to magnetic fields (Laurent, Dutz, Häfeli, & Mahmoudi, 2011). Therefore, there has been a
continual desire to develop more effective SPIONs. The magnetic moment of a particle is typically proportional to its size
(Rosensweig, 2002; Sutens et al., 2016); therefore, numerous strategies have been developed to increase SPION size. For
example, seed growth is a well-studied method of gradually growing monodisperse SPIONs up to 20 nm in diameter (S. Sun
et al., 2004); unfortunately, although this process produces very monodisperse particles, the gradual size increase in multiple
steps lengthens synthesis time. Therefore, others have developed methods to synthesize large nanoparticles in a single step.
For example, Hufschmid et al. (2015) have reported a large-scale synthesis of SPIONs 30 nm in diameter via thermal
decomposition.
Others have also studied the effect of transition element dopants such as cobalt, manganese, and zinc on SPIONs' specific
absorption rate (SAR) for heating. For example, Jang et al. (2009) found that by using Mn0.6Zn0.4Fe2O4 particles, they are able
to demonstrate a ×4 improvement in heating. Others have also doped cobalt into SPIONs at various proportions to make
highly magnetic particles (R. Chen, Christiansen, & Anikeeva, 2013; Mahmoudi, Sant, Wang, Laurent, & Sen, 2011; S. Sun
et al., 2004).
For spherical particles, the synthesis method can affect SPION properties and crystal structure. For example, R. Chen et al.
(2013) found that syntheses using iron (III) acetylacetonate as a precursor produced particles with better magnetic saturation
values than those that used iron oleate, though the resultant particles were typically smaller. Recently, Unni et al. (2017) have
also suggested that typical SPION synthesis methods such as thermal decomposition can lead to particles with multiple mag-
netic domains due to defects in the crystal structure, resulting in an effective magnetic particle size that is smaller than the
measured particle size. By controlled addition of 20% oxygen and 80% argon to the reaction, they were able to synthesize
FIGURE 2 Controlled addition

of oxygen during thermal
decomposition results in synthesis of
particles with improved magnetic
properties. (a) In the absence of
oxygen, the physical diameter of the
nanoparticles is well controlled.
However, the magnetic diameter
(Dm) of the particles is smaller and
more polydisperse than the physical
diameter (Dp). (b) When oxygen is
added in a controlled manner to the
synthesis, the physical and magnetic
diameters of the particles is similar,
leading to a threefold increase in the
specific absorption rate of the
particles. (Reprinted with permission
from Unni et al. (2017). Copyright
2017 American Chemical Society)
4 of 18 LIU ET AL.
single-domain nanoparticles with a >×4 improvement in the magnetic saturation compared to particles synthesized via
oxygen-free thermal decomposition (Figure 2). Moreover, while typical SAR values for spherical, undoped, single core
SPIONs synthesized by typical thermal decomposition and seed growth methods range from ~100 to 200 W/g (El-Dek, Ali,
El-Zanaty, & Ahmed, 2018), SPIONs synthesized via the controlled oxygen method developed by Unni et al. (2017) had
SARs threefold higher.
Another method of improving SPIONs' magnetic properties is through the synthesis of geometrically complex particles
such as core/shell SPIONs and other shapes. For example, nanoparticles with an iron core and an iron oxide shell exhibit
improved hyperthermic properties because of the extremely magnetic iron core (Balivada et al., 2010; H. Lee, Yoon, &
Weissleder, 2009). Others have also developed iron-cobalt core/cobalt iron oxide shell particles for improved hyperthermia
(Habib, Ondeck, Chaudhary, Bockstaller, & McHenry, 2008) and iron core/magnesium oxide shell particles that modulate the
dipole–dipole interactions between particles for improved hyperthermia (Martinez-Boubeta et al., 2012). In these formulations,
the shell also typically helps improve magnetic properties by preventing oxidation of the core.
Other shapes have been synthesized to improve magnetization by minimizing surface anisotropy and maximizing exchange
anisotropy. For example, Noh et al. (2012) have synthesized a 60-nm cubic structure comprising an zinc iron oxide core and
cobalt iron oxide shell. This particle was demonstrated to have an extremely high SAR of >4,000 W/g. Similarly, Guardia
et al. (2012) synthesized a 19-nm iron oxide nanocube with a SAR of nearly 2,500 W/g for magnetic hyperthermia treatments
in vitro. Iron oxide nanoflowers, have also been developed for magnetic heating applications. These particles comprise multi-
ple magnetic cores stably encapsulated in a matrix. The small distance and strong interactions between cores allows for
exchange coupling between cores (Lartigue et al., 2012), resulting in stronger magnetic moments than single core particles.
Multicore particles have been shown to exhibit improved hyperthermia properties compared to single core particle (Guardia
et al., 2012; Hemery et al., 2017). Others have shown that larger core sizes and larger complex sizes in multicore particles lead
to improved heating properties (Blanco-Andujar, Ortega, Southern, Pankhurst, & Thanh, 2015). Iron oxide nanoflowers have
also been modified in the same ways as traditional spherical iron oxide nanoparticles. For instance, Curcio et al. (2019)
recently synthesized an iron oxide nanoflower core/copper sulfide shell particle. Manganese-doped iron oxide nanoflowers
have also been developed with improved heating properties compared to conventional nanoparticles (X. L. Liu et al., 2016).
3 | USING M AGNETIC FIELDS T O IMPROVE ACCUMULATION OF

MAGNETIC NANOPARTICLES IN TUMORS
3.1 | Nanoparticle accumulation and penetration within tumors

Nanoparticles tend to exhibit fairly low levels of accumulation within tumors. In a review of the literature, Wilhelm et al.
(2016) found that the median injected dose of nanoparticles accumulated in solid tumors was 0.6% using passive targeting,
and only improved to 0.9% using active targeting. They propose that one of the major challenges to high nanoparticle accumu-
lation in solid tumors may be the hydrostatic pressure, which can be as much as ×10–40 greater in tumors than in normal tis-
sues. Drug delivery to solid tumors is also complicated by the heterogeneous tissue structure, vasculature, and
microenvironment within the tumor (Baronzio, Parmar, & Baronzio, 2015; Sriraman, Aryasomayajula, & Torchilin, 2014).
Nanocarriers that passively accumulate in tumors are often located perivascularly, with little penetration into the interstitium.
Areas that are far away from blood vessels may not be exposed to drug because the interstitial hydrostatic pressure and extra-
cellular matrix both interfere with diffusion of the drug carrier out of the vasculature (Baronzio et al., 2015; Goodman,
Olive, & Pun, 2007; Sugahara et al., 2009; Wong et al., 2011). Therefore, there has been a great deal of interest in developing
techniques to improve the accumulation and penetration of nanoparticles within tumors.
3.2 | Magnetic drug targeting

Magnetic targeting, also referred to as magnetophoresis, has been proposed as a potential mechanism to improve the accumu-
lation and penetration of magnetic drug carriers in tumors (C. Sun et al., 2008). For magnetic targeting, drug and magnetic
nanoparticles are encapsulated into a nanocarrier, and a strong external static magnet is used to accumulate the drug carrier at
a target near the static magnet. For example, Marie et al. (2015) used a static external magnet to encourage magnetoliposome
accumulation in glioblastoma tumors in mice (Figure 3), while C. Huang et al. (2012) have developed and tested doxorubicin-
loaded magnetic micelles in a squamous cell carcinoma model in rabbits. Magnetic targeting has even been validated in
humans. In fact, as early as 1996, Lübbe et al. showed that magnetic drug targeting could be used to concentrate epirubicin-
LIU ET AL. 5 of 18
FIGURE 3 Magnetic drug targeting of magnetic

