Development and use of iron oxide nanoparticles (Part 2): The application of iron oxide contrast agents in MRI
1 Division of Medical Radiations, School of Medical Sciences, RMIT University, Victoria, Australia
2 Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia
Magnetic resonance imaging (MRI) is a medical imaging tool
that can incorporate contrast agents to enhance its ability to identify and
characterise pathologies. MRI contrast agents can be paramagnetic such as
gadolinium, or superparamagnetic such as iron oxide. Significant concerns of
Nephrogenic Systemic Fibrosis (NSF) have arisen involving gadolinium-based
Recent research has focused on iron oxide nanoparticles
because their sizes are more comparable to biological units. These can give MRI
the potential to detect a broader range of pathology, while also track and
observe biological processes.
This is the second article of a two-part series and will
review iron oxide nanoparticles as a MRI contrast agent, and the potential
applications of iron oxide nanoparticles to a range of pathologies and
processes involving MRI. � 2010 Biomedical Imaging and Intervention
Journal. All rights reserved.
Keywords: Iron oxide nanoparticles, MRI
Since its clinical introduction, Magnetic Resonance
Imaging (MRI) has been viewed as a highly advanced imaging modality. In
particular, over the past decade, MRI has demonstrated its capability to
generate images of anatomy and pathology with excellent contrast and spatial
resolution. Also noteworthy has been MRI�s capability of imaging physiological
processes with functional MRI (fMRI), Diffusion Weighted Imaging (DWI) and
Perfusion Weighted Imaging (PWI). This of course has coincided with improved
hardware and software developments. Overall, this has resulted in the medical
community having a greater understanding and awareness of biological processes.
Therefore, the clinical role and utility of MRI has evolved and is continually
Broadly defined, a contrast agent or medium is any
substance that can be used together with an imaging technique to provide
additional and useful information. Contrast media can be either exogenous or
endogenous. Endogenous material which can be used include water molecules
inherent within the blood stream when performing Arterial Spin Labelling (ASL)
or Tagging (AST). Exogenous substances include the already well-known paramagnetic
gadolinium-based agents and now emerging from literature, we are noting an
increasing experimental usage of superparamagnetic iron oxide nanoparticles.
This is the second publication in a two-part series
reviewing the potential use of iron oxide nanoparticles. Specifically, we will
discuss the characteristics essential in iron oxide nanoparticles for MR
imaging (as a contrast agent) as well as their potential clinical applications
for a range of pathologies and physiological processes.
Contrast media in radiology and the current intravascular MRI contrast
Intravascular contrast agents have been continually used
since the early 1900�s across all imaging modalities in the field of radiology
. Over the past century, there has been a continual evolution of contrast
media in medical imaging. These changes have been based on safety concerns
(adverse reactions by patients), improved chemical technology (oil-based,
water-soluble, ionic, non-ionic) and designing contrast agents dedicated to a
particular imaging modality or technique [1, 2]. Additional concerns
surrounding their implementation and use include the cost of contrast media,
the need for certain contrast media preparations to be warmed to body
temperature (viscosity, minimise adverse reactions) and also the need to have a
recent reading of a patient's renal function (prior to administration of
contrast media). There are also concerns surrounding compatibility, whereby a
patient having an intravenous contrast media administered for a computed tomography
(CT) study will be unable to have a nuclear medicine thyroid examination for
several months; furthermore, this same contrast media is incompatible with
metformin-based diabetic medication.
When MRI first became a clinical reality, it was thought
that no contrast media would ever be needed because of MRI�s superior contrast
and spatial (isotropic voxels) resolution compared with other modalities .
It was soon realised that a contrast media was needed to improve the
specificity of MRI . In 1988 the first MRI-specific contrast media
preparation was approved by the Food and Drug Administration (FDA) for
intravascular administration in clinical use [3, 5]. This was needed to define
a pattern of contrast enhancement so that a characteristic enhancement pattern
of a particular disease process could be recognised and also to narrow the
differential diagnosis. This contrast media preparation contained gadolinium as
its base. However, there have always been some concerns in relation to this
preparation. These include its expense (cost per millilitre and patents are
strongly held and continually renewed) and its degradation with exposure to
The way that such gadolinium-based contrast media is
chemically altered and eliminated by the body is not entirely understood .
For some time now, a condition known as �cross reactivity� has existed. It
cannot be entirely explained, however, it is thought to result either from the
chelated molecules or elements, or the chelated structure themselves .
Within the last several years, a more serious condition
has been attributed to gadolinium-based preparations. This condition is
referred to as nephrogenic systemic fibrosis (NSF) and can lead to eventual
death. This condition is almost always seen in patients with reduced renal
function (less than normal glomeruli filtration rate, GFR) and there have been
a number of deaths recorded and attributed to NSF. In early 2008, the Royal
Australian and New Zealand College of Radiologists (RANZCR) has recommended that
all clinical centres offering gadolinium-based contrast media for MRI scanning
examinations to establish a new policy concerning intravascular administration
and, in particular, with respect to NSF and patients with impaired renal
function . Due to the above trends, anecdotal reports suggest more caution
and less reliance upon gadolinium-based contrast media even though no
alternative currently exists in Australia.
The current commercially available contrast media is gadolinium-based
and also referred to as para-magnetic and only benefits T1-weighted MR imaging.
No mainstream commercially available contrast media for T2-weighted imaging is
currently available in Australia. There are benefits attributed to contrast
media if it can be prepared for T2-weighted MR imaging . Coincidently, an
increasing trend is underway towards clinical MRI scanners with higher field
strengths such as 3 Tesla (6). The main drivers are improved capital and
running costs and increased signal-to-noise (SNR) ratio. However, at higher
field strengths such as 3 Tesla, T1 and T2 relaxation times of human tissue are
altered compared to 1.5 Tesla. Gadolinium-based contrast media �works� by
shortening T1 tissue relaxivity values and therefore only T1 optimised
sequences can be used (T2 relaxivity values are not altered significantly for
MR imaging practicality).
It is proposed that contrast media preparations based on
nanoparticles can overcome all of the abovementioned challenges related to MRI
scanning while simultaneously addressing the current medical safety concerns
[6, 9]. More specifically, iron oxide-based nanoparticles have the following
- it can offer T2-weighted imaging opportunities
- it has a well-recognised and understood pathway for breakdown and excretion
from the human body
Degradation causes iron to enter plasma, where it is processed by the
Risk of iron overload is minimal
Average dose of iron in contrast agent is comparable to iron contained
in less than one unit of blood
- It provides �negative� enhancement
Depending on the physio-chemical property of the coating
(surrounding the iron oxide nanoparticle), both generalised and specific
contrast media can be created [9, 10]. The term �specific� means that contrast
media preparations can be targeted to a particular organ within the body or a
particular disease process. If this can be achieved, then it follows that not
only can diagnostic imaging be successful, but also therapeutic
drugs/medication can be tagged to the preparation so that it can reach and work
on the target tissue.
At one point, it was estimated that 30% to 40% of MR
examinations were performed with intravascular contrast media . With the
awareness of NSF, no hard data currently exists to determine if the use of
intravascular contrast media has decreased or remains at the same level.
The most commonly available intravenous contrast media
contains gadolinium. A gadolinium ion has seven unpaired electrons in its outer
shell  and is considered a paramagnetic substance because it has an overall
positive effect on the local magnetic field . In brief, when placed within a
magnetic field, the negatively charged gadolinium ion demonstrates
characteristics such as a magnetic moment, producing a large time-varying
magnetic field in its vicinity, allowing rapid exchange of bulk water, altering
the relaxation rates (both T1 and T2, or longitudinal and horizontal) of
adjacent water protons [7, 11, 12]. Gadolinium is referred to as a T1
enhancement contrast agent as it affects T1 to a greater extent than it does
T2. The act of molecular tumbling and local magnetic field alterations occur
near the Larmor frequency value. This leads to a reduction of the T1 relaxation
value of adjacent water protons, which in turn, leads to an increased signal
strength on T1 weighted images . This is due to an increased rate of
longitudinal magnetisation recovery . For acceptable biocompatibility,
gadolinium is chelated to other molecules. This reduces any acute toxicity
effects, and also allows the gadolinium-based agent to remain circulating
within the body for a relatively longer period (than without chelation) 
with an elimination half life of 1 hour to 2 hours.
Currently available paramagnetic contrast agents are
commonly administered intravenously. Its biodistribution is into the blood
stream and then into the extra cellular space. It is therefore not taken up by
any specific body organ, tissue type or pathologic lesion. Hence, gadolinium
compounds are also regarded as non-specific contrast agents . However,
enhancement patterns are known to be characteristic of certain pathology
groups. For example, a hyperintense circular rim with a hypointense centre may
be representative of a cystic lesion.
Current concerns with nephrogenic systemic fibrosis and gadolinium
Up until about ten years ago, gadolinium-based contrast
agents have been regarded as having a relatively excellent safety record .
NSF was originally referred to as nephrogenic fibrosing dermopathy by Cowper et
al. in 2000 . It was described as being scleromyxoedema-like cutaneous
disorder and thought to only affect the skin or dermis. It was noted in
patients undergoing renal dialysis [14, 15]. As additional cases became
recorded and further understanding of the pathology grew, the currently used
term of NSF has become accepted. This is due to the now recognised systemic
nature of the pathology [16, 17]. Commonly, NSF commences with swelling at the
distal aspects of the extremeties. This may then resolve, however, leaving behind
thick, firm plaques over the affected skin.
In the majority of patients, initial skin lesions appear
on the legs, then the arms and lastly on the trunk of the body. It has also
been reported that the skin lesions are often symmetrical and bilateral. It may
then progress to a point where the patient has significantly reduced range of
motion of their extremities and joints . In addition to the flexion and
joint contractures accompanying extremity skin lesions [19, 20], fibrotic
effects may also be widespread and penetrating; involving organs including the
liver, lungs and heart, among others [20, 21].
Today, the only successful approach in treating NSF is to
restore the normal renal function. This can only be achieved by renal
transplant surgery [18, 20]. NSF is almost always seen in patients with less
than normal renal function or patients requiring ongoing renal dialysis.
Therefore, NSF may be a resulting consequence in patients with renal impairment
because the contrast media excretion half life is markedly increased . This
situation then permits disassociated or de-chelated gadolinium ions an
increased circulation time. Some authors consider NSF to be an, �adverse
reaction to gadolinium contrast agents in particular the less stable
Even though all gadolinium-based preparations carry a
level of risk, there is published evidence to suggest that some
gadolimium-based contrast agents offer a greater risk than others in inducing
NSF . This variation in risk is linked to the overall molecular structure
of the gadolinium-based contrast agent and in particular, its level of chemical
stability within the human body . Gadodiamide has been associated with the
greatest incidence of induced NSF [23, 24]. On its own, gadolinium is highly
toxic. Not only can it cause injury to the liver and spleen, but it can also
inhibit secretions of certain enzymes and it can induce haematological ailments
[24-26]. To minimise such toxic consequences, the gadolinium ion is chelated to
other chemical elements and compounds . This improves its biocompatibility.
The molecule or atom that is bonded to the gadolinium can be referred to as a
ligand. The gadolinium ion is chelated in either a linear or macrocyclic
fashion and prepared as either ionic or non-ionic formulations [7, 24].
Published data reflect that the least stable preparations are non-ionic linear
chelate formulations such as gadodiamide (Omniscan, GE healthcare, Chalfort, ST
Giles, UK) and Gadoversetamide (OptiMark, Covidien, St Louis, USA). Gadodiamide has been reported to have a kinetic stability of 35 seconds. That is, at a pH of
1.0, half of the preparation will shed the linearly chelated material; thus
leaving free gadolinium ions to search for other metals (body cations) to bind
to within the body. These would include iron, copper, zinc and calcium. This
process is referred to as transmetallation. Of the above body cations, zinc has
the highest relative concentration (55-125 micromole per litre) within the
blood stream .
The most stable gadolinium-based preparation is the ionic,
macrocyclic chelate formulation; namely, gadoterate. As of April 2009, no cases
of NSF linked to any macrocyclic formulation has been reported  or
confirmed by the International Centre For Nephrogenic Fibrosing Dermopathy
This is because a macrocyclic structure provides
relatively superior protection of the gadolinium ion. That is, the gadolinium
ion is caged by the chelating agent [7, 24, 28, 29]. Conversely, a linear
chelate is referred to as being a flexible open chain and thus not providing a
strong bond to the gadolinium ion. Gadoterate is documented to have kinetic
stability of greater than one month .
High et al.  obtained paraffin embedded tissue
samples from the NSF registry (the International Centre for Nephrogenic
Fibrosing Dermopathy Research). These tissue samples had histopathologic
diagnosis of NSF. This research group demonstrated with energy dispersive
spectroscopy (EDS), a device used to characterise chemical elements, that in
four of seven patients, gadolinium was able to be identified and all detectable
gadolinium particles were less than 1 micrometre in size. Further analysis
with field emission scanning electron microscope (FESEM) demonstrated that in
all of the positive tissue samples, gadolinium particles were present within
the intracellular space and most probably located within, or adjacent to, the
lysosome structures. Also noteworthy was an excessive amount of iron deposition
within the tissue samples.
While the exact cause of NSF has not been conclusively
established [20, 21, 29-33] and precise pathologic pathways are yet to be
determined , there is however, convincing evidence that gadolinium may be
responsible somehow [32, 34]. The most probable theory is that de-chelation
occurs , resulting in the release of free gadolinium ions, which in turn
may or may not lead to transmetallation [36, 37].
Iron oxide nanoparticles as MRI contrast agents
The most common form of iron oxides used in nanoparticle
preparations are magnetite (Fe3O4) and maghemite
(γFe2O3) [38, 39], and research with these has been
intensive for about a decade now. They are both insoluble in water and because
of their size, these superparamagnetic substances only exhibit their magnetic
properties when placed within a magnetic field [12, 40]. The hydrodynamic size
of a nanoparticle preparation is the term used to describe its overall size,
that is, the iron oxide core plus the coating plus any additional ligand
attachments (see Figure 1). If the overall hydrodynamic size is greater than
50nm, then the preparation is referred to as a superparamagnetic iron oxide
nanoparticle (SPION). If the hydrodynamic size is less than this, then the
preparation is termed ultra small superparamagnetic iron oxide (USPION). For
the purpose of this manuscript, the authors will use the term iron oxide
nanoparticle (IONP) as a generic term to refer to nanosystems containing a core
of iron oxide.
Iron oxide nanoparticle preparations are highly complex.
There are numerous production methods which can be used to generate them. Each
method can result in iron oxide nanoparticles having specific dimensions, as
well as unique imaging and therapeutic characteristics. Each manufacturing
method is undertaken in a strict controlled environment to ensure consistency
of dimensions, characteristics and biostability.
The physiochemical properties of iron oxide nanoparticles
are determined by the size of the iron oxide core, its overall charge and the
zeta charges between coatings and the overall hydrodynamic size. With respect
to magnetic resonance imaging, the above factors also play a fundamental role
in determining their efficacy (or imaging efficacy), stability within the
body�s environment, biodistribution, opsonisation, metabolism, clearance from
vascular system and then excretion from the body .
Part one of this journal article series discussed the
variety of production methods. The advantages and disadvantages of this method
were also presented and therefore that information will not be presented here.
An understanding of the bonding and the geometry of the
coating will help us appreciate the pharmokinetic pathways and biodistribution
of contrast agents composed with iron oxide nanoparticles [40, 42-44]. From a
chemical perspective, the iron oxide core is coated for four main reasons. Firstly,
to prevent destabilisation; secondly, to prevent agglomeration (aggregation or
sedimentation) as it will be a colloidal suspension; thirdly, it allows for the
iron oxide nanoparticle formulation to be soluble in an aqueous solution or a
biological medium; fourthly, it determines either the role it performs within
the body (diagnostic magnetic resonance imaging, cell tracking or therapeutic
purposes such as tailored drug delivery) or the ligand that can be bonded to it
to support the imaging, tracking or therapeutic roles.
The coating used can also facilitate the method of
endocytosis . For example, it has been shown that IONP coated with monomer
citrate (overall hydrodynamic size of 8nm) demonstrated cell entry via
phagocytosis. When the same iron oxide nanoparticles were coated with polymer
carboxydextran (overall hydrodynabic size of 31nm), cell entry or penetration
was demonstrated by pinocytosis. In both examples, the same cell line was used.
In the literature, high density coatings have been
reported to be effective in stabilising iron oxide nanoparticles [40, 46-48].
Such high density coatings are commonly polymeric and monomeric materials or
species. Polymeric coatings include dextran, carboxymethylated dextran, carboxy
dextran and starch. Whereas monomeric coatings include dimercaptosuccinic acid
(DMSA), amino acids and α‑hydroxamates (such as citric, tartaric or
The Hydrodynamic Size
There is evidence to suggest that USPION is less prone to
phagocytosis by the liver; whereas SPION greater than 50nm are rapidly
phagocytosed . Therefore, hydrodynamic size can affect biodistribution and
blood half life in a time dependent manner . Eventually, USPIO will
actually be processed by the liver.
Iron oxide nanoparticles greater than 50nm are readily
macrophaged by the reticuloendothelial system (RES). This namely refers to the
Kuppfer cells of the liver, the spleen and bone marrow . Iron oxide
nanoparticles less than 50nm have been used to demonstrate uptake by lymph
nodes [40, 41, 50-53]. Of the available iron oxide-based contrast agents which
are currently on the market and also undergoing clinical trials, the blood half
life values can vary considerably from 40 mins to up to 36 hours. There is a
link between the hydrodynamic size and the biodistribution and blood half life.
As has been established, particles greater than 50nm are
readily taken up by the liver in a matter of minutes. USPION are not readily
phagocytosed by the liver and can have a longer blood half life and thus reach
other structures within the body . It must also be emphasised that the
coating itself can be responsible for aspects of biodistribution as well as
ligands; for example the targeting of specific cells or organs [40, 41, 51].
Metabolism and excretion
The manner in which the body metabolises iron oxide
nanoparticles is determined by their overall chemical composition. In
particular the immediate coating and any ligands are strong determinants as to
the site (that is, which particular organ or body system) of metabolism and
thus also the rate of metabolism and excretory pathways.
The commonly used dextran coating should ideally be of low
molecular weight. This is vital as higher molecular weight dextrans, such as
those used as plasma substitutes, have a reported association with adverse
reactions. Immunoglobulin G (IgG) antibodies have been reported to be reactive
to such high molecular weight dextrans . Low molecular weight dextrans will
initially undergo dextranases which is an intracellular level breakdown
process. The majority of the breakdown components are excreted with urine over
a period of nearly 2 months . Once the low molecular dextran has
metabolised in this manner, the iron oxide core has been found to enter the
normal iron store of the body. Such iron elements can also be found as
haemoglobin with the body�s red blood cells . This iron then follows the
same excretory pathway as endogenous iron. That is, approximately one-fifth is
eliminated mostly with the faeces and over a three-month period. Therefore, as
both dextran and iron from iron oxide nanoparticles are incorporated into the
body�s normal metabolic pathways, without raising these levels noticeably, and
with the evidence available today, it can thus be stated that these substances
do not trigger any long-term toxicity.
In the average healthy adult, normal total human iron
stores is about 3500mg with the liver containing an average of 0.2mg of iron
per gram . From the currently approved iron oxide nanoparticles for
diagnostic MR imaging, a regular adult dose can contain 50-200mg of iron. This
value can be considered relatively small compared to the human body�s iron
store. Chronic iron toxicity is known to occur when the concentration of iron
within the liver reaches a level of 4mg of iron per gram of liver .
MRI imaging with iron oxide nanoparticles
Phenomenon of superparamagnetism
Iron oxide nanoparticles, as discussed here, are referred
to as being superparamagnetic. The superparamagnetic phenomenon is observed
when the thermal energy of the medium is sufficient to alter the crystallite or
nanoparticles�s magnetisation direction by overcoming coupling forces. When
crystallite or nanoparticles are placed within an external magnetic field, its
magnetic moment will align with the externally applied magnetic field.
At least two points distinguish superparamagnetism from
paramagnetism. Firstly, with paramagnetism, it is each individual atom or ion
that becomes aligned with an externally applied magnetic field. Secondly,
superparamagnetism will occur when the crystal or hydrodynamic size is less
than its ferromagnetic domain. Authors report this size to be less than 30nm
, with the �critical size� being about 15nm [44, 56, 57].
When not in the presence of an externally applied magnetic
field, superparamagnetic particles are not magnetised, nor do they demonstrate
any remnents of magnetism once removed from the magnetic field. When the
crystals or particles are under the influence of an applied magnetic field,
their magnetic spins are considered to be in perfect alignment and very high
local magnetic field gradients are generated. These gradients then cause spin
dephasing of the surrounding water protons; thus reducing their T1 and T2
relaxivity [12, 56, 58].
It must also be noted that there is a relationship between
the iron oxide nanoparticle size and the level of superparamagnetic saturation.
As the particle size decreases, so too does the superparamagnetic saturation.
This then has an effect on reducing the observed relaxivity or further reducing
T1 and T2 relaxation.
IONP Influence on magnetic resonance image characteristics
Compared to a paramagnetic material such as gadolinium,
the relatively high magnetic moment of superparamagnetic species, such as iron
oxides, are sometimes referred to as super spins [40, 59]. The dipolar
interactions between the super spins and adjacent water protons result in both
high longitudinal (r1) and transverse (r2) relaxation values. IONPs therefore
increase T2* relaxation rates through the susceptibility effect and thus have
their greatest visual impact on T2*‑weighted images produced with
gradient echo-based pulsed sequences [48, 60-62]. The accelerated phase loss
due to local field gradients generated by super spins, all stem from the
(induced magnetisation) high susceptibility level of iron oxide.
At the common clinically available field strengths of 1.5T
and 3.0T, published data  indicate that any aggregation of SPION will only
slightly decrease r1 (longitudinal relaxation) and dramatically increase
r2 (horizontal relaxation).
Magnetic resonance imaging with iron oxide nanoparticles
Even though images composed with gradient echo pulse
sequences posses lower signal-to-noise ratio and spatial resolution compared to
spin echo pulse sequences, they are currently the most appropriate imaging
sequence to use with SPIONs. This is often termed magnetic susceptibility
imaging [4, 12, 48, 63]. The contrast enhancement captured on an MR image is
dependant upon a number of factors. Most notable are the biodistribution and opsonisation
Iron oxide nanoparticles as contrast agents for MRI
In addition to their superior biocompatibility, IONP MRI
contrast agents have been documented to increase diagnostic sensitivity and
specificity [41, 45, 64-66] in both animal model experimentation and in human
This improved accuracy has been attributed to their
superparamagnetic effects and relaxation times [41, 64, 66]. Efficacy of IONPs
as MRI dedicated contrast media also largely depends upon their physiochemical
properties . Such attributes include: size (both of the iron oxide core and
the overall hydrodynamic dimensions); coating (dextran derivative or other);
and the zeta surface charges. Their efficacy can be further increased with
complex surface modifications. This is achieved by bonding or attaching active
material such as monoclonal antibodies, receptor ligands and also proteins
For intravascular administration, the hydrodynamic
diameter of IONPs are very rarely greater than 150nm. The iron oxide core
itself is usually no more than about 15nm . The coating itself is
preferably composed of dextran, or a derivative, of a low molecular weight.
These are positive properties, as the dextran is biodegradable and its low
molecular weight minimises possibilities of adverse reactions . IONPs have
also been incorporated into oral contrast media .
Imaging challenges to consider and overcome
There are a few imaging challenges with the use of IONPs
. They are in relation to commonly encountered artefacts in MRI imaging. On
their own, they can be frustrating to deal with in everyday imaging. However,
when IONPs are included in the imaging regime, a further layer of complication
The first criticism is that it is difficult to determine
or differentiate a signal void induced by IONPs compared to signal voids
generated as artefacts by materials such as metal (susceptibility artefact).
The second artefact is that of partial volume averaging. IONPs are capable of
being involved in processes occurring at a cellular level. Hence, signal voids
induced by IONPs that are smaller than the spatial resolution of the MRI image
will not be represented as distinct and within a voxel; as individual signal
intensities within a voxel are averaged together [4, 11, 12, 68].
Emerging trends: applications of iron oxide nanoparticles and the role of
Where possible and practicable, medical investigators and
clinicians would prefer an investigation means that is non-invasive or
minimally invasive. This approach is safer for patients, it expedites the
medical management of patients, and can negate morbidity and mortality
consequences. IONP preparations, combined with MRI, have the potential to
revolutionise a number of investigative and treatment procedures. This would be
achieved by combining the advantages provided by IONP together with MRI,
leading to safer and superior imaging alternatives. IONPs as MRI contrast
agents have already been discussed in this manuscript. To re-iterate, they
promise improved levels of toxicity and increased diagnostic sensitivity and
specificity. These are achieved through careful chemical preparations, leading
to IONPs having the required characteristics for biocompatibility and MRI image
enhancement. It is recognised that further research is required to overcome the
We now follow with a discussion on the innovative uses of
IONPs combined with MR techniques. These promise to revolutionise clinical
therapies and improve patient outcomes.
Molecular imaging is a broad term concerning the imaging
of biological events at the cellular or molecular level. It should also be
non-invasive and the imaging characteristics representing the biological
activity should be quantifiable . MRI is seen as having an emerging and
innovative role. Molecular imaging can be possible with MRI when IONPs are
conjugated with biologically active materials such as antibodies.
The near future looks promising for MRI, together with
IONPs, to have a positive impact in leading non-invasive imaging of biological
and biochemical processes. Not only can such processes be diagnosed; but also
progression and treatment can be imaged over time.
Angiogenesis, the growth of new blood vessels (for development,
wound repair or tissue reproduction), is related to tumour growth and
progression . There are several known molecular markers associated with
angiogenesis. That is, endothelial cells active in angiogenesis express known
surface receptors compared to endothelial cells not partaking in angiogenesis
. The commonly occurring receptors include integrins and vascular
endothelial growth factor receptors. Antibodies or drugs to seek out angiogenic
markers, can be conjugated to IONPs and imaged with MRI. Thus, the angiogenic
process can be identified and any success in treatment can be accurately
monitored. This can be achieved by exploiting the increased permeability of
newly formed tumour vessels compared to normal healthy vessels .
Apoptosis is the self destruction of cells. When
determined by cell age or cell health status, the nucleus triggers this
process. It requires metabolic activity by the dying cell and is commonly
characterised by a redistribution of phosphatidylsenine in the cell membrane
. It can even be associated with tissue development and homeostasis .
The degree of apoptosis can determine how successful
chemotherapy and radiation therapy can be. Identifying apoptotic events in vivo
would hence further evaluate treatment regimes and progression of pathology
. It is known that apoptotic cells express lipid phospatidylserine (a
phospholipid) on their cell membrane. Synaptotagmin I is a protein that is used
to detect this phospholipid. When this protein was conjugated to IONPs,
apoptosis was demonstrated in vivo with mice .
The capability to image apoptosis can allow for almost
real-time monitoring of efficacy of drug therapies .
Targeted drug delivery with IONP and MRI
Many therapeutic drugs that are available, can be
considered non-specific in nature. By non-specific, it is meant that such drugs
are administered intravascularly and are thus distributed randomly. This can
lead to unwanted effects on healthy tissue . Specificity for target tissue
or cells can be achieved by conjugating IONPs with ligands . Such ligands
include antibodies (in particular for targeting cancerous tissue or cells),
proteins, peptides and other biological markers.
Targeted drug delivery, as provided by superparamagnetic
colloid suspensions, can be guided by an external magnetic field to the site of
interest , thus, having the capability to minimise both side effects and
required dose [57, 74, 75]. Therefore, pharmaceutical drugs can be binded to
IONPs designed to reach a specific, or target, organ, and then be released
there [41, 44]. The emerging breakthroughs that make magnetic drug targeting
possible and promising are the new classes of IONPs less than 50nm. This allows
for improved circulation time, thereby permitting delivery to the target site
without the likelihood of being sequestrated by the RES before this can occur
. With the original classes of IONPs that became commercially available
over ten years ago, RES uptake occurred within a few minutes following
intravascular administration (hence, their original application as dedicated
contrast agents for the liver) .
Drug targeting can be achieved by passive, active or
physical means . Magnetic drug targeting falls into the category of
physical means; as the pharmaceutical is attached to a carrier system (the
IONP) and its distribution is facilitated with an external influence (the
Not all therapeutic drugs can be conjugated to one single
variety of IONP. Characteristics of IONPs that can determine attachment of
therapeutic drugs include their size, surface charges (zeta charges) and
capacity for protein absorption . The process of cell uptake is determined
by the overall size of the nano-system (IONP, surface coating/s and pharmaceutical);
phagocytosis or pinocytosis. Pinocytosis occurs for items less than 150nm [41,
74]. The condition under which a cell finds itself in, may alter its
susceptibility to a nano-system. For example, under normal conditions, walls of
endothelial cells are permeable to objects 10nm or smaller. However, when
involved in pathologic processes such as tumour infiltration and inflammation,
the endothelial wall can be permeable to objects up to as large as 700nm .
Zeta charges need to be carefully managed. They determine whether or not
nanoparticles aggregate or if they remain suspended in its medium. More
importantly, they also play a part in endocytosis. It is noted that the
likelihood of phagocytosis increases with a higher zeta charge [41, 76], while
time spent within the circulatory system is reduced. There is an electrostatic
process involved when particles and substances are absorbed by a cell�s outer
membrane . Understanding nanosystem interaction with proteins is vital, as
when they are injected into the vascular system, their first interaction is
with the plasma proteins. Therefore, the manner in which nanosystems are
capable of interacting with opsonins (proteins that encourage phagocytosis such
as IgG) and dysopsonins (proteins inhibiting phagocytosis) also determine if
they are readily phagocytosed by the RES or if they can reach their intended
target and release their pharmaceuticals. Hence, protein repulsive molecules
such as polyethylene glycol (PEG) can be used to modify the surface of
nano-systems to reduce their recognition by the RES  and reduce
non-specific cellular uptake .
A phase I/II clinical trial of IONPs combined with
epirubicin designed to image and treat solid tumours (such as sarcomas), showed
that these nanosystems were reasonably well tolerated by the fourteen patients
involved. No organ toxicity attributable to iron oxide was noted. However,
toxicity responses to epirubicin were recorded at doses greater than 50 mg/m3
Thermal applications for cancer cells: magnetocytolysis and hyperthermia
with IONP and MRI
Compared to normal healthy cells, cancer cells are known
to be sensitive to temperatures above 42 degrees Celsius. Normal cells can
survive at higher temperatures . In cancer cells, at temperatures above 42
degrees Celsius, protein function is disrupted which can lead to apoptosis
. Thus, hyperthermia is a proposed treatment regime for certain cancers.
Until recently, hyperthermic approaches have included irradiation with
radiofrequency, ultrasound and microwaves. One known criticism of these
approaches is the likelihood of hyperthermic injury extending to healthy
tissue. The term, magnetic induction hyperthermia, now refers to cancer tissue
being exposed to an alternating magnetic field .
Hyperthermia using IONPs together with MRI has
demonstrated positive results in pre-clinical evaluation studies. With this
combined approach, magnetic nanoparticles can be either directly injected into
a tumour volume or designed to be selectively uptaken by a tumour site. This
target-selective capability improves local heating treatment to the tumour
while dramatically minimising potential for injury to surrounding healthy
tissue . Furthermore, the alternating magnetic field (not absorbed by
tissue), together with appropriately prepared IONP, can allow hyperthermia
treatment  to be applied to areas deep within the body . Radiofrequency
pulses provided by MRI can be designed to provide frequencies and amplitudes to
increase local cell temperature up to 55 degrees Celsius , thereby inducing
cytolysis. This process, therefore, can be used to generate heat to target
However, for magnetic hyperthermia to be successful, it
requires accurate delivery of magnetic nanoparticles to the tumour site.
A number of experiments report successful use of magnetic
induction hyperthermia in cancerous cell models and also in animal models [44,
Salado et al.  successfully demonstrated in a
rat model, with in vivo MRI imaging, that the IONPs which they developed were
capable of providing positive contrast enhancement of induced liver tumour and
also successfully treated these liver tumours with MRI-induced hyperthermia.
Thereby, demonstrating that IONPs can have both a diagnostic and therapeutic
use. Analysis of the rats following the experimental study demonstrated no
vascular embolisms (the IONP preparation was injected through the ileo-colic
vein) and specimens of the liver demonstrated insignificant inflammatory
Xu et al.  have produced nanoparticles
containing a core composed of iron and cobalt and a gold shell. These
nanoparticles demonstrated a specific magnetisation value far greater (226
emu/g) than that achievable with commercially available iron oxides (78.8
emu/g). This higher magnetic moment is claimed to improve heating efficiency in
hyperthermia applications. However, their publication did not mention any
results or discussion of toxicity or biocompatibility studies.
Initial success of magnetic hyperthermia with small groups
of human patients provides a promising outlook for future clinical
applications. Plotkin et al.  reports a study on eleven consecutive
patients (mean age 44 years), each with recurrent supratentorial glioblastoma.
All patients had previously undergone surgery, nine patients also had radiation
therapy and eight patients also had chemotherapy. Based on the prognosis
following these treatments, these eleven patients were eligible as candidates
for hyperthermia using nanoparticles and MRI. Nanoparticles were then
administered directly into the tumour volume. MRI hyperthermia, or nano cancer
therapy, followed and in ten patients, the mean reduction in gross tumour
volume (GTV) was 74% as indicated with PET-CT fusion imaging.
Cancer imaging with IONP and MRI
Diagnosing cancer in its early stages significantly
improves patient outcomes and survival rates. The initial use for IONPs was
directed at imaging liver tumours . This was due to the nanoparticles being
greater than 60nm and therefore readily phagocytosed by the liver. This has
been occurring for several years now and there are a few commercially available
preparations for this specific purpose. The authors will therefore discuss
IONPs in relation to other cancers.
Current MRI techniques allow for the detection of tumour
sizes in the order of one centimetre cubed. By conjugating known cancer
antibodies with IONPs, then MRI can be used to identify cancerous tissue of
smaller dimensions through molecular interactions. This is an improved sensitivity
for cancer markers, compared with current cancer marker detection probes .
IONP can be coated with (DMSA), a bi-functional chelating
agent and ligand. Herceptin, a monoclonal antibody, uses elements from within
the immune system to stop tumour progression by binding to HER2 receptor and
triggering a response by natural killer (NK) cells . With a 1.5 Tesla
clinical MRI scanner, Lee et al.  successfully demonstrated how to
identify cancer sizes as small as 50mg in mice using IONPs conjugated with
The above approach improves patient outcomes compared with
just chemotherapy alone.
This principle has also been used to target other tumour
antigens. IONPs conjugated with peptide EPPT1 (synthetic peptide EPPT1, also
known as alpha-M2 peptide (YCAREPPTRTFAYWG), derived from the CDR3 Vh
region of a monoclonal antibody, ASM2) are able to target underglycosylated
MUC-1 (mucin 1); which is a tumour antigen expressed by many epithelial cell
adenocarcinomas such as pancreatic, colorectal, gastric and prostate .
