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Clinical applications of iron oxide nanoparticles

for magnetic resonance imaging of brain
tumors

Article in Nanomedicine · March 2015

DOI: 10.2217/nnm.14.203 · Source: PubMed

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Clinical applications of iron oxide

nanoparticles for magnetic resonance
imaging of brain tumors

Current neuroimaging provides detailed anatomic and functional evaluation of brain Michael Iv*,1, Nicholas
tumors, allowing for improved diagnostic and prognostic capabilities. Some challenges Telischak1, Dan Feng2,
persist even with today’s advanced imaging techniques, including accurate delineation Samantha J Holdsworth3,
of tumor margins and distinguishing treatment effects from residual or recurrent Kristen W Yeom2
& Heike E Daldrup-Link2
tumor. Ultrasmall superparamagnetic iron oxide nanoparticles are an emerging tool 1
Department of Radiology, Stanford
that can add clinically useful information due to their distinct physiochemical features University & Stanford University Medical
and biodistribution, while having a good safety profile. Nanoparticles can be used as Center, Stanford, CA 94305, USA
a platform for theranostic drugs, which have shown great promise for the treatment 2
Pediatric Radiology Section, Department
of CNS malignancies. This review will provide an overview of clinical ultrasmall of Radiology, Lucile Packard Children’s
Hospital, Stanford University, Stanford,
superparamagnetic iron oxides and how they can be applied to the diagnostic and
CA 94305, USA
therapeutic neuro-oncologic setting. 3
Department of Radiology, Lucas Center,
Stanford University, Stanford, CA 94305,
Keywords:  brain tumor • ferucarbotran • ferumoxtran • ferumoxytol • macrophage • MRI USA
• ultrasmall superparamagnetic iron oxide nanoparticles *Author for correspondence:
Tel.: +1 650 725 5384
Fax: +1 650 498 5374
Neuroimaging plays an important role in between treatment effects that arise from miv@ stanford.edu
patients with brain tumors. It provides for chemoradiation and true disease progres-
detailed anatomic evaluation of intracra- sion [11–17] .
nial neoplasms for surgical localization and This article provides an overview of current
intervention, and it allows for biological and clinical applications of ultrasmall superpara-
physiological characterization of these lesions magnetic iron oxide (USPIO) nanoparticles
to diagnose, prognosticate, assess treatment for use in MRI of brain tumors. We begin by
effects and monitor therapeutic responses. introducing the physiochemical, biodistribu-
Several MRI techniques have been employed tion and safety profiles of these agents and
to acquire such information including imag- then discuss their diagnostic capabilities in
ing with gadolinium-based contrast agents, detecting and characterizing tumor, imaging
perfusion-weighted imaging, diffusion- treatment effects and monitoring response to
weighted imaging and proton magnetic reso- therapy. Within this context, we review the
nance (MR) spectroscopy [1–10] . However, preclinical and clinical data present in the lit-
some challenges remain with current imag- erature. Finally, we highlight key therapeutic
ing that can impact survival and quality of uses of iron oxide nanoparticles in the man-
life in patients with brain cancer. These chal- agement of central nervous system neoplasms
lenges include the abilities to precisely delin- including delivery of drugs and monitoring
eate tumor margins for surgical resection (as stem cell therapies.
tumor cells can often be found outside areas
of enhancement or nonenhancing T2 signal Iron oxide nanoparticles
abnormality); to differentiate benign post- Iron oxide nanoparticles currently used in the
operative changes (such as blood products clinical arena are classified into two groups
and enhancement) from potential residual based on their mean hydrodynamic particle
part of
tumor following surgery; and to distinguish size: superparamagnetic iron oxide (SPIO)

10.2217/NNM.14.203 © 2015 Future Medicine Ltd Nanomedicine (Lond.) (2015) 10(6), 993–1018 ISSN 1743-5889 993
Review  Iv, Telischak, Feng, Holdsworth, Yeom & Daldrup-Link
and ultrasmall superparamagnetic iron oxide (USPIO)
particles. SPIOs have a mean particle diameter greater
than 50 nm, whereas USPIOs have a mean diameter of
less than 50 nm [18] . Due largely in part to their smaller
size and longer blood half-life, USPIOs are better suited
for neuro-oncologic imaging [19] and are the focus of
this review. USPIO particle design is similar between
available formulations but key differences exist in the
nature of the coating, particle size and particle charge.
As a class, USPIOs are characterized by high longitudi-
nal (r1 = 1/T1) and transverse (r2 = 1/T2) relaxivities.
These ‘T1- and T2-reducing’ agents can be used to rep-
resent the degree of contrast agent uptake within a tis-
sue [20–22] . Higher relaxivity agents allow for improved
quality of imaging and lesion depiction [22,23] .
There are currently three USPIOs that are under-
going clinical evaluation as a MR contrast agent:
ferumoxtran-10, ferumoxytol and ferucarbotran
C  [21,24–26] . Table 1 summarizes the physiochemical
features of these USPIOs, none of which is approved
for therapeutic or diagnostic use in children.
Ferumoxtran-10 (Sinerem™; Guerbet, Paris, France
and Combidex™, AMI-227; Advanced Magnetics,
MA, USA) is a first-generation USPIO that has to be
administered as a slow infusion in order to avoid hypo-
tensive side effects. It has the longest blood half-life of
the three USPIOs. The agent has been used in Phase
I to Phase III clinical trials, primarily for lymph node
imaging  [27–30] , but did not achieve US FDA approval
due to inconclusive impact on patient management
and was discontinued by the pharmaceutical industry.
Recently, ferumoxtran-10 has been re-introduced to
clinical trials in Europe.
Ferumoxytol (Feraheme™, AMI-7228, Advanced
Magnetics) is a second-generation USPIO with a car-
boxymethyl dextran coating that allows for adminis-
tration as a bolus without mast cell degranulation [31] .
Of the three USPIOs, ferumoxytol has the fastest r1
and r2 relaxivity, allowing for improved lesion detec-
tion compared with the other agents. On 30 June
2009, the US FDA approved ferumoxytol for the treat-
ment of iron deficiency anemia in adults with chronic
kidney disease [32] . More recently, the agent was also
approved for anemia treatment in Canada and several
countries in Europe. Thus, ferumoxytol has the advan-
tage of being immediately and widely available for
clinical imaging of inflammation and tumors through
utilization as an ‘off label’ agent.
Ferucarbotran C (Supravist™, SHU 555 C, Scher-
ing AG) is a carboxy-dextran-coated USPIO and has
the smallest hydrodynamic diameter of the three
USPIOs. This agent has been approved for clinical
use in Europe, but was recently discontinued by the
pharmaceutical industry.
994 Nanomedicine (Lond.) (2015) 10(6)
Biodistribution & metabolism
After intravenous injection, USPIO nanoparticles cir-
culate in the lumen of blood vessels (vascular phase),
transiently escaping sequestration and phagocyto-
sis by macrophages of the reticuloendothelial system
(RES), which is comprised of the liver, spleen, lymph
nodes and bone marrow (Figure 1) . This phenom-
enon leads to a prolonged blood half-life compared
with the larger SPIO. USPIOs do not extravasate
across intact vascular endothelia into the interstitial
space because of their relatively large size [24,26,33] .
As such, USPIOs (particularly ferumoxytol due to
its ability to be administered as a bolus) can serve as
good vascular blood pool agents during the first-pass
(arterial) and equilibrium (delayed) phases of imag-
ing (Figure 2)  [34–38] . In tumors or other tissues with
increased microvascular permeability, the nanopar-
ticles gradually cross a disrupted blood–tissue barrier
and enter the interstitium (‘interstitial phase’), where
they exert T1 and T2 signal effects on MR [24,26,33] .
The positive T1 signal effect (increased signal inten-
sity on T1) is dependent on the quantity of protons
and their degree of interaction with USPIOs [24,39–41] .
Therefore, T1-effects are more pronounced for inter-
stitial compared with intracellular iron. On the other
hand, the negative T2 and T2* signal effect (decreased
signal intensity on T2- and T2*-weighted MR images)
is less dependent on iron oxide compartmentalization
(Figure 3)  [42] . While the exact route of transport of
USPIOs across an altered blood–brain barrier has not
yet been fully elucidated, proposed mechanisms that
may help to explain increased vascular permeability in
tumors include presence of endothelial fenestrations
and/or interendothelial junctions and increased trans-
port of particles via a single vesicle or chain of vesicles
through endothelial cells [43–47] . Moreover, the rate
of USPIO leakage across the blood–brain barrier also
depends on the histologic type of tumor; for example,
Beaumont  et al. observed that during a specific time
frame, ferumoxtran-10 remained intravascular in a rat
C6 glioma model but extravasated in a RG2 glioma
model [48] .
Several hours to days after USPIO administra-
tion, nanoparticles are slowly phagocytosed by
macrophages in the tumor interstitium (‘cellular
phase’)  [33] . Iron oxides in macrophages cause a pre-
dominant T2 and T2* effect but have a markedly
diminished T1-effect compared with that of the
interstitial phase [39,49] . Some residual ‘free’ iron
oxide particles in the interstitium diffuse back into
the blood pool once their interstitial concentration
exceeds their blood concentration. Other ‘free’ iron
oxides may be retained in necrotic tumor areas result-
ing in a marked T1-effect, which may help to dif-
future science group
 Iron oxides for neuro-oncology  Review

ferentiate these necrotic areas from intracellular iron

relaxivity
oxides [Golovko et al., Unpublished Data] .