nanoparticle-loaded liposomes has been used to target
glioblastoma in mice. Upon exposure to a 0.4-T external
magnet, the iron oxide nanoparticle-loaded liposomes
localized to the tumor in an orthotopic U87 glioblastoma
mouse model (left). In contrast, in the absence of the
external magnetic targeting field, fewer nanocarriers
accumulated in the tumor (right). Scale = 1 mm. (Reprinted
with permission from Marie et al. (2015). Copyright 2015
John Wiley and Sons)
conjugated nanoparticles in sarcomas in Phase I and II clinical trials (Lübbe et al., 1996; Lübbe, Alexiou, &
Bergemann, 2001).
However, the primary challenge of magnetic targeting is that magnetic gradients drop off rapidly with distance from the
surface of a magnet. As a result, magnetic capture strategies are generally only able to target surface tumors. For example, in
Lübbe et al.'s (2001) clinical studies, magnetic drug targeting was limited to tumors within 5 mm of the body surface.
Rotariu & Strachan (2005) have also calculated that using small (<500 nm) particles with typical magnetic properties com-
bined with the fields generated using typical permanent rare earth element magnets, only tumors within 18 mm of the surface
can be targeted. For large particles up to 5 μm, targeting is achievable up to depths of 15 cm. Unfortunately, intravenously
injected particles are typically designed to be <200 nm to improve circulation time in the body (Bertrand & Leroux, 2012),
rendering magnetic capture ineffective for targeting deep tissues.
With an eye on improving magnetic nanocarrier targeting, recent work has focused on using nanocarriers loaded with many
magnetic nanoparticles to improve magnetic drug targeting by improving both the particle circulation time and its response to
magnetic fields. For instance, Al-Jamal et al. (2016) have encapsulated SPIONs in polylactic acid-co-glycolic acid-polyethyl-
ene glycol at increasing concentrations to optimize magnetic nanocarrier formulations for magnetic drug targeting. Interest-
ingly, they found that initially, increasing the SPION concentration within the nanocarrier improved tumor accumulation.
However, past a certain limit, there was no further improvement in magnetic accumulation, which they attributed to decreased
stability of the carrier resulting in decreased circulation time. Meanwhile, others have loaded cell-derived vesicles with mag-
netic nanoparticles and drug for cancer therapy: Silva et al. (2015) have shown that magnetic nanoparticles can be loaded into
macrophage-derived microvesicles to enhance drug accumulation via magnetophoresis, while Qi et al. (2016) have used
SPION-tagged, doxorubicin-loaded exosomes to target a hepatoma in a mouse model.
3.3 | Improving magnetic targeting with steering coils and multi-magnet systems
In addition to designing better nanocarriers for magnetic targeting, numerous attempts have also been made to utilize steering
coils and/or develop multi-magnet systems with unique geometries that can create large field gradients at greater depths within
a patient. In one study, Pouponneau et al. utilized a catheter-based method to release magnetic particles in the vicinity of a
tumor blood vessel. Steering coils were then used to guide the particles into the tumor (Pouponneau, Leroux, & Martel, 2009;
Pouponneau, Leroux, Soulez, Gaboury, & Martel, 2011). However, despite using an extremely strong magnetic field from a
modified magnetic resonance imaging (MRI), this method still required a 50-μm particle (Pouponneau et al., 2009, 2011).
Similar catheter-aided approaches have used particles up to 1.5 mm in diameter. Because of their size, these particles cannot
pass through pulmonary circulation (Bertrand & Leroux, 2012), and therefore cannot be injected intravenously. Rather, it is
6 of 18 LIU ET AL.
necessary to inject these particles into the arterial circulation near the target site and catheter-based methods are invasive
(Martel et al., 2007).
Recently, unique multi-magnet configurations have also been used to achieve higher targeting fields and “steer” particles
through blood vessels to their target sites. For instance, multiple groups have used Halbach arrays (Figure 4a) to achieve
strong local targeting fields (Barnsley et al., 2015; Shen et al., 2017). In one study, a linear Halbach array was used to trap
magnetic microbubbles that were under a shear rate of 124.5 s−1 (Barnsley et al., 2015), while a cylindrical Halbach array has
been used to enhance SPION-tagged neural progenitor cell accumulation in the brain (Shen et al., 2017). To achieve even
higher magnetic gradients, some groups have also used steel yokes (Figure 4b) to “concentrate” the magnetic field and accu-
mulate magnetic nanoparticles within a small region. Because magnetic fields preferentially pass through susceptible materials
like steel, by applying a strong magnetic field to a steel yoke and tapering the steel, it is possible to generate strong gradients
at the tip of the steel device for magnetic targeting (Voronin et al., 2017). As an alternative to permanent magnets, it is also
possible to use electromagnetic coils that can be preferentially switched on, to generate complex patterned fields for greater
spatial control of magnetic drug targeting (Hajiaghajani & Abdolali, 2018). However, while these methods are able to achieve
strong magnetic gradients for targeting, they still tend to localize particles near the device, and therefore continue to be limited
to use for drug targeting to surface regions. Interestingly, Krzyminiewski et al. (2018) have recently constructed a system of
two sets of oppositely polarized magnets rotating about an axis that is able to drive magnetic nanoparticles toward the center
of the device. Although their approach has not yet been tested in tissue, the ability to accumulate magnetic particles away from
the surface of a magnet would solve a long-standing problem in the field and could allow for noninvasive magnetic drug
targeting to deep tissues (Figure 4c).
4 | MAGNET I C A L L Y I N D U C E D D R U G R E L E A S E
Once magnetic drug carriers accumulate within a tumor, an externally applied alternating magnetic field (AMF) can be
coupled with SPIONs to generate heat. In the presence of an AMF, the SPIONs continually realign their magnetic moment
with the direction of the field, dissipating energy as heat in the process (Laurent et al., 2011). When the SPIONs are exposed
to a magnetic field that changes rapidly the SPIONs release sufficient heat to change their local temperature (Corot, Robert,
Idée, & Port, 2006; Laurent et al., 2011). The heat can be harnessed for various applications, including induction of tumor cell
death, either via hyperthermia (Hedayatnasab et al., 2017; Périgo et al., 2015) or ablation (Altanerova et al., 2017; Bobo, Rob-
inson, Islam, Thurecht, & Corrie, 2016), as well as inducing release of tumor-targeting drugs from temperature-sensitive
nanocarriers (Guisasola, Vallet-Regí, & Baeza, 2018; Moros et al., 2019).
FIGURE 4 Novel magnetic

targeting device designs. (a) Halbach
arrays can be used to achieve higher
targeting fields compared to single
magnets. The configuration of magnets in
a Halbach array leads to a “strong” side
with high magnetic fields, and a “weak”
side where most of the field has been
cancelled. (b) A steel yoke design can be
used to achieve extremely high magnetic
fields within a small area by
“concentrating” the magnetic field lines.
(Reprinted with permission from Voronin
et al. (2017). Copyright 2017 American
Chemical Society) (c) Recently,
Krzyminiewski et al. have developed a
system of rotating magnets to localize
magnetic nanoparticles away from the
surface of the device. (Reprinted with
permission from Krzyminiewski, Dobosz,
Schroeder, and Kurczewska (2018).
Copyright 2018 Elsevier)
LIU ET AL. 7 of 18
A primary challenge of magnetic heating strategies for hyperthermia and ablation is that extremely high SPION concen-
trations are necessary to achieve therapeutic temperatures, typically in the range of 10–100 mg/mL (Laurent et al., 2011).
As a result, current magnetic hyperthermia strategies often continue to rely on intratumoral injection to deliver a sufficient
concentration of nanoparticles to the target site (Tay et al., 2018; Yoo et al., 2013). In contrast, with many thermally
responsive magnetic nanocarrier designs, an AMF can be used to trigger the release of drugs in the absence of high
SPION concentrations, due to the strong temperature gradient at the surface of the magnetic nanoparticles. This is some-
times referred to as the “hot spot” effect. Various studies have shown experimentally that magnetic nanoparticles are able
to generate extremely localized heating, with little to no effect on the global temperature (H. Huang, Delikanli, Zeng, Fer-
key, & Pralle, 2010; Romero, Christiansen, Stocche Barbosa, Garcia, & Anikeeva, 2016). For example, in one study by
Rühle et al., it was reported that the temperature 20 nm from the SPION surface could be as high as 65 C, under condi-
tions where there is no increase in the global temperature of the sample (Rühle, Datz, Argyo, Bein, & Zink, 2016). Others
have reported similar findings, with temperatures reaching >43 C and triggering drug release at distance ~20 nm from the
SPION surface (Guisasola et al., 2015). However, some studies have reported more modest findings, with temperatures
reaching only 45 C within 0.5 nm of the SPION surface and dropping off exponentially with distance (Riedinger et al.,
2013). In one study where DNA hybridization was used to assess temperature at the SPION surface, it was determined
that the temperature only increased 8.3 C at a distance of 5 nm from the nanoparticle surface. Of course, the change in
temperature is highly dependent on the SAR of the SPION utilized, which could be at least partly responsible for the dif-
ferences observed.
4.1 | Thermally responsive magnetic nanoparticles

4.1.1 | Magnetic nanoparticles with thermally sensitive bonds
Many different approaches have been taken to prepare thermally responsive magnetic nanoparticles. Perhaps the most
straightforward approaches involve directly attaching drugs to magnetic nanoparticles via either covalent or noncovalent
bonds that can be broken or destabilized when the temperature is increased (Moros et al., 2019). An advantage of
noncovalent bonds is that the drug may not need to be modified (Mertz, Sandre, & Bégin-Colin, 2017; Moros et al., 2019).
Noncovalent interactions can simply involve hydrogen bonding between the drug and SPION surface or polymer (Griffete
et al., 2015; T.-J. Li et al., 2013), although this type of approach may be more prone to premature drug release. DNA
hybridization has also been explored as an approach to noncovalently associate drugs with magnetic nanoparticles. The
length and composition of the DNA strand can be tuned to precisely control the melting temperature and also allows for the
use of multiple strands that can release different cargos at different temperatures (Banchelli et al., 2014; Derfus et al., 2007;
Niemeyer, 2010).
Over the past decade, several thermally sensitive covalent linkages have also been identified that cleave with an increase
in temperature. One such bond can be formed via a thermally reversible Diels–Alder reaction (N'Guyen et al., 2013; Xu,
Zhu, Cui, Wojtas, & Zhang, 2013). Hammad, Nica, and Hempelmann (2017) have used a Diels–Alder reaction to link
doxorubicin to the surface of a core/shell particle, allowing for AMF-induced release of the drug to target HeLa cells
in vitro. Recently, Fan, Trant, Hemery, Sandre, and Gillies (2017) have also synthesized SPION-containing micelles from a
polymer containing a Diels–Alder bond. Upon exposure to an AMF, the SPIONs generated heat, cleaving the thermally
labile bond to release cargo loaded within the micelle. An alternative type of bond involves the formation of thermally
labile azo linkages. For instance, Yoo et al. (2013) linked geldanamycin, a heat shock protein inhibitor, to the surface of
SPIONs via a thermally sensitive azo bond. The drug releasing particles were shown to be a more effective tumor therapy
than nondrug releasing particles.
Thermally labile bonds have also been used to “cap” drug-loaded mesoporous silica nanoparticles. One common strategy
for doing so is to link a bulky group (e.g., small nanoparticle or polymer) to the surface of the mesoporous silica nanoparticle
via a Diels–Alder reaction. When the nanocarrier is exposed to heat, the temperature sensitive bond is cleaved, releasing the
cargo embedded in the carrier (Rühle et al., 2016). Others have also used thermally labile azo bonds for the same purpose
(Saint-Cricq, Deshayes, Zink, & Kasko, 2015). Finally, a heat cleavable oligo(ethylene glycol) methyl ether methacrylate
polymer has been used to coat a copper sulfide nanoparticle for thermally controlled release of the anesthetic bupivacaine,
although this was demonstrated via near infrared irradiation, not magnetically induced release (Ortiz de Solorzano
et al., 2019).
8 of 18 LIU ET AL.
4.1.2 | Magnetic nanoparticles containing thermally responsive materials

