Superparamagnetic Iron Oxide Nanoparticles

Journal of Cerebral Blood Flow & Metabolism (2010) 30, 1535
& 2010 ISCBFM All rights reserved 0271-678X/10 $32.00

www.jcbfm.com
Review Article
Superparamagnetic iron oxide nanoparticles:

diagnostic magnetic resonance imaging and
potential therapeutic applications in
neurooncology and central nervous system
inflammatory pathologies, a review
Jason S Weinstein1, Csanad G Varallyay2,3, Edit Dosa2, Seymur Gahramanov2,
Bronwyn Hamilton4, William D Rooney5, Leslie L Muldoon2 and Edward A Neuwelt1,2,6
1
Department of Neurological Surgery, Oregon Health and Science University, Portland, Oregon, USA;
Department of Neurology, Oregon Health and Science University, Portland, Oregon, USA; 3Department of
Neuroradiology, Universitatsklinikum Wurzburg, Wurzburg, Germany; 4Department of Radiology, Oregon
Health and Science University, Portland, Oregon, USA; 5Advanced Imaging Research Center, Oregon
Health and Science University, Portland, Oregon, USA; 6Portland Veterans Affairs Medical Center,
Portland, Oregon, USA
Superparamagnetic iron oxide nanoparticles have diverse diagnostic and potential therapeutic
applications in the central nervous system (CNS). They are useful as magnetic resonance imaging
(MRI) contrast agents to evaluate: areas of bloodbrain barrier (BBB) dysfunction related to tumors
and other neuroinflammatory pathologies, the cerebrovasculature using perfusion-weighted MRI
sequences, and in vivo cellular tracking in CNS disease or injury. Novel, targeted, nanoparticle
synthesis strategies will allow for a rapidly expanding range of applications in patients with brain
tumors, cerebral ischemia or stroke, carotid atherosclerosis, multiple sclerosis, traumatic brain
injury, and epilepsy. These strategies may ultimately improve disease detection, therapeutic
monitoring, and treatment efficacy especially in the context of antiangiogenic chemotherapy and
antiinflammatory medications. The purpose of this review is to outline the current status of
superparamagnetic iron oxide nanoparticles in the context of biomedical nanotechnology as they
apply to diagnostic MRI and potential therapeutic applications in neurooncology and other CNS
inflammatory conditions.
Journal of Cerebral Blood Flow & Metabolism (2010) 30, 1535; doi:10.1038/jcbfm.2009.192; published online
16 September 2009
Keywords: bloodbrain barrier; CNS tumors; magnetic resonance imaging; ultrasmall superparamagnetic iron
oxide nanoparticles
Introduction
The diagnosis and treatment of pathologies that
affect the central nervous system (CNS) are currently
undergoing a renaissance because of the marked
proliferation of nanoscale technologies. Nanotechnology, as it relates to biomedicine, can broadly be
defined as nano-sized structures that contain at least
Correspondence: Dr EA Neuwelt, Department of Neurological
Surgery, Oregon Health and Science University, 3181 SW Sam
Jackson Park Road, L603, Portland, OR 97239, USA.
E-mail: neuwelte@ohsu.edu
Received 3 April 2009; revised 11 August 2009; accepted 13
August 2009; published online 16 September 2009
one dimension between 1 to 100 nm in sizeyand

possess new or enhanced properties that are unattainable at both smaller (quantum) [and] larger
(macromolecular) levels (Hartman et al, 2008).
Superparamagnetic iron oxide nanoparticles are
based on magnetite (Fe3O4), which has received the
most attention for biomedical applications, or maghemite (gFe2O3) molecules encased in polysaccharide, synthetic polymers, or monomer coatings
(Laurent et al, 2008; Thorek et al, 2006). The utility
of superparamagnetic iron oxides as magnetic resonance imaging (MRI) contrast agents has been
studied for more than two decades (Weissleder
et al, 1990) and the list of available agents is
rapidly expanding (Table 1). These particles can be
Superparamagnetic iron oxide nanoparticles in brain

JS Weinstein et al
16
Table 1 Available superparamagnetic iron oxide agents and prohance (Gd-based agent) for comparison
Name
Developer
Coating agent
Size (nm)a
Ferumoxides AMI-25
Feridex/Endorem
Ferucarbotran SH U 555 A
Resovist
Ferumoxtran-10 AMI-227
Combidex/Sinerem
Ferumoxytol Code 7228
Guerbet AMAG
Pharm. Inc
Bayer Schering
Pharma AG
Guerbet
AMAG Pharm. Inc
AMAG Pharm. Inc
Dextran T10
120180 (SPIO)
Carboxydextran
60 (SPIO)
Dextran T10, T1
1530 (USPIO)
30 (USPIO)
1874
SH U 555 C Supravist
Bayer Schering
Pharma AG
GE-Healthcare
Polyglucose sorbitol
carboxymethyl ether
Carboxydextran
21 (USPIO)
40
Pegylated starch
20 (USPIO)
36
Ferropharm
Citrate
7 (VSPIO)
1575
Bracco Diagnostics, Inc
1 (GBCA)
100 (umol (Gd) /kg)
Feruglose NC-100150
Clariscan
VSOP-C184
Gadoteridol (ProHance)
Clinical dose
(mmol Fe/kg)
30
812
45
Relaxivity
(mM1 sec1)b
r1 = 10.1
r2 = 120
r1 = 9.7
r2 = 189
r1 = 9.9
r2 = 65
r1 = 15
r2 = 89
r1 = 10.7
r2 = 38
n.a.
r1 = 14
r2 = 33.4
r1 = 4
r2 = 6
Currently available intravenous iron oxide nanoparticle contrast agents. Modified from Corot et al (2006).
a
Hydrodynamic diameter, laser light scattering.
b
Relaxometric properties (mM1 sec1) at 1.5 T, 37 1C, water or in plasma; per mM Gd, or Fe.
organized according to their hydrodynamic diameter

into several categories (Corot et al, 2006): standard
superparamagnetic iron oxide particles (SPIOs) (50
to 180 nm), ultrasmall superparamagnetic iron oxide
particles (USPIOs) (10 to 50 nm), and very small
superparamagnetic iron oxide particles (VSPIOs)
( < 10 nm). Most contemporary investigations use
USPIOs; therefore, for the sake of consistency we
will refer to superparamagnetic iron oxide nanoparticles, in general, as USPIOs unless specifically
discussing SPIOs or VSPIOs.
Particles of iron oxide have been administered
intravenously (IV) for over 50 years, initially for the
treatment of anemia (Cameron et al, 1951). Emerging
experimental and clinical applications in the CNS
capitalize on both the physical and magnetic properties of iron oxide nanoparticles; the list of biomedical
imaging applications for these nanoparticles continues to expand. There are a number of important
qualities of USPIOs that make them attractive as
complimentary or alternative MRI contrast agents
compared with gadolinium-based contrast agents
(GBCAs). These can be summarized as follows:
USPIOs are virus-sized molecules with a very long
circulating half-life (B14 h for ferumoxytol); USPIOs
are avidly taken up by phagocytic cells such as the
Kupffer cell fraction of the liver, circulating monocytes/macrophages and mononuclear T cells, as well
as reactive astrocytes, microglia, and dendritic cells
within the brain. Neutrophils have not been found to
take up USPIO. The USPIOs are cleared from the
circulation primarily by the reticuloendothelial
system (Bourrinet et al, 2006); these properties (i.e.,
degree of cellular labeling and rate of clearance) are
dependent on size, coating, and method of delivery
and will be discussed in detail below. Limitations of
these agents for current CNS imaging applications
are primarily related to the inability to reliably

differentiate USPIO signal from resident brain iron
signal (i.e., in the setting of hemorrhage related to
stroke or trauma). There are also very little data in
humans regarding the long-term clearance of these
agents from the brain.
Ferumoxides (Endorem, Guerbet in Europe; Feridex, AMAG Pharmaceuticals Inc in the USA and
Japan) and ferucarbotran (Resovist, Schering Bayer in
Europe and Japan) are commercially available SPIOs
approved for MR imaging of liver tumors (Ros et al,
1995). Clinical CNS imaging studies have also been
performed with these compounds (Rose et al, 2006;
Varallyay et al, 2002). The USPIO, ferumoxytol
(Feraheme, AMAG Pharmaceuticals Inc, Cambridge
MA, USA) is approved for iron-replacement therapy
in patients with chronic renal failure (Kidney Daily,
6/30/2009). Ferumoxtran-10 (Manninger et al, 2005;
Saleh et al, 2007), SHU555C (Vellinga et al, 2008), and
ferumoxytol (Neuwelt et al, 2007) have been investigated in humans for various CNS imaging applications. Preliminary studies using ferumoxides, ferumoxtran-10 (Combidex), and ferumoxytol have not
revealed significant toxicities (Muldoon et al, 2006;
Neuwelt et al, 2007). Ferumoxytol, in particular, is
attractive as an MRI contrast agent because it can be
given as a bolus for first-pass perfusion imaging and
appears to be safe in patients with chronic kidney
disease; at later time points (i.e., 24 h), ferumoxytol
accumulation is evident in areas of bloodbrain
barrier (BBB) dysfunction that may be fundamentally
related to inflammation from any cause.
This review will focus primarily on USPIOs,
specifically ferumoxtran-10 and ferumoxytol, for
diagnostic applications in the CNS with an emphasis
on their utility as MRI contrast agents in the setting
of CNS tumors. It will also highlight the utility of