The role that lymph nodes play in cancer staging has not
gone unnoticed by researchers in this field. IONPs and MRI can be used to image
the condition of lymph nodes and more accurately determine the extent of
metastatic spread . Oghabian et al.  demonstrated 98% detection
sensitivity with in vivo imaging of a rat model at 1.5 Tesla. They also
concluded that the type of surface coating and its thickness were factors in
determining MRI signal intensity.
Today, prostate cancer is still a leading cause of death
in men. Current treatment, among others, involves brachytherapy, and as a
procedure, it has its own level of invasiveness, morbidity and mortality. Wang et
al.  have conjugated IONPs with prostate specific membrane antigen
(PSMA) and also with doxorubicin, a chemotherapy drug. By performing whole cell
assays on human cell lines, Wang et al. demonstrated that their
conjugate can detect, with high sensitivity, prostate cancer cells expressing
PSMA, thereby, promising the possibility of a multifunctional (diagnostic and
therapeutic) nanoparticle system.
IONPs can also be used to better identify tumour
boundaries within the brain [69, 87, 92, 93]. This leads to improved
quantification of tumour volumes. Compared with gadolinium-based contrast
agents for MRI and also taking into consideration oedema surrounding a tumour
volume, IONPs can define tumour margins for longer time periods [69, 92, 94].
This is as a result of the IONPs being endocytosed by tumour cells. Thus being
internalised, their elimination rate from the tumour is longer compared to
extracellular gadolinium-based contrast media.
Cell labelling and tracking; including stem cell therapies
MRI imaging of cells labelled or endocytosed with IONPs is
considered an indirect imaging technique. This is because changes in MRI signal
intensity is in relation to the amount of IONPs and not due to the number of
cells. One concern is the MRI signal characteristic and change over a time
period. As stem cells rapidly divide, the fixed amount of IONPs is spread
throughout the volume of newly divided daughter cells [68, 75]. This will be a
relative decrease in MRI signal not accurately reflecting the activity of
cells. The second noteworthy concern is the possibility of false positive signal
findings. This is a result of iron presented from cells undergoing apoptosis or
lysis . Despite these challenges, possibilities are being created for many
biomedical applications .
The possibility of imaging stem cells in therapeutic
applications with MRI is becoming an ever increasing area of active research.
Published research so far indicates that IONPs combined with peptides or
transfection agents can be used for stem cell uptake .
A study using stem cells with IONPs injected into the
infarcted myocardium of pigs was able to be successfully imaged at 1.5 Tesla in
vivo . Following this, histological analysis revealed that the MRI signal
appearance attributed to IONPs corresponded with stem cells that had taken up
Heymer et al.  combined human mesenchymal stem
cells (hMSCs) with IONPs; placed these in collage type I hydrogel (clinically
approved for the repair of articular cartilage) and imaged them in a 11.7 Tesla
MRI scanner. Iron uptake was confirmed by histological analysis and correlated
with hypo-intense regions demonstrated on the MRI images. Their technique
offers the possibility to use MRI to track the migration of IONPs loaded with
hMSCs following implantation for articular cartilage repair.
Stem cell research is highly regarded as offering possible
treatment solutions for patients with neuronal pathologies and injuries. Guzman
et al.  proved that IONPs themselves do not alter survival rates,
migration patterns or differentiation capabilities of stem cells from the human
central nervous system (CNS), compared with unlabelled human CNS stem cells.
They demonstrated this by administering the combined human CNS stem cells and
IONPs into neonatal, adult and injured rodent brains. They used MRI to track
the migration of stem cells and confirmed the image findings histologically.
Stem cells labelled with IONPs have been widely used in
animal models (mice, rats and pigs) to demonstrate regeneration of the
myocardium following infarction . The limitation of this technique is that
the conjugation of IONPs and stem cells need to be injected directly into the
myocardium. This introduces an element of invasiveness. However, the region of
infarct can be clearly delineated . So far, administration of stem cell and
IONP conjugations for myocardial regeneration via a vascular route (intravenous
or intracoronary), has not been as successful as direct injection into the
infarcted myocardium. Furthermore, comparative high volumes are needed [98,
Cardiovascular imaging with IONP and MRI
IONPs have also demonstrated capabilities in imaging
cardiovascular pathologies including atherosclerosis, thrombosis and myocardial
infarcts [56, 101].
Atherosclerosis is considered both a progressive disease
and chronic inflammation. The endothelial cells of the vascular wall express
receptors from their cell membrane to attract monocytes. Monocytes establish
themselves in the subendothelial space and then differentiate into macrophages.
The macrophages then take up oxidised low density lipoproteins. Therefore, this
lipoprotein can be conjugated to IONPs and used to identify active regions of
atherosclerosis with MRI. This approach has been often used in studies
involving animal models . Furthermore, apoptosis leads to plaque instability
and is known to occur before plaque rupture . Identifying apoptic plaques
in vivo with MRI is seen as advantageous in improving patient outcomes, as
inflammatory activity of atherosclerotic plaques may be associated with an
increased risk of rupture .
Aortic valve disease is also an inflammatory response with
macrophage involvement . Ruehm et al.  successfully used
commercially available IONPs to demonstrate (with MR imaging) in hyperlipidemic
rabbits that atherosclerotic plaques containing macrophages take up these
nanoparticles. This was confirmed with histopathogical evaluation techniques on
samples removed from the aorta. The MRI appearance demonstrated an aorta with
irregular pattern where the signal dropout occurred at plaque sites containing
macrophages endocytosing the IONPs.
IONPs can also be used to target fibrin containing
thrombi. This approach may be considered a sensitive method of identifying
patients at risk of more serious cardiovascular consequences . A study by
Winter et al.  demonstrated that by using antifibrin antibodies
together with nanoparticles, clots in canine plasma in vitro could be
identified with MRI (at 4.7 Tesla).
Blood pool contrast agent
There has been a high level of success in using IONPs as
blood pool agents; in both animal models and in human subjects.
One study  investigated size and dose of IONPs as a
blood pool agent for MR angiography in New Zealand White rabbits. The rabbits
were divided into a control group (administered with gadopentate dimeglumine),
and three other groups (each receiving a different concentration of IONPs). MR
angiography was performed at varying time points; ranging from first pass to 24
hours post-intravascular administration. Assessment included signal enhancement
of the abdominal aorta, renal arteries and the iliac arteries. Results
demonstrated that the highest level of signal enhancement was identified during
the first pass imaging strategy. It was also noted that enhancement in the
abdominal aorta was greatest with the smallest nano particle size of 21nm. In
addition to this, a concentration of 40micromole of iron per kilogram was
recognised as the dose providing signal enhancement comparable to gadopentate
dimeglumine. The size and dose of IONPs provided sufficient signal changes to
allow imaging from first pass time-point up to 25 minutes post-intravascular
administration. In this 25-minute window, multiple imaging acquisitions and
measurements are possible.
Another study  successfully demonstrated the use of
IONPs as a blood pool agent in rats with induced myocardial injuries. Here, a
commercially available blood pool agent, Clariscan, was used with an MRA
technique. The image findings were also compared with post-mortem histochemical
stains of the infracted rat myocardium. It was found that the
Clariscan-enhanced MR angiogram images over-estimated the infracted myocardial
regions when compared with histology inspection. The use of Clariscan
identified the presence and dimensions of both transmural and non transmural
microvasculature insults. The peri-infracted zone was seen to be over-estimated
to a greater extent in rats with non-transmural ischaemic injuries. Overall,
there was an over-estimation of the size of the true infarct but an under-estimation
of the region at risk.
Another commercially available IONP preparation (Resovist)
has been used to assess the abdominal aorta and the inferior vena cava in a
human pilot study . With a 3D MRA (T1-weighted) acquisition technique at
1.5 Tesla, first pass imaging was achievable with results being comparable to
those obtained by MRA with conventional Gadolinium based contrast agents.
Ferumoxytol has also been used for first pass enhanced 3D
MRA of blood vessels of varying dimensions in 12 human subjects. The following
vessels were investigated: the carotid arteries, thoracic aorta, abdominal
aorta and peripheral arteries . With delayed MRA imaging it was noted that
both arterial and venous structures displayed enhancement characteristics.
A critical and relatively new-found application of IONPs
is to include them in preparations to produce what is now termed �nanosensors�.
Nanosensors, in their broadest definition, are IONP preparations that have been
designed to detect the presence of a specific biological interaction.
Protease specific nanosensors have been developed for in
vivo detection of enzyme activity with MRI . In particular, T2* MRI
together with nanosensors of 25 nm (hydrodynamic size) have demonstrated the
involvement of the metalloproteinase 9 (MMP-9) enzyme in processes including
inflammation, atherosclerosis and tumour spread. This opens the potential for
early diagnosis of pathologies with altered protease activity and also the
monitoring of treatment and therapies that act on protease enzymes.
Protein functionalised nanosensors have also demonstrated
capabilities in identifying and measuring the concentration of anti-human serum
albumin antibodies . One of the additional benefits of the combined
approach of MRI with nanosensors is that the NMR capabilities can allow for
detection in natural human substances such as blood and urine.
Nanosensors have also been developed with the capability
to detect single human alveolar cancer cells (A549) within 15 mins in blood in
vitro . High density folic acid, when conjugated to polyacrylic acid
coated IONPs were designed to interact with A549 cancer cells expressing the
Metal doped IONPs
Metal doping of IONPs is designed to provide a
comparatively higher level of magnetism at the nano scale and also allow
successful magnetic tuning . Such metal doped IONPs can increase MRI
signal contrast by as much as 14 times compared to conventional IONPs. The
implication of this is that a lower dose or lower concentration can be
administered to the patient. Their magneto-thermic effects can also increase by
a factor of 4.
Lanthanide metals have also been used to dope IONPs .
The advantages that lanthanide metals can offer include optical imaging
properties, detection by neutron activation, utilised in neutron capture
therapy procedures and also being detectable by time resolved fluorescence.
IONPs doped with manganese have shown to improve the
quality of contrast-enhanced MR imaging of the liver . These nano systems
have a mean diameter of 80nm. The highest level or change in signal intensity
occurs at 5 mins post-intravascular administration. However, unlike early
IONPs, the imaging window for IONPs doped with manganese can last for
approximately 36 hours.
In the immediate future, the reviewers see that perhaps
the most likely application of IONPs will be as an MRI contrast agent. This is
because IONPs offer several important advantages over commonly available
gadolinium based contrast agents; including, but not limited to, lower
toxicity. They can be used to diagnose a variety of pathologies and biological
activities such as inflammation, infarction and tissue repair.
In addition to improved diagnostic outcomes, there can
also be tailored therapeutic functions, in particular with tumour treatment.
IONPs can be binded with antibodies, drugs, enzymes and proteins. They can be
directed to specific organs or tissues and can also be guided with magnetic
fields to target tumours and induce hyperthermic effects.
Multifunctional IONPs, together with MRI, offer unique
advantages with diagnostic and therapeutic capabilities. In particular,
molecular imaging with IONPs and MRI has the potential to heavily impact upon
early detection of a variety of diseases and pathologic processes. It can also
be used to devise treatment approaches dedicated to individual patient
circumstances. This should all lead to improved patient outcomes. These are
areas of high research activity and there is no doubt that this will lead to a
new frontier in magnetic resonance imaging.
Figure 1 Schematic representation of a basic iron oxide nanoparticle, or nanosystem.
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|Received 14 October 2009; received in revised form 22
December 2009; accepted 25 January 2010
Correspondence: Division of Medical Radiations, School of Medical Sciences, RMIT University, Bundoora West campus, PO Box 71, Bundoora 3083, Victoria Australia. Tel.: + 61 3 9925 7908; Fax: + 61 3 9925 7466; E-mail: firstname.lastname@example.org (Giovanni Mandarano).
Please cite as: Mandarano G, Lodhia J, Eu P, Ferris NJ, Davidson R, Cowell SF,
Development and use of iron oxide nanoparticles (Part 2): The application of iron oxide contrast agents in MRI, Biomed Imaging Interv J 2010; 6(2):e13