Both liposomes and micelles have been engineered to efficiently release their encapsulated cargo at elevated temperatures
(Ganta, Devalapally, Shahiwala, & Amiji, 2008). Temperature sensitive micelles fall into two categories: lower critical solu-
tion temperature (LCST) formulations and upper critical solution temperature (UCST) formulations. In LCST micelles, the
polymer becomes less water soluble as the solution temperature increases. Most LCST micelle formulations incorporate
poly(N-isopropylacrylamide) (p(NIPAAm)) as their outer shell. Various groups have encapsulated magnetic nanoparticles in
p(NIPAAm)-containing polymers for thermally controlled drug release (Patra et al., 2015; Pernia Leal et al., 2012; Yadavalli
et al., 2015). Recently, Deng et al. (2015) have also developed a SPION-containing LCST micelle containing a novel star-
block copolymer for AMF-triggered release of drug to target hepatocellular carcinoma cells in vitro. Similarly, Hervault et al.
(2016) have coated an LCST polymer to the surface of a magnetic nanoparticle, allowing for magnetically triggered release of
doxorubicin.
UCST micelles disintegrate as the temperature is increased, releasing the encapsulated cargo (Jia, Chen, & Jiang, 2006;
W. Li et al., 2015). Although UCST formulations are less well studied than LCST formulations, UCST micelles have begun
to be applied for triggered drug release. In a recent study, magnetic nanoparticle loaded UCST micelles were used to deliver
doxorubicin to tumors in vivo via microwave-induced hyperthermia, and showed improved efficacy compared to controls
(W.-S. Li, Wang, et al., 2017). Although the thermal gradient in this study was not magnetically generated, the ability to
encapsulated magnetic nanoparticles within the micelle indicates that it may be possible to use AMF-induced heating to trigger
drug release from these nanocarrier formulations in the future.
In thermally sensitive liposomes, the liposomal membrane usually becomes permeable as the temperature increases.
Magnetoliposomes—liposomes containing magnetic particles—have been designed to codeliver SPIONs with drug. For
instance, Guo et al. (2018) have recently developed a doxorubicin-loaded dipalmoylphosphatidylcholine-based thermally sen-
sitive liposomes with magnetic nanoparticles embedded in the lipid membrane for combined imaging, magnetic targeting, and
magnetically triggered drug release in an in vivo mouse HeLa cell model. Similarly, Ferreira et al. (2016) have encapsulated
hydrophilic magnetic nanoparticles within the lumen of a thermally sensitive liposome to magnetically trigger gemcitabine
release from the nanocarrier.
Several thermally sensitive polymersome formulations have been developed that similarly rely on increasing mem-
brane porosity with increasing temperature to allow for triggered drug release. Various groups have used polymersomes
with membrane-embedded SPIONs for AMF-induced release of doxorubicin and fluorescent dyes (Bixner, Kurzhals,
Virk, & Reimhult, 2016; Oliveira et al., 2013; Sanson et al., 2011). Though less common, the same strategy has been
employed with hydrophobic SPIONs embedded in liposomal membranes (Y. Chen, Bose, & Bothun, 2010; Y. Chen
et al., 2014).
Finally, although most of the studies use Néel relaxation to generate heat for thermally triggered drug release because it is
independent of the viscosity of the medium, some groups have also reported that Brownian relaxation may be harnessed for
drug release by mechanically disrupting the liposomal membrane. For example, Peiris et al. (2015) have developed a nanopar-
ticle comprising three 10 nm SPIONs linked in series to a 30 nm liposome. This unique structure can be disrupted with a low-
frequency AMF for drug delivery to glioblastoma tumors. Others have also suggested that low-frequency AMFs can induce
oscillations in SPIONs encapsulated in the lumen of liposomes to mechanically trigger drug release from the nanocarriers
(Nappini, Bombelli, Bonini, Nordèn, & Baglioni, 2010; Spera et al., 2015; Box 1).
4.1.3 | Focusing of the alternating magnetic field

One challenge associated with AMF-induced magnetic hyperthermia and drug release is that SPIONs are typically most
responsive to frequencies in the range of 100–500 kHz (R. Chen et al., 2013; Jang et al., 2009; Laurent et al., 2011; Mehdaoui
et al., 2011). As electromagnetic waves, AMFs are limited by diffraction. Therefore, it is difficult to target AMFs for magnetic
heating to resolutions of better than ~1 m. As a result, it continues to be common practice to introduce particles to target tis-
sues by direct injection before applying the AMF in order to avoid off-target effects (Laurent et al., 2011; Yoo et al., 2013),
which negates the advantages of using magnetism and nanoparticles as a noninvasive therapeutic strategy. To improve the
specificity of magnetically induced drug delivery, most strategies continue to rely on traditional biomolecular targeting strate-
gies, such as small molecule (Pradhan et al., 2010) and antibody (Yang et al., 2016) targeting. Unfortunately, these methods
are limited by the same challenges as typical biological strategies, including heterogeneous expression of ligands and recep-
tors, and off-target binding (Muro, 2012; Tredan et al., 2007; Vaupel et al., 1989).
LIU ET AL. 9 of 18
BOX 1 VISION AND CHALLENGES OF THERMALLY SENSITIVE NANOCARRIERS

Thermally sensitive nanocarriers are used in conjunction with AMFs for magnetically triggered drug release. Ther-
mally sensitive micelles can be modified to incorporate hydrophobic iron oxide nanoparticles into their core, while
thermally sensitive liposomes and polymersomes can have hydrophilic or hydrophobic magnetic nanoparticles incor-
porated in the lumen or embedded in the lipid/polymer bilayer, respectively. When these nanoparticles are exposed to
an AMF, the rapid change in the direction of the field causes them to generate heat, which increases the temperature
in the vicinity of the thermally sensitive nanocarrier, leading to drug release. Unfortunately, many magnetically trig-
gered drug release strategies can be limited by the difficulty in focusing the AMF to trigger spatially localized drug
release.
Unlike alternating fields, static fields have no inherent length scale and are not subject to diffraction. Therefore, one way
to “focus” AMFs is to superimpose a strong static field containing a field-free region onto the AMF. SPIONs within the
low field region will respond to the AMF, whereas particles outside the field-free region will have their magnetic moment
pinned, preventing their response to the AMF (Figure 5a). This concept has been applied for magnetic particle imaging as
well as magnetic hyperthermia. For example, Gleich and Weizenecker (2005) have used a static field containing a field-free
point generated using two oppositely polarized static magnets to improve the resolution of magnetic particle imaging. By
scanning the field-free region over the sample to be imaged, they were able to achieve an imaging resolution of 1 mm.
Others have also applied the concept of a field-free region to hyperthermia. For example, Ma et al. (2015) demonstrated
spatially targeted magnetic hyperthermia in phantoms using a static field containing a field-free region, while Tay et al.
(2018) have recently demonstrated spatially specific, tumor targeted hyperthermia with 7 mm resolution in small animal
models (Figure 5b).
Recently, we have expanded the use of static gating fields for spatial targeting of AMFs to trigger drug release from ther-
mally sensitive liposomes using a three-magnet system (J. F. Liu et al., 2018). The presence of a third magnet “tethers” the
field lines to allow for independent control of the size and location of the field-free region (Figure 5c). Future work will focus
on combining this targeting system with membrane-decorated liposomes and polymersomes for extremely localized drug
release without requiring bulk hyperthermia.
5 | B I O L O G I C A L I N T E R A C T I O N S OF MAGNETIC NANOPARTICLES
Iron oxide has long been considered relatively safe (Arami, Khandhar, Liggitt, & Krishnan, 2015; Weissleder et al., 1989).
However, in the last two decades, it has become increasingly clear that they can induce cytotoxicity and oxidative stress at
high concentrations and with chronic exposure (Naqvi et al., 2010; Nemmar et al., 2015; N. Singh, Jenkins, Asadi, & Doak,
2010). Furthermore, the addition of dopants to improve heating properties may trade magnetic response for toxicity. To reduce
toxicity, SPIONs are often coated with biocompatible polymers such as dextran, PEG, and PEI (Muthiah, Park, & Cho, 2013).
There have also been attempts to encapsulate nanoparticles in lipids (H.-C. Huang et al., 2009; Liang, Zhang, Miao, Li, &
Gan, 2017) and peptides (Chee et al., 2018) to reduce toxicity and improve circulation time. Others have also found that cyto-
toxicity is both coating- and size-dependent (Feng et al., 2018). Finally, although there have been many toxicity studies of
SPIONs (with various coatings) in animal models, the safety in humans of these various formulations is less well established
(Arami et al., 2015). To achieve high concentrations of SPIONs in target tissues without causing unintended local or systemic
toxicity, further work is necessary to synthesize more biocompatible particle cores and coatings, and to establish the clinical
safety of existing formulations.
Magnetic nanoparticles and nanocarriers have also been shown to interact with tumor-associated immune cells. For
instance, macrophages associated with breast cancer have been shown to selectively uptake ultrasmall SPIONs
(Daldrup-Link et al., 2011). In another study, SPIONs were also tagged with glucan to specifically target tumor-
associated macrophages to image liver metastases (Vu-Quang et al., 2012). Because tumor-associated macrophages are
generally considered a poor prognostic sign, both of these methods may allow for noninvasive predictions of outcome
via imaging. Once taken up by tumor-associated macrophages, SPIONs have also been shown to increase the inflamma-
tory response by the macrophages, potentially harnessing the body's immune system to improve tumor cell killing
10 of 18 LIU ET AL.
FIGURE 5 Strong static fields containing field-free regions can be used to target alternating magnetic fields for magnetic heating and drug
release. (a) In the low-field region, magnetic nanoparticles respond to the applied alternating magnetic field (AMF) to generate heat. Outside of the
field-free region, the nanoparticles are “pinned” in the direction of the static field, preventing their response to the AMF and thereby suppressing
heating. (b) Static fields containing field-free regions have been used for high-resolution magnetic particle imaging and targeted tissue ablation via
magnetic hyperthermia. (Reprinted with permission from Tay et al., 2018. Copyright 2018 American Chemical Society) (c) By adding a third
magnet, it is possible to independently control the size and location of the field-free targeting region. (Reprinted with permission from J. F. Liu et al.
(2018). Copyright 2018 John Wiley and Sons)
(Reichel, Tripathi, & Perez, 2019; Zanganeh et al., 2016). Finally, in preliminary studies, others have also attempted to
drive immune cells (microglia) toward regions of interest by functionalizing them with magnetic nanoparticles (White
et al., 2015). Future work may focus on modulating the SPION/immune system interaction to more effectively target
tumor cells.
6 | FUTURE DIRECTIONS
6.1 | Challenges in nanoparticle synthesis

As described above, there have been significant recent advances in synthesizing magnetic nanoparticles with improved imag-
ing and heating properties. The use of these particles promises to improve drug release from thermally sensitive nanocarriers.
By decreasing both the field strengths and particle concentrations necessary to induce a temperature gradient, these develop-
ments put the goal of noninvasive, magnetically triggered drug release closer within reach. However, by virtue of being newer
geometries, the synthesis methods for these novel particles are less well developed, less well understood, and less consistent
than for traditional spherical iron oxide nanoparticles (Cotin et al., 2018). Answering these questions will be an important
future step in making these particles easily usable for downstream applications.
LIU ET AL. 11 of 18
BOX 2 A SCALE-UP CHALLENGE

Magnetic fields are bio-orthogonal. Therefore, magnetic nanoparticles introduced into the body allow for high-
contrast delivery of magnetic energy for drug delivery. Magnetic fields and nanoparticles are commonly used to trig-
ger drug release from nanocarriers via magnetic hyperthermia, and to encourage drug accumulation at target sites via
magnetic drug targeting. However, one major challenge that remains is difficulty in system scale-up. While small
animal-sized device prototypes can be built using permanent magnets and benchtop amplifiers, building larger sys-
tems will likely require a shift to high-power electromagnets. Developments in coil technology are needed to make
resource-efficient system scale-up possible.
6.2 | Maximum amplitude of an alternating magnetic field