JS Weinstein et al
17
USPIOs for imaging tumor neovasculature and

assessing therapeutic response to antiangiogenic
chemotherapeutic agents.
Basic science review

Ultrasmall Superparamagnetic Iron Oxide Particle
Synthesis and Pharmacology
The most common methods of USPIO synthesis for

biomedical applications are coprecipitation of ferric
and ferrous salts in an alkaline medium, with or
without surface complexing agents such as dextran
or polyethylene glycol, or microemulsion techniques
with small amounts of iron ions trapped inside
surfactant bubbles in an oil medium (Hartman et al,
2008; Laurent et al, 2008). The USPIOs consist of two
components: an iron oxide core and a hydrophilic
coating. It is the combination of these two components that determines their pharmacology. Passive
targeting is perhaps most dependent on the hydrodynamic radius and the surface charge (factors
related to the coating material), as these characteristics determine circulation time, accessibility to
tissues, opsonization, and rate of cell-type uptake
(Thorek et al, 2006). Active targeting in the CNS
takes advantage of nanoparticle surface modifications (e.g., the addition of monoclonal antibodies or
peptides) such as chlorotoxin, for glioma imaging.
Current clinical trials primarily involve passive
targeting.
With respect to passive targeting, USPIOs behave
differently than GBCAs for a number of reasons.
First, because of their larger molecular sizeup to
50 nm (compared with the 1 nm gadolinium chelate),
USPIOs extravasate much more slowly than standard
GBCA, even in areas of severe BBB dysfunction (i.e.,
malignant glioma). Most GBCAs, in comparison,
rapidly extravasate into the extravascular space in
areas of BBB dysfunction and are rapidly cleared
from the circulation via the kidneys. There are
numerous formulations based on the gadolinium
ion [Gd(III)], each with unique properties and safety
profiles (Harpur et al, 1993).
Ferumoxtran-10 is a first-generation USPIO that
may have a slight advantage over ferumoxtyol for
anatomic imaging of inflammatory lesions; however,
it is not safe for angiographic imaging procedures,
which require a rapid infusion. Ferumoxytol was
developed as an IV iron-replacement therapy, specifically for anemic patients with chronic kidney
disease; after bolus IV administration, it follows a
useful distribution that is conceptionally based on
the conservation of mass. Over time, a combination
of events occur leading to contrast enhancement:
USPIOs slowly leak across the BBB (mechanism
incompletely understood); there may also be uptake
of USPIO by circulating monocytes/macrophage,
which then cross the BBB in response to inflammation and injury. Histologic samples from resected
brain tumors of patients, who received USPIOs,

reveal that part of the extravasated iron oxide
particles are taken up by parenchymal cells. Thus,
their localization is both intracellular and interstitial (Figure 1A) (Varallyay et al, 2002).
Measurable T1-weighted signal enhancement (hyperintensity) in brain tumors is seen as early as 4 to
6 h after USPIO injection; contrast enhancement
intensity peaks B24 h after injection and can
generally be visualized even 72 h after injection,
although it is usually faint and more diffuse
(Neuwelt et al, 2007). In contrast to GBCAs, there is
no renal elimination of USPIO, which accounts for
the enhanced safety profile in patients with renal
dysfunction who appear to be at increased risk for
contrast-induced nephropathy or nephrogenic systemic fibrosis (Neuwelt et al, 2008).
Unlike USPIOs, the plasma half-life of SPIOs is on
the order of minutes. This is due to their larger
particle size ( > 50 nm) and negative surface charge,
which lead to rapid elimination. Iron-loaded mononuclear cells can actively cross a relatively intact
BBB in cases of an active inflammatory process
(Oude Engberink et al, 2007), but because of their
large size, SPIOs do not leak across BBB defects
like free USPIOs (as in malignant gliomas). In the
clinical setting, FDA-approved doses of ferumoxides
(SPIOs) were given to 20 patients with intrinsic
or metastatic brain tumors. No enhancement was
visualized in any patient at 30 mins or 4 h (Varallyay
et al, 2002).
The safety profile of clinically useful USPIOs
varies based on their molecular structure. After
cellular internalization, iron oxide nanoparticles
accumulate in lysosomes in which the low pH breaks
the iron oxide core down into iron ions. These ions
are then incorporated back into the hemoglobin pool
(Thorek et al, 2006). The type of coating used has a
significant impact on the immunologic response to
USPIOs; to date, studies have shown that polymercoated nanoparticles have minimal impact on cell
viability and function (Bourrinet et al, 2006; Thorek
et al, 2006). Trypan blue exclusion-based toxicity
studies, using high concentrations of USPIOs, show
good tolerance with minimal cell death. However,
there have been reports of free radical generation,
decreased cell proliferation, and even cell death with
some formulations, highlighting the uniqueness of
different nanoparticle configurations (Modo et al,
2005). Whereas earlier agents, such as ferumoxtran10, were administered via slow infusion to avoid
mast cell degranulation, newer agents, such as SHU
555 C and ferumoxytol can be safely given as a rapid
IV bolus.
Ferumoxytol has been tested as an iron supplement therapy in patients with renal failure up to the
dose of 510 mg (Landry et al, 2005; Spinowitz et al,
2005). For MRI contrast agent applications, the
amount of iron administered (typically < 4 mg/kg)
is much lower than doses resulting in acute systemic
toxicity (above 60 mg/kg) or chronic iron overload

JS Weinstein et al
18
Figure 1 (A) 18: Adapted with permission from Varallyay et al (2002). Patient with anaplastic oligodendroglioma. A.12:
nonenhanced (A.1) and gadolinium-enhanced (A.2) SE T1-weighted images of a right temporal tumor. The gadolinium-enhanced
image shows strong, lobulated peripheral enhancement with a central nonenhancing region. A.3: at 24 h after ferumoxtran-10
(Combidex) infusion, SE T1-weighted image shows high-signal intensity in a similar distribution, but with less peripheral lobulation,
compared with the gadolinium-enhanced image. Also note that the nongadolinium-enhancing central zone became isointense to
white matter, suggesting some ferumoxtran accumulation. A.46: fast SE T2-weighted image obtained before ferumoxtran-10
infusion (A.4) and fast SE T2-weighted (A.5) and GRE T2*-weighted (A.6) images obtained 24 h after ferumoxtran-10 infusion show
a heterogeneous tumor mass with peripheral decreased signal intensity that is more prominent on the GRE T2*-weighted image. The
distribution of low-signal intensity is similar to that of the high-signal intensity areas on the SE T1-weighted image (A.3). A.78:
photomicrographs of pathologic specimens stained for iron (DAB-enhanced Perls stain). A.7: (original magnification7.5 ; bar
indicates 1 mm), tumor (T) and reactive brain interface (RB) show intense staining for iron at the periphery of the tumor. A.8: (original
magnification100 ; bar indicates 0.1 mm), cellular iron staining at the tumor-reactive brain interface shows iron uptake by
parenchymal cells with fibrillar processes (arrows) rather than within the round tumor cells (T) themselves. (B) Adapted with
permission from Muldoon et al (2005). Iron particle imaging of human small-cell lung cancer (LX-1 cell line) xenografts in a rodent
model. B.18: T1 MRI scans (1.5 T) comparing ferumoxtran-10 (top), ferumoxytol (middle), and ferumoxides (bottom) 24 h after
intravenous administration in nude rats with LX-1 intracerebral tumors. All animals were imaged at 9 days after tumor cell
implantation except #3 and #4, which were imaged on day 6. B.910: iron histochemistry photomicrographs. Intense iron staining
was found at the LX-1 tumor/reactive brain interface 24 h after administration of ferumoxtran-10 or ferumoxytol.
(above 20 g stored iron). Over 1700 patients have

received ferumoxytol in its clinical development
program, and at least 1500 of these were patients
with chronic kidney disease in Phase 3 iron-replacement studies. To date, only one patient, with a
history of multiple drug allergies, has experienced an
anaphylactoid reaction (hot flashes and itching,
without respiratory compromise) and severe hypotension a few minutes after receiving ferumoxytol.
There have been no deaths that were considered to
be related to ferumoxytol treatment (Neuwelt et al,
2008). The long-term fate of iron from ferumoxytol in
the brain remains unknown, however. There is
growing evidence that iron accumulation in the
brain, as in nigrostriatal dopaminergic neurons
associated with Parkinsons disease for example, is
not merely an epiphenomenon but a result of
misregulation of iron homeostasis within the brain
(Ke and Ming Qian, 2003). Preclinical studies of
USPIOs injected directly into the rat brain, or
delivered transvascularly, have not revealed any
acute or midterm toxicity. As early as 7 days after
transvascular delivery of ferumoxytol, no iron was
detectable in the brain using MRI and histology

(Muldoon et al, 2005). After direct intracerebral
injection of USPIO or SPIO, iron was still easily
detected in brain parenchyma by MRI and histology,
with no sign of pathology at 3 months.
Magnetic Resonance Imaging Physics
Magnetic resonance imaging is a noninvasive technique that uses magnetic fields to produce high
resolution and high-contrast images of tissue structure and function. The principal tissue signal of
interest in essentially all clinical MRI arises from
water protons. Water concentration can vary significantly between biological tissues and this property is
exploited to produce a fundamental contrast in MRI
that is known as proton density contrast. In proton
density-weighted MRI, the signal intensity of each
voxel is proportional to the local proton concentration. Another fundamental class of MRI contrast
relies on spatial differences in the relaxation properties of the MR signal.

JS Weinstein et al
19
There are two principal relaxation processes that

characterize MR signals, one that relates how rapidly
magnetization parallel to the strong static magnetic
field recovers after a perturbation, and the other that
describes how rapidly magnetization transverse to
the static magnetic field decays after it has been
produced by a series of radiofrequency pulses. The
constants that characterize these two kinetic processes are referred to as longitudinal and transverse
relaxation time constants, T1, and T2, respectively. In
general, T1 relaxation processes are sensitive to
fluctuating magnetic fields at or about the MRI
operational frequency (i.e., the Larmor frequency).
Transverse relaxation processes are sensitive to
magnetic fields that fluctuate at the Larmor frequency, but also are significantly determined by
fluctuations at low frequency. In complex samples
such as tissues, the density of low-frequency
fluctuating fields is much greater than those at or
near the Larmor frequency. This is why 1H2O T2
values are typically much smaller than T1 values in
tissue. An apparent transverse relaxation time constant (T2*) can also be defined. In addition to
contributions from T2 mechanisms, T2* relaxation
processes are sensitive to microscopic magnetic field
distributions. Such magnetic field distributions can
be produced by compartmental differences in magnetic susceptibility, such as occurs in areas proximal
to blood vessels with significant deoxyhemoglobin
concentration and is exploited in functional MRI
experiments. Therefore, T2* values are always
smaller than T2 values.
For most MRI studies, the intrinsic contrast
provided by spatial differences in proton density
and relaxation times is sufficient. However, it is
important to appreciate that most MRI acquisitions,
although strongly weighted to a particular type of
contrast, are invariably sensitive to more than one
type of contrast. The amount of mixed weighting in
an MRI acquisition depends on a number of factors,
but becomes important when discussing contrast
agent applications.
Magnetic Resonance Imaging Contrast Agents
Although intrinsic contrast is sufficient for most MRI

applications, exogenous contrast agents are used in
B40% of all clinical MRI studies. Typically, these
agents are used to increase lesion conspicuity and to
improve characterization of blood vessels. Unlike
tracers used in x-ray or nuclear medicine imaging,
MRI contrast agents are detected indirectly through
their ability to catalyze water proton relaxation and
perturb MRI signal intensity. By far, the most widely
used MRI contrast agents are those based on the
paramagnetic gadolinium [Gd(III)] ion. The Gd(III)
ion has seven unpaired electrons and favorable
electronic spin relaxation properties that make for
very efficient catalysis of water proton relaxation.
The Gd(III) ion is chelated to a low-molecular weight
ligand to reduce toxicity. These low-molecular

weight GBCAs are injected IV, most will distribute
rapidly into all accessible extracellular spaces, and
are eliminated from the body through the kidneys
with a typical elimination half-life of B1.6 h. Contrast agents catalyze relaxation rate constants (the
inverse of the time constants described above) in a
concentration-dependent manner. In simple solutions, the 1H2O T11 increases linearly with contrast
agent concentration. The slope of this dependence is
known as the relaxivity, typically reported in units of
mmol1 sec1, and is a measure of how potent the
agent is for catalyzing relaxation. Relaxivities typically differ for longitudinal and transverse relaxation
and vary with magnetic field strength. The GBCAs
typically are used in combination with T1-weighted
MRI acquisitions and produce a hyperintense
(bright) signal in tissue regions in which the agent
accumulates. The low-molecular weight and weak
protein binding characteristics of most GBCAs lead
to avid extravasation of GBCAs from normal blood
vessels in most tissue and abnormal blood vessels in
the CNS. These agents have found widespread use
for investigations of bloodCNS barrier disruption
found in many disease pathologies.
The USPIOs are based on magnetite (Fe3O4)
nanocrystals and are classified as superparamagnetic
compounds because the net magnetic dipole moment
realized exceeds that expected from the unpaired
[Fe(II), Fe(III)] electrons alone. Like GBCAs, the
USPIOs do not retain any net magnetism once
removed from the strong magnetic field; thermal
energy is sufficient to destroy the net magnetic order
within the nanocrystal established by the strong
magnetic field. The USPIOs have excellent relaxivities and on a per iron-atom basis compare very
favorably with GBCAs (Table 1). Unlike the GBCAs,
which have similar transverse and longitudinal
relaxivities at clinically relevant magnetic fields,
the USPIOs have significantly greater transverse
relaxivities compared with longitudinal relaxivities
(Table 1). Thus, USPIOs tend to find greater application on magnetic susceptibility-based acquisitions in
T2-weighted or T2*-weighted MRI, in which they
produce a hypointense (dark) signal (Figure 2A). The
strong magnetic susceptibilities of these compounds
can result in a significant distribution of microscopic
magnetic fields and severe MR signal quenching.
This can be appreciated in Figure 2A that compares
minimum intensity projection susceptibilityweighted images obtained without exogeneous contrast, with a standard dose GBCA, and with 4 mg/kg
ferumoxytol. The image collected after ferumoxytol
shows significantly greater MR signal quenching
(hypointensity) in areas in and surrounding blood
vessels than either the GBCA or no exogeneous
contrast agent conditions. Nevertheless, USPIOs do
have significant longitudinal relaxivities and have
been used as agents in T1-weighted and even
dynamic contrast-enhanced acquisitions, in which
tissue regions that accumulate the agent appear

JS Weinstein et al
20
no contrast
no contrast
GBCA
ferumoxytol
3T
1
GBCA
7T
Normallzed Signal
Intensity
60
2
ferumoxytol
50
40
30
20
10
0
1.5 Tesla
3 Tesla
Signal Intensity curves on

1.5 and 3 Tesla
10
20
30 40 50
Time (Hours)
60
70
80
Figure 2 (A) MRI showing cerebral vasculature at 7 T. Minimum intensity projection (mIP) susceptibility-weighted images were
obtained without contrast agent (A.1), with GBCA (gadoteridol, 0.1 mmol/kg, A.2), and immediately after USPIO injection
(ferumoxytol 510 mg, A.3). The USPIO enhancement results in superior visualization of small intracerebral vessels. (B) 3D MPRAGE
T1-weighted MRI in a patient at 3 T and 7 T without contrast (B.1 and B.4), with GBCA (B.2 and B.5), and with ferumoxytol
(510 mg, 24 h after infusionB.3 and B.6). GBCA associated T1-weighted signal intensity increases at higher magnetic field
strength because of the increased nominal brain tissue T1 relaxation time constant, whereas ferumoxytol enhancement signal
intensity is reduced because of increased T2* contributions at 7 T. (C) Adapted with permission from Neuwelt et al (2007). Time
course of ferumoxytol enhancement in a patient with recurrent GBM. GBCA-enhanced T1-weighted (C.1), T2-weighted (C.2), and
post-ferumoxytol T1-weighted (C.37) MRI scans were obtained using a 1.5 T MRI at five time points (C.3 = 46 h; C.4 = 620 h;
C.5 = 2428 h; C.6 = 4852 h; C.7 = B72 h). Peak intensity is observed at the 24 to 28 h time point; much later than that
observed with GBCA (not shown), which enhances maximally 3.5 to 25 mins after injection. The figure shows comparison of
ferumoxytol-enhancement intensity curves at 1.5 T and 3 T MRI. Maximum ferumoxytol T1 enhancement is greater at 1.5 T than on 3 T.
hyperintense. It should be noted that the transverse

relaxivities increase supralinearly with magnetic
field strength, whereas the longitudinal relaxivities
typically decrease slightly (Blockley et al, 2008).
Therefore, the hyperintense T1-weighted enhancement is more readily achieved at lower magnetic
field strengths and the potential for mixed weighting
effects in USPIO-based MRI applications increases
markedly with magnetic field strength (Muldoon
et al, 2005; Neuwelt et al, 1994). Comparing
postcontrast T1-enhancement at 3 T and 7 T in the
same subject at similar times reveals improved
sensitivity for GBCA detection but reduced sensitivity for USPIO detection at 7 T (Figure 2B). The
observation of increasing GBCA detection sensitivity
with magnetic field is consistent with predictions
based on increased nominal brain tissue T1 relaxation time constants with increasing magnetic field
(Rooney et al, 2007). Increased nominal T1 values
imparts increased sensitivity for detecting lower
concentration of GBCA despite a slight decrease in
longitudinal relaxivity and increase in transverse
relaxivity with increasing magnetic field (Chang
et al, 1994; Rohrer et al, 2005).

JS Weinstein et al
21
Generally, the r1/r2 ratios decrease with increasing

field strength and these alterations are especially
pronounced for USPIOs (Rohrer et al, 2005). Hence,
USPIOs show superior T1-weighted contrast at lower
magnetic field strengths, as in a 0.15 T intraoperative
MRI (Hunt et al, 2005), using standard T1-weighted
sequences. A comparison of 1.5 T versus 3 T scans,
with analogous imaging sequences, using ferumoxytol in patients with CNS malignancies revealed that
turbo spin echo (TSE), a rapid T1-weighted sequence,
at 1.5 T resulted in greater changes in signal intensity
than TSE sequences at 3 T (Neuwelt et al, 2007).
Furthermore, similar patient groups have been
studied at 3 T versus 7 T; the lower magnetic field
provided a larger area of signal enhancement on
T1-weighted magnetic prepared rapid gradient echo
(MPRAGE) MRI (unpublished data; Figure 2B). At
12 T, no T1-weighted enhancement was found with
USPIOs in preclinical tumor models (unpublished
data). Newer imaging sequences, such as Ultrashort
echo time sequences (Idiyatullin et al, 2006), and
Inversion-Recovery with ON Resonant Water Suppression, open new avenues for obtaining hyperintense enhancement with USPIOs (Korosoglou et al,
2008; Stuber et al, 2007). However, thus far no
applications in CNS imaging have been reported.
Diagnostic and potential therapeutic

applications
Imaging Central Nervous System Tumors with
Ultrasmall Superparamagnetic Iron Oxide Particles
There are B16,900 new cases of primary CNS tumors

diagnosed in the United States each year. Contrastenhanced MRI of CNS malignancies is a crucial
diagnostic tool and a key parameter for follow-up
imaging of tumor response to therapy (Macdonald
et al, 1990). Enhancement of residual or recurrent
tumors using standard GBCAs reflect both cerebral
blood flow (CBF) and alterations in the BBB appearing as increased signal on T1-weighted images within
minutes after injection (Akeson et al, 1997). Unlike
GBCAs, USPIO enhancement at early time points
after administration is not a clear marker of BBB
deficiency. The mechanism of USPIO tissue accumulation is not fully understood but is likely related
to its prolonged circulation time and as a cellular label
following uptake by inflammatory cells within and
around tumors. For CNS tumor imaging, T1-weighted
scans have proven to be superior for the evaluation of
low concentrations of iron oxide nanoparticles traversing the BBB (Muldoon et al, 2005; Neuwelt et al,
1994; Varallyay et al, 2002). But as discussed above,
this observation is dependent on details of the MRI
acquisition including the magnetic field strength.
The BBB is a special feature of CNS capillaries that
results from a continuous layer of endothelial cells
bound together with tight junctions that allow very
little transcellular or pericellular transport of blood
borne molecules (Banks, 1999). Micrometastases that

lack neovascularity remain protected by the BBB and
may be undetectable using GBCAs. In contrast to the
normal BBB, the bloodtumor barrier (BTB) may be
highly permeable and allows conventional contrast
agents to leak from the vessels into the perivascular
space (Groothuis et al, 1991; Long, 1979). The
permeability of the BTB may be variable not only
in different histologic types of tumors but also within
one tumor mass (Barnett et al, 1995; Kraemer et al,
2001; Kroll and Neuwelt, 1998; Varallyay et al, 2002),
increasing the difficulty of accurately determining
tumor size and type. Furthermore, any of a variety of
inflammatory or infectious CNS lesions may show
similar patterns of GBCA enhancement complicating
the differential diagnosis (Enochs et al, 1999).
The USPIOs, which can be used both as intravascular contrast agents and as a cellular imaging agent,
may be useful in the reduction of the abovementioned problems (Corot et al, 2004). In animal
studies, ferumoxtran-10 shows slightly better tumor
imaging at the same dose as ferumoxytol; however, it
must be administered over B30 mins to limit adverse
reactions (Figure 1B) (Neuwelt et al, 2004). Enhancement after IV infusion of ferumoxtran-10 increases
slowly and peaks at B24 h after administration; then
declines during the next several days (Figure 2C)
(Manninger et al, 2005; Neuwelt et al, 2004;
Varallyay et al, 2002). Indeed, after resection, our
group found that residual lesions were still readily
visible on the T1-weighted postoperative MRI at 48 h.
This property of ferumoxtran-10 allows for assessment of residual tumor without the need to readminister a contrast material during intraoperative
MRI (0.15 T) or on postoperative MRI (Hunt et al,
2005). In additional clinical trials, three patients
with glioblastoma multiforme (GBM) who received
earlier radiation showed fewer areas of enhancement
with ferumoxytol than with GBCA. When compared
with ferumoxtran-10, ferumoxytol seemed to provide
somewhat less enhancement. In another study, 6 out
of 14 patients with GBM had MRIs, which revealed
more intense enhancement with ferumoxtran-10
than with GBCA, whereas our group found 1 patient
out of 5 with GBM had an MRI showing slightly
increased enhancement with ferumoxytol versus
GBCA (Neuwelt et al, 2007).
In an attempt to improve diagnostic specificity,
multifunctional modifications are increasingly used
to more specifically target USPIOs to the intended
target. One example of this involves attachment of
chlorotoxin, a 4-kDa peptide purified from the
Leiurus quinquestriatus scorpion. It is a highly
specific marker for glioma cells in biopsy tissues
(Soroceanu et al, 1998) that can target tumors in
animal models (Lyons et al, 2002).
Early clinical applications of USPIOs as MRI
contrast agents focused on investigations of blood
CNS barrier breakdown in neuroinflammation and
neoplasm. More recently, these agents have found
widespread use in dynamic MRI examinations,

JS Weinstein et al
22
including dynamic susceptibility contrast (DSC). The

DSC techniques are useful for quantifying tissue
perfusion (blood volume and blood flow) and are
accomplished with time-series T2*-weighted MRI
data that are collected during the bolus administration of a contrast agent. Dynamic contrast enhancement measurements are collected using a T1weighted MRI time series, and are useful for
quantifying contrast agents vascular permeability
and tissue distribution volumes. Early experimental
data suggest that the combination of GBCA-enhanced
T1-weighted MRI and USPIO-enhanced T2-weighted
MRI reveals complimentary information in patients
with CNS tumors (Neuwelt et al, 2007).
Perfusion-weighted imaging (PWI) is generally
performed using first-pass, dynamic susceptibilityweighted contrast-enhanced (DSC) MRI echo-planar
imaging approaches (Cha et al, 2002). The basic
principle of PWI using DSC MRI is as follows: the
first-pass effect of a contrast bolus in brain tissue is
monitored using a series of T2*-weighted MR images
from the same brain regions, which are scanned
repeatedly. The susceptibility effect of a paramagnetic (GBCA) or superparamagnetic (USPIO) contrast
agent causes signal loss that can be converted into a
contrast agent concentration (Essig et al, 2006).
From these data, parametric maps of CBF, cerebral
blood volume (CBV), and mean transit time (MTT =
CBV/CBF) are calculated in regions of interest
(Ostergaard, 2005). The CBF can be defined as the
amount of blood delivered to a standard volume of
brain per unit time, such as 50 mL/100 gm/mins in
gray matter. The CBV is the amount of blood per
volume of brain or pathologic lesion. The MTT refers
to the time it takes for a bolus of contrast to pass
through a region of tissue; it can be calculated by
comparing a signal washout curve in the region of
interest with the contrast signal in a cerebral artery
(Figure 3A). These data parameters, alone or in
combination, provide information on cerebral hemodynamics and serve as surrogates to quantify angiogenesis. The USPIOs may provide more accurate
measurements of these vascular parameters, compared with GBCAs, because of their propensity to
remain intravascular at early time points (Figure 3B).
Molecular Imaging of Inflammation with Ultrasmall

Superparamagnetic Iron Oxide Particles
Molecular imaging is an important new diagnostic

tool for studying in vivo cellular and molecular
biology across a wide range of disciplines. Molecular
imaging, outlined as the noninvasive, quantitative,
and repetitive imaging of targeted macromolecules
and biological processes in living organisms
(Herschman, 2003) could allow for earlier disease
detection; more accurate prognostic information and
personalized treatment strategies; an enhanced ability to monitor the efficacy of treatment; and an
improved understanding of how cells behave and
interact in their microenvironment in vivo (Thorek et

al, 2006). There are a number of interesting investigations being conducted using SPIO-labeled dendritic cells in the setting of neurooncology (Verdijk et al,
2007) as well as molecular imaging of inflammation
and stem cell tracking using GBCAs and other
bioactive agents such as fluorine (Brekke et al,
2007; Ruiz-Cabello et al, 2008). The field of molecular imaging is expanding rapidly and is beyond the
scope of this review; however, we will touch on some
of the studies completed by our group and others
using USPIOs.
Phagocytic cellular uptake of iron oxides increases
with particle size (Daldrup-Link et al, 2003; Matuszewski et al, 2005). SPIOs, with a hydrodynamic
diameter of 50 to 180 nm, are more efficiently
phagocytosed than USPIOs with sizes of 20 to
50 nm. The maximum intracellular iron oxide concentration of in vitro-labeled, isolated human macrophages is 50 pg Fe/cell for the SPIO Ferucarbotran,
whereas for USPIO (SHU 555 C), it is < 8 pg Fe/cell
(Metz et al, 2004). Besides the particle size of the iron
oxides, phagocytic uptake is also dependent on
nanoparticle surface properties (i.e., neutral versus
charged). The relative surface properties may have a
greater impact on the effectiveness of phagocytosis
than particle size. For example, the ionic Ferucarbotran, with a mean diameter of 62 nm, has a
significantly higher cellular uptake compared with
nonionic ferumoxides, with a mean diameter of
150 nm (Metz et al, 2004). Complex formation
between ferumoxides and a variety of transfection
agents occurs through electrostatic interactions and
enhances the iron uptake in multiple cell types.
Arbab et al showed that the low-molecular weight
cationic peptide, protamine sulfate, enhances the
uptake of ferumoxides in vitro (Arbab et al, 2004a;
Arbab et al, 2004b). Protamine sulfate also doubled
the in vivo uptake of ferumoxides in rats (Wu et al,
2007). In our groups study, in vivo peripheral
mononuclear cells showed minimal uptake of
ferumoxtran-10 or ferumoxytol even in the presence of IV protamine sulfate (Wu et al, 2007).
However, other groups have shown enhanced
uptake of USPIOs by activated monocytes in vitro
(Metz et al, 2004).
With respect to contrast-enhancement imaging
properties of CNS tumors, besides their vascularity,
the number and the distribution of activated inflammatory cells seems to be the most relevant. A large
number of macrophages and activated microglia have
been reported to be present within and around
malignant brain tumors. The microglial infiltration
is typically most prominent at the periphery of a
lesion and in the surrounding brain tissue. The
ability to track USPIO-labeled cells using MRI and
then correlate them with histology is an important
new technology in the investigation of many CNS
pathologies. Our group has tracked ferumoxtran-10
from brain into the cervical lymph nodes of rats
(Muldoon et al, 2004). This connection has not been

JS Weinstein et al
23
Figure 3 (A) Cartoon depiction of cerebral blood volume (CBV) and mean transit time (MTT) calculation using DSC first-pass MRI.
The first-pass effect of a contrast agent bolus in brain tissue is monitored using a series of T2*-weighted MR images from the same
brain region, which is scanned repeatedly. The susceptibility effect of a paramagnetic (GBCA), or superparamagnetic (USPIO),
contrast agent causes decreased signal intensity that can be converted into a contrast agent concentration. This concentration can
then be converted into quantitative measurements of CBV proportional to the area under the curve (hatched area) assuming that the
longitudinal relaxation time T1 of bulk tissue remains constant during bolus passage. This assumption holds true if the contrast agent
is confined to the vascular space and the vascular volume fraction is so small that its contribution to the overall signal intensity may
be neglected. (B) Comparison of gadodiamide versus ferumoxytol perfusion imaging in a highly vascular and permeable human
glioma (U87 MG cell line) xenograft at 12 T. The curves depicted (B.1 and B.4) show the signal intensitytime course using
standard rapid T2*-weighted gradient echo MR sequences during gadodiamide (B.1) and ferumoxytol (B.4) first-pass boli. Regions of
interest were defined on the T2-weighted anatomical images (B.2 and B.5) in the tumor (red) and normal-appearing brain tissue
(blue). Because of extravasation of the smaller molecular weight gadodiamide from the vasculature, CBV calculations (area under the
curve proportional to area of DSC dip) will be inappropriately low. The CBV parametric maps (B.3 and B.6) show the discrepancy
between CBV calculations using these two agents; ferumoxytol-based perfusion imaging correctly delineates elevated CBV in this
aggressive tumor model. Adapted with permission from Neuwelt et al (2007) and Varallyay et al (2009).
well characterized in humans, but may be implicated

in the pathogenesis of diseases such as multiple
sclerosis (MS) and Alzheimers disease through
peripheral immune responses to CNS proteins.
Fleige et al have shown that microglia can readily
be labeled with magnetic particles, and labeled,
activated microglia very precisely represents tumor
morphology. They found that labeled microglia can
be detected with MRI in vivo and then visualized
histologically using specific stains for iron (e.g.,
Perls stain) (Fleige et al, 2001). Other groups
have similarly found that labeling cells in culture
with USPIOs, combined with MR imaging, provides
a noninvasive method for serially tracking and
quantifying the fate of transplanted cells in vivo

(Wu et al, 2008).
In another study, fragments of human malignant
glioma were orthotopically xenografted into the
brains of nude mice. All mice underwent MRI
examination 24 h after IV administration of ferumoxtran-10. In this study, Kremer et al observed a strong
correlation between tumor-to-background contrast
and proliferative index, between tumor-to-background contrast and tumor growth, and between
tumor-to-background contrast and Perls staining
score, indicating the potential for improved diagnostic specificity with respect to tumor progression
(Kremer et al, 2007).

JS Weinstein et al
24
Monitoring Antiangiogenic Therapy in Central

Nervous System Tumors with Ultrasmall
The blockade of neoangiogenic signaling pathways is

one of the several key strategies in the treatment of
high-grade malignant brain tumors. Bevacizumab,
which neutralizes the vascular endothelial growth
factor-A, is the most commonly used monoclonal
antibody for the treatment of high-grade gliomas in
humans (Claes et al, 2008). Growing evidence suggests that USPIO-enhanced MRI will be useful in the
evaluation of tumor response to antiangiogenic
therapy.
Claes et al compared conventional T1-weighted
GBCA-enhanced MRI with T2*-weighted USPIO
(ferumoxtran-10)-enhanced MRI in mice carrying
orthotopic U87 glioma treated with or without the
antiangiogenic compound vandetanib. In untreated
animals, vessel leakage within the tumor, and a
relatively high tumor blood volume resulted in good
MRI visibility with GBCA- and USPIO-enhanced
MRI. Vandetanib treatment restored the integrity of
the BTB, resulting in loss of tumor detectability with
GBCA, but not with USPIO-enhanced MRI, most
likely because of continued infiltration of USPIOlabeled macrophages (Claes et al, 2008). In a separate
preclinical study, Robinson et al investigated the
utility of susceptibility contrast MRI with a USPIO
(feruglose) to assess rat GH3 prolactinomas
before and 24 h after treatment with either saline or
50 mg/kg ZD6126. ZD6126 (N-acetylcolchinol-Ophosphate) is a water-soluble phosphate pro-drug
of the tubule-binding agent N-acetylcolchinol. It
inhibits tubulin polymerization that disrupts the
cytoskeleton of proliferating tumor endothelial cells
thereby leading to endothelial cell detachment,
tumor vessel occlusion, and central hemorrhagic
necrosis. Irrespective of treatment, tumor volume
significantly increased over 24 h. However, salinetreated tumors showed no statistically significant
change in tumor fractional blood volume, whereas a
significant 70% reduction in tumor fractional blood
volume was observed in the ZD6126-treated cohort.
Uptake of the nuclear stain Hoechst 33342, indicative of viable tumor cells, was significantly reduced
and restricted to the rim of the ZD6126-treated
tumors. A significant positive correlation between
posttreatment tumor fractional blood volume and
Hoechst 33342 uptake was also observed, providing
validation of the MRI-derived measurements of
fractional tumor blood volume as a method of
tracking therapeutic response to antiangiogenic
agents (Robinson et al, 2007).
Ongoing clinical trials conducted by our group
show that USPIOs, combined with PWI, are an
important adjuvant for monitoring tumor response
and for discrimination of pseudo-progression from
true tumor progression. It is generally accepted that
increased malignancy is associated with increased
vascularity and tumor growth is correlated with
neoangiogenesis. In CNS malignancies, CBV has been

one of the most commonly used parameters to
estimate microvascular density (Cha et al, 2002).
However, in tumors with a disrupted BTB (such as
malignant glioma) leakage of GBCAs from tumor
vessels causes inaccurate estimation of tumor CBV
using PWI (Figure 3B) (Neuwelt et al, 2007; Uematsu
and Maeda, 2006). Although the clinical impact of
this inaccuracy is not known, it could be significant in
cases in which PWI is used to monitor therapeutic
response to antiangiogenic chemotherapies, such as
bevacizumab. In this scenario, the use of a blood-pool
agent, such as the bolus-injectable USPIO ferumoxytol, would be favorable by eliminating the permeability dependence of CBV estimation (Figure 3B).
The evidence regarding CBV normalization and
survival of patients with brain tumors is not
straightforward, however. One clinical study involving 19 patients with grades 2, 3, and 4 gliomas
revealed a stronger correlation of survival with
normalized CBV than with intensity of GBCA
enhancement (Lev et al, 2004). Another study
investigating 28 patients with GBM found no
significant relationship between median CBV and
survival (Oh et al, 2004). However, one must
consider that median CBV ignores the intrinsic
heterogeneity of tumor perfusion (Aronen et al,
1994; Donahue et al, 2000; Knopp et al, 1999; Kremer
et al, 2002; Lev et al, 2004; Sugahara et al, 1998). In
23 patients with high-grade gliomas, the fractional
tumor volume of high CBV, which accounts for the
heterogeneity of CBV, was analyzed before radiotherapy and it predicted survival. Subsequent
changes in CBV during conformal radiotherapy were
also predictive (Cao et al, 2006). More accurate CBV
maps, generated using USPIOs, may also be useful in
the evaluation of treatment response and helpful in
the differentiation of recurrent tumor from postsurgical/postirradiation changes.
It is hypothesized that CBV measurements may
provide a mechanism to distinguish pseudoprogression versus true progression of malignant gliomas
after chemoradiotherapy using temozolomide. Up to
50% of patients treated with temozolomide have
increased areas of GBCA enhancement in the first 3
months after completion of radiation (Brandsma
et al, 2008). The PWI using blood-pool agents
(USPIOs, such as ferumoxytol) may allow differentiation of true tumor progression from pseudoprogression based on increased versus decreased CBV,
respectively (Figure 4) (unpublished data).
Imaging Stroke with Ultrasmall Superparamagnetic

Iron Oxide Particles
Imaging ischemic CNS lesions is time dependent.

In the past, parenchymal ischemic injury could only
be detected 6 to 12 h after the onset of symptoms
using standard MRI sequences (Yuh et al, 1991).
Diffusion- and perfusion-weighted MRI, using

JS Weinstein et al
25
Figure 4 (A) Discordance of rCBV calculated using ferumoxytol versus GBCA enhancement suggestive of pseudoprogression. At the
middle of radiation time point (middle row), rCBV with ferumoxytol clearly shows increased blood flow (yellow/green area on rCBV
with Fe parametric map marked with small red arrow) in a second posterior frontal lobe lesion (this lesion was not initially radiated
after the patients first resection of a left frontal GBM). After completion of radiation (bottom row), the area of GBCA enhancement is
increased; however, DSC-MRI with ferumoxytol (third column) shows decreased rCBV compared with surrounding normal brain. (B)
A 19-year-old man with GBM imaged pre- and postoperatively, after standard radiochemotherapy (RCT) and at multiple time points
after treatment with bevacizumab. B.1: GBCA-enhanced, T1-weighted MRI before surgery shows a large ring enhancing lesion in the
right parietooccipital lobe with mass effect and midline shift; B.2: postoperative image, before initiating RCT. B.3: MRI 1 month after
completion of RCT revealed increased area of GBCA enhancement on T1-weighted images (see white arrow) with predominantly low
blood volume except for a thin area of high blood volume at the periphery of the Gd- and Fe-rCBV parametric maps (B.4 and B.5).
Note that the peripheral rCBV is more prominent (intense green/yellow circle marked by white arrow in image 5; the red area in
image 4 is likely artifact) using ferumoxytol versus gadoteridol. Adjuvant temozolomide treatment was continued and bevacizumab
treatment was then initiated. B.67: GBCA-enhanced, T1-weighted MRIsafter first and second courses of treatment with
bevacizumab show significant improvements in mass effect and diminished contrast enhancement. B.810: after six treatments with
bevacizumab and temozolomide, there is a slight increase in GBCA enhancement, but decreased rCBV on both gadoteridol and
ferumoxytol perfusion imaging.
USPIOs or GBCAs, allows for the identification

of ischemic lesions earlier and may permit the
monitoring of the effects of therapeutic strategies
(Chenevert et al, 1991; Moseley et al, 1990; Rosen
et al, 1990; Stroke, 1989. Recommendations on
stroke prevention, diagnosis, and therapy. Report

of the WHO Task Force on Stroke and Other
Cerebrovascular Disorders, 1989). Contrast agents
that cause a regional signal loss because of magnetic
susceptibility-induced T2* shortening (e.g., USPIOs)

JS Weinstein et al
26
have been shown to provide substantial contrast

between ischemic and normally perfused brain
areas (Gore and Majumdar, 1990; Villringer et al,
1988). The MTT abnormalities, taken together
with areas of restricted diffusion on diffusionweighted imaging, are the preferred techniques for
determining regions of infarction versus penumbra
(Schaefer et al, 2008).
In addition to ischemic changes, according to
experimental data, brain inflammation is present
during the acute stage of an ischemic stroke, which
may be optimally imaged using MRI in combination
with USPIOs (del Zoppo et al, 2000; Stoll et al, 1998).
There is a growing appreciation for the dual role of
inflammation in stroke, with microglia implicated
early and macrophages (both bone-marrow derived
and brain parenchymal) implicated later in the
establishment of a chronic, deleterious, proinflammatory state. Audebert et al showed that an increase
in systemic inflammatory parameters correlates significantly with lesion volume and stroke severity
(Audebert et al, 2004; Nighoghossian et al, 2007).
The microglia, activated within minutes of ischemic
onset, are involved not only in tissue damage, but
ultimately may protect the brain against further
ischemic injury (Jander et al, 2007; Schilling et al,
2003; Schroeter et al, 1997; Tanaka et al, 2003).
Denes et al showed that in mice, after transient
middle cerebral artery occlusion, microglial proliferation was the main factor behind the increased
number of mononuclear phagocytes seen during the
first 3 days; the number of activated microglial cells
negatively correlated with the extent of ischemic
brain damage (Denes et al, 2007).
Work in other experimental stroke models showed
that diffusion- and perfusion-weighted MRI using
GBCAs is not able to differentiate inflamed from
noninflamed infarct subareas (Schroeter et al, 2001).
However, using USPIOs and T2*-weighted imaging,
hypointense areas indicative of USPIO-laden inflammatory cells can be visualized. These areas of
hypointensity were then confirmed by histologic
and electron microscopic analyses to correspond
with brain sections infiltrated with USPIO-laden
macrophages (Rausch et al, 2001; Saleh et al, 2004b).
Several experimental and clinical investigations
have been performed to identify the optimal timewindow for detecting inflammation after ischemic
injury. Experimental data reveal reproducible USPIO-induced enhancement as early as 24 h after
ischemia. In animal studies, ED1 + cells, a cell
marker for macrophages, were found around the core
of the infarct within the first 24 h after occlusion of
the middle cerebral artery. On days 2 to 4, USPIOs
were found mainly between the core and the
periphery of the lesions and, by day 7, they were
seen only at low concentration both within and
around the lesion (Rausch et al, 2001). These
findings may be important in the design and
monitoring of future neuroprotective trials, especially those involving antiinflammatory agents.
In a single-center, open-labeled, clinical phase II

study, the potential for USPIO-enhanced MRI versus
conventional GBCA-enhanced MRI to image macrophages in human ischemic stroke lesions was tested.
Ten consecutive patients received IV ferumoxtran-10
at the end of the first week after symptom onset.
Two follow-up MRI scans were performed 24 to 36 h
and 48 to 72 h after infusion. The USPIO-induced
signal alterations in the ischemic area were evident
on both T1-weighted and T2/T2*-weighted imaging.
Contrast enhancement was observed primarily at the
periphery of the infarcted parenchyma. Digital
subtraction of GBCA-enhanced regions revealed
distinct areas of USPIO enhancement, indicating
that these areas of enhancement were not because of
BBB disruption, but rather a consequence of ironlabeled macrophage infiltration (Figure 5A) (Saleh et
al, 2004a; Saleh et al, 2007). There are very limited
data on the utility of USPIOs in stroke. However,
Henning et al recently completed an excellent
preclinical study, which provides further proof-ofprinciple that this type of imaging may be useful in
the development of future neuroprotective strategies
(Henning et al, 2009).
Imaging Carotid Atherosclerosis with Ultrasmall

Carotid artery atherosclerosis can be determined by

MR angiography using GBCA or USPIO (especially in
patients with renal failure), which also helps to
verify the severity of stenosis (Figure 5B). However,
recently it has been recognized that the composition
and stage of atherosclerotic carotid plaques, rather
than the severity of stenosis they induce, are
important properties for assessing stroke risk. In
experimentally induced hyperlipidemic rabbits, USPIOs of a diameter similar to that of low-density
lipoprotein, 15 to 25 nm, enter and accumulate in
atherosclerotic plaques with high macrophage content (Ruehm et al, 2002; Tang et al, 2006). Cappendijk
et al studied 11 patients with recurrent transient
ischemic attacks and ultrasound-proven carotid
stenosis scheduled for carotid endarterectomy using
ferumoxtran-10 (Cappendijk et al, 2008). Significant,
detectable signal changes were found on in vivo T2*weighted gradient echo MR images acquired 24 h
after IV administration of USPIO. After surgery,
immunohistochemistry of plaque samples showed
ferumoxtran-10 accumulation predominantly within
macrophages in ruptured and rupture-prone atherosclerotic lesions. In an additional study, 20 patients
with symptomatic carotid stenosis, all scheduled for
carotid endarterectomy, were imaged before and 36 h
after ferumoxtran-10 infusion (Tang et al, 2006).
Symptomatic carotid plaques showed significantly
more inflammatory activity than did the contralateral
carotid artery. Despite a mean contralateral carotid
stenosis of only 46%, 95% of these asymptomatic
plaques showed USPIO uptake, suggesting an

JS Weinstein et al
27
Figure 5 (A) Reprinted with permission from Saleh et al (2007). The USPIO-enhanced MRI of a 54-year-old man with infarction
involving the left middle cerebral artery distribution reveals the differential development of USPIO-related signal changes over time.
Compared with the nonenhanced, T1-weighted image 5 days after stroke (A.1), T1-weighted images 24 h (A.2), and 48 h (A.3) after
USPIO infusion show increasing hyperintense signal enhancement in the periphery of the infarcted parenchyma. Nonenhanced, T2*weighted image (A.4) displays hyperintense demarcation of the infarcted territory. T2*-weighted images 24 h (A.5) and 48 h (A.6)
after USPIO infusion show signal change from hyperintense to hypointense attributable to USPIO perfusion. (B) Ferumoxytol MR
angiography at 3 T of the supraaortic arteries in a kidney transplant patient with a glomerular filtration rate (GFR) < 60 mL/mins/
1.73 m2. Large plaque causes significant luminal narrowing at the origin of the innominate artery (red arrows). A significant stenosis
was also observed at the origin of the left subclavian artery (not shown). Carotid bulb shows moderate stenosis on both sides (white
arrows). Note the difference in diameter between the left and right carotid as well as the vertebral arteries. The color reproduction of
this figure is available on the html full text version of the manuscript.
inflammatory burden within the carotid atheromas

bilaterally. This finding correlates with the propensity for patients with symptomatic carotid stenosis
to have bilateral disease. As the majority (80%) of
embolic infarcts related to carotid stenosis present
without any warning, USPIO-enhanced detection of
inflammation within plaques may serve as an
important screening tool to reduce the incidence of
stroke. It may also be useful for tracking treatment
response to lipid-clearing medications. Other novel
techniques for studying atherosclerotic carotid plaques include very interesting work by Strijkers
group using GBCA-loaded lipososomes in combination with MRI for detection of intimal thickening
(Mulder et al, 2006).
Imaging Autoimmune Disorders with Ultrasmall

Multiple Sclerosis and acute disseminated encephalomyelitis (ADEM) are immune-mediated disorders
of the CNS. Several observations suggest a major role
of macrophages in axonal injury, but the triggers for

this autoimmune response have yet to be discovered
(Bitsch et al, 2000; Brochet et al, 2006). Experimental
autoimmune encephalomyelitis (EAE) is an animal
model of human MS. It can be induced in several
species by administration of myelin antigens or
myelin-reactive CD4 + cells (Rausch et al, 2003). In
EAE, USPIO-enhanced MRI reveals areas of hypointensity on T2*-weighted images, which correspond to
USPIO-laden mononuclear cells within inflammatory lesions. Immunohistochemical analysis also
shows that the iron particles are specifically localized within newly infiltrated ED1 + cells, but not in
ED2 + perivascular macrophages (Floris et al, 2004).
In both animal and human studies of MS and
ADEM, USPIO-enhancement patterns differ from
GBCA enhancement in time (Figure 6) (Bendszus
et al, 2005; Dousset et al, 2006; Floris et al, 2004;
Rausch et al, 2003; Rausch et al, 2004; Vellinga et al,
2008). Rausch et al found that this discrepancy was
most prominent during the first relapse, in which a
large number of USPIO-enhancing areas did not
show any GBCA uptake (Rausch et al, 2003; Rausch

JS Weinstein et al
28
Coronal
Coronal
1
Figure 6 Adapted with permission from Manninger et al (2005). Patient with ADEM. Axial, T1-weighted images without (1), and
with (2) gadolinium (inset, coronal) show faint, subtle enhancement in multiple brain stem lesions. Six days later, significant and
more prominent enhancement can be seen at the same sites (3) using ferumoxtran-10 (inset, coronal). Three months later, the
lesions no longer enhance on T1-weighted images with gadolinium (4).
et al, 2004). Intracellularly located USPIO particles

were concluded to be responsible for enhancement
in 19 patients with MS, even in areas of intact BBB
(Vellinga et al, 2008). One might conclude that
macrophages enter the brain during acute flares of
MS independently from breakdown of the BBB as
defined by GBCA enhancement (Manninger et al,
2005).
Baeten et al showed that the timing of USPIO
injection and imaging determines the amount and
distribution of inflammatory lesions visualized. At
disease onset, USPIOs detected lesions in the caudal
part of the brainstem, whereas at the peak of plaque
severity, USPIOs mainly target inflammatory regions
in the midbrain with only small amounts in the
caudal part of the brainstem (Baeten et al, 2008). In
rats with EAE, neurologic deficits correlate with the
MRI results.
Miki et al found a negative correlation between
GBCA-enhancing lesion volume and duration of
disease, suggesting that the BBB abnormalities are
less important over time (Miki et al, 1999). Furthermore, when the disease evolves to the secondaryprogressive stage, decreasing levels of enhancement
are observed despite increasing neurologic deficits,
again suggesting a diminished role of the BBB
abnormality revealed by GBCAs (Miki et al, 1997).
Acute axonal injury and irreversible axonal loss
are generally accepted to be major factors in the
pathophysiology of MS. Brochet et al studied the
relationship with inflammation and demyelination
in Dark Agouti rats with severe protracted-relapsing
EAE. This model, characterized by an initial attack
with very early axonal damage, shows the consequence of early inflammation and demyelination.
The second attack is characterized by both macrophage infiltration of the CNS, axonal loss, and
increased areas of demyelination. Compared with
acute models of EAE, where all animals present with
MRI signal changes in the CNS at clinical disease
onset, relapsing EAE models show MRI signal
alterations after USPIO injection, which are not
constant (Brochet et al, 2006). To validate the use

of USPIOs as a noninvasive tool for evaluating
therapeutic strategies in EAE, Floris et al treated
EAE animals with the immunomodulator, 3-hydroxy-3-methylglutaryl Coenzyme A reductase inhibitor
or lovastatin; MRI revealed that the USPIO load in
the brain was significantly diminished in lovastatintreated animals and this correlated with improved
clinical scores (Floris et al, 2004).
Improvements in early disease detection are
clearly needed in this field; an exciting alternative
to USPIO-enhanced MRI is work being conducted by
Sibson et al, using antibody-conjugated iron oxide
microparticles. Antibodies to vascular cell adhesion
molecule-1 conjugated to an MRI contrast agent may
allow for earlier detection, estimates of disease
severity, and monitoring of therapy (McAteer et al,
2007).
Imaging Central Nervous System Trauma with

Ultrasmall Superparamagnetic Iron Oxide Particles
The development of neuroregenerative therapies for

patients with traumatic brain or spinal cord injuries
is no longer science fiction. Embryonic stem cells
and other progenitor cell populations, combined
with biocompatible structural matrices, are being
investigated for their potential to restore function
after trauma (Sykova and Jendelova, 2007). Critical
factors for the successful application of these
regenerative cell therapies include, the ability of
transplanted cells to migrate from the site of
transplantation to the lesioned area; to survive,
differentiate, and/or produce growth factors and
cytokines for the prolonged periods of time necessary
for the patient to benefit from their regenerative
properties (Sykova and Jendelova, 2007). Implantation of stem cells may improve functional recovery
after experimental models of brain and spinal
cord injury (Bareyre, 2008; Kulbatski et al, 2005;
McDonald et al, 1999; Sykova and Jendelova, 2007).

JS Weinstein et al
29
Figure 7 (A) Pre- and postferumoxtyol (15 mins, middle row; 24 h, bottom row) enhanced 12 T MRIs after controlled cortical injury
in a rat model of traumatic brain injury. At 72 h after injury, there is marked signal loss visualized on T2* (Fe 24 h images);
(B) Phagocytic inflammatory cells, seen on H&E (B.1) and stained with CD68 (B.2) and fibronectin (B.3). (C) The inflammatory cells
are at least in part derived from peripheral circulating monocytes as illustrated in panels (C.1) and (C.2), which show quantum dot
(Invitrogen, Carlsbad, CA)-labeled peripheral mononuclear cells infiltrating around the cortical injury (#1; 800 magnification) or
within blood vessels on the uninjured side (C.2; 800 magnification).
The USPIOs may serve as useful adjuncts for

noninvasive anatomic and temporal tracking of stem
cells in CNS trauma and stroke (Hoehn et al, 2007;
Weber et al, 2006).
Although there are limitations to USPIO-based
molecular imaging, preclinical studies may benefit
from the combination of magnetic cell labeling and
tracking in vivo with MRI. An IV delivery of USPIOlabeled embryonic stem cells into rats injured with
photochemical cortical lesions led to MR-visible
migration of labeled cells into the lesion. Histology
confirmed that 70% differentiated into astrocytes,
< 1% oligodendrocytes, and B5% became neurons
(Sykova and Jendelova, 2007). This same group also
investigated balloon-induced spinal cord injury
treated with ferumoxide-labeled nonhematopoietic
mesenchymal stem cells. The labeled cells could be
tracked with MRI and led to improved locomotor and
plantar test results compared with control animals
(Sykova and Jendelova, 2007).
In a controlled cortical injury model of TBI in rat,
pooled leukocytes labeled with ferumoxides can be
detected histologically around the periphery of the
lesion. In the setting of experimental TBI, MRI
tracking of USPIO-labeled inflammatory cells is

difficult acutely using T2*-weighted imaging sequences because of the presence of free red blood
cells. However, pre- and postferumoxytol-enhanced
images may be useful for quantifying inflammation
(Figure 7) (unpublished data). Dynamic imaging
using ferumoxytol for the evaluation of cerebral
perfusion and BBB permeability in the acute and
chronic stages after TBI, may improve our understanding of the effects of TBI on cerebral hemodynamics. Information about edema formation, and
monitoring therapeutic responses to treatments designed to reduce edema and inflammation, will be
important in the translation of these novel strategies
to humans.
Imaging Epilepsy with Ultrasmall Superparamagnetic

Iron Oxide Particles
Akhtari et al used a rat model of temporal lobe

epilepsy and a-methyl tryptophan (AMT)-tagged
dextran-coated USPIOs to evaluate the potential for
functional MRI localization of epileptogenic foci

JS Weinstein et al
30
(Akhtari et al, 2008). AMT is preferentially taken up

in epileptogenic foci and reflects increased serotonin
production or induction of the kynurenine pathway
(Juhasz et al, 2004). In acute studies, AMT USPIOs
injected 3 days after kainic acid-induced status
epilepticus localized to bilateral hippocampi,
whereas plain USPIOs were only observed unilateral
to the lesion, presumably because of inflammation
(Akhtari et al, 2008). In chronic studies, the authors
correlated AMT USPIO uptake with the occurrence
of spontaneous seizures; MRI-localization of the
USPIOs agreed with electroencephalography. Advantages of this technique, compared with current
diagnostic algorithms, are multiple: no radiation
exposure as with single photon emission computed
tomography allows for repeat imaging; uses standard
MRI; the tracer is easy to synthesize in a short time
frame and is inexpensive. Although USPIOs have
shown no evidence of CNS toxicity as discussed
above, the long-term fate of these agents in the brain
needs to be determined, as free iron is known to be
epileptogenic (Willmore et al, 1978).
Emerging Therapeutic Applications Using Ultrasmall

The therapeutic applications of USPIOs are also

rapidly expanding as the chemistry and throughput
for production is streamlined. These agents can be
conjugated to drugs, proteins, enzymes, antibodies,
or nucleotides and can be directed to an organ,
tissue, or tumor using an external magnetic field
(Laurent et al, 2008). These same surface modifications, used for diagnostic specificity, will enhance
targeting for drug-delivery, gene therapy, radiosensitization, radiation therapy planning with MRI, tissue
repair, detoxification, and magnetic fluid hyperthermia (Chertok et al, 2008; Hartman et al, 2008; Khoo
and Joon, 2006; Maier-Hauff et al, 2007; Thorek et al,
2006; van Landeghem et al, 2009).
The USPIOs can be used for hyperthermic ablation
of CNS tumors after direct inoculation into tumors,
or IV administration, depending on the agents
biodistribution. Once targeted, particles are exposed
to an alternating magnetic field, which produces
electrical current and subsequent energy dispersion
in the form of heat. Superparamagnetic species with
single magnetic domains, dissipate heat as a result of
relaxation of the domain dipole, a process known as
Neel relaxation (Hartman et al, 2008). It takes far
lower-strength magnetic fields, using VSPIOs (3 to
7 nm), to achieve the same level of heating as larger
ferromagnetic agents. One limitation of this treatment strategy has been target specificity. However, a
feasibility trial was recently conducted using aminosilane-coated iron oxide nanoparticles in patients
with recurrent glioblastoma (Maier-Hauff et al, 2007).
In this study, Maier-Hauff et al inoculated 14
patients, using multiple stereotactic-guided injections. Multiple sessions of thermotherapy were well
tolerated; the median maximum temperature was

44.61C (431C is generally felt to be necessary for
tumor cell ablation) and there were signs of local
tumor control. A phase II trial is currently underway.
Additionally, postmortem studies of patients enrolled in the feasibility trial showed that dispersed
particles and particle aggregates were phagocytosed
mainly by macrophages, whereas glioblastoma cells
showed uptake to a minor extent. Van Landeghem et
al did not observe deleterious bystander effects of
magnetic fluid hyperthermia such as sarcomatous
tumors or sterile abscess formation, nor did they
observe any foreign body giant cell reaction (van
Landeghem et al, 2009).
Risk and Utility of Ultrasmall Superparamagnetic Iron

Oxide Particles in Comparison to Gadolinium-based
Contrast Agents
Although there is solid evidence of the deleterious

effects of nanoparticles and in some cases iron oxide
nanoparticles, SPIOs appear quite safe and USPIOs,
in particular ferumoxytol, appear to be remarkably
safe, as evidenced by the recent FDA approval. The
FDA-approved package insert for ferumoxytol (Feraheme) reviews three randomized clinical trials with
a total of 1726 patients of whom 1562 had chronic
kidney disease and were thereby chronically ill
patients. Despite this, only two patients had significant reactions to ferumoxytol and these reactions
were transient. It appears that in patients who do not
suffer from iron overload, ferumoxytol even in
seriously ill patients is quite safe.
With regard to its use in comparison to GBCAs, as
we have tried to show in this review, except in
patients with compromised kidney function, USPIOs
are a supplement, rather than a replacement for
GBCAs as contrast agents. In a head-to-head comparison, GBCAs are clearly a better screening agent, in
part because of the rapid leak into CNS pathologic
lesions. With ferumoxytol, it takes 24 h after contrast
administration to get analogous images. In addition,
in dynamic imaging it appears that Gd is superior to
assess permeability (dynamic contrast enhancement), whereas when assessing blood volume and
flow, USPIOs such as ferumoxytol act as a blood-pool
agent at early time points, and thereby may give more
accurate measurements of blood volume and blood
flow. As USPIOs specifically target phagocytic cells,
that is macrophages, they may also be better for
assessing inflammation.
Conclusions
Superparamagnetic iron oxide nanoparticles are an
important development for investigation and potential therapeutics across a wide variety of systemic
and CNS pathologies. Although there is no perfect
MRI contrast agent yet, USPIOs satisfy many of the

JS Weinstein et al
requirements that limit paramagnetic gadoliniumchelate contrast agents. The USPIOs appear to be
safe, are easy to administer, and provide significant
contrast enhancement, even on low tesla magnets.
They may serve as complimentary agents to improve
localization, characterization, and follow-up in diverse neurologic lesions. In CNS tumors, USPIOs
may improve detection and diagnosis and, using
dynamic studies, will be invaluable in the future for
monitoring therapeutic responses to antiangiogenic
chemotherapies and for differentiating true tumor
progression from pseudoprogression. The USPIOs
may also serve as safe alternative contrast agents in
patients with renal dysfunction who are at risk for
nephrogenic systemic fibrosis with GBCA-based
contrast agents. Although USPIOs such as ferumoxytol are not the answer to all diagnostic and
therapeutic applications currently envisioned, many
of these ideas are years, if not decades, from clinical
practice. Ferumoxytol, in particular, is an exciting
and powerful tool that is FDA approved and can be
used to study a variety of CNS pathologies.
Acknowledgements
We thank Ms. Audrey Selzer for her assistance with
12T MRI acquisitions, Mr. William Woodward for
collecting data for Figure 5b, and Ms. Emily
Hochhalter for her administrative assistance. This
research was funded in part by the National
Institutes of Health grants NS33618, NS34608,
NS053468, and NS44687 from the National Institute
of Neurological Disorders and Stroke, a Department
of Defense Center of Excellence Award, AMAG
Pharmaceuticals Inc, and by the Department of
Veterans Affairs, all to EAN. This research was also
funded in part by a Neurosurgery Research and
Education Foundation grant sponsored by Codman,
a Johnson & Johnson Company to JSW, NIH RO1EB007258 to WDR, The Oregon Opportunity and a
grant from the WM Keck Foundation.
Disclosure/conflict of interest
The authors declare no conflict of interest.
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Journal of Cerebral Blood Flow & Metabolism (2010) 30, 1535

& 2010 ISCBFM All rights reserved 0271-678X/10 $32.00

Superparamagnetic iron oxide nanoparticles:

one dimension between 1 to 100 nm in sizeyand

Superparamagnetic iron oxide nanoparticles in brain

Bracco Diagnostics, Inc

100 (umol (Gd) /kg)

organized according to their hydrodynamic diameter

are primarily related to the inability to reliably

Superparamagnetic iron oxide nanoparticles in brain

USPIOs for imaging tumor neovasculature and

Basic science review

The most common methods of USPIO synthesis for

brain tumors of patients, who received USPIOs,

Superparamagnetic iron oxide nanoparticles in brain

(above 20 g stored iron). Over 1700 patients have

detectable in the brain using MRI and histology

Magnetic Resonance Imaging Physics

Superparamagnetic iron oxide nanoparticles in brain

There are two principal relaxation processes that

Magnetic Resonance Imaging Contrast Agents

Although intrinsic contrast is sufficient for most MRI

ligand to reduce toxicity. These low-molecular

Superparamagnetic iron oxide nanoparticles in brain

Signal Intensity curves on

hyperintense. It should be noted that the transverse

Superparamagnetic iron oxide nanoparticles in brain

Generally, the r1/r2 ratios decrease with increasing

Diagnostic and potential therapeutic

There are B16,900 new cases of primary CNS tumors

borne molecules (Banks, 1999). Micrometastases that

Superparamagnetic iron oxide nanoparticles in brain

including dynamic susceptibility contrast (DSC). The

Molecular Imaging of Inflammation with Ultrasmall

Molecular imaging is an important new diagnostic

interact in their microenvironment in vivo (Thorek et

Superparamagnetic iron oxide nanoparticles in brain

well characterized in humans, but may be implicated

quantifying the fate of transplanted cells in vivo

Superparamagnetic iron oxide nanoparticles in brain

Monitoring Antiangiogenic Therapy in Central

The blockade of neoangiogenic signaling pathways is

neoangiogenesis. In CNS malignancies, CBV has been

Imaging Stroke with Ultrasmall Superparamagnetic

Imaging ischemic CNS lesions is time dependent.

Superparamagnetic iron oxide nanoparticles in brain

USPIOs or GBCAs, allows for the identification

stroke prevention, diagnosis, and therapy. Report

Superparamagnetic iron oxide nanoparticles in brain

have been shown to provide substantial contrast

In a single-center, open-labeled, clinical phase II

Imaging Carotid Atherosclerosis with Ultrasmall

Carotid artery atherosclerosis can be determined by

Superparamagnetic iron oxide nanoparticles in brain

inflammatory burden within the carotid atheromas

Imaging Autoimmune Disorders with Ultrasmall

of macrophages in axonal injury, but the triggers for

Superparamagnetic iron oxide nanoparticles in brain

et al, 2004). Intracellularly located USPIO particles

constant (Brochet et al, 2006). To validate the use

Imaging Central Nervous System Trauma with

The development of neuroregenerative therapies for

Superparamagnetic iron oxide nanoparticles in brain

The USPIOs may serve as useful adjuncts for