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480J Huazhong Univ Sci Technol［Med Sci］ 36(4):2016
Neuroprotective Potential of Cerium Oxide Nanoparticles for Focal
Cerebral Ischemic Stroke
Da ZHOU (周 达), Ting FANG (方 婷), Lin-qing LU (陆林清), Li YI (易 黎)#
Department of Neurology, Peking University Shenzhen Hospital, Shenzhen 518036, China
© Huazhong University of Science and Technology and Springer-Verlag Berlin Heidelberg 2016
Summary: During the previous years, with the emerging of nanotechnology, the enormous capabilities
of nanoparticles have drawn great attention from researchers in terms of their potentials in various as-
pects of pharmacology. Cerium oxide nanoparticles (nanoceria), considered as one of the most widely
used nanomaterials, due to its tempting catalytic antioxidant properties, show a promising potential in
diverse disorders, such as cerebral ischemic stroke (CIS), cancer, neurodegenerative and inflammatory
diseases. Overwhelming generation of reactive oxygen species (ROS) and reactive nitrogen species
(RNS) during cerebral ischemia and reperfusion periods is known to aggravate brain damage via sophis-
ticated cellular and molecular mechanisms, and therefore exploration of the antioxidant capacities of
nanoceria becomes a new approach in reducing cerebral ischemic injury. Furthermore, utilizing
nanoceria as a drug carrier might display the propensity to overcome limitations or inefficacy of other
conceivable neuroprotectants and exhibit synergistic effects. In this review, we emphasize on the princi-
ple features of nanoceria and current researches concerning nanoceria as a potential therapeutic agent or
carrier in improving the prognosis of CIS.
Key words: Cerium oxide nanoparticles; nanotechnology; reactive oxygen species; cerebral ischemic
stroke
Cerebral ischemic stroke (CIS) is considered as one
of the leading causes of severe disability, or even death
in the world. According to the latest statistics, it ranks the
fourth most common cause of death in the United
States[1]. The high incidence of death and disability
among CIS patients poses a significant burden on indi-
vidual patients, their families and society as a whole.
Under conditions of ischemia or reperfusion, the over-
whelming production of free radicals often leads to a
condition known as oxidative stress, which increases the
susceptibility of cerebral tissues to further injury.
Although cerium oxide nanoparticles (nanoceria)
have already been widely used in various fields, includ-
ing solar cells, oxygen pumps and gas sensors[2], their
applications on biomedical aspects still await more re-
search. Nanoceria can reversibly bind oxygen and switch
between Ce3+ (reduced) and Ce4+ (oxidized) states at
surface of particles depending on external stimuli, thus
producing a redox couple that exhibits catalytic antioxi-
dant functions[2, 3]. A large number of diseases have also
been demonstrated to be associated with dysregulation of
reactive oxygen species (ROS) levels. Recent studies
have implicated that naoceria might play an effective role
in anti-cancer[4, 5], anti-inflammation[6], neuro-protec-
tion[7–9], cardio-protection[10] therapies. Therefore, nano-
ceria have drawn increasing attention from researchers
throughout the world as a promising antioxidant agent in
many medical fields. Herein we mainly summarized po-
tential investigations and future prospects of nacoceria in
the protection against CIS.
Da ZHOU, E-mail: 18588475981@163.com
#Corresponding author, E-mail: yilitj@hotmail.com
1 ISCHEMIC STROKE AND ROLES OF OXIDA-
TIVE STRESS
1.1 Ischemic Stroke
Stroke is one of the biggest killers in the world and
accounts for nearly half of all hospitalized patients in
acute neurological cases. More than 80% of all strokes
are ischemic in origin. Presently, only recombinant tissue
plasminogen activator (rt-PA) has been approved by the
Food and Drug Administration (FDA) in US as the first
option in the clinical practice of acute CIS. The main
mechanism of rt-PA in treating acute CIS is its capability
of converting plasminogen to plasmin, thus breaking
down or dissolving blood clots so as to re-establish blood
flow reperfusion and oxygen supply in the ischemic
cerebral tissues, especially in penumbra areas. The new
protocol guideline suggests intravenous administration of
rt-PA be accomplished within 4.5 h from onset of symp-
toms[11]. However, in real clinical settings, only around
one-quarter of patients with ischemic stroke got admitted
to hospitals within this narrow therapeutic window[12, 13].