Because AMFs can induce eddy currents in electrically conductive materials (such as human tissue), it has been well-
established that the product of the amplitude of the alternating field, its frequency, and the square of the diameter of the coil
used to apply the field should not exceed approximately 4 × 107 A m s−1 (Atkinson, Brezovich, & Chakraborty, 1984;
Laurent et al., 2011) for 1 hour. Because the frequency of the field is often set to match the particles' optimum heating fre-
quency, and the diameter of the coil is limited by the patient, the most easily tunable parameter affecting this limit is the ampli-
tude of the field applied. Therefore, the development of more magnetically responsive particles will also allow for better
heating, and therefore drug release, without encroaching upon this limit.
6.3 | Developments in thermally responsive nanocarriers

Thermally sensitive SPION-loaded micelles are an attractive nanocarrier for triggered release of hydrophobic drugs via
magnetic heating. In addition to having high encapsulation efficiencies compared to liposome and polymersome
formulations, the high density of particles inside the micelle core would be more likely to rapidly generate the heat
necessary to disrupt the membrane. Because hydrophobic SPIONs have already been encapsulated in micelles
(McQuade et al., 2015; Nasongkla et al., 2006), the main barrier to AMF-induced release from magnetic micelles is
the polymer formulation of the carrier. Unfortunately, many of these polymers have broad transition points (Roy,
Brooks, & Sumerlin, 2013), which hinders rapid drug release from the micelles. Polymers with higher transition tem-
peratures and sharper transition points would enable further development of thermally sensitive drug-loaded magnetic
micelles.
6.4 | System scale-up

Another challenge for all magnetic systems is in scale-up of the system. Because static magnetic fields have no inherent length
scale, scaling up of the system does not require a redesign of the magnetic configuration. However, achieving sufficiently high
fields for targeted drug release and nanocarrier delivery does require replacing the static permanent magnets used in prototypes
with costly high-power electromagnets. Fortunately, significant progress has been made in this area: Matter et al. (2006) have
demonstrated that copper coils can be used as a resource-efficient means of generating strong fields over short timescales. Fur-
ther work may help to make scale-up more achievable and resource-efficient (Box 2).
7 | CONCLUSION
Magnetic fields and nanoparticles have been harnessed for therapy and drug delivery in cancer by increasing drug accumula-
tion in tumor tissues, ablating diseased tissues, and triggering drug release in tissues. Recent developments have aimed to
increase the spatial specificity of triggered drug release, as well as improve magnetic drug targeting to deep tissues. Future
work is needed to continue to improve the properties of magnetic particles and drug carriers, as well as developing technolo-
gies for cost-effective scale-up of magnetic systems.
12 of 18 LIU ET AL.
C ON F L I C T O F IN T E RE S T
The authors have declared no conflicts of interest for this article.
R ELA T E D W I R E s A R T I C L E S
Thermally responsive polymer-nanoparticle composites for biomedical applications
Functional magnetic hybrid nanomaterials for biomedical diagnosis and treatment
Strategies to improve tumor penetration of nanomedicines through nanoparticle design
O R C ID
Jessica F. Liu https://orcid.org/0000-0002-2663-8438