(mM -1s-1)
Following phagocytosis, intracellular nanoparticles

60‡
83†
53†
in macrophages are slowly metabolized and cleared by

r1 relaxivity r2
the RES with biodegradation predominantly occur-
ring within lysosomes [33,50–53] . Elemental iron (ferri-

(mM -1s-1)
tin) contained within the nanoparticles is incorporated
into the body’s iron stores or is transferred to plasma

38†

24‡
23†
transferrin for incorporation into hemoglobin within
red blood cells. The dextran coat of ferumoxtran-10

half-life in half-life in
is cleaved by intracellular dextranases and excreted

humans

10–14 h
Blood
almost exclusively through the kidneys. The small

>24 h

6h
remainder is excreted in feces [21,54] . The carboxy-
methyl dextran coating of ferumoxytol is negligibly
degraded by dextranases when it is used to treat ane-

rodents

67 min

35 min
Blood
mia, and the amount of low molecular weight dex-

2–3 h
trans actually released from the coating and retained
in the kidneys is probably quite low although this has

Hydrodynamic
not yet been well defined [Claire Corot & Jean-Marc Idee,
Pers. Comm.] . Due to this overall slow metabolic process,

size (nm)
MR signal intensities of RES tissues gradually return

20–50

28–32
to baseline after several weeks [33] . There is currently Table 1. Physiochemical features of ultrasmall superparamagnetic iron oxide nanoparticles.†

20
no data available that reports how long USPIOs are
retained in tumors.
core (nm)
5.8–6.2

6.4–7.2
Size of
crystal

Safety

<5
Since the development of the first USPIO over two
decades ago, USPIOs have been tested and used as a
MR contrast agent in thousands of patients [50] . They
Carboxy-dextran

Carboxy-dextran
are generally well-tolerated when used in single dose.
Bernd  et al. examined 37 Phase I to Phase III clini-
Dextran T-10

cal trials for ferumoxtran-10 in 1777 adults. A total

Coating

of 23.2% of all patients had at least one adverse event,

86.3% of which were graded as mild to moderate in
severity. Common adverse events included back pain,
pruritus, headache and urticaria. About 2.6% of the
Ferumoxytol (Feraheme™; Advanced Magnetics) AMI-
Combidex™; Advanced Magnetics, MA, USA) AMI-227
Ferumoxtran-10 (Sinerem™; Guerbert, Paris, France;

patients developed severe adverse events, although only

Ferucarbotran C (Supravist™; Schering AG, Berlin,

0.42% of these events were considered to be treatment-

related (e.g., decreased oxygen saturation, chest pain,
dyspnea and skin rash). There were 12 deaths, but only
one was attributed to ferumoxtran-10 (anaphylactic
shock)  [55] . These findings are consistent with a pre-
vious Phase III trial in 152 adults, in which 28% of
all patients had one or more adverse effects [28] . Other
USPIOs have similar safety profiles. A Phase II clinical
trial showed that 22% of 63 subjects receiving feru-
Data taken from [21,24,25,26].

glose (Clariscan™, Amersham Health, UK) developed

Germany) SHU 555 C

mild-to-moderate adverse events, and no subject devel-

oped serious adverse effects [56] . Ferucarbotran C was
At 0.47T and 40°C.
At 0.47T and 39°C.

also well tolerated in all subjects in a Phase I clinical

trial [57,58] .
While most USPIOs have only been tested as con-
Name

7228

trast agents using a single dose, ferumoxytol showed

a satisfactory safety profile in adult patients with
†
‡

future science group www.futuremedicine.com 995

Review  Iv, Telischak, Feng, Holdsworth, Yeom & Daldrup-Link

Vascular phase Interstitial phase Cellular phase

Disrupted
blood–brain barrier

Tumor blood vessel

Normal blood vessel

Intact blood–brain barrier

Endothelium Tumor cell

Macrophage Iron oxide nanoparticle

Figure 1. Biodistribution of ultrasmall superparamagnetic iron oxide nanoparticles. Ultrasmall superparamagnetic iron oxides
(USPIOs) distribute and remain in the intravascular space early after injection (vascular phase). Tumors that cause increased
permeability allow for slow leakage of these particles into the interstitial space (interstitial phase). An intact blood–brain barrier
shields USPIOs from entering the interstitium of normal brain tissue. Over time, USPIOs are progressively phagocytosed by cellular
agents such as tumor-associated macrophages/microglia, astrocytes (not shown) and, to a lesser extent, primary tumor cells (cellular
phase). The blood–brain barrier is depicted in a simplified form for illustration purposes.

chronic kidney disease when used in a two-dose
regime  [32] . An FDA report following its approval as
an iron supplement showed that out of 1726 subjects
recruited in three randomized clinical trials, 3.7%
of patients developed adverse events associated with
hypersensitivity (e.g., rash, urticaria, pruritus, wheez-
ing) and only 0.2% developed serious hypersensitiv-
ity reactions (anaphylaxis). Although hypotension is
another concerning side effect with iron oxide use, it
only occurred in 1.9% of all subjects. It is more com-
mon with rapid bolus injections and can be alleviated
or avoided with slow injections. Other common but
less-severe adverse events (observed in greater than
1% of subjects) included nausea, dizziness, peripheral
edema, headache, edema, vomiting, abdominal pain,
chest pain, cough, pyrexia, back pain, muscle spasm
and dyspnea [32] .
The rates of adverse reactions observed with USPIOs
are similar to but slightly higher than those seen with
gadolinium-based contrast agents. For the latter, the
frequency of all acute adverse events after administra-
tion ranges from less than 1 to 2.4%, the vast majority
of which are mild in severity [59–61] . Individuals with
a history of allergy or asthma or previous reaction to
gadolinium had increased adverse reaction rates: 3.7
and 21.3%, respectively [60] . Severe anaphylactoid
reactions, on the other hand, are extremely rare occur-
ring in only 0.001–0.01% of cases [59] . In an accumu-

996 Nanomedicine (Lond.) (2015) 10(6) future science group

 Iron oxides for neuro-oncology  Review

lated series of 20 million administered doses of a gado-
linium chelate, there were 55 cases (<0.01%) of severe
anaphylaxis and nine deaths that may have been drug-
related [61] . In addition, the administration of gadolin-
ium chelates in patients with severe renal impairment
is associated with the development of nephrogenic sys-
temic fibrosis, a widespread fibrotic tissue disorder that
is potentially fatal [62] . The occurrence rate of this dis-
order in patients with end stage renal disease exposed
to gadolinium is not yet known, although incidences
of 4.3 cases per 1000 patient-years in and around
Bridgeport, CT (a city and state in the USA) [63] and
12 cases per million inhabitants in Denmark have been
reported [64] .
As of today, various clinical trials have suggested
that USPIOs (ferumoxytol in particular) can be used
safely as contrast agents in adults. Of importance, iron
oxides are slowly metabolized in lysosomes within
macrophages, predominantly Kupffer cells within the
liver, and are not excreted via the kidneys [21,52,65] . Ele-
mental iron is deposited to the body’s iron reserve and
in the liver in the form of ferritin and/or hemosiderin.

A B

Figure 2. MRI of normal brain following ferumoxytol injection. High resolution (A) pre- and (B) immediate
post-ferumoxytol-enhanced T2*-weighted image of a healthy volunteer acquired with a 3D multi-echo
gradient-recalled echo imaging sequence at 3 Tesla. Note improved visualization of vessels on the (B) post-
ferumoxytol image due to presence of intraluminal iron oxide nanoparticles. (C) Ferumoxytol-enhanced MR
T1-weighted image shows excellent visualization of vessels in the brain confirming the utility of this ultrasmall
superparamagnetic iron oxide as a good blood pool agent.

future science group www.futuremedicine.com 997

Review  Iv, Telischak, Feng, Holdsworth, Yeom & Daldrup-Link

T2 FSE T2* FGRE FSPGR

A B C
Pre-contrast

D E F
1 h Post-contrast

G H I
24 h Post-contrast

Figure 3. MRI of a mouse brain model implanted with glioblastoma multiforme. Precontrast (A) T2 FSE, (B) T2* fGRE and (C) T1 FSPGR
images show the tumor mass in the left brain. The mass shows (D & E) decreased T2 and T2* signal intensity and (F) increased T1
signal intensity 1 h after ferumoxytol injection. 24 h after administration, there is persistent and further (G & H) decreased T2 and T2*
signal intensity and (I) increased T1 signal intensity. Of note, the high concentration of iron uptake in the tumor causes such a marked
T2* shortening effect that such areas appear dark even on T1-weighted images (F & I).
FGRE: Fast gradient-recalled-echo; FSE: Fast spin echo; FSPGR: Fast spoiled gradient-recalled-echo.