Additionally, other adverse effects such as increased risk
of intracerebral hemorrhage, ischemia-reperfusion injury,
and various contraindications have made the clinical ap-
plication of this agent less feasible. Therefore, invention
of alternative neuroprotective drugs that can efficiently
go across blood brain barrier (BBB) and confer protec-
tion to damaged ischemic tissues has become an immi-
nent issue.
Many attempts have been made so far, whereas few
successes have been achieved. Limitation of application
can be summarized as follows: (1) they are unable to
cross BBB efficiently; (2) they have unsolved, lurking
36(4):480-486,2016
J Huazhong Univ Sci Technol［Med Sci］
DOI 10.1007/s11596-016-1612-9
J Huazhong Univ Sci Technol［Med Sci］ 36(4):2016 481
toxicity to biological systems; (3) they possess a short
half-life in blood circulation; (4) they lack the ability of
being selectively taken up by targeted cells or tissues; (5)
they have poor solubility in circulation and rapid elimi-
nation; and (6) some antioxidants such as SOD and cata-
lase (CAT), can scavenge only one type of free radicals,
whereas multiple types are generated during ischemia-
reperfusion periods, thus restricted effects are expected.
1.2 Roles of Oxidative Stress
Various complicated, bizarre, poorly understood
mechanisms such as excitotoxic injury, inflammation,
oxidative stress, nitrative stress, membrane depolariza-
tion are associated with cerebral ischemia[14, 15]. When
ischemia occurs, reactive oxygen species (ROS) and re-
active nitrogen species (RNS), especially the most preva-
lent ones, including hydrogen peroxide (H2O2), superox-
ide anion (O2
−), hydroxyl radical (·OH), nitric oxide
(NO), are massively generated and accumulated, result-
ing in oxidative damage to cerebral tissues. Oxidative
damage could further induce even worse consequences
including cell apoptosis via nucleus damage, lipid
peroxidation, protein oxidation and so on[7, 16–18].
Free radicals, as intermediates or byproducts gener-
ated from sophisticated reactions in living cells, causing
the production of reactive oxygen and nitrogen species,
normally remain in a homeostatic state[19]. Within a nor-
mal range, ROS/RNS can not only help eliminate bio-
logical intermediate metabolic wastes, but also act as
essential mediators in various cell signal transduction
pathways. However, ROS/RNS can also potentially pose
deleterious effects on cells and generally be scavenged
by endogenous antioxidant systems, like enzymes includ-
ing CAT, superoxide dismutase (SOD), and glutathione
peroxidase (GSH-Px)[20, 21]. Under pathological circum-
stances, excessive accumulation of ROS and insufficient
supply of antioxidants lead to a condition, namely oxida-
tive stress. Oxidative stress has been proven to be in-
volved in a great deal of human disorders, including neu-
rodegenerative diseases, stroke, tumors, acute or chronic
inflammatory diseases. Consequently, antioxidants have
become a prevalent issue in the field of neurological sci-
ence due to their potent and promising application poten-
tial in CIS therapy[18, 22, 23].
2 INTRODUCTION OF ANTIOXIDANT ACTIVI-
TIES OF NANOCERIA
2.1 Antioxidant Activities of Nanoceria
Nanoceria, as one of the most noticeable catalysts,
offer the possibility to be investigated as a novel ap-
proach for treatment of CIS and other diseases involved
with oxidative stress. Cerium oxide, with specific fluorite
crystalline lattice structure, exhibits powerful antioxidant
capacity by reversibly binding oxygen and switching
between Ce3+ (reduced) and Ce4+ (oxidized) states (fig.
1). The valence shift creates a redox couple with a highly
reactive surface for scavenging free radicals, and this
characteristic allows nanoceria to participate in various
biological reactions[3, 24, 25]. It was reported that nanoceria
could react with various types of ROS, in particular with
H2O2 and O2
−, and possessed so called SOD-mimetic and
CAT-mimetic activities. Generally, SOD transforms the
superoxide into H2O2 and oxygen under the catalytic
effect of Cu2+ and Zn2+ while H2O2 is further eliminated
by CAT into water and oxygen.
Fig. 1 The antioxidant mechanism of nanoceria
A very classic research carried out by Self. et al[26]
showed a dramatically increased generation of H2O2 lev-
els with the addition of nanoceria and the level of H2O2
was even greater with higher ratio of Ce3+/Ce4+ in the
nanoparticles. In order to test the SOD-mimetic activity
of nanoceria, they also used ceria nanopaticles with dif-
ferent concentrations and Ce3+/Ce4+ ratios to compete
with ferricytochrome C, and found that a higher ratio
displayed more efficacy in reducing superoxides, sug-
gesting nanoceria might be a more efficient catalyst than
SOD. Moreover, a recent study by Ganesana et al[27]
found that 1 μg/mL of nanoceria was equivalent to 527 U
of SOD in terms of superoxide scavenging activity. The
same team led by Self[28] also confirmed nanoceria ex-
hibited CAT-mimetic activity in a redox-state dependent
manner, and a lower ratio of Ce3+/Ce4+ was found to be
more powerful in the presence of hydrogen peroxide.
Besides, they proved that molecular oxygen was one of
the products of the catalytic reactions. Other than the
scavenging capabilities of H2O2 and O2
−, several other
catalytic potentials were also recently confirmed. NO can
react with O2
− to form a more dangerous and lethal free
radical, peroxynitrite (ONOO−), under the facilitation of
SOD. According to the study, nanoceria might inhibit the
formation of NO or even directly act on ONOO−[7]. Inter-
estingly, Self supported this theory later by obtaining the
proof that naoceria was able to exhibit their scavenging
feature for nitric oxide radical, which was especially
prominent in the presence of nanoparticles with a lower
ratio of Ce3+/Ce4+[29]. Hydroxyl radical, if exceeds ho-
meostatic threshold, could transform into one of the most
deleterious free radicals, causing unpredictable injuries
in the biological systems. Another study drew a conclu-
sion that nanceria exhibited hydroxyl radical scavenging
activity, which was likely influenced by the size and
Ce3+/Ce4+ ratio of the particles[30]. Asati et al[31] demon-
strated that polymer-coated nanoceria possessed a unique
intrinsic oxidase ability in a slightly acidic environment
without assistance from any oxidizing agents like hydro-
gen peroxide or enzymes such as peroxidase and oxi-
dases. Furthermore, although the precise mechanisms are
not fully understandable, the possible self-regenerating
activities make this nanoparticle an astonishingly pre-
cious and useful antioxidant to be potentially applied in
biological systems. Therefore, taken the above features
together, nanoceria has been studied in various disease
models both in vivo and vitro.
2.2 Application of Nanoceria in Cerebral Ischemic
482J Huazhong Univ Sci Technol［Med Sci］ 36(4):2016
Models
Due to the multipotent enzyme-like activities, as we
mentioned in the previous context, nanoceria displays the
potential to scavenge almost all the uncontrolled ROS.
Efforts aimed at eliminating ROS for the treatment of
various disorders associated with oxidative stress injury
are being explored. Given its biological tolerability and
minimal systemic toxicity[32], nanoceria is receiving
much more attention nowadays for the purpose of being
studied as therapeutic antioxidants. Free oxygen species
such as ROS and RNS play vital roles in the ischemia
and post-ischemia processes of CIS. Therefore, nanoceria,
with the ability of targeting these free radicals, has been
proposed as a potential neuroprotective reagent in cere-
bral ischemic or other injury models in vivo and vitro.
Das and his colleagues[33] presented that nanoceria
could successfully protect cells of adult rat spinal cords
from H2O2 induced oxidative damage. Administration of
nanoceria, prepared by microemulsion methods, to a se-
rum-free cell culture model of the adult rat spinal cord
showed good functional biocompatibility, obvious neu-
roprotection and retention of neuronal function, which is
basically in agreement with a previous study, reporting
that nanoceria had a protective effect against exogenous
natural pro-oxidant, glutamate for rodent nervous system
derived HT22 cells[34]. In conclusion, nanoceria may be
proven to be a potential new therapeutic strategy for
ischemic insults and other oxidative injuries in other neu-
rodegenerative diseases.
A very classic experiment conducted by Estevez et
al[7] demonstrated that nanoceria reduced the ischemic
cell death in a hippocampal brain slice of mouse model
of cerebral ischemia. They introduced nanoceria with
doses ranging from 0.1 to 2 μg/mL into the slices at the
beginning of ischemia, and a dose-dependent reduction
in cell death was observed. In order to investigate the
appropriate timing of nanoceria administration, 1 μg/mL
nanoceria were added to the ischemic brain slices 0, 2
and 4 h after ischemia, and neuroprotective effects were
decreased in a time-dependent manner. Moreover, they
also proposed that these protective effects were due to
the scavenging activities of ROS/NOS and reduction in
peroxynitrite (formed from the reaction of NO and su-
peroxide) might be a pivotal mechanism through which
the nanoceria exert functions during the ischemic and
post-ischemic damage periods.
Interestingly, a recent review[35] concluded that tar-
geting RNS, especially peroxynitrite (ONOO−) and NO
might be a potent approach to ameliorate cerebral ische-
mia-reperfusion damage. Excessive generation of
ONOO− from the reaction of superoxide and NO, were
discovered in both middle cerebral artery occlusion
(MCAO) animal models and blood samples obtained
from CIS patients. In terms of the complicated and bi-
zarre mechanisms, ONOO− not only exhibited cytotoxic
effects through lipid peroxidation, tyrosine nitration,
DNA modification, but induced disruption of BBB via
MMPs modulation and FeTMPyP decomposition. Thus,
development of therapeutic agents with ONOO− scav-
enging ability might be a promising and novel strategy
for CIS. Actually, several peroxynitrite scavengers, in-
cluding uric acid, resveratrol, curcumin, green tea cate-
chins and caffeic acid, have been demonstrated to exert
protective effects on ischemic stroke models either in
vivo or vitro. However, there is still lack of convincing
evidence to support the neuoprotective effect of
nanoceria in cerebral ischemia-reperfusion injury, and
therefore further studies are required.
Kim and his coworkers[8] proposed the protective
effect of nanoceria against CIS in a rat model. They syn-
thesized phospholipid-polyethylene glycol (PEG) encap-
sulated nanoceria to get better colloidal stability and
lower nonspecific uptake. They found that intravenously
introduced nanoceria with optimal doses (0.5 and 0.7
mg/kg) could significantly mitigate the brain damage in
vivo, as represented by reduced infarct volumes and
apoptotic cells, and penetrate ischemic cerebral tissues,
accumulate in the peri-infarct area. In vitro, they also
demonstrated nanoceria, when added into CHO-K1 cells
which had been pre-processed with tert-butyl hydroper-
oxide (tBHP), exhibited protective effect against ROS-
induced cell death. Taken together, this study elucidated
the neuroprotective effect of nanoceria after ischemic
injury and provided possibility of the application in fu-
ture clinical practice.
3 THE POTENTIAL OF NANOCERIA: PROS AND
CONS
In recent years, application of nanoparticles them-
selves or as therapeutic carriers in the treatment of CIS
has provided endless possibilities for researchers. It was
presented that pharmacokinetics of nanoparticles in bio-
logical circumstances were greatly influenced by their
size, dosage, solubility, surface chemical modification[36].
Surface modifications with biocompatible and biode-
gradable polymers such as polyethylene glycol (PEG),
polybutylcyanoacrylate (PBCA) and poly lactic acid-co-
glycolic acid (PLGA) could remit nanoparticles from
elimination by the reticuloendothelial system (RES),
prolong systemic circulation time, increase permeability
to BBB and maintain satisfactory, sustained drug re-
lease[37, 38].
Several studies suggested that nanoparticles with
surface modifications could assist delivery of exogenous
agents such as SOD to exert biological functions. For
example, Reddy et al[39] demonstrated that PLGA
nanoparticles encapsulated SOD, when introduced into
rats of MCAO via the intracarotid route, dramatically
ameliorated ischemic insult. On the contrary, the simple
use of SOD did not show significant neuroprotective
effects. In another literature[40], N-methyl-D-aspartate
receptor 1 (NR1) targeted antibody was decorated on the
surface of SOD-loaded PBCA nanoparticles and this
composite, not only showed better permeability across
BBB and localization into cerebral tissue, but also sug-
gested efficient neuro-protection with evidence of obvi-
ously less infarct volume, reduced inflammatory media-
tors, decreased free radicals and improved neurological
behavior.
Nanoceria, as a vital component of the nanoparticle
family, has emerged as a novel therapeutic agent or vec-
tor for various intractable diseases, including cancer,
neurodegenerative disorders, ischemic stroke, radiation
associated injury[18], cardiovascular disorders, retinal
disorders by itself or as a drug carrier (table 1). However,
to date, nanoceria targeted delivery of antioxidants or
other neuroprotectives to the brain in the context of
J Huazhong Univ Sci Technol［Med Sci］ 36(4):2016 483
ischemia-reperfusion has not been elucidated yet.
Table 1 Examples of potential applications of nanoceria in other oxidative stress-associated diseases
Subjects Protocol of syn-
thesis
Doses Size Method of
entry
Duration of ob-
servation
Outcome References
1 Retinal
diseases
(1) SD rats Simple wet
chemistry
methods
1 µmol/L
or 0.344
ng to 1
mmol/L
or 344 ng
3–5 nm IV injec-
tion
1 h to 120 days
post-injection
Preferentially
taken up; non-toxic
effects on retinal
functions
[41, 42]
(2) Vldlr
knockout mice
Simple wet
chemistry
methods
172 ng 3–5 nmIV injec-
tion
1 to 4 weeks Inhibit the rise in
ROS/VEGF/the
formation of ne-
ovascular tufts
[43]
2 Neurode-
generative
disease
(1) Aβ (25–35)
incubated human
neuroblastoma-
SH-SY5Y cells
(ATCC)
PEG-CNPs-Aβ
Ab (CNPs-Ab)
200
nmol/L
3–5 nm / 20 h Non-toxic to neu-
ron cells; selec-
tively delivered to
Aβ plaques
[44]
(2) Murine
model of EAE
Citrate/EDTA
coated CeNP
10, 20
and 30
mg/kg
2.9 nm IV via tail
vein
/ Able to penetrate
brain, reduce ROS,
alleviate clinical
symptoms
[9]
3 Cardio-
myopathy
(1) MCP-1 trans-
genic mice
NanoActive™
cerium oxide
nanoparticles
(NanoScale mate-
rials, Inc, USA)
15 nmol 7 nm IV via tail
vein
Twice a week for
2 weeks
Protect against the
progression of car-
diac dysfunction
and remodeling
[10]
(2) CPC / 10, 25,
and 50
μg/mL
5–8 nm / 1, 3 and 7 days Protect CPC from
H2O2 induced
cytotoxicity
[45]
4 Cancer (1) Human bron-
choalveolar carci-
noma-derived cell
line (A549)
Homogenous
nucleation
method
3.5, 10.5,
and 23.3
μg/mL
20 nm / 24, 48 and 72 h Decrease cell vi-
ability significantly
[46]
(2) Squamous
tumor cells SCL-
1/ human dermal
fibroblasts/ myo-
fibroblastic cells
Dextran-coated
nanoparticles
50, 150,
300
μmol/L
5 nm / 24/48 h Increase ROS lev-
els; lower the inva-
sive capacity
of tumor cells
[47, 48]
5 Chronic
inflamma-
tion
J774A.1 murine
macrophages
Simple wet chem-
istry methods
0 to 10
μmol/L
5 nm / 24 h nanoceria
pretreated; vari-
ous time sets for
observation
Protect against
ROS damage; sup-
press iNOS protein
levels
[6]
IV: intravitreal; SD: Sprague-Dawley; EAE: experimental autoimmune encephalomyelitis; CPC: cardiac progenitor cells; MCP:
monocyte chemoattractant protein
Many studies reported that nanoceria were biocom-
patible and able to penetrate brain tissues. For example,
to investigate whether nanoceria could cross the BBB
and further exhibit the free radicals scavenging abilities,
Portioli et al[49] injected in-house synthesized nanoceria
into living animal models and 24 h later, they found the
presence of fluorescein isothiocyanate conjugated
nanoceria, also in limited amount, in the cerebral tissues
under confocal microscopy and electron microscopy.
Heckman et al[9] demonstrated that custom-synthesized
nanoceria, when introduced intravenously to mice with
autoimmune encephalomyelitis of multiple sclerosis, was
able to pass through the brain to lower the level of ROS
and ameliorate clinical symptoms. Another report pre-
sented by Kim[8] also analyzed the biodistribution of
nanoceria in a rat ischemic stroke model and confirmed
that intravitreal administered PEG-encapsulated particles
were increased markedly in the penumbra area of the
ischemic hemisphere.
Many pilot studies have proven that nanoceria is
non-toxic. Hirst and colleagues[6] introduced nanoceria
into mice and tracked them for one month; the result
revealed that nanoceria were well tolerated and no obvi-
ous toxicity was found. Additionally, a recent published
paper also suggested that nanoceria only selectively tar-
geted cancerous cells, but normal structures in the organ-
ism were exempted from them[32]. However, in contrast
to the above positive evidence, some researchers re-
484J Huazhong Univ Sci Technol［Med Sci］ 36(4):2016
vealed relatively unsatisfactory aspects of nanoceria. Ma
et al[50] concluded that exposure of nanceria to rats in-
duced pulmonary inflammation and damage, possibly via
alveolar macrophages involved cellular signaling path-
ways. Later, the same laboratory conducted another ex-
periment aiming at clarifying the mechanisms underlying
the pulmonary injury caused by intra-tracheal instillation
of nanoceria; the results showed that nanoceria contrib-
uted to the over-expression of a variety of pulmonary
fibrosis-associated mediators, including hydroxyproline,
TGF-β1, OPN, MMPs, some of which were increased in
a time- and/or dose-dependent manner[51]. Furthermore, it
is worth noticing that numerous parameters, such as sur-
face charge, pH, particle size, surface coating, and ratio
of Ce3+/Ce4+ might endow naoceria with distinct toxicity,
stability and even catalytic abilities[4, 52–55]. Given the
possible application of nanoceria in central nervous sys-
tem (CNS), concerns regarding neurotoxicity have arisen,
although no overt adverse effect on neuronal cells or
cerebral tissues in neurodegenerative or ischemic models
has been reported so far.
Das et al[33] reported the possible autoregenerative
mechanism of nanoceria. As has been stated before,
nanoceria exhibited both SOD-mimetic and CAT-
mimetic activities. Therefore, when we combine them
together, a possible non-stop recycle reaction might oc-
cur, which may render it to become a valuable antioxi-
dant with self-cycling potential. This new antioxidant
candidate would be different from other antioxidants in
that no repetitive dose is needed. Furthermore, nanoceria
could also scavenge other free radicals, such as nitric
oxide radical, peroxynitrite anion and even hydroxyl
radical, all of which are well-known to exacerbate neu-
ronal insult and cytotoxicity in cerebral ischemia-
reperfusion period (fig. 2).
Fig. 2 Potential advantages for application of nanoceria in
cerebral ischemic stroke
Similar to other nanoparticles, novel development of
nanoceria-based drug delivery or targeting systems are
also appearing in recent years. A research group pro-
posed to use nanoceria as a carrier for carboxybenzene-
sulfonamide, a type of human carbonic anhydrase, to
investