DRUG DEVELOPMENT RESEARCH 67:55–60 (2006)

DDR
Research Overview
Magnetic Nanoparticles for Drug Delivery
Jon Dobson
Institute for Science & Technology in Medicine, Keele University, Stoke-on-Trent,
United Kingdom

Strategy, Management and Health Policy

Enabling Preclinical Development Clinical Development

Technology, Preclinical Toxicology, Formulation Phases I-III Postmarketing
Genomics, Research Drug Delivery, Regulatory, Quality, Phase IV
Proteomics Pharmacokinetics Manufacturing

ABSTRACT Targeting specific sites in vivo for the delivery of therapeutic compounds presents a major
obstacle to the treatment of many diseases. One targeted delivery technique that has gained prominence in
recent years is the use of magnetic nanoparticles. In these systems, therapeutic compounds are attached to
biocompatible magnetic nanoparticles and magnetic fields generated outside the body are focused on
specific targets in vivo. The fields capture the particle complex resulting in enhanced delivery to the target
site. This review will focus on technical aspects of magnetic targeting as well as nanoparticle design and
animal and clinical trials. Drug Dev. Res. 67:55–60, 2006.
c 2006 Wiley-Liss, Inc.

Key words: magnetic nanoparticles; drug targeting; drug delivery; cancer therapy

INTRODUCTION cells. The rationale for magnetic micro- and nanopar-

Within the last two decades, the use of magnetic
micro- and nanoparticles in biomedical applications has
become relatively commonplace. Primarily, these
particles are used as contrast agents in magnetic
resonance imaging (MRI) and for magnetic cell sorting
and immunoassay in pathology laboratories. However,
experimental work is also underway that is aimed at the
development of magnetic particle/fluid hyperthermia
treatment for cancerous tumors and the controlled and
directed transport of pharmaceuticals and therapeutic
genes [Pankhurst et al., 2003]. Up to now, these latter
two uses have met with more limited success. However,
their potential is still very exciting, particularly with
regard to the treatment of cancer through tumor
targeting.
The major disadvantage of most chemotherapeu-
tic approaches to cancer treatment is that most are
non-specific. Therapeutic (generally cytotoxic) drugs
are administered intravenously leading to general
systemic distribution. The non-specific nature of this
technique results in the well-known side-effects of
chemotherapy as the cytotoxic drug attacks normal,
healthy cells in addition to its primary target, tumor
ticle-based targeting lies in the potential to reduce or
eliminate the side effects of chemotherapy drugs by
reducing their systemic distribution as well as the
possibility of administering lower but more accurately
targeted doses of the cytotoxic compounds used in
these treatments.
The idea of using magnetic micro- and nanopar-
ticles to act as therapeutic drug carriers in order to
target specific sites in the body dates to the late 1970s
[Widder et al., 1978; Senyei et al., 1978; Mosbach and
Schröder, 1979]. Widder and others developed mag-
netic micro- and nanoparticles to which cytotoxic drugs
could be attached. The drug/carrier complex is then
injected into the subject either via intravenous or intra-
arterial injection. High-gradient, external magnetic
fields generated by rare earth permanent magnets are
Correspondence to: Jon Dobson, Institute for Science &
Technology in Medicine, Keele University, Thornburrow Drive,
Hartshill, Stoke-on-Trent, ST4 7QB UK.
E-mail: j.p.dobson@bemp.keele.ac.uk
Published online in Wiley InterScience (www.interscience.wiley.
com). DOI: 10.1002/ddr.20067

c

2006 Wiley-Liss, Inc.
56
Fig. 1. Schematic representation of a magnetic nanoparticle-based drug delivery system. Figure redrawn after Pankhurst et al. [2003].
used to guide and concentrate the drugs at tumor
locations (Fig. 1). Once the magnetic carrier is
concentrated at the tumor or other target in vivo, the
therapeutic agent is then released from the magnetic
carrier, either via enzymatic activity or through changes
in physiological conditions such as pH, osmolality, or
temperature, leading to increased uptake of the drug
by the tumor cells at the target sites [e.g., Alexiou et al.,
2000]. Similar principles have recently been applied to
the delivery of therapeutic genes to specific targets in
vivo [e.g., Mah et al., 2002].
In theory, magnetic targeting offers some major
advantages for drug delivery, in particular, the ability
to target a specific site, such as a tumor, in vivo thereby
reducing the systemic distribution of cytotoxic com-
pounds, and enhancing uptake at the target site
resulting in effective treatment at lower doses. In
practice, however, there are difficulties in achieving
these objectives.
Many factors must be considered when designing
a magnetic nanoparticle-based targeting system, in-
cluding both physical parameters, such as magnetic
properties and size of the carrier particles, field
strength, field geometry, and drug/gene binding
capacity, and physiological parameters such as the
depth to target, the rate of blood flow, vascular supply,
and body weight [Neuberger et al., 2005]. In most
cases where magnetic drug targeting has been
attempted, theoretical underpinning of these para-
meters has been lacking and there has been great
difficulty in moving this technology from animal studies
into successful clinical trials. Recent work on the
development of a sound, theoretical basis for this
technique, should lead to advances in experimental
design [Grief and Richardson, 2005].
Drug. Dev. Res. DOI 10.1002/ddr
DOBSON
PHYSICAL PRINCIPLES
Magnetic targeting is based on the attraction of
magnetic nanoparticles to an external magnetic field
source. In the presence of a magnetic field gradient, a
translational force will be exerted on the particle/drug
complex, effectively trapping it in the field at the target
site and pulling it towards the magnet [for a
comprehensive review of the underlying physical
principles, see Pankhurst et al., 2003; Grief and
Richardson, 2005]. This magnetic force is governed
by the equation:
1
Fmag ¼ ðw2  w1 ÞV BðrBÞ:
m0
Where B is the magnetic field strength, rB is field
gradient and can be reduced to qB/qx, qB/qy, qB/qz; w2
is the magnetic susceptibility of the magnetic particle;
w1 is the magnetic susceptibility of the medium (which
is very small in comparison to w2 and therefore can be
disregarded in the case of biological systems).
It is clear from this equation that the important
parameters in regards to effective capture of the
nanoparticles are the magnetic properties and volume
of the particles, the magnetic field strength, and the
magnetic field gradient. It is also clear that as the field
strength decreases, the ability to capture the nanopar-
ticles also decreases. This is one of the main reasons
that scale-up of magnetic targeting from small animals
to humans has been so difficult.
Preliminary theoretical investigations of the
hydrodynamic conditions of magnetic nanoparticle
targeting and estimations from experimental work
indicate that for most magnetic carriers field strength
(flux density) at the target site should be on the order of
 MAGNETIC NANOPARTICLES FOR DRUG DELIVERY
200–700 milliTesla (mT) with gradients along the z-axis
of approximately 8–100 T/m depending on the flow rate
(higher blood flow rates will require either stronger
fields or higher gradients) [Voltairas et al., 2002; Ruuge
and Rusetski, 1993]. These results indicate that
magnetic targeting is likely to be more effective for
targets that are near the surface and in regions of
slower blood flow. However, this model is rather
idealized and limited, and a more recent model has
been developed in which particle capture has been
modelled for a variety of field/particle configurations in
a two-dimensional branching network [Grief and
Richardson, 2005].
This newer model also incorporates the effects of
sheer-induced diffusion due to the presence of cells
within the blood plasma. The results indicate that it will
not be possible to target a specific site in vivo without
some degree of distribution to surrounding tissue. For
this reason, Grief and Richardson [2005] also conclude
that magnetic targeting is likely to be most effective for
targets which are close to the surface of the body.
MAGNETIC NANOPARTICLES/CARRIERS
There are several strategies for synthesis of
magnetic nanoparticles for drug delivery. Particles
may be produced that have a core-shell structure,
where the core is a magnetic iron oxide (usually
magnetite – [Fe3O4] or maghemite [gFe2O3]) and the
shell is generally a polymer such as silica, dextran, or
PVA, or metals such as gold to which functional groups
can be attached via cross-linkers [e.g., Santra et al.,
2001; Pardoe et al., 2001; Carpenter, 2001; Harris et al.,
2003; Wilson et al., 2005]. This type of structure can be
synthesised using both ionic and non-ionic surfactant
techniques or encapsulated within a structure such as a
carbon cage or ferritin protein [for example, see
Meldrum et al., 1992; Sun et al., 2000; Santra et al.,
2001]. These particles can then be functionalized by
attaching carboxyl groups, amines, biotin, streptavidin,
antibodies, and others.
In addition to these polymers, a number of
groups have developed techniques for the synthesis of
magnetoliposomes [Shinkai et al., 1995; Gonzales and
Krishnan, 2005]. These nanoparticles have a typical
core-shell structure with a magnetic iron oxide core
surrounded by an artificial liposome. These are
generally used for magnetic hyperthermia but may
also be useful in drug delivery. Particles may also be
embedded within hydrogels, which can carry a
therapeutic agent that is released upon heating, or
the particles themselves may be used for hyperthermia
applications [Kondo and Fukuda, 1997; Lao and
Ramanujan, 2004; Chen et al., 2005].
57
More recently, gold/cobalt nanoparticles with a
core-shell structure and tailorable morphology have
been synthesized in the size range of 5–25 nm [Bao and
Krishnan, 2005]. These particles have been produced
via the rapid decomposition of organometallic pre-
cursors in the presence of surfactants that control the
size and shape of the particles. One of the major
advantages of these particles is that cobalt has a
magnetic moment nearly twice that of magnetite or
maghemite.
Another strategy for the synthesis of magnetic/
polymer nanoparticles involves the precipitation of
magnetic iron oxide nanoparticles within a porous
polymer micro- or nanoparticle scaffold [Hans and
Lowman, 2002]. One advantage of this technique is
that it is often possible to produce particles with a
relatively tight size distribution as well as a well-
defined, spherical morphology. Again, as with core-
shell structures, the particles can be functionalized so
that drugs or genes may be attached or therapeutic
compounds can be embedded within a degradable
polymer matrix [for a comprehensive review, see
Neuberger et al., 2005].
OBSTACLES TO CLINICAL APPLICATIONS
In order to retain the magnetic nanoparticle/drug
complex at a particular location, the externally applied
field must have a relatively strong gradient, as
discussed previously. In the absence of this gradient,
no translational forces will act on the particles and they
will be affected only by rotational torque if they are
magnetically blocked. Additionally, once the drug is
released from the magnetic complex, it no longer
responds to the applied magnetic field. It is then free to
resume its normal distribution patterns in the body.
Therefore, if the drug or gene is released while the
carrier particles are still within the vasculature, even if
they are held at the target site, there will still be some
degree of systemic distribution.
Another problem with these systems is the
potential for embolization as the particles accumulate
within the bloodstream, blocking blood flow. The
particles also can become concentrated in the liver
where cytotoxicity may be an unwelcome side-effect.
However, both of these problems potentially may be
turned to good advantage as it may be possible to
enhance targeting of tumors in the liver and block the
blood supply to the tumor mass [Lübbe et al., 1999].
Further and more difficult problems with mag-
netic targeting arise due to constraints on the spatial
geometry of the magnetic field with respect to the
target site. The problem of the depth to which
magnetic guidance systems may function has been
demonstrated theoretically by Grief and Richardson
Drug. Dev. Res. DOI 10.1002/ddr
58 DOBSON
[2005] as discussed above, but it is also clearly shown
by the difficulties encountered in scaling-up these
techniques from small animals with near-surface
targets to large animals and humans. As most magnetic
targeting systems rely on external, rare-earth perma-
nent magnets (generally NdFeB magnets with a
maximum surface flux density of a little over one
Tesla), there is a limit to the strength of field and field
gradient that can be achieved at any site within the
tissue. In addition, magnetic carriers will also tend to
accumulate in the intervening tissue between the
magnet and the target where the fields and gradients
are higher. This point was also illustrated in the work of
Grief and Richardson [2005].
Though these difficulties are not easy to over-
come, there has been some limited success with
magnetic micro- and nanoparticle-based targeting
systems in larger animals, and even in early clinical
trials. Further work on overcoming these difficulties
is continuing.
APPLICATIONS
Since the work of Widder and others [1978],
other groups have developed and refined magnetic
micro- and nanoparticle-based drug and gene delivery
systems with varying results. The method has been
successful in several animal studies, including the first
study by Widder and others [1983] in which (doxor-
ubicin) was coupled to magnetic particles and targeted
to sarcoma tumors implanted in rat tails. Total
remission was achieved in the magnetic-targeting
group whereas there was no evidence of remission in
the control group, which was administered 10 times the
dosage but without magnetic targeting.
Tumor remission has been achieved in a variety of
other animal studies including not only small animals
such as rabbits and rats [e.g., Alexiou et al., 2000;
Lübbe et al., 1999; Pulfer et al., 1999], but also larger
swine [Goodwin et al., 1999, 2001], and targeting depth
had been extended in one study to approximately 10 cm
[Scott et al., 1999]. Recently, Alexiou and others [2005]
have had success in quantifying the distribution of
magnetically targeted carriers in a rabbit model using
HPLC analysis of mitoxantrone bound to ferrofluids
and have demonstrated, via light microscopy, uptake of
magnetically targeted carriers in HeLa cells in vitro.
In an effort to overcome problems with the
spatial configuration of these delivery systems, Kubo
and others [2000] implanted permanent magnets at
solid osteosarcoma sites in hamsters followed by
delivery of cytotoxic compounds via magnetoliposomes.
This resulted in a fourfold increase in drug delivery to
the tumor site in comparison with normal intravenous
(non-magnetic) delivery. In addition, the group re-
Drug. Dev. Res. DOI 10.1002/ddr
ported a significant increase in anti-tumor activity and a
reduction of weight-loss side effects. Theoretical and
experimental analysis of implanted magnetic grids for
targeting to the heart muscle point to another potential
solution to the geometry problem [Yellen et al., 2005].
To date, application of magnetic targeting in
humans has not reached the marketplace although
there have been two Phase I/II clinical trials. A Phase I
clinical trial was conducted by Lübbe and others on
14 patients [Lübbe et al., 1999]. This was primarily
aimed at evaluating the potential toxicity of the particle
carrier complex and, though targeting was not examined
in detail, particle accumulation was observed in the
tumor masses of six of the patients. Though the particles
accumulated in the liver, the study demonstrated that
magnetic carriers are generally well tolerated.
A more recent Phase I/II trial was conducted on
four patients using technology developed by FeRx
Corporation. This study was aimed at evaluating the
potential for magnetic nanoparticle-based targeting of
hepatocellular carcinomas [Wilson et al., 2004]. The
magnetic carrier was bound to doxorubicin and
targeted to the liver via transcatheter delivery through
the hepatic artery under concurrent MR imaging. The
study demonstrated that the final fraction of treated
tumor volume ranged from 0.64 to 0.91 while the
fraction of affected normal liver volume ranged from
0.07 to 0.30. This result provides an indication that the
combination of MR imaging and angiography could be
used in some cases to optimize magnetic targeting.
The principles described thus far can be applied
not only to drug targeting but also to magnetic
nanoparticle-based hyperthermia and gene delivery.
Magnetic hyperthermia involves the delivery of mag-
netic nanoparticles to target sites following the
techniques outlined above. Once the particles have
been take up by a tumor, for instance, an alternating
field is applied that couples to the particles, resulting in
efficient heating. If the tumor cell is heated to
40–421C for 30 min., apoptosis may be induced,
effectively killing the tumor. Again, this technique has
been demonstrated effectively in animal models but
translation to the clinic has been slow [for review see
Pankhurst et al., 2003].
Magnetic targeting for gene delivery has been
demonstrated in vitro and, in conjunction with
associated viral vectors, in vivo in animal models
[Mah et al., 2002; Schillinger et al., 2005].
CONCLUSIONS
Though many obstacles remain to be overcome
before magnetic nanoparticle-based drug and gene
delivery can achieve clinical success and reach the
 MAGNETIC NANOPARTICLES FOR DRUG DELIVERY
marketplace, recent advances are promising. New
materials are being used to design nanoparticles with
higher magnetic moments that will be easier to
capture. There are continuing advances in permanent
magnet technology and novel, implantable materials
capable of generating high magnetic fields and high
gradients look set to greatly enhance the ability to
target sites deeper in the tissue. Patients with tumor
sites near the body’s surface and in the liver are likely to
be the first to benefit from this technique. But the
potential for clinical application of magnetic targeting
to a range of tumors and other diseases makes this an
extremely fertile field of applied research.
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Drug. Dev. Res. DOI 10.1002/ddr