Ferritin is also incorporated into hemoglobin begin-
ning 1–2 days after injection. While the iron compo-
nent of USPIOs is not excreted through the kidneys
following its biodegradation, the leftover coating mate-
rial of feruxmotran-10 is eliminated in the urine [21,54] .
As previously mentioned, it is not yet known how the
coating material of feruxomytol is exactly degraded and
eliminated although it is suspected that the quantita-
tive amount of dextrans produced and retained in the
kidneys is low [claire corot and jean-marc idee,
pers. comm.]. This may be important because as with
other colloids, dextrans may induce acute renal failure,
usually seen after administration of high amounts of
dextran-40 or dextran-70 [66,67] . Additionally, there is a
theoretical risk of acute renal failure with ferumoxytol
due to iron-induced oxidative stress, which has been
implicated as a cause of acute renal failure in patients
with chronic kidney disease who receive intravenous
sucrose  [68,69] . It is also important to note that the
blood half-life of ferumoxytol increases and the body
clearance decreases with increasing doses. Moreover,
ferumoxytol is not removed with dialysis [70] . Despite
these potential safety risks, no ferumoxytol-induced
acute nephrotoxicity has been found in clinical stud-

998 Nanomedicine (Lond.) (2015) 10(6) future science group


ies  [32,70] . Ferumoxytol is, therefore, relatively safe to
use in patients with renal insufficiency and is not asso-
ciated with any risk of nephrogenic systemic fibrosis as
is the case with gadolinium chelates [71] . In contrast,
relatively little is known about the safety profile of
iron oxides in the pediatric population. With regard
to severe adverse effects including the reported death
associated with ferumoxtran-10 injection, evidence
has suggested that infusion dose and rate may play a
role  [55,72] . Future studies using a lower infusion rate
may result in improved safety profiles.
Brain tumor detection & characterization
USPIOs are characterized by specific tumor micro-
vascular permeability and perfusion, accumulation in
tumor interstitium and retention in tumor-associated
macrophages (TAM). Many histopathologic studies
following sampling or resection of brain tumors in
humans have shown iron oxide particles in both the
tumor interstitium and in peritumoral reactive cells
such as astrocytes, dendritic cells, microglia, TAM
and, to a much lesser degree, in viable primary tumor
cells  [19,73–77] . Similar findings have also been dem-
onstrated in rodent studies [51,78–82] . Table 2 reviews
and summarizes many of these clinical and preclini-
cal studies. Of significance is the fact that USPIOs
can be used to detect and quantify TAM [26] , which
play an important role in promotion of tumor angio-
genesis, tumor progression and metastasis [83–86] . In
fact, clinical studies have shown a correlation between
TAM density and poor prognosis, particularly with
regard to malignancy of the breast, cervix and blad-
der  [87] . While evidence for a significant correlation
between the number of TAM and prognosis has been
conflicting for human gliomas [88,89] , quantification
of TAM densities in malignant gliomas has shown
to be potentially useful for monitoring response to
new TAM-modulating immunotherapies [26] . None-
theless, USPIOs can be used as both a blood pool
agent during the ‘early’ vascular phase to probe tumor
angiogenesis and increased perfusion associated with
aggressive tumors, and as a cellular imaging agent at a
later phase [21,26,40] .
Following progressive phagocytosis of iron oxide
particles by macrophages, intracellular iron causes a
negative signal effect on T2- and T2*-weighted imag-
ing, while no observable difference is seen in tissues
without macrophage infiltration (Figure 4)  [33,40,90] .
Malignant or aggressive tumors that more readily
disrupt the integrity of the blood–brain barrier and
recruit phagocytic inflammatory cells to the tumor
microenvironment may therefore have a different
appearance than benign or nonaggressive tumors on
post-USPIO imaging [19] . This is corroborated by a
future science group
Iron oxides for neuro-oncology  Review
study by Moore et al. that found a positive linear cor-
relation (r = 0.929) between USPIO internalization
and tumor cell proliferation rate across multiple dif-
ferent cell lines including C6 glioma, 9L gliosarcoma,
U87 glioma and J774 sarcoma lines [78] . For a group
of malignant brain tumors comprised of oligoden-
drogliomas, high-grade gliomas and glioblastomas,
Neuwelt  et al. showed that the peak intensity of T1
enhancement occurs between 24 and 28 h after feru-
moxytol injection followed by progressively decreas-
ing T1 enhancement which persisted even after 72 h
post injection [31] , likely corresponding to nanopar-
ticle accumulation in the tumor interstitium followed
by TAM phagocytosis and intracellular compartmen-
talization (Figure 5) . Studies utilizing other USPIOs
such as ferumoxtran-10 and monocrystalline iron
oxide (MION) particles, a USPIO used in the pre-
clinical setting, have demonstrated similar results
with the peak intensity of T1 enhancement occur-
ring at 24 h with enhancement waning between 4 and
7 days [51,73,76] ; in these studies, ferumoxtran-10 was
evaluated in humans with predominantly high-grade
gliomas, and MION was used in rats injected with C6
glioma cells.
In a preclinical study of 13 rats implanted with
C6 glioma cells, Zimmer et al. showed increased
T1 hyperintensity and T2 hypointensity within the
brain tumors, which were most pronounced within
smaller tumors, following injection of MION. His-
tologic evaluation showed iron deposits predomi-
nantly within the cytoplasm of tumor cells, allow-
ing for sharp demarcation of the tumor and normal
brain interface [51] . In a follow-up study using 22 rats
injected with thymidine kinase-positive 9L gliosar-
coma cells, Zimmer et al. again showed increased
MION uptake within the cytoplasm of tumor cells
and endothelial cells but not within normal brain
or non-MION injected controls. A small amount of
iron was also noted in the tumor interstitium and
in reactive glial cells at the periphery of the tumor.
Potential additional MION uptake by TAM was not
investigated in these studies. Overall, the pattern of
uptake within these tumors was heterogeneous with
the largest concentration located at the tumor-brain
interface  [81] . Similar MR signal changes and histo-
logic findings were found in a study by Moore et al.
of ten rats implanted with 9L gliosarcoma cells and
injected with long-circulating dextran-coated iron
oxide (LCDIO) particles. The use of tumor cells that
expressed the green-fluorescent protein marker, anti-
dextran antibodies to visualize the dextran coating of
LCDIO particles in tumoral tissue and radiolabeled
LCDIO particles allowed for compartmental analy-
sis of iron oxide accumulation and distribution. In
www.futuremedicine.com 999
 Table 2. Summary of clinical and preclinical studies using ultrasmall superparamagnetic iron oxide nanoparticles in brain tumor imaging.

1000
Study (year) Type of USPIO used Subjects Results Ref.
  study
Rainov et al. Preclinical MION 66 rats, some injected • Iron staining showed uptake in the periphery of tumor following MION injection  [80]
(1995) with 9L gliosarcoma without bradykinin infusion
cells • Significant increase of uptake in center of tumor following bradykinin infusion,
presumably due to disruption of brain-tumor barrier
• MRI in select rats showed distribution of iron throughout the tumor, primarily
along the periphery
Zimmer et al. Preclinical MION 13 rats implanted with • Glioma cells showed increased uptake of iron oxides, demonstrated as  [51]
(1995) C6 glioma cells hyperintensity on T1 and hypointensity on T2
• Signal characteristics at MR peaked at 12 h after administration of MION and
lasted up to 5 days
• Iron staining showed uptake in tumors (cytoplasm of tumor cells) after MION
administration

Nanomedicine (Lond.) (2015) 10(6)

Zimmer et al. Preclinical MION 22 rats injected with TK- • MION accumulates in tumor cells with uptake predominantly along the periphery  [81]
(1997) positive 9L gliosarcoma • Good correlation between histology and MRI to evaluate iron oxide uptake
cells • MR showed hypointensity on T2* images along the tumor periphery with more
heterogeneous center following MION injection
Dennie et al. Preclinical MION Rats implanted with C6 • Higher ΔR2*/ΔR2 ratio obtained with MRI in tumors relative to contralateral gray  [121]
matter suggesting a higher relative density of larger vessels in tumors; good
Review  Iv, Telischak, Feng, Holdsworth, Yeom & Daldrup-Link

(1998) glioma cells

correlation with predicted histological assessment
Enochs et al. Clinical Ferumoxtran-10 4 human patients with • USPIO enhancement in tumors on T1 images less than with gadolinium [73]
(1999) brain tumors (3 primary • Less consistent findings on T2* UPSIO images
gliomas, 1 metastatic • Tumor enhancement on T1 decreased more rapidly with gadolinium than with
melanoma) USPIO over time leading to faster blurring of tumor margin
• In 1 biopsy case, areas of enhancement on T1 with USPIO corresponded to tumor;
iron deposits seen in interstitium and viable tumor cells
Moore et al. Preclinical MION 10 rats implated with • Accumulation of long-circulating dextran-coated iron oxide nanoparticles seen in [78]
(2000) 9L-GFP glioma cells tumor cells and tumor-associated macrophages
Knauth et al. Preclinical MION 36 rats divided into • Surgically induced intracranial contrast seen on T1 in all rats who were imaged  [94]
(2001) three groups with gadolinium (group 1)
• No hyperintensities caused by MION in normal rat brains or brains with surgically
induced lesions (group 2)
• No surgically induced enhancement seen in brains of rats who were initially
implanted with C6 glioma cells, partially resected and then imaged with MION
(group 3)
ADC: Apparent diffusion coefficient; BCNU: 1,3-bis(2-chloroethyl)-1-nitrosourea; DDAH: dimethylarginine dimethylaminohydrolase; MION: Monocrystalline iron oxide nanoparticles; MR: Magnetic resonance;
rCBV: Relative cerebral blood volume; SPIO: Superparamagnetic iron oxide nanoparticles; TTP: Time to peak; USPIO: Ultrasmall superparamagnetic iron oxide nanoparticles; VSI: Vessel size index.

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 Table 2. Summary of clinical and preclinical studies using ultrasmall superparamagnetic iron oxide nanoparticles in brain tumor imaging (cont.).
Study (year) Type of USPIO used Subjects Results Ref.
  study
Varallyay et al. Clinical Ferumoxtran-10 20 human patients with • No change in T1 or T2 signal intensity in 3 patients after ferumoxide  [19]
(2002) and Ferumoxides various brain tumors administration

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(SPIO) • Comparable but more variable enhancement on T1 with ferumoxtran than with
gadolinium
• All malignant tumors showed ferumoxtran enhancement
• Histology from 1 case showed distribution of ferumoxtran particles similar to MR
findings with iron uptake primarily by parenchymal cells with fibrillary processes
(astrocytes vs microglia) at tumor margin
Kostourou Preclinical NC100150 Rats implanted with C6 • Greater R2* and R2 rates and larger blood volume in glioma model  [125]
et al. (2003) glioma cells overexpressing DDAH, which metabolizes inhibitors of nitric oxide synthesis,
suggesting increased vascular development; similar VSI between this model and
wild-type glioma model
Neuwelt et al. Clinical Ferumoxtran-10 7 patients with brain • All tumors showed increased T1 and loss of signal on T2* following USPIO  [76]
(2004) tumors (6 primary administration; the effect was more pronounced on T1, where USPIO enhancing
gliomas, 1 metastatic lesions persisted for 2–5 days
unspecified) • Histochemistry staining showed iron uptake in reactive astrocytes and
macrophages (not tumor cells)
• Two patients showed enhancing lesions with USPIO not observed with
gadolinium
Tropres et al. Preclinical Ferumoxtran-10 12 rats implanted with • Null blood volume in areas of necrosis [105]
(2004) C6 glioma cells • In viable tumors, lower blood volume and higher VSI than in the contralateral
cortical area
• In the periphery, equal or higher blood volume and higher VSI than in the
contralateral cortical area
• Good correlation between VSI measurements obtained by MRI and histology
Hunt et al. Clinical Ferumoxtran-10 2 human patients with • Persistent T1 enhancement in tumoral tissue 24 h after USPIO administration as  [74]
(2005) primary gliomas detected by intraoperative MRI
• Histochemistry staining in one patient showed iron accumulation within
peritumoral reactive astrocytes (not tumor cells)
Manninger Clinical Ferumoxtran-10 5 human patients with • Variable results on T1, T2 and T2* with one patient showing increased size [92]
et al. (2005) primary central nervous and intensity of enhancing lesions on T1 and low-intensity on T2 and T2*
system lymphoma following USPIO injection compared with gadolinium, two patients showing
little difference between the two agents and two patients showing increased

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enhancement of lesions with gadolinium compared with USPIO
ADC: Apparent diffusion coefficient; BCNU: 1,3-bis(2-chloroethyl)-1-nitrosourea; DDAH: dimethylarginine dimethylaminohydrolase; MION: Monocrystalline iron oxide nanoparticles; MR: Magnetic resonance;
rCBV: Relative cerebral blood volume; SPIO: Superparamagnetic iron oxide nanoparticles; TTP: Time to peak; USPIO: Ultrasmall superparamagnetic iron oxide nanoparticles; VSI: Vessel size index.
Iron oxides for neuro-oncology 

1001
Review
 Table 2. Summary of clinical and preclinical studies using ultrasmall superparamagnetic iron oxide nanoparticles in brain tumor imaging (cont.).

1002
Study (year) Type of USPIO used Subjects Results Ref.
  study
Muldoon et al. Preclinical Ferumoxtran-10, Rats • Evaluated imaging characteristics, distribution, time course and safety of USPIOs  [79]
(2005) Ferumoxytol, and one SPIO following intracerebral injection and transvascular delivery in rat
MION, brains
Ferumoxides • No parenchymal injury after iron oxide delivery
(SPIO) • Ferumoxtran showed best visualization of brain tumor in rats implanted with
LX-1 SCLC
compared with ferumoxytol and ferumoxides; iron staining showed uptake in
reactive cells at the tumor margin and within necrotic areas with ferumoxtran
and ferumoxytol
• Less enhancement seen with other tumor models (U87 glioblastoma and CALU6
SCLC) after ferumoxtran infusion; iron staining on U87 showed uptake along the
margin of tumor and iron staining on CALU6 showed minimal uptake

Nanomedicine (Lond.) (2015) 10(6)

Murillo et al. Clinical Ferumoxtran-10 55 human patients with • T2* images less informative than T1 due to iron-induced magnetic susceptibility  [75]
(2005) 56 intracranial lesions artifact
(various brain tumors) • Increased tumor enhancement on T1 with USPIO comparable to gadolinium (seen
in 19/34 glial tumors and 7/22 nonglial tumors)
• Most iron deposits were seen in inflammatory cells in cases with surgery
although some were seen in tumor cells
Review  Iv, Telischak, Feng, Holdsworth, Yeom & Daldrup-Link

Taschner et al. Clinical Ferumoxtran-10 9 human patients with • Heterogeneous and variable pattern of USPIO enhancement on T1 when [77]
(2005) various brain tumors compared with gadolinium
• Lack of USPIO enhancement on T1 in areas of presumed radiation necrosis
• Improved delineation of vascular structures on T2* USPIO images
• Histochemistry staining showed intracellular iron deposits within macrophages
(not in tumor) in 2 patients, iron-laden macrophages at the tumor-host interface
in 1 patient, few iron deposits in intratumoral macrophages in one patient and
absence of iron uptake in 5 patients
Claes et al. Preclinical Ferumoxtran-10 Mice implanted with • In untreated group, vessel leakage within tumor and relative high tumor  [100]
(2007) U87 glioma cells, blood volume yielded good visibility with gadolinium and T2* USPIO images,
split into treatment respectively
(vandetanib) and • Loss of tumor detectability with gadolinium in treated group due to restoration
nontreatment groups of blood–brain barrier following treatment, although decreased blood volume
could be detected with T2* USPIO
Kremer et al. Preclinical Ferumoxtran-10 40 mice implanted with • Increased enhancement on T1 along the margins of tumor following USPIO  [82]
(2007) four xenografts (TCG2, administration, corresponding to iron uptake within macrophages and microglia
TCG3, TCG4, U87) (not within tumor cells) on iron stains
ADC: Apparent diffusion coefficient; BCNU: 1,3-bis(2-chloroethyl)-1-nitrosourea; DDAH: dimethylarginine dimethylaminohydrolase; MION: Monocrystalline iron oxide nanoparticles; MR: Magnetic resonance;
rCBV: Relative cerebral blood volume; SPIO: Superparamagnetic iron oxide nanoparticles; TTP: Time to peak; USPIO: Ultrasmall superparamagnetic iron oxide nanoparticles; VSI: Vessel size index.

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 Table 2. Summary of clinical and preclinical studies using ultrasmall superparamagnetic iron oxide nanoparticles in brain tumor imaging (cont.).
Study (year) Type of USPIO used Subjects Results Ref.
  study
Neuwelt et al. Clinical Ferumoxytol 12 patients with • Maximal intensity of ferumoxytol enhancement was at 24–28 h following  [31]
(2007) malignant brain tumors administration

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(10 with primary
gliomas, 1 with breast
cancer metastasis, 1
with pineal tumor)
Quarles et al. Preclinical MION 18 rats implanted with
(2007) 9L gliosarcoma cells,
split into treatment
(SU11657) and control
groups
Gambarota Preclinical Ferumoxtran-10 Mice implanted with
et al. (2008) E34 glioblastoma
xenograft, U87 glioma
cells and Mel57-
VEGF-A165 (melanoma)
cells
Serduc et al. Preclinical Ferumoxtran-10 70 mice implanted
(2008) with 9L gliosarcoma
cells, split into
treatment (microbream
radiation therapy) and
nontreatment groups
Beaumont Preclinical Ferumoxtran-10 14 rats implanted with
et al. (2009) C6 glioma cells and 6
rats with RG2 glioma
cells
Christoforidis Preclinical Ferucarbotran C 27 rats implanted with
et al. (2009) F98 glioma cells
Varallyay et al. Preclinical Ferumoxytol 17 rats implanted with
(2009) U87MG human glioma
• Gadolinium leaks out of blood vessels early in contrast to ferumoxytol which
remains intravascular in the ‘early’ phase after injection; therefore, ferumoxytol
better evaluated tumor perfusion
• SU11657 group showed significantly decreased mean vessel diameter, decreased [126]
blood volume, decreased mean transit time and increased blood flow
• All three tumor models showed increased delineation of tumor as well as [104]
evidence of vascular leakage and high blood volume following gadolinium and
USPIO administration; confirmed with immunohistochemical stainings
• Mel57-VEGF-A165 showed the highest blood volume
• U87 showed higher blood volume in the rim than in the core
• Tumor vascular morphology best seen with T2* USPIO images
• Microbeam radiation therapy group showed significant increase in mean survival  [127]
time and increase in ADC 24 h after treatment
• Radiation therapy delays the time it takes for VSI to increase in treated as
compared with untreated tumors
• No significant difference in blood volume between treated and untreated
tumors
• VSI MRI using USPIO can be combined with dynamic contrast-enhanced MRI  [48]
using gadolinium to characterize tumor microvasculature
• Blood volume fractions and VSI of C6 and RG2 gliomas correlated well with
histology
• Good correlation of Ktrans value obtained with gadolinium ± USPIO for C6 glioma
but not for RG2 glioma (USPIO extravasation observed in the latter model)
• Significantly increased visualization of tumor vascularity on T2* images with [103]
USPIO, confirmed with histopathology
• Bevacizumab significantly decreased rCBV and increased TTP (indicating  [102]
decreased permeability) in tumors; rCBV assessed with dynamic MRI

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cells with ferumoxytol and vascular permeability assessed with dynamic
gadolinium-enhanced MRI
ADC: Apparent diffusion coefficient; BCNU: 1,3-bis(2-chloroethyl)-1-nitrosourea; DDAH: dimethylarginine dimethylaminohydrolase; MION: Monocrystalline iron oxide nanoparticles; MR: Magnetic resonance;
Iron oxides for neuro-oncology 

rCBV: Relative cerebral blood volume; SPIO: Superparamagnetic iron oxide nanoparticles; TTP: Time to peak; USPIO: Ultrasmall superparamagnetic iron oxide nanoparticles; VSI: Vessel size index.

1003
Review
1004
Table 2. Summary of clinical and preclinical studies using ultrasmall superparamagnetic iron oxide nanoparticles in brain tumor imaging (cont.).
Study (year) Type of USPIO used Subjects Results Ref.
  study
Bouchet et al. Preclinical Ferumoxtran-10 59 rats implanted with • Microbeam radiation therapy increased the median survival time of treated rats  [124]
(2010) 9L gliosarcoma cells and significantly increased blood vessel; decreased blood volume fraction and
vessel diameter in tumors were also observed from 8 days after treatment
• Preferential damage of tumor vessels vs normal vessels with microbeam radiation
therapy
Dosa et al. Clinical Ferumoxytol 26 human patients with • USPIO enhancement on T1 in all tumors at 24 h post injection; only 16 patients  [91]
(2011) various brain tumors showed T2 hypointensity
• Lesions seen in 6 patients with USPIO in areas without gadolinium enhancement
• Ferumoxytol-rCBV significantly higher compared with gadolinium-rCBV
Gahramanov Preclinical Ferumoxytol 13 rats implanted with • rCBV of vascularized tumors with disrupted brood brain barrier is  [101]
et al. (2011) U87MG tumor cells underestimated with gadolinium without the preload method and is dose
dependent with preload

Nanomedicine (Lond.) (2015) 10(6)

• rCBVs were high and independent of preload with ferumoxytol
• Decrease of rCBV after bevacizumab treatment was dependent on dose of
preload with gadolinium whereas it was constant and independent of preload
with ferumoxytol
Lemasson Preclinical Ferumoxtran-10 60 rats implanted • Higher ADC, blood volume fraction and VSI in tumor tissue than in contralateral  [112]
Review  Iv, Telischak, Feng, Holdsworth, Yeom & Daldrup-Link

et al. (2011) with U87MG human tissue

glioblastoma cells, • Sorafenib group showed decreased blood volume fraction, increased VSI,
randomized into increased ADC and decreased tumor growth rate 4–14 days after treatment
three equally sized • BCNU group showed increased ADC and decreased tumor growth 14 days after
groups (treatment treatment; no significant change in microvascular properties
with sorafenib,
treatment with BCNU
chemotherapy, no
treatment)
Pannetier Preclinical Ferumoxtran-10 12 rats implanted with • Comparable results of VSI in brain tumor tissues and contralateral tissues [123]
et al. (2012) C6 glioma cells obtained with dynamic susceptibility contrast MRI using gadolinium and steady-
state MRI using USPIO
• Higher VSI in brain tumor tissues than in contralateral tissue
Tani et al. Preclinical P904 9 rhesus monkeys • Successful localization of subthalamic nuclei with contrast enhanced MRI  [146]
(2011) using P904 (using subtraction images obtained from pre and post T2* images
following USPIO injection)
Burrell et al. Preclinical Ferumoxtran-10 24 rats implanted • Significant decrease in fractional blood volume, decrease in plasma perfusion, [147]
(2012) with C6 glioma cells increase in hemodynamic functionality (ΔR2*carbogen) and increase in tumor
(12 treated with hypoxia following treatment
cediranib and 12 treated
with vehicle)

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ADC: Apparent diffusion coefficient; BCNU: 1,3-bis(2-chloroethyl)-1-nitrosourea; DDAH: dimethylarginine dimethylaminohydrolase; MION: Monocrystalline iron oxide nanoparticles; MR: Magnetic resonance;
rCBV: Relative cerebral blood volume; SPIO: Superparamagnetic iron oxide nanoparticles; TTP: Time to peak; USPIO: Ultrasmall superparamagnetic iron oxide nanoparticles; VSI: Vessel size index.
 Table 2. Summary of clinical and preclinical studies using ultrasmall superparamagnetic iron oxide nanoparticles in brain tumor imaging (cont.).
Study (year) Type of USPIO used Subjects Results Ref.
  study
Thompson Clinical Ferumoxytol 7 human patients (4 • Use of ferumoxytol for dynamic susceptibility weighted contrast MR and  [99]
et al. (2012) with primary gliomas, 3 gadolinium for dynamic contrast-enhanced MR during a single imaging session is

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with medulloblastomas) clinically useful to assess tumor perfusion and vascular permeability
• Tumor rCBV <1.75 suggestive of pseudoprogression rather than true progression
Gahramanov Clinical Ferumoxytol 19 human patients • With ferumoxytol and gadolinium with leakage correction, tumor rCBV values [97]
et al. (2013) with progressive ≤1.75 correlated with significantly improved survival; improved survival that was
glioblastoma following not statistically significantly was also seen with gadolinium without leakage
chemoradiation correction
Lemasson Preclinical Ferumoxtran-10 15 rats implanted with • Good correlation between steady state MRI and histology with regard to mean [122]
et al. (2013) C6 glioma cells and 12 vessel diameter, density and VSI
rats implanted with RG2 • Both tumor models showed increase in mean vessel diameter and VSI and
glioma cells decrease in density
Gutova M Preclinical Ferumoxytol Mice implanted with • T2-weighted MRI showed dynamic in vivo distribution of neural stem cells  [141]
et al. (2013) U251T.eGFP.ffluc human labeled with heparin, protamine sulfate and ferumoxytol at multiple time points
glioma cells following injection into glioma-bearing mice; results correlated with histology
• USPIO safe for clinical use
Varallyay et al. Clinical Ferumoxytol 49 human patients with • Consistent rCBV values in normal brain and tumor between steady-state imaging  [107]
(2013) various brain tumors with ferumoxytol (using a dose of 510 mg) and leakage-corrected dynamic
susceptibility contrast perfusion imaging with gadolinium; the former technique
also provided higher resolution images
ADC: Apparent diffusion coefficient; BCNU: 1,3-bis(2-chloroethyl)-1-nitrosourea; DDAH: dimethylarginine dimethylaminohydrolase; MION: Monocrystalline iron oxide nanoparticles; MR: Magnetic resonance;
rCBV: Relative cerebral blood volume; SPIO: Superparamagnetic iron oxide nanoparticles; TTP: Time to peak; USPIO: Ultrasmall superparamagnetic iron oxide nanoparticles; VSI: Vessel size index.

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Iron oxides for neuro-oncology 

1005
Review
Review  Iv, Telischak, Feng, Holdsworth, Yeom & Daldrup-Link

general, the USPIO was distributed throughout the
tumors, with the greatest amount occurring in the
tumor periphery. Iron oxide nanoparticles were iden-
tified in both the extracellular (comprised of the vas-
cular and interstitial spaces accounting for 23.5% of
the total tumor area) and intracellular (accounting
for 76.5% of the total tumor area) compartments.
Intracellular compartmentalization occurred prefer-
entially in glioma tumor cells (49%) and to a lesser
degree in TAM (21%) and tumor vascular endothe-
lial cells (6.5%) [78] . Other studies revealed that iron
oxide uptake occurs chiefly in peritumoral and intra-
tumoral macrophages/microglia and astrocytes with
minimal or no uptake in primary tumor cells [79,82] .
This suggests that areas of predominant T2 enhance-
ment and little T1 enhancement on delayed MR
images (>24h post nanoparticle injection) are
representative of TAM.
With regard to the locoregional distribution of
USPIO, Rainov et al. reported that the highest den-

Precontrast-T1w and T2w Gadoteridol 25-min ferumoxytol 24-h ferumoxytol

A B C D

E F G H

I rCBV – gadoteridol J rCBV – ferumoxytol High

Low

Figure 4. MRI characteristics of a patient with glioblastoma multiforme. (A) Precontrast and (B) gadoteridol-
enhanced T1-weighted images demonstrate an avidly enhancing left frontoparietal tumor crossing midline.
Ferumoxytol-enhanced T1-weighted image obtained (C) 25 min after injection shows faint areas of enhancement
and (D) 24 h after injection shows mixed signal intensity in the region where gadoteridol enhancement is seen. (E)
Precontrast and (F) gadoteridol-enhanced T2-weighted images. T2-weighted image obtained (G) 25 min and (H) 24 h
after ferumoxytol injection. Marked areas of decreased T2 signal are present 24 h after ferumoxytol injection. The
distribution of decreased T2 signal is similar to the area of mixed signal intensities on T1. (I & J) Color maps of relative
cerebral blood volume shows (J) high relative cerebral blood volume within the tumor on the postferumoxtyol image
but not on the (I) postgadoteridol image. The postgadoteridol image did not undergo leakage correction.
rCBV: Relative cerebral blood volume.
Reproduced with permission from [91] .

1006 Nanomedicine (Lond.) (2015) 10(6) future science group

 Iron oxides for neuro-oncology  Review

A Diameters of ferumoxytol enhancement B C

(5 GBM patients average)
Relative average diameters

2.0
1.8
1.6 T2
Fe
1.4
1.2
1.0
0.8
Gd
0.6
0.4
0.2
0
0 20 40 60 80
Time (h)

D E F G H

Figure 5. Timeline of ferumoxytol enhancement in a patient with glioblastoma multiforme. (A) Line graph
comparing average diameter changes of ferumoxytol enhancement (solid line), average diameter changes of
gadolinium enhancement (dashed) and T2-weighted signal abnormalities (dash dot) over time. (B) Gadolinium-
enhanced T1-weighted, (C) T2-weighted and (D–H) ferumoxytol-enhanced T1-weighted images of a patient with
GBM. MRIs in (D–H) were obtained at the following time points: (D) 4–6 h, (E) 6–20 h, (F) 24–28 h, (G) 48–52 h
and (H) >72 h.
GBM: Glioblastoma multiforme.
Reproduced with permission from [31] .
sity of iron stained cells following MION admin- results when compared with the preclinical studies,
istration was at the periphery of glioma xenografts, in large part due to the heterogeneous population of
which correlated with the area of highest microvas- brain tumors included in the studies [19,73–77,91,92] .
cular density. Since vascularization in most human Dosa  et al. showed that T1 enhancement was seen
gliomas is different, animal models are needed that in all 26 patients with benign (n = 3, comprised of
better reflect human tumor physiology. However, two meningiomas and one pituitary adenoma) and
the authors did make an important observation: iron malignant (n = 23, comprised of 19 primary glio-
oxide nanoparticle delivery to the tumor center could mas, one angiocentric T-cell lymphoma and three
be significantly increased after bradykinin infusion, secondary metastasis) tumors 24 h post-ferumoxytol
which increases permeability of the brain tumor bar- injection, while T2 hypointensity was detected in
rier [80] . This intervention could be used for improved only 16 patients 24 h after administration [91] . The
delivery of theranostic nanoparticles to tumors with authors did note that they observed minimal to no
limited tumor microvascular permeability. signal intensity changes at the tumor margin of the
In comparison to animal and cell-culture mod- benign lesions although they did not further elabo-
els, clinical studies of human brain tumors evalu- rate. A possible explanation for the lack of T2 sig-
ated with USPIO-enhanced imaging also suggest nal seen in some of the masses may have been due
that USPIOs undergo intravascular and tumor to the relatively lower concentration of ferumoxytol
interstitium uptake as well as subsequent intracel- used (17 ml or 510 mg diluted with 17 ml of saline
lular compartmentalization. However, these stud- regardless of body weight), which may not have been
ies have some variation in imaging and histologic concentrated enough to produce distinct T2 signal

future science group www.futuremedicine.com 1007

Review  Iv, Telischak, Feng, Holdsworth, Yeom & Daldrup-Link
effects. In addition, six patients had enhancement on
T1- and hypointensity on T2-weighted images 24 h
post-ferumoxytol injection in areas around tumor
that did not enhance with gadolinium, perhaps due
to intracellular accumulation of iron oxide particles
within macrophages. Following ferumoxtran-10
administration in five of seven patients with either
anaplastic oligodendroglioma or glioblastoma, Neu-
welt et al. also demonstrated areas of T1 enhancement
on ferumoxtran-enhanced scans that were not pres-
ent on the gadolinium-enhanced scans; the enhance-
ment extended beyond the margin of the main tumor
seen on the gadolinium images or was seen in new
lesions altogether. In one of these patients with a mul-
ticentric anaplastic oligodendroglioma, three tumor
foci that were identified on post-gadolinium images
at five month follow-up had already been apparent
on the initial preoperative post-ferumoxtran images,
but not on preoperative postgadolinium images [76] .
Extensive experience by this author and his group
has shown that tumor and its margin are best
detected by increased signal on USPIO-enhanced
T1-weighted images while T2-weighted images were
less sensitive [19,75,76] . In addition, it was noted that
T2* images showed a ‘blooming effect’ (an apparent
larger volume of tumor than seen on histology) due
to magnetic susceptibility artifact induced by the
iron oxide nanoparticles [75] .
The appearance of brain metastasis often differs
in morphology from that of a malignant glioma on
imaging. The degree of enhancement observed within
a lesion depends on the histologic type of tumor
amongst other factors that can change the permeability
of the blood–brain barrier such as abnormal vascular-
ity or drug or radiation treatment [75] . Muldoon et al.
observed that postferumoxtran enhancement was dif-
ferent in three intracerebral tumor models in rats (U87
glioblastoma, LX-1 SCLC [small-cell lung carcinoma]
and CALU6 SCLC [a second SCLC tumor model]).
Marked central ferumoxtran enhancement was seen
with the LX-1 SCLC tumor, which is a rapidly grow-
ing tumor, while minimal enhancement was seen
with the other two models, which are slower growing
tumors  [79] . Interestingly, the latter two models did
show prominent gadolinium enhancement, suggest-
ing some differential leakiness of the blood–brain bar-
rier or lack of inflammatory activity. Clinical studies
have reported on the appearance of metastatic dis-
ease in individual human patients following USPIO
administration but the results have been variable with
enhancement observed in some lesions but not in oth-
ers [31,73,75–77,91] . Future studies with larger sample size
and histologic correlation are needed to fully investi-
gate the effect of USPIO in different metastatic tumors.
1008 Nanomedicine (Lond.) (2015) 10(6)
Unlike malignant neoplasms, benign tumors tend
to demonstrate minimal or no USPIO enhance-
ment  [91] . Varallyay et al. showed only slight to mod-
erate ferumoxtran enhancement of low-grade gliomas,
hamartoma, meningioma and pituitary adenoma as
opposed to more prominent gadolinium enhance-
ment observed with these lesions. This difference may
be due to easier passage of smaller gadolinium mol-
ecules through an incompetent blood–brain barrier as
opposed to larger USPIO molecules as well as a rela-
tive paucity of phagocytic cells capable of accumulat-
ing the iron oxide particles [19] . Mixed results were
observed in a study of five patients with primary cen-
tral nervous system lymphoma who were given feru-
moxtran-10 [92] . Only one of the five subjects had more
pronounced T1 and T2 signal changes post USPIO.
In addition, Murillo et al. found variable enhance-
ment in nonglial tumors with a tendency for more
aggressive tumors such as lymphoma, metastasis and
primitive neuroectodermal tumors to enhance more
intensely after ferumoxtran-10 administration than
with gadolinium (seen in five out of 22 patients) [75] .
This may again relate to the degree of blood–brain
barrier disruption. On the contrary, malignant glial
neoplasms are more infiltrative and proliferative; they
disrupt the blood–brain barrier, promote neoangio-
genesis and recruit phagocytic inflammatory cells to
the local environment, biological events that allow for
increased signal on USPIO-enhanced images.
TAM in malignant gliomas have been associated
with tumor aggressiveness and tumor grade [88] . The
vast majority of histochemistry studies performed
in humans have overwhelmingly shown iron oxide
accumulation within peritumoral and intratumoral
reactive cells (macrophages/microglia and astro-
cytes), located primarily at the tumor margin, with
minimal or no uptake within tumor cells [19,74–77] .
Many of these studies only used cellular morphology
at staining to determine specific cell types [19,74–76] .
One study [77] did use CD68, a marker that is highly
expressed on human monocytes and tissue macro-
phages  [93] , in two patients with malignant brain
tumors (anaplastic ependymoma and glioblastoma
multiforme) to show iron deposits located in TAM
while none was found in tumor cells nor in tumor
interstitium. Therefore, ferumoxytol enhancement
in human tumors can serve as a biomarker for TAM.
Further studies in patients are needed to confirm evi-
dence from preclinical studies that TAM enhance-
ment correlates with tumor aggressiveness and
prognosis. One early study, however, did show iron
deposits within viable tumor cells and tumor intersti-
tium in a patient with recurrent grade III/IV mixed
cell glioma [73] , although it is unclear how tumor
future science group

cells were identified or if there was any assessment
for the presence of TAM.
The use of USPIOs in brain tumor imaging may
offer additional advantages over routine imaging with
gadolinium. First, due to its longer half-life, larger
size and decreased diffusion coefficient, USPIOs can
cause persistent tumor enhancement over several days
thereby bypassing the need for additional contrast
administration on short-term follow-up imaging. Gad-
olinium enhancement, on the other hand, peaks within
minutes and resolves within hours leading to progres-
sive blurring of tumor margins [73,74,76] . The prolonged
ferumoxytol-tumor enhancement could be utilized to
guide surgeries with intraoperative MR exams.
The ability to accurately differentiate postsurgical
changes following resection from residual tumor is
yet another problem not entirely solved with today’s
standard imaging. In general, an area of gadolinium
enhancement that remains after resection of a tumor
in the early postoperative period (during the first four
days after surgery) is worrisome for residual tumor [16] .
However, ‘benign’ surgically induced enhancement,
possibly a result of blood–brain barrier breakdown and
vascular injury, may also occur in the immediate post-
operative period and complicates imaging interpreta-
tion  [71,76] . In a preclinical study by Knauth et al., T1
enhancement with gadolinium was seen in all rat brains
following the creation of surgically induced lesions.
However, after MION injection, no signal change on
T1-weighted imaging was detected in a similar group.
This allowed for the detection of residual tumor using
USPIO without the confounding presence of early
postsurgical enhancement seen with gadolinium [94] . It
is important to note, however, that some clinical stud-
ies have shown that the application of hemostatic and
oxidizing agents (such as Surgicel or H2O2) during sur-
gery can influence the signal of blood products in and
around the resection cavity during the early postopera-
tive period, often with resulting prolonged T1 hyper-
intense and T2 hypointense signal [16,17] . Residual
USPIO enhancement may therefore be difficult to dif-
ferentiate from applied hemostatic agents and subacute
hemorrhage (which also appears T1 hyperintense) [76] ,
and future studies are needed to address this potential
problem.
Imaging treatment effects & therapy
monitoring
Dynamic susceptibility-weighted contrast-enhanced
(DSC) perfusion MRI is a helpful diagnostic tool in
brain tumor imaging and allows for the measurement
of tumor angiogenesis, a biomarker that can be used to
grade gliomas and assess the prognosis of patients with
gliomas  [1] . Relative cerebral blood volume (rCBV) is
future science group
Iron oxides for neuro-oncology  Review
the most widely used quantitative parameter derived
from perfusion imaging for the assessment of tumor
vascular density and proliferation [1,95,96] . High rCBV
values are associated with increased tumor vascularity
and viable tumor as well as more rapid time to progres-
sion of disease [7,95–97] . rCBV has been shown to be
helpful in differentiating residual or recurrent tumor
from treatment effects due to chemoradiation [97–99]
and can be used to monitor tumor response to anti­
angiogenic therapy [100–102] . Given these features,
rCBV may be utilized to determine short- and long-
term treatment strategies and to predict patient out-
comes. Accurate measurement of tumor rCBV is,
therefore, imperative.
USPIOs are good blood pool agents on the basis
of their long plasma half-life and macromolecular
size, qualities that allow for longer circulation time in
the intravascular space [21] . This allows for improved
visualization of tumor vascularity and blood volume
on MR [77,103–105] . In contrast to gadolinium, which
is used in routine perfusion imaging, USPIOs do not
cross a disrupted blood–brain barrier early after injec-
tion (minutes to hours) [31,101] . This is an important
quality for a reliable vascular contrast agent as early
leakage may result in underestimation of rCBV [101] .
Of the USPIOs, ferumoxytol has emerged as a good
candidate for perfusion imaging because of its abil-
ity to be injected as a bolus [34] . Dosa et al. showed
higher rCBV values obtained with ferumoxytol than
with gadolinium [91] . Comparable rCBV values were
seen following ferumoxytol and gadolinium admin-
istration but only after leakage correction techniques
were applied to the latter [97] . An alternative approach
for obtaining CBV maps is steady-state susceptibility
contrast imaging, which is feasible given ferumoxytol’s
relatively long half-life and confinement to the intra-
vascular space early after injection. Unlike with DSC
imaging, the steady-state technique does not rely on
bolus tracking, bolus arrival, or transit times, thereby,
avoiding the need to determine arterial input function.
Higher spatial resolution and distortion-free images
can be obtained with the steady-state approach allow-
ing for improved characterization and localization of
malignant tumors associated with elevated cerebral
blood volume [106,107] .
Residual or recurrent tumor may be differentiated
from chemoradiation-induced changes with rCBV
measurements  [97–99] . Gahramanov et al. evaluated
patients with glioblastomas who underwent surgi-
cal resection and chemoradiation and had conven-
tional MRI showing apparent tumor progression.
With ferumoxytol, patients with areas of suspected
tumor showing low rCBV (≤1.75) had significantly
improved survival than in those patients with tumors
www.futuremedicine.com 1009
Review  Iv, Telischak, Feng, Holdsworth, Yeom & Daldrup-Link

No contrast Gadoteridol

Before
CRT
0.1 1.0 3.0 5.0 7.0

Fe-rCBV Gd-rCBV Gd-rCBV LC

After
CRT

Fe Gd

Leakage map

Figure 6. Imaging of treatment effects (pseudoprogession) in a 73-year-old man with glioblastoma. Precontrast
and gadoteridol-enhanced T1-weighted magnetic resonance images obtained before and 3 months after
chemoradiotherapy demonstrate increased mass-like enhancement after treatment, concerning for disease
progression. The enhancing area shows no increase in rCBV on perfusion color maps obtained with ferumoxytol
(Fe-rCBV), gadoteridol (Gd-rCBV) and gadoteridol with leakage correction (Gd-rCBV LC) indicative of treatment
effects (pseudoprogression) rather than true disease progression. The leakage map shows gadoteridol contrast
leakage that can confound Gd-enhanced perfusion studies (arrow). No contrast leakage can be seen on the
ferumoxytol (Fe) image.
CRT: Chemoradiotherapy; rCBV: Relative cerebral blood volume.
Reproduced with permission from [97] .

showing high rCBV (>1.75). Low rCBV indicated
pseudoprogression (treatment effects), whereas
high rCBV indicated viable tumor (Figure 6) . Simi-
lar results were seen after gadolinium administra-
tion. However, improved survival between the two
rCBV groups became statistically significant with
gadolinium only after leakage correction techniques
were applied [97] . Thompson et al. also found that
low rCBV (<1) was suggestive of pseudoprogres-
sion in a study of seven pediatric patients with brain
tumors  [99] . In a recent retrospective observational
study of 68 patients with newly diagnosed glioblas-
toma who were, for the most part, treated upfront
with combination temozolomide and radiation ther-
apy followed by adjuvant temozolomide, DSC perfu-
sion imaging with ferumoxytol was used to differ-
entiate pseudoprogression (defined as rCBV <1.75 in
an area of gadolinium enhancement) from tumor
progression (defined as rCBV >1.75). The authors
found that the median survival was 34.7 months in
patients with pseudoprogression and 13.4 months in
patients without pseudoprogression. The longest sur-
vival (54.1 months) was seen in patients with both
pseudoprogression and MGMT gene promoter meth-
ylation [108] . The MGMT gene encodes a DNA-repair
enzyme that is associated with resistance to alkylat-
ing chemotherapeutic agents, and methylation of the
promoter region of the gene is predictive of a more
favorable response to alkylating drugs in patients
with glioblastoma [109] . These results emphasize the
importance of accurately differentiating pseudopro-
gression from tumor progression and the significant
role perfusion MRI may play in this assessment.
Relative cerebral blood volume can also be used
to monitor response to antiangiogenic therapy,
which has been used in many patients with high