David Issadore https://orcid.org/0000-0002-5461-8653
Andrew Tsourkas https://orcid.org/0000-0001-7758-1753
R E F E REN CE S
Alexiou, C., Arnold, W., Klein, R. J., Parak, F. G., Hulin, P., Bergemann, C., … Lübbe, A. S. (2000). Locoregional cancer treatment with magnetic
drug targeting. Cancer Research, 60(23), 6641–6648.
Al-Jamal, K. T., Bai, J., Wang, J. T.-W., Protti, A., Southern, P., Bogart, L., … Pankhurst, Q. A. (2016). Magnetic drug targeting: Preclinical in vivo
studies, mathematical modeling, and extrapolation to humans. Nano Letters, 16(9), 5652–5660. https://doi.org/10.1021/acs.nanolett.6b02261
Altanerova, U., Babincova, M., Babinec, P., Benejova, K., Jakubechova, J., Altanerova, V., … Altaner, C. (2017). Human mesenchymal stem cell-
derived iron oxide exosomes allow targeted ablation of tumor cells via magnetic hyperthermia. International Journal of Nanomedicine, 12,
7923–7936. https://doi.org/10.2147/IJN.S145096
Andrews, D. L., Lipson, R. H., & Nann, T. (2019). Comprehensive nanoscience and nanotechnology (Vol. 3, 2nd ed., pp. 193–210). Elsevier.
Arami, H., Khandhar, A., Liggitt, D., & Krishnan, K. M. (2015). In vivo delivery, pharmacokinetics, biodistribution and toxicity of iron oxide
nanoparticles. Chemical Society Reviews, 44(23), 8576–8607. https://doi.org/10.1039/C5CS00541H
Atkinson, W. J., Brezovich, I. A., & Chakraborty, D. P. (1984). Usable frequencies in hyperthermia with thermal seeds. IEEE Transactions on Bio-
Medical Engineering, 31(1), 70–75. https://doi.org/10.1109/TBME.1984.325372
Bae, Y. H., & Park, K. (2011). Targeted drug delivery to tumors: Myths, reality and possibility. Journal of Controlled Release, 153(3), 198–205.
https://doi.org/10.1016/j.jconrel.2011.06.001
Balivada, S., Rachakatla, R. S., Wang, H., Samarakoon, T. N., Dani, R. K., Pyle, M., … Troyer, D. L. (2010). A/C magnetic hyperthermia of mela-
noma mediated by iron(0)/iron oxide core/shell magnetic nanoparticles: a mouse study. BMC Cancer, 10(1), 119.
Banchelli, M., Nappini, S., Montis, C., Bonini, M., Canton, P., Berti, D., & Baglioni, P. (2014). Magnetic nanoparticle clusters as actuators of
ssDNA release. Physical Chemistry Chemical Physics, 16(21), 10023–10031. https://doi.org/10.1039/c3cp55470h
Barnsley, L. C., Carugo, D., Owen, J., & Stride, E. (2015). Halbach arrays consisting of cubic elements optimised for high field gradients in mag-
netic drug targeting applications. Physics in Medicine and Biology, 60(21), 8303–8327. https://doi.org/10.1088/0031-9155/60/21/8303
Baronzio, G., Parmar, G., & Baronzio, M. (2015). Overview of methods for overcoming hindrance to drug delivery to tumors, with special attention
to tumor interstitial fluid. Frontiers in Oncology, 5, 165. https://doi.org/10.3389/fonc.2015.00165
Bertrand, N., & Leroux, J.-C. (2012). The journey of a drug-carrier in the body: An anatomo-physiological perspective. Journal of Controlled
Release, 161(2), 152–163. https://doi.org/10.1016/J.JCONREL.2011.09.098
Bixner, O., Kurzhals, S., Virk, M., & Reimhult, E. (2016). Triggered release from thermoresponsive polymersomes with superparamagnetic mem-
branes. Materials, 9(1), 29.
Blanco-Andujar, C., Ortega, D., Southern, P., Pankhurst, Q. A., & Thanh, N. T. K. (2015). High performance multi-core iron oxide nanoparticles for
magnetic hyperthermia: Microwave synthesis, and the role of core-to-core interactions. Nanoscale, 7(5), 1768–1775. https://doi.org/10.1039/
C4NR06239F
Bobo, D., Robinson, K. J., Islam, J., Thurecht, K. J., & Corrie, S. R. (2016). Nanoparticle-based medicines: A review of FDA-approved materials
and clinical trials to date. Pharmaceutical Research, 33(10), 2373–2387. https://doi.org/10.1007/s11095-016-1958-5
Boissenot, T., Bordat, A., Fattal, E., & Tsapis, N. (2016). Ultrasound-triggered drug delivery for cancer treatment using drug delivery systems: From
theoretical considerations to practical applications. Journal of Controlled Release, 241, 144–163. https://doi.org/10.1016/J.JCONREL.2016.
09.026
Chang, D., Lim, M., Goos, J. A. C. M., Qiao, R., Ng, Y. Y., Mansfeld, F. M., … Kavallaris, M. (2018). Biologically targeted magnetic hyperther-
mia: Potential and limitations. Frontiers in Pharmacology, 9, 831. https://doi.org/10.3389/fphar.2018.00831
Chee, H. L., Gan, C. R. R., Ng, M., Low, L., Fernig, D. G., Bhakoo, K. K., & Paramelle, D. (2018). Biocompatible peptide-coated ultrasmall super-
paramagnetic iron oxide nanoparticles for in vivo contrast-enhanced magnetic resonance imaging. ACS Nano, 12(7), 6480–6491. https://doi.org/
10.1021/acsnano.7b07572
LIU ET AL. 13 of 18
Chen, B., Dai, W., He, B., Zhang, H., Wang, X., Wang, Y., & Zhang, Q. (2017). Current multistage drug delivery systems based on the tumor
microenvironment. Theranostics, 7(3), 538–558. https://doi.org/10.7150/thno.16684
Chen, R., Christiansen, M. G., & Anikeeva, P. (2013). Maximizing hysteretic losses in magnetic ferrite nanoparticles via model-driven synthesis and
materials optimization. ACS Nano, 7(10), 8990–9000. https://doi.org/10.1021/nn4035266
Chen, Y., Bose, A., & Bothun, G. D. (2010). Controlled release from bilayer-decorated magnetoliposomes via electromagnetic heating. ACS Nano,
4(6), 3215–3221. https://doi.org/10.1021/nn100274v
Chen, Y., Chen, Y., Xiao, D., Bose, A., Deng, R., & Bothun, G. D. (2014). Low-dose chemotherapy of hepatocellular carcinoma through
triggered-release from bilayer-decorated magnetoliposomes. Colloids and Surfaces B, 116, 452–458. https://doi.org/10.1016/j.colsurfb.2014.
01.022
Cheng, C. J., Tietjen, G. T., Saucier-Sawyer, J. K., & Saltzman, W. M. (2015). A holistic approach to targeting disease with polymeric nanoparticles.
Nature Reviews Drug Discovery, 14(4), 239–247. https://doi.org/10.1038/nrd4503
Corot, C., Robert, P., Idée, J.-M., & Port, M. (2006). Recent advances in iron oxide nanocrystal technology for medical imaging. Advanced Drug
Delivery Reviews, 58(14), 1471–1504. https://doi.org/10.1016/j.addr.2006.09.013
Cotin, G., Kiefer, C., Perton, F., Ihiawakrim, D., Blanco-Andujar, C., Moldovan, S., … Bégin-Colin, S. (2018). Unravelling the thermal decomposi-
tion parameters for the synthesis of anisotropic iron oxide nanoparticles. Nanomaterials (Basel, Switzerland), 8(11), E881. https://doi.org/10.
3390/nano8110881
Curcio, A., Silva, A. K. A., Cabana, S., Espinosa, A., Baptiste, B., Menguy, N., … Abou-Hassan, A. (2019). Iron oxide nanoflowers @ CuS hybrids
for cancer tri-therapy: Interplay of photothermal therapy, magnetic hyperthermia and photodynamic therapy. Theranostics, 9(5), 1288–1302.
https://doi.org/10.7150/thno.30238
Daldrup-Link, H. E., Golovko, D., Ruffell, B., Denardo, D. G., Castaneda, R., Ansari, C., … Coussens, L. M. (2011). MRI of tumor-associated mac-
rophages with clinically applicable iron oxide nanoparticles. Clinical Cancer Research, 17(17), 5695–5704. https://doi.org/10.1158/1078-0432.
CCR-10-3420
Deng, L., Ren, J., Li, J., Leng, J., Qu, Y., Lin, C., & Shi, D. (2015). Magnetothermally responsive star-block copolymeric micelles for controlled
drug delivery and enhanced thermo-chemotherapy. Nanoscale, 7(21), 9655–9663. https://doi.org/10.1039/C5NR00642B
Derfus, A. M., von Maltzahn, G., Harris, T. J., Duza, T., Vecchio, K. S., Ruoslahti, E., & Bhatia, S. N. (2007). Remotely triggered release from mag-
netic nanoparticles. Advanced Materials, 19(22), 3932–3936. https://doi.org/10.1002/adma.200700091
Dewhirst, M. W., Lee, C.-T., & Ashcraft, K. A. (2016). The future of biology in driving the field of hyperthermia. International Journal of Hyper-
thermia, 32(1), 4–13. https://doi.org/10.3109/02656736.2015.1091093
Duro-Castano, A., Movellan, J., & Vicent, M. J. (2015). Smart branched polymer drug conjugates as nano-sized drug delivery systems. Biomaterials
Science, 3(10), 1321–1334. https://doi.org/10.1039/C5BM00166H
El-Dek, S. I., Ali, M. A., El-Zanaty, S. M., & Ahmed, S. E. (2018). Comparative investigations on ferrite nanocomposites for magnetic hyperthermia
applications. Journal of Magnetism and Magnetic Materials, 458, 147–155. https://doi.org/10.1016/J.JMMM.2018.02.052
Fan, B., Trant, J. F., Hemery, G., Sandre, O., & Gillies, E. R. (2017). Thermo-responsive self-immolative nanoassemblies: Direct and indirect trig-
gering. Chemical Communications, 53(89), 12068–12071. https://doi.org/10.1039/C7CC06410A
Feng, Q., Liu, Y., Huang, J., Chen, K., Huang, J., & Xiao, K. (2018). Uptake, distribution, clearance, and toxicity of iron oxide nanoparticles with
different sizes and coatings. Scientific Reports, 8(1), 2082. https://doi.org/10.1038/s41598-018-19628-z
Ferreira, R. V., Martins, T. M., Da, M., Goes, A. M., Fabris, J. D., Cavalcante, L. C. D., … Domingues, R. Z. (2016). Thermosensitive gemcitabine-
magnetoliposomes for combined hyperthermia and chemotherapy. Nanotechnology, 27(8), 085105. https://doi.org/10.1088/0957-4484/27/8/
085105
Ganta, S., Devalapally, H., Shahiwala, A., & Amiji, M. (2008). A review of stimuli-responsive nanocarriers for drug and gene delivery. Journal of
Controlled Release, 126(3), 187–204. https://doi.org/10.1016/J.JCONREL.2007.12.017
Gleich, B., & Weizenecker, J. (2005). Tomographic imaging using the nonlinear response of magnetic particles. Nature, 435(7046), 1214–1217.
https://doi.org/10.1038/nature03808
Goodman, T. T., Olive, P. L., & Pun, S. H. (2007). Increased nanoparticle penetration in collagenase-treated multicellular spheroids. International
Journal of Nanomedicine, 2(2), 265–274.
Griffete, N., Fresnais, J., Espinosa, A., Wilhelm, C., Bée, A., & Ménager, C. (2015). Design of magnetic molecularly imprinted polymer
nanoparticles for controlled release of doxorubicin under an alternative magnetic field in athermal conditions. Nanoscale, 7(45), 18891–18896.
https://doi.org/10.1039/C5NR06133D
Guardia, P., Di Corato, R., Lartigue, L., Wilhelm, C., Espinosa, A., Garcia-Hernandez, M., … Pellegrino, T. (2012). Water-soluble iron oxide nan-
ocubes with high values of specific absorption rate for cancer cell hyperthermia treatment. ACS Nano, 6(4), 3080–3091. https://doi.org/10.1021/
nn2048137
Guisasola, E., Baeza, A., Talelli, M., Arcos, D., Moros, M., de la Fuente, J. M., & Vallet-Regí, M. (2015). Magnetic-responsive release controlled
by hot spot effect. Langmuir, 31(46), 12777–12782. https://doi.org/10.1021/acs.langmuir.5b03470
Guisasola, E., Vallet-Regí, M., & Baeza, A. (2018). Magnetically responsive polymers for drug delivery applications. Stimuli Responsive Polymeric
Nanocarriers for Drug Delivery Applications, 1, 143–168. https://doi.org/10.1016/B978-0-08-101997-9.00008-4
Guo, Y., Zhang, Y., Ma, J., Li, Q., Li, Y., Zhou, X., … Zhu, X. (2018). Light/magnetic hyperthermia triggered drug released from multi-functional
thermo-sensitive magnetoliposomes for precise cancer synergetic theranostics. Journal of Controlled Release, 272, 145–158. https://doi.org/10.
1016/J.JCONREL.2017.04.028
14 of 18 LIU ET AL.
Habib, A. H., Ondeck, C. L., Chaudhary, P., Bockstaller, M. R., & McHenry, M. E. (2008). Evaluation of iron-cobalt/ferrite core-shell nanoparticles
for cancer thermotherapy. Journal of Applied Physics, 103(7), 07A307. https://doi.org/10.1063/1.2830975
Hajiaghajani, A., & Abdolali, A. (2018). Magnetic field pattern synthesis and its application in targeted drug delivery: Design and implementation.
Bioelectromagnetics, 39(4), 325–338. https://doi.org/10.1002/bem.22107
Hammad, M., Nica, V., & Hempelmann, R. (2017). On-command controlled drug release by Diels-Alder reaction using bi-magnetic core/shell nano-
carriers. Colloids and Surfaces B, 150, 15–22. https://doi.org/10.1016/j.colsurfb.2016.11.005
Haume, K., Rosa, S., Grellet, S., Śmiałek, M. A., Butterworth, K. T., Solov'yov, A. V., … Mason, N. J. (2016). Gold nanoparticles for cancer radio-
therapy: A review. Cancer Nanotechnology, 7(1), 8. https://doi.org/10.1186/s12645-016-0021-x
Hedayatnasab, Z., Abnisa, F., & Daud, W. M. A. W. (2017). Review on magnetic nanoparticles for magnetic nanofluid hyperthermia application.
Materials & Design, 123, 174–196. https://doi.org/10.1016/J.MATDES.2017.03.036
Hemery, G., Keyes, A. C., Garaio, E., Rodrigo, I., Garcia, J. A., Plazaola, F., … Sandre, O. (2017). Tuning sizes, morphologies, and magnetic prop-
erties of monocore versus multicore iron oxide nanoparticles through the controlled addition of water in the polyol synthesis. Inorganic Chemis-
try, 56(14), 8232–8243. https://doi.org/10.1021/acs.inorgchem.7b00956
Hervault, A., Dunn, A. E., Lim, M., Boyer, C., Mott, D., Maenosono, S., & Thanh, N. T. K. (2016). Doxorubicin loaded dual pH- and thermo-
responsive magnetic nanocarrier for combined magnetic hyperthermia and targeted controlled drug delivery applications. Nanoscale, 8(24),
12152–12161. https://doi.org/10.1039/C5NR07773G
Hörmann, K., & Zimmer, A. (2016). Drug delivery and drug targeting with parenteral lipid nanoemulsions—A review. Journal of Controlled
Release, 223, 85–98. https://doi.org/10.1016/J.JCONREL.2015.12.016
Huang, C., Tang, Z., Zhou, Y., Zhou, X., Jin, Y., Li, D., … Zhou, S. (2012). Magnetic micelles as a potential platform for dual targeted drug deliv-
ery in cancer therapy. International Journal of Pharmaceutics, 429(1–2), 113–122. https://doi.org/10.1016/J.IJPHARM.2012.03.001
Huang, H., Delikanli, S., Zeng, H., Ferkey, D. M., & Pralle, A. (2010). Remote control of ion channels and neurons through magnetic-field heating
of nanoparticles. Nature Nanotechnology, 5(8), 602–606. https://doi.org/10.1038/nnano.2010.125
Huang, H.-C., Chang, P.-Y., Chang, K., Chen, C.-Y., Lin, C.-W., Chen, J.-H., … Chang, F.-H. (2009). Formulation of novel lipid-coated magnetic
nanoparticles as the probe for in vivo imaging. Journal of Biomedical Science, 16(1), 86. https://doi.org/10.1186/1423-0127-16-86
Hufschmid, R., Arami, H., Ferguson, R. M., Gonzales, M., Teeman, E., Brush, L. N., … Krishnan, K. M. (2015). Synthesis of phase-pure
and monodisperse iron oxide nanoparticles by thermal decomposition. Nanoscale, 7(25), 11142–11154. https://doi.org/10.1039/
C5NR01651G
Jang, J., Nah, H., Lee, J.-H., Moon, S. H. H., Kim, M. G. G., & Cheon, J. (2009). Critical enhancements of MRI contrast and hyperthermic effects
by dopant-controlled magnetic nanoparticles. Angewandte Chemie, 48(7), 1234–1238. https://doi.org/10.1002/anie.200805149
Jia, X., Chen, D., & Jiang, M. (2006). Preparation of PEO-b-P2VPH+–S2O82− micelles in water and their reversible UCST and redox-responsive
behavior. Chemical Communications, 2006(16), 1736–1738. https://doi.org/10.1039/B600859C
Kanamala, M., Wilson, W. R., Yang, M., Palmer, B. D., & Wu, Z. (2016). Mechanisms and biomaterials in pH-responsive tumour targeted drug
delivery: A review. Biomaterials, 85, 152–167. https://doi.org/10.1016/J.BIOMATERIALS.2016.01.061
Kim, D., Lee, J., Lee, S., Park, J., & Lee, D. (2016). Predicting unintended effects of drugs based on off-target tissue effects. Biochemical and Bio-
physical Research Communications, 469(3), 399–404. https://doi.org/10.1016/J.BBRC.2015.11.095
Krzyminiewski, R., Dobosz, B., Schroeder, G., & Kurczewska, J. (2018). Focusing of Fe3O4 nanoparticles using a rotating magnetic field in various
environments. Physics Letters A, 382(44), 3192–3196. https://doi.org/10.1016/J.PHYSLETA.2018.07.051
Lartigue, L., Hugounenq, P., Alloyeau, D., Clarke, S. P., Lévy, M., Bacri, J.-C., … Gazeau, F. (2012). Cooperative organization in iron oxide multi-
core nanoparticles potentiates their efficiency as heating mediators and MRI contrast agents. ACS Nano, 6(12), 10935–10949. https://doi.org/10.
1021/nn304477s
Laurent, S., Dutz, S., Häfeli, U. O., & Mahmoudi, M. (2011). Magnetic fluid hyperthermia: Focus on superparamagnetic iron oxide nanoparticles.
Advances in Colloid and Interface Science, 166(1–2), 8–23. https://doi.org/10.1016/j.cis.2011.04.003
Lee, H., Yoon, T.-J., & Weissleder, R. (2009). Ultrasensitive detection of bacteria using core-shell nanoparticles and an NMR-Filter system.
Angewandte Chemie International Edition, 48(31), 5657–5660. https://doi.org/10.1002/anie.200901791
Li, T.-J., Huang, C.-C., Ruan, P.-W., Chuang, K.-Y., Huang, K.-J., Shieh, D.-B., & Yeh, C.-S. (2013). In vivo anti-cancer efficacy of magnetite
nanocrystal-based system using locoregional hyperthermia combined with 5-fluorouracil chemotherapy. Biomaterials, 34(32), 7873–7883.
https://doi.org/10.1016/J.BIOMATERIALS.2013.07.012
Li, W., Huang, L., Ying, X., Jian, Y., Hong, Y., Hu, F., & Du, Y. (2015). Antitumor drug delivery modulated by a polymeric micelle with an upper
critical solution temperature. Angewandte Chemie, 54(10), 3126–3131. https://doi.org/10.1002/anie.201411524
Li, W.-S., Wang, X.-J., Zhang, S., Hu, J.-B., Du, Y.-L., Kang, X.-Q., … Du, Y.-Z. (2017). Mild microwave activated, chemo-thermal combinational
tumor therapy based on a targeted, thermal-sensitive and magnetic micelle. Biomaterials, 131, 36–46. https://doi.org/10.1016/j.biomaterials.
2017.03.048
Li, Y., Li, N., Pan, W., Yu, Z., Yang, L., & Tang, B. (2017). Hollow mesoporous silica nanoparticles with tunable structures for controlled drug
delivery. ACS Applied Materials & Interfaces, 9(3), 2123–2129. https://doi.org/10.1021/acsami.6b13876
Liang, J., Zhang, X., Miao, Y., Li, J., & Gan, Y. (2017). Lipid-coated iron oxide nanoparticles for dual-modal imaging of hepatocellular carcinoma.
International Journal of Nanomedicine, 12, 2033–2044. https://doi.org/10.2147/IJN.S128525
Linsley, C. S., & Wu, B. M. (2017). Recent advances in light-responsive on-demand drug-delivery systems. Therapeutic Delivery, 8(2), 89–107.
https://doi.org/10.4155/tde-2016-0060
LIU ET AL. 15 of 18
Liu, J. F., Neel, N., Dang, P., Lamb, M., McKenna, J., Rodgers, L., … Issadore, D. (2018). Radiofrequency-triggered drug release from
nanoliposomes with millimeter-scale resolution using a superimposed static gating field. Small, 14(44), e1802563. https://doi.org/10.1002/smll.
201802563
Liu, X. L., Ng, C. T., Chandrasekharan, P., Yang, H. T., Zhao, L. Y., Peng, E., … Fan, H. M. (2016). Synthesis of ferromagnetic Fe0.6Mn0.4 O Nan-
oflowers as a new class of magnetic theranostic platform for in vivo T1–T2 dual-mode magnetic resonance imaging and magnetic hyperthermia
therapy. Advanced Healthcare Materials, 5(16), 2092–2104. https://doi.org/10.1002/adhm.201600357
Lübbe, A. S., Bergemann, C., Riess, H., Schriever, F., Reichardt, P., Possinger, K., … Huhn, D. (1996). Clinical experiences with magnetic drug
targeting: A phase I study with 40 -epidoxorubicin in 14 patients with advanced solid tumors. Cancer Research, 56(20), 4686–4693.
Lübbe, A. S., Alexiou, C., & Bergemann, C. (2001). Clinical applications of magnetic drug targeting. Journal of Surgical Research, 95(2), 200–206.
https://doi.org/10.1006/JSRE.2000.6030
Ma, M., Zhang, Y., Shen, X., Xie, J., Li, Y., & Gu, N. (2015). Targeted inductive heating of nanomagnets by a combination of alternating current
(AC) and static magnetic fields. Nano Research, 8(2), 600–610. https://doi.org/10.1007/s12274-015-0729-7
Maeda, H. (2015). Toward a full understanding of the EPR effect in primary and metastatic tumors as well as issues related to its heterogeneity.
Advanced Drug Delivery Reviews, 91, 3–6. https://doi.org/10.1016/J.ADDR.2015.01.002
Mahmoudi, M., Sant, S., Wang, B., Laurent, S., & Sen, T. (2011). Superparamagnetic iron oxide nanoparticles (SPIONs): Development, surface
modification and applications in chemotherapy. Advanced Drug Delivery Reviews, 63(1–2), 24–46. https://doi.org/10.1016/J.ADDR.2010.
05.006
Marie, H., Lemaire, L., Franconi, F., Lajnef, S., Frapart, Y.-M., Nicolas, V., … Lesieur, S. (2015). Superparamagnetic liposomes for MRI monitor-
ing and external magnetic field-induced selective targeting of malignant brain tumors. Advanced Functional Materials, 25(8), 1258–1269.
https://doi.org/10.1002/adfm.201402289
Martel, S., Mathieu, J.-B., Felfoul, O., Chanu, A., Aboussouan, E., Tamaz, S., … Mankiewicz, M. (2007). Automatic navigation of an untethered
device in the artery of a living animal using a conventional clinical magnetic resonance imaging system. Applied Physics Letters, 90(11),
114105. https://doi.org/10.1063/1.2713229
Martinez-Boubeta, C., Simeonidis, K., Serantes, D., Conde-Leborán, I., Kazakis, I., Stefanou, G., … Angelakeris, M. (2012). Adjustable hyperther-
mia response of self-assembled ferromagnetic Fe-MgO core-shell nanoparticles by tuning dipole-dipole interactions. Advanced Functional Mate-
rials, 22(17), 3737–3744.
Matter, N. I., Scott, G. C., Venook, R. D., Ungersma, S. E., Grafendorfer, T., Macovski, A., & Conolly, S. M. (2006). Three-dimensional prepo-
larized magnetic resonance imaging using rapid acquisition with relaxation enhancement. Magnetic Resonance in Medicine, 56(5), 1085–1095.
https://doi.org/10.1002/mrm.21065
McQuade, C., Al Zaki, A., Desai, Y., Vido, M., Sakhuja, T., Cheng, Z., … Tsourkas, A. (2015). A multifunctional nanoplatform for imaging, radio-
therapy, and the prediction of therapeutic response. Small, 11(7), 834–843. https://doi.org/10.1002/smll.201401927
Mehdaoui, B., Meffre, A., Carrey, J., Lachaize, S., Lacroix, L.-M., Gougeon, M., … Respaud, M. (2011). Optimal size of nanoparticles for magnetic
hyperthermia: A combined theoretical and experimental study. Advanced Functional Materials, 21(23), 4573–4581. https://doi.org/10.1002/
adfm.201101243
Merino, S., Martín, C., Kostarelos, K., Prato, M., & Vázquez, E. (2015). Nanocomposite hydrogels: 3D polymer–nanoparticle synergies for on-
demand drug delivery. ACS Nano, 9(5), 4686–4697. https://doi.org/10.1021/acsnano.5b01433
Mertz, D., Sandre, O., & Bégin-Colin, S. (2017). Drug releasing nanoplatforms activated by alternating magnetic fields. Biochimica et Biophysica
Acta, 1861(6), 1617–1641. https://doi.org/10.1016/J.BBAGEN.2017.02.025
Moros, M., Idiago-López, J., Asín, L., Moreno-Antolín, E., Beola, L., Grazú, V., … de la Fuente, J. M. (2019). Triggering antitumoural drug release
and gene expression by magnetic hyperthermia. Advanced Drug Delivery Reviews, 138, 326–343. https://doi.org/10.1016/J.ADDR.2018.10.004
Mura, S., Nicolas, J., & Couvreur, P. (2013). Stimuli-responsive nanocarriers for drug delivery. Nature Materials, 12(11), 991–1003. https://doi.org/
10.1038/nmat3776
Muro, S. (2012). Challenges in design and characterization of ligand-targeted drug delivery systems. Journal of Controlled Release, 164(2),
125–137. https://doi.org/10.1016/J.JCONREL.2012.05.052
Muthiah, M., Park, I.-K., & Cho, C.-S. (2013). Surface modification of iron oxide nanoparticles by biocompatible polymers for tissue imaging and
targeting. Biotechnology Advances, 31(8), 1224–1236.
Nappini, S., Bombelli, F. B., Bonini, M., Nordèn, B., & Baglioni, P. (2010). Magnetoliposomes for controlled drug release in the presence of low-
frequency magnetic field. Soft Matter, 6(1), 154–162. https://doi.org/10.1039/B915651H
Naqvi, S., Samim, M., Abdin, M., Ahmed, F. J., Maitra, A., Prashant, C., & Dinda, A. K. (2010). Concentration-dependent toxicity of iron oxide
nanoparticles mediated by increased oxidative stress. International Journal of Nanomedicine, 5, 983–989. https://doi.org/10.2147/IJN.S13244
Nasongkla, N., Bey, E., Ren, J., Ai, H., Khemtong, C., Guthi, J. S., … Gao, J. (2006). Multifunctional polymeric micelles as cancer-targeted, MRI-
ultrasensitive drug delivery systems. Nano Letters, 6(11), 2427–2430. https://doi.org/10.1021/NL061412U
Nemmar, A., Beegam, S., Yuvaraju, P., Yasin, J., Tariq, S., Attoub, S., & Ali, B. H. (2015). Ultrasmall superparamagnetic iron oxide nanoparticles
acutely promote thrombosis and cardiac oxidative stress and DNA damage in mice. Particle and Fibre Toxicology, 13(1), 22. https://doi.org/10.
1186/s12989-016-0132-x
N'Guyen, T. T. T., Duong, H. T. T., Basuki, J., Montembault, V., Pascual, S., Guibert, C., … Fontaine, L. (2013). Functional iron oxide magnetic
nanoparticles with hyperthermia-induced drug release ability by using a combination of orthogonal click reactions. Angewandte Chemie, 52(52),
14152–14156. https://doi.org/10.1002/anie.201306724
16 of 18 LIU ET AL.
Niemeyer, C. M. (2010). Semisynthetic DNA-protein conjugates for biosensing and nanofabrication. Angewandte Chemie, 49(7), 1200–1216.
https://doi.org/10.1002/anie.200904930
Noh, S.-H., Na, W., Jang, J.-T., Lee, J.-H., Lee, E. J., Moon, S. H., … Cheon, J. (2012). Nanoscale magnetism control via surface and exchange
anisotropy for optimized ferrimagnetic hysteresis. Nano Letters, 12(7), 3716–3721. https://doi.org/10.1021/nl301499u
Ojha, T., Pathak, V., Shi, Y., Hennink, W. E., Moonen, C. T. W., Storm, G., … Lammers, T. (2017). Pharmacological and physical vessel modula-
tion strategies to improve EPR-mediated drug targeting to tumors. Advanced Drug Delivery Reviews, 119, 44–60. https://doi.org/10.1016/j.addr.
2017.07.007
Oliveira, H., Pérez-Andrés, E., Thevenot, J., Sandre, O., Berra, E., & Lecommandoux, S. (2013). Magnetic field triggered drug release from
polymersomes for cancer therapeutics. Journal of Controlled Release, 169(3), 165–170. https://doi.org/10.1016/J.JCONREL.2013.01.013
Ortiz de Solorzano, I., Alejo, T., Abad, M., Bueno-Alejo, C., Mendoza, G., Andreu, V., … Arruebo, M. (2019). Cleavable and thermo-responsive
hybrid nanoparticles for on-demand drug delivery. Journal of Colloid and Interface Science, 533, 171–181. https://doi.org/10.1016/j.jcis.2018.
08.069
Patra, S., Roy, E., Karfa, P., Kumar, S., Madhuri, R., & Sharma, P. K. (2015). Dual-responsive polymer coated superparamagnetic nanoparticle for
targeted drug delivery and hyperthermia treatment. ACS Applied Materials & Interfaces, 7(17), 9235–9246. https://doi.org/10.1021/acsami.
5b01786
Peiris, P. M., Abramowski, A., Mcginnity, J., Doolittle, E., Toy, R., Gopalakrishnan, R., … Karathanasis, E. (2015). Treatment of invasive brain
tumors using a chain-like nanoparticle. Cancer Research, 75(7), 1356–1365. https://doi.org/10.1158/0008-5472.CAN-14-1540
Périgo, E. A., Hemery, G., Sandre, O., Ortega, D., Garaio, E., Plazaola, F., & Teran, F. J. (2015). Fundamentals and advances in magnetic hyperther-
mia. Applied Physics Reviews, 2(4), 041302. https://doi.org/10.1063/1.4935688
Pernia Leal, M., Torti, A., Riedinger, A., La Fleur, R., Petti, D., Cingolani, R., … Pellegrino, T. (2012). Controlled release of doxorubicin loaded
within magnetic thermo-responsive nanocarriers under magnetic and thermal actuation in a microfluidic channel. ACS Nano, 6(12),
10535–10545. https://doi.org/10.1021/nn3028425
Pouponneau, P., Leroux, J.-C., & Martel, S. (2009). Magnetic nanoparticles encapsulated into biodegradable microparticles steered with an upgraded
magnetic resonance imaging system for tumor chemoembolization. Biomaterials, 30(31), 6327–6332. https://doi.org/10.1016/J.
BIOMATERIALS.2009.08.005
Pouponneau, P., Leroux, J.-C., Soulez, G., Gaboury, L., & Martel, S. (2011). Co-encapsulation of magnetic nanoparticles and doxorubicin into bio-
degradable microcarriers for deep tissue targeting by vascular MRI navigation. Biomaterials, 32(13), 3481–3486. https://doi.org/10.1016/J.
BIOMATERIALS.2010.12.059
Pradhan, P., Giri, J., Rieken, F., Koch, C., Mykhaylyk, O., Döblinger, M., … Plank, C. (2010). Targeted temperature sensitive magnetic liposomes
for thermo-chemotherapy. Journal of Controlled Release, 142(1), 108–121. https://doi.org/10.1016/j.jconrel.2009.10.002
Qi, H., Liu, C., Long, L., Ren, Y., Zhang, S., Chang, X., … Kang, C. (2016). Blood exosomes endowed with magnetic and targeting properties for
cancer therapy. ACS Nano, 10(3), 3323–3333. https://doi.org/10.1021/acsnano.5b06939
Reichel, D., Tripathi, M., & Perez, J. M. (2019). Biological effects of nanoparticles on macrophage polarization in the tumor microenvironment.
Nanotheranostics, 3(1), 66–88. https://doi.org/10.7150/ntno.30052
Riedinger, A., Guardia, P., Curcio, A., Garcia, M. A., Cingolani, R., Manna, L., & Pellegrino, T. (2013). Subnanometer local temperature probing
and remotely controlled drug release based on azo-functionalized iron oxide nanoparticles. Nano Letters, 13(6), 2399–2406. https://doi.org/10.
1021/nl400188q
Roch, A., Muller, R. N., & Gillis, P. (1999). Theory of proton relaxation induced by superparamagnetic particles. Journal of Chemical Physics, 110
(11), 5403–5411. https://doi.org/10.1063/1.478435
Rohovie, M. J., Nagasawa, M., & Swartz, J. R. (2017). Virus-like particles: Next-generation nanoparticles for targeted therapeutic delivery. Bioengi-
neering & Translational Medicine, 2(1), 43–57. https://doi.org/10.1002/btm2.10049
Romero, G., Christiansen, M. G., Stocche Barbosa, L., Garcia, F., & Anikeeva, P. (2016). Localized excitation of neural activity via rapid mag-
netothermal drug release. Advanced Functional Materials, 26(35), 6471–6478. https://doi.org/10.1002/adfm.201602189
Rosensweig, R. E. (2002). Heating magnetic fluid with alternating magnetic field. Journal of Magnetism and Magnetic Materials, 252, 370–374.
https://doi.org/10.1016/S0304-8853(02)00706-0
Rotariu, O., & Strachan, N. J. C. (2005). Modelling magnetic carrier particle targeting in the tumor microvasculature for cancer treatment. Journal of
Magnetism and Magnetic Materials, 293(1), 639–646. https://doi.org/10.1016/J.JMMM.2005.01.081
Roy, D., Brooks, W. L. A., & Sumerlin, B. S. (2013). New directions in thermoresponsive polymers. Chemical Society Reviews, 42(17), 7214–7243.
https://doi.org/10.1039/c3cs35499g
Rühle, B., Datz, S., Argyo, C., Bein, T., & Zink, J. I. (2016). A molecular nanocap activated by superparamagnetic heating for externally stimulated
cargo release. Chemical Communications, 52(9), 1843–1846. https://doi.org/10.1039/C5CC08636A
Saint-Cricq, P., Deshayes, S., Zink, J. I., & Kasko, A. M. (2015). Magnetic field activated drug delivery using thermodegradable azo-functionalised
PEG-coated core–shell mesoporous silica nanoparticles. Nanoscale, 7(31), 13168–13172. https://doi.org/10.1039/C5NR03777H
Sánchez-Moreno, P., de Vicente, J., Nardecchia, S., Marchal, J. A., & Boulaiz, H. (2018). Thermo-sensitive nanomaterials: Recent advance in syn-
thesis and biomedical applications. Nanomaterials (Basel, Switzerland), 8(11), E395. https://doi.org/10.3390/nano8110935
Sanson, C., Diou, O., Thévenot, J., Ibarboure, E., Soum, A., Brûlet, A., … Lecommandoux, S. (2011). Doxorubicin loaded magnetic polymersomes:
Theranostic nanocarriers for MR imaging and magneto-chemotherapy. ACS Nano, 5(2), 1122–1140. https://doi.org/10.1021/nn102762f
Sensenig, R., Sapir, Y., MacDonald, C., Cohen, S., & Polyak, B. (2012). Magnetic nanoparticle-based approaches to locally target therapy and
enhance tissue regeneration in vivo. Nanomedicine (London, England), 7(9), 1425–1442. https://doi.org/10.2217/nnm.12.109
LIU ET AL. 17 of 18
Shapiro, B., Kulkarni, S., Nacev, A., Muro, S., Stepanov, P. Y., & Weinberg, I. N. (2015). Open challenges in magnetic drug targeting. WIREs
Nanomedicine and Nanobiotechnology, 7(3), 446–457. https://doi.org/10.1002/wnan.1311
Sharma, A. K., Gothwal, A., Kesharwani, P., Alsaab, H., Iyer, A. K., & Gupta, U. (2017). Dendrimer nanoarchitectures for cancer diagnosis and
anticancer drug delivery. Drug Discovery Today, 22(2), 314–326. https://doi.org/10.1016/J.DRUDIS.2016.09.013
Sharma, H., Mishra, P. K., Talegaonkar, S., & Vaidya, B. (2015). Metal nanoparticles: A theranostic nanotool against cancer. Drug Discovery
Today, 20(9), 1143–1151. https://doi.org/10.1016/J.DRUDIS.2015.05.009
Shen, W.-B., Anastasiadis, P., Nguyen, B., Yarnell, D., Yarowsky, P. J., Frenkel, V., & Fishman, P. S. (2017). Magnetic enhancement of stem cell-
targeted delivery into the brain following MR-guided focused ultrasound for opening the blood–brain barrier. Cell Transplantation, 26(7),
1235–1246. https://doi.org/10.1177/0963689717715824
Silva, A. K. A., Luciani, N., Gazeau, F., Aubertin, K., Bonneau, S., Chauvierre, C., … Wilhelm, C. (2015). Combining magnetic nanoparticles with
cell derived microvesicles for drug loading and targeting. Nanomedicine: Nanotechnology, Biology, and Medicine, 11(3), 645–655. https://doi.
org/10.1016/j.nano.2014.11.009
Singh, N., Jenkins, G. J. S., Asadi, R., & Doak, S. H. (2010). Potential toxicity of superparamagnetic iron oxide nanoparticles (SPION). Nano
Reviews, 1(1), 5358. https://doi.org/10.3402/nano.v1i0.5358
Singh, R., & Lillard, J. W. (2009). Nanoparticle-based targeted drug delivery. Experimental and Molecular Pathology, 86(3), 215–223. https://doi.
org/10.1016/J.YEXMP.2008.12.004
Spera, R., Apollonio, F., Liberti, M., Paffi, A., Merla, C., Pinto, R., & Petralito, S. (2015). Controllable release from high-transition temperature
magnetoliposomes by low-level magnetic stimulation. Colloids and Surfaces B, 131, 136–140. https://doi.org/10.1016/J.COLSURFB.2015.
04.030
Srinivasarao, M., Galliford, C. V., & Low, P. S. (2015). Principles in the design of ligand-targeted cancer therapeutics and imaging agents. Nature
Reviews Drug Discovery, 14(3), 203–219. https://doi.org/10.1038/nrd4519
Sriraman, S. K., Aryasomayajula, B., & Torchilin, V. P. (2014). Barriers to drug delivery in solid tumors. Tissue Barriers, 2, e29528. https://doi.org/
10.4161/tisb.29528
Sugahara, K. N., Teesalu, T., Karmali, P. P., Kotamraju, V. R., Agemy, L., Girard, O. M., … Ruoslahti, E. (2009). Tissue-penetrating delivery of
compounds and nanoparticles into tumors. Cancer Cell, 16(6), 510–520. https://doi.org/10.1016/J.CCR.2009.10.013
Sun, C., Lee, J. S. H., & Zhang, M. (2008). Magnetic nanoparticles in MR imaging and drug delivery. Advanced Drug Delivery Reviews, 60(11),
1252–1265. https://doi.org/10.1016/j.addr.2008.03.018
Sun, S., Zeng, H., Robinson, D. B., Raoux, S., Rice, P. M., Wang, S. X., & Li, G. (2004). Monodisperse MFe2O4 (M = Fe, Co, Mn) nanoparticles.
Journal of the American Chemical Society, 126(1), 273–279. https://doi.org/10.1021/ja0380852
Sutens, B., Swusten, T., Zhong, K., Jochum, J. K., Van Bael, M. J., Van der Eycken, E. V., … Verbiest, T. (2016). Tunability of size and magnetic
moment of iron oxide nanoparticles synthesized by forced hydrolysis. Materials (Basel, Switzerland), 9(7), E554. https://doi.org/10.3390/
ma9070554
Tay, Z. W., Chandrasekharan, P., Chiu-Lam, A., Hensley, D. W., Dhavalikar, R., Zhou, X. Y., … Conolly, S. M. (2018). Magnetic particle
imaging-guided heating in vivo using gradient fields for arbitrary localization of magnetic hyperthermia therapy. ACS Nano, 12(4), 3699–3713.
https://doi.org/10.1021/acsnano.8b00893
Thambi, T., Park, J. H., & Lee, D. S. (2016). Hypoxia-responsive nanocarriers for cancer imaging and therapy: Recent approaches and future per-
spectives. Chemical Communications, 52(55), 8492–8500. https://doi.org/10.1039/C6CC02972H
Tipler, P. (1999). Physics for scientists and engineers (4th ed.). New York, NY: W. H. Freeman.
Tredan, O., Galmarini, C. M., Patel, K., & Tannock, I. F. (2007). Drug resistance and the solid tumor microenvironment. Journal of the National
Cancer Institute, 99(19), 1441–1454. https://doi.org/10.1093/jnci/djm135
Ulbrich, K., Holá, K., Šubr, V., Bakandritsos, A., Tucek, J., & Zbořil, R. (2016). Targeted drug delivery with polymers and magnetic nanoparticles:
Covalent and noncovalent approaches, release control, and clinical studies. Chemical Reviews, 116(9), 5338–5431. https://doi.org/10.1021/acs.
chemrev.5b00589
Unni, M., Uhl, A. M., Savliwala, S., Savitzky, B. H., Dhavalikar, R., Garraud, N., … Rinaldi, C. (2017). Thermal decomposition synthesis of iron
oxide nanoparticles with diminished magnetic dead layer by controlled addition of oxygen. ACS Nano, 11(2), 2284–2303. https://doi.org/10.
1021/acsnano.7b00609
Vandooren, J., Opdenakker, G., Loadman, P. M., & Edwards, D. R. (2016). Proteases in cancer drug delivery. Advanced Drug Delivery Reviews,
97, 144–155. https://doi.org/10.1016/J.ADDR.2015.12.020
Vaupel, P., Kallinowski, F., & Okunieff, P. (1989). Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: A
review. Cancer Research, 49(23), 6449–6465.
Voronin, D. V., Sindeeva, O. A., Kurochkin, M. A., Mayorova, O., Fedosov, I. V., Semyachkina-Glushkovskaya, O., … Sukhorukov, G. B. (2017).
In vitro and in vivo visualization and trapping of fluorescent magnetic microcapsules in a bloodstream. ACS Applied Materials & Interfaces, 9
(8), 6885–6893. https://doi.org/10.1021/acsami.6b15811
Vu-Quang, H., Muthiah, M., Lee, H. J., Kim, Y.-K., Rhee, J. H., Lee, J.-H., … Park, I.-K. (2012). Immune cell-specific delivery of beta-glucan-
coated iron oxide nanoparticles for diagnosing liver metastasis by MR imaging. Carbohydrate Polymers, 87(2), 1159–1168. https://doi.org/10.
1016/J.CARBPOL.2011.08.091
Weissleder, R., Stark, D. D., Engelstad, B. L., Bacon, B. R., Compton, C. C., White, D. L., … Lewis, J. (1989). Superparamagnetic iron oxide: Phar-
macokinetics and toxicity. American Journal of Roentgenology, 152(1), 167–173. https://doi.org/10.2214/ajr.152.1.167
18 of 18 LIU ET AL.
White, E. E., Pai, A., Weng, Y., Suresh, A. K., Van Haute, D., Pailevanian, T., … Berlin, J. M. (2015). Functionalized iron oxide nanoparticles for
controlling the movement of immune cells. Nanoscale, 7(17), 7780–7789. https://doi.org/10.1039/C3NR04421A
Wilhelm, S., Tavares, A. J., Dai, Q., Ohta, S., Audet, J., Dvorak, H. F., & Chan, W. C. W. (2016). Analysis of nanoparticle delivery to tumours.
Nature Reviews Materials, 1(5), 16014. https://doi.org/10.1038/natrevmats.2016.14
Wong, C., Stylianopoulos, T., Cui, J., Martin, J., Chauhan, V. P., Jiang, W., … Fukumura, D. (2011). Multistage nanoparticle delivery system for
deep penetration into tumor tissue. Proceedings of the National Academy of Sciences of the United States of America, 108(6), 2426–2431.
https://doi.org/10.1073/pnas.1018382108
Wu, H.-Q., & Wang, C.-C. (2016). Biodegradable smart nanogels: A new platform for targeting drug delivery and biomedical diagnostics. Lang-
muir, 32(25), 6211–6225. https://doi.org/10.1021/acs.langmuir.6b00842
Xu, X., Zhu, S., Cui, X., Wojtas, L., & Zhang, X. P. (2013). Cobalt(II)-catalyzed asymmetric olefin cyclopropanation with α-ketodiazoacetates.
Angewandte Chemie, 52(45), 11857–11861. https://doi.org/10.1002/anie.201305883
Yadavalli, T., Ramasamy, S., Chandrasekaran, G., Michael, I., Therese, H. A., & Chennakesavulu, R. (2015). Dual responsive PNIPAM–chitosan
targeted magnetic nanopolymers for targeted drug delivery. Journal of Magnetism and Magnetic Materials, 380, 315–320. https://doi.org/10.
1016/J.JMMM.2014.09.035
Yang, R., An, L. Y., Miao, Q. F., Li, F. M., Han, Y., Wang, H. X., … Tang, S. Q. (2016). Effective elimination of liver cancer stem-like cells by
CD90 antibody targeted thermosensitive magnetoliposomes. Oncotarget, 7(24), 35894–35916. https://doi.org/10.18632/oncotarget.9116
Yoo, D., Jeong, H., Noh, S.-H., Lee, J.-H., & Cheon, J. (2013). Magnetically triggered dual functional nanoparticles for resistance-free apoptotic
hyperthermia. Angewandte Chemie, 52(49), 13047–13051. https://doi.org/10.1002/anie.201306557
Zanganeh, S., Hutter, G., Spitler, R., Lenkov, O., Mahmoudi, M., Shaw, A., … Daldrup-Link, H. E. (2016). Iron oxide nanoparticles inhibit tumour
growth by inducing pro-inflammatory macrophage polarization in tumour tissues. Nature Nanotechnology, 11(11), 986–994. https://doi.org/10.
1038/nnano.2016.168
How to cite this article: Liu JF, Jang B, Issadore D, Tsourkas A. Use of magnetic fields and nanoparticles to trigger
drug release and improve tumor targeting. WIREs Nanomed Nanobiotechnol. 2019;11:e1571. https://doi.org/10.1002/
wnan.1571

Magnet 10

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Magnet 10

Uploaded by

Copyright:

Available Formats

19390041, 2019, 6, Downloaded from https://wires.onlinelibrary.wiley.com/doi/10.1002/wnan.1571 by University Of Oslo Central 340, Wiley Online Library on [01/11/2022].

Use of magnetic fields and nanoparticles to trigger drug release

Jessica F. Liu | Bian Jang | David Issadore | Andrew Tsourkas

Department of Bioengineering, University of

This article is categorized under:

WIREs Nanomed Nanobiotechnol. 2019;11:e1571. wires.wiley.com/nanomed © 2019 Wiley Periodicals, Inc. 1 of 18

FIGURE 1 Magnetic fields and

FIGURE 2 Controlled addition

3 | USING M AGNETIC FIELDS T O IMPROVE ACCUMULATION OF

3.1 | Nanoparticle accumulation and penetration within tumors

3.2 | Magnetic drug targeting

FIGURE 3 Magnetic drug targeting of magnetic

FIGURE 4 Novel magnetic

4.1 | Thermally responsive magnetic nanoparticles

4.1.2 | Magnetic nanoparticles containing thermally responsive materials

4.1.3 | Focusing of the alternating magnetic field

BOX 1 VISION AND CHALLENGES OF THERMALLY SENSITIVE NANOCARRIERS

6.1 | Challenges in nanoparticle synthesis

BOX 2 A SCALE-UP CHALLENGE

6.2 | Maximum amplitude of an alternating magnetic field

6.3 | Developments in thermally responsive nanocarriers

6.4 | System scale-up

Jessica F. Liu https://orcid.org/0000-0002-2663-8438

You might also like