1010 Nanomedicine (Lond.) (2015) 10(6) future science group


grade gliomas to target neovascularization. Among
the antiangiogenic drugs, bevacizumab (Avastin™;
Genentech, CA, USA) is a monoclonal antibody that
targets vascular endothelial growth factor [110] . Pre-
clinical studies with ferumoxytol have shown reduc-
tion in rCBV values [101,102] and decreased permeabil-
ity  [102] in tumors following bevacizumab treatment.
Decreased blood volume of tumors detected on T2*-
weighted imaging following ferumoxtran-10 admin-
istration was also reported in mice implanted with
U87 glioma cells and treated with vandetanib [100] .
A Phase I clinical trial using ferumoxytol and gado-
linium to assess differences between the effects of
bevacizumab and dexamethasone in human subjects
with high-grade gliomas is ongoing [111] . Although
the radiographic response of decreasing rCBV over
time with antiangiogenic treatment may suggest
the successful targeting of angiogenesis, this effect
has been shown to relate to normalization of tumor
blood vessels and may not hold any significance
with respect to prognosis [112–115] . In early 2014, two
large Phase III multicenter randomized control tri-
als (AVAglio study and Radiation and RTOG 0825)
evaluated the effect of adding bevacizumab to radio-
therapy-temozolomide for the treatment of patients
with newly diagnosed glioblastoma and found no
improvement in overall survival in those patients
who received first-line bevacizumab therapy [116,117] .
The AVAglio trial did find maintenance of baseline
quality of life and functional status and improved
progression-free survival with bevacizumab use [116] .
This is in contrast to the RTOG 0825 study, which
reported a greater degree of neurocognitive function
decline with bevacizumab therapy [117] . While there
are differing opinions for the current role of antian-
giogenic drugs for the treatment of newly diagnosed
glioblastomas, the trend appears to be to reserve
bevacizumab therapy for patients with recurrent
disease and/or for patients with moderate or severe
neurologic symptoms [114,118] .
Beyond rCBV mapping, USPIOs have been used
to image the tumor microvasculature with MR-based
assessment of the mean vessel diameter, microvascu-
lar density and vessel size index (VSI) [119,120] . This is
important as the formation and development of ves-
sels in cancers play a significant role in their progres-
sion and in their response to antitumor therapy [119] .
Several preclinical validation studies have shown
good correlation between MRI using iron oxide con-
trast agents and histologic determination of vessel
caliber in C6 and RG2 glioma models [48,105,121,122] .
Collectively, these studies have demonstrated
increased VSI, which represents the average vessel
caliber in an image voxel, in tumors [48,105,121–123] .
future science group
Iron oxides for neuro-oncology  Review
Therapeutic applications of this imaging technique
in the preclinical setting have been used to evalu-
ate response to angiogenic stimulus (nitric oxide),
antiangiogenic therapy, chemotherapy and radio-
therapy  [112,124–127] . Quarles et al. showed decreased
mean vessel diameter, blood volume and mean tran-
sit time as well as increased blood flow in tumors
treated with SU11657, an antiangiogenic drug [126] .
Lemasson  et al. observed that sorafenib, another
antiangiogenic agent, increased VSI and decreased
tumor growth rate 4–14 days after treatment, while
the cytotoxic drug, 1,3-bis(2-chloroethyl)-1-nitro-
sourea (BCNU), reduced tumor growth but had no
significant effect on microvascular properties [112] . In
two different studies, Serduc et al. and Bouchet et al.
showed that microbeam radiation therapy signifi-
cantly impacted the tumor microvasculature and
increased the mean and median survival time of
treated rats, respectively [124,127] . In human subjects,
there is an overall paucity of data using vessel cali-
ber imaging in the evaluation of brain tumors spe-
cifically with regard to imaging of treatment effects
(even less so with USPIOs), likely in part related to
the complexity of imaging acquisition which employs
both gradient-echo and spin-echo techniques [119] .
Although studies from Massachusetts General Hos-
pital have shown reduced vessel caliber after anti-
angiogenic therapy [113,119,128–130] , it is still unclear if
this technique will play an important role in predict-
ing patient outcomes in this setting especially given
the results of the AVAglio and RTOG 0825 studies.
Of note, it has been observed that influx of circulat-
ing proangiogenic CD11b + monocytes into tumors
can restore depleted tumor vasculature by a process
known as ‘vasculogenesis’ [131–133] . USPIOs can visu-
alize this process and may help to guide improved or
alternative treatment strategies.
Therapeutic uses of nanoparticles
USPIO nanoparticles are an emerging technology
to treat central nervous system malignancies. Their
capacity to be conjugated to antibodies and peptides
allow for specific targeting of tumors and disruption
of associated active signaling pathways, delivery of
drugs to target tissues across the blood–brain barrier,
monitoring and tracking neural stem cells used for
therapy and hyperthermic ablation of tumors in ther-
motherapy. Peptides such as RGD and F3 have been
used to target nanoparticles to molecules on the sur-
face of glioma cells [134–136] . Larger peptides such as
monoclonal antibodies and cytokines have been used
as vehicles for drug delivery. Madhankumar et al.
effectively delivered the cytotoxic drug, doxorubicin,
to implanted gliomas in mice via liposomes conju-
www.futuremedicine.com 1011
Review  Iv, Telischak, Feng, Holdsworth, Yeom & Daldrup-Link
gated with human interleukin-13. Tumors in mice
receiving this method of treatment were found to
be smaller than in those injected with nontargeted
liposomes  [137] . Hadjipanayis et al. conjugated an
antibody specific to the EGFRvIII deletion mutant
expressed by human glioblastoma cells to iron oxide
nanoparticles and delivered them to mice implanted
with glioblastoma xenografts. Significant increase
in survival was found in animals after nanoparticle
targeted cell therapy [138] . Neural stem cells have
additionally been used in conjunction with drugs
to target and treat gliomas and medulloblastomas
in preclinical studies [139,140] . These stem cells can
be monitored and tracked by preloading them with
USPIOs, a method which provides for easy identifi-
cation and detection on susceptibility-sensitive T2-
and T2*-weighted MR sequences [140–142] . Another
promising application of USPIOs is thermotherapy.
Hyperthermic ablation of tumors involves uptake
of nanoparticles within a tumor with subsequent
exposure to an alternating magnetic field, which
produces electrical current resulting in heat genera-
tion [143,144] . A prospective, two-center Phase II clini-
cal trial found that a combination of thermotherapy
using magnetic nanoparticles and reduced fraction-
ated stereotactic radiotherapy in patients with recur-
rent glioblastoma resulted in longer overall survival
following diagnosis of the first tumor recurrence. A
high concentration of nanoparticles (112 mg/ml) was
needed to generate sufficient heat within the tumor
for effective thermotherapy, with a median peak
temperature of 51.2°C within the tumor [145] .
Conclusion
Ultrasmall superparamagnetic iron oxide nanopar-
ticles are an important tool for detecting and char-
acterizing brain tumors, imaging treatment effects
and monitoring treatment efficacy. Due to their
relatively long circulation time, they can be used to
better evaluate tumor vascularity without requiring
repeat injections on short-term follow-up imaging.
Their capacity for early retention in the intravascu-
lar space also allows for more accurate assessment of
tumor perfusion and determination of relative cere-
bral blood volume, a robust imaging marker that is
important in grading cancers and predicting patient
outcomes. Due to their phagocytosis by macro-
phages, USPIOs can be used to quantify the intrin-
sic immune response to malignant gliomas, which is
associated with tumor aggressiveness and prognosis,
and to monitor new cancer immunotherapies. Thus
far, ferumoxytol has been well tolerated in patients,
and its relative kidney-independent pharmacokinet-
ics makes it a suitable alternative contrast agent to
1012 Nanomedicine (Lond.) (2015) 10(6)
gadolinium chelates for patients with chronic kidney
disease. Future potential applications include cancer-
targeted drug therapy and monitoring. The clinical
utility of iron oxide nanoparticles is continuing to
evolve as we learn more about these powerful agents.
Future perspective
The future of USPIOs in neuro-oncology is excit-
ing. Its use in diagnostic imaging may improve early
tumor detection, help distinguish between benign
and malignant tumors and further characterize
tumor microenvironment. Future studies have to
prove initial case reports that suggest that USPIOs
can delineate small malignant tumors that may not
be detected with conventional gadolinium-enhanced
MRI. Differentiating infiltrating neoplasm from
normal brain tissue is critical as this information
could alter surgical options, including biopsies and
resections. In addition, the potential of USPIOs to
monitor therapeutic efficacy via accurate measure-
ments of tumor perfusion is paramount in develop-
ing and fine-tuning treatment strategies. Quantify-
ing TAM through ferumoxytol-enhanced MRI can
be used to grade gliomas, predict prognosis and out-
comes and guide immune-modulating cancer thera-
pies. The use of USPIOs in the treatment of central
nervous system neoplasms is especially provocative
as they can be used as vehicles for cancer-targeted
chemotherapeutic drug delivery. Specifically target-
ing tumor cells and TAM with delivery of activatable
cytotoxic drugs to these targets across a formidable
blood–brain barrier can change the way we currently
treat malignancy. Other useful applications includ-
ing monitoring and tracking stem cells and other
less conventional therapies offer different avenues in
neuro-oncology.
Acknowledgements
The authors would like to thank Amy (Morris) Thomas for
helping them to design Figure 1, Michael Moseley, for provid-
ing the images for Figure 2 and Olga Lenkov for providing the
images for Figure 3. They also thank Edward Neuwelt for all of
his valuable suggestions and input.
Financial & competing interests disclosure
The authors acknowledge and thank the Stanford Depart-
ment of Radiology Angel Grant for generously supporting
their initial investigations. The authors have no other relevant
affiliations or financial involvement with any organization or
entity with a financial interest in or financial conflict with the
subject matter or materials discussed in the manuscript apart
from those disclosed.
No writing assistance was utilized in the production of this
manuscript.
future science group
 Iron oxides for neuro-oncology  Review

Executive summary
Iron oxide nanoparticles
• Ultrasmall superparamagnetic iron oxide (USPIO) particles have a mean diameter of less than 50 nm and a
relatively long blood half-life.
• USPIOs are characterized by high longitudinal and transverse relaxivities, allowing for improved quality of
imaging and lesion depiction on MRI.
Biodistribution & metabolism
• USPIOs remain in the intravascular space early after injection, allowing it to serve as a good blood pool agent.
• They gradually cross a disrupted blood–brain barrier in tumors and into the interstitial space. They are
progressively phagocytosed by tumor-associated macrophages/microglia, astrocytes and, to a lesser extent,
tumor cells.
Safety
• USPIOs are well-tolerated by patients and have a good safety profile.
• USPIOs are eliminated by the reticuloendothelial system, predominantly by hepatic macrophages (Kupffer
cells). They do not get eliminated by the kidneys and are therefore deemed safe for use in adult patients with
chronic renal failure.
• Ferumoxytol is currently US FDA approved for the treatment of iron deficiency anemia in adults with chronic
kidney disease and is, therefore, widely available for use as an ‘off-label’ contrast agent.
Brain tumor detection & characterization
• Malignant gliomas show increased T1 signal intensity and decreased T2/T2* signal intensity on
postferumoxytol magnetic resonance images.
• Signal intensity on T1 peaks at approximately 24 h and persists for days in contrast to gadolinium-based
contrast agents.
Imaging treatment effects & therapy monitoring
• Ferumoxytol allows for accurate measurement of relative cerebral blood volume, an important imaging
marker used to grade gliomas and monitor treatment effects.
• Beyond cerebral blood volume mapping, USPIOs can be used to image the tumor microvasculature with MR-
determined values of mean vessel diameter, microvascular density and vessel size index.
Therapeutic uses of nanoparticles
• Therapeutic applications of USPIOs include direct targeting of tumors, delivery of drugs to tumors across
the formidable blood–brain barrier, monitoring and tracking neural stem cells and hyperthermic ablation of
tumors.

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Iron oxides for neuro-oncology  Review
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Iron oxides for neuro-oncology  Review
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1018 Nanomedicine (Lond.) (2015) 10(6)
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delivery and targeted therapy of glioblastoma. Cancer Res.
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•• Provides excellent review of iron oxide nanoparticles in
brain tumor imaging.
145 Maier-Hauff K, Ulrich F, Nestler D et al. Efficacy and safety
of intratumoral thermotherapy using magnetic iron-oxide
nanoparticles combined with external beam radiotherapy
on patients with recurrent glioblastoma multiforme.
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147 Burrell JS, Walker-Samuel S, Baker LC et al. Evaluation
of novel combined carbogen USPIO (CUSPIO) imaging
biomarkers in assessing the antiangiogenic effects of
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131(8), 1854–1862 (2012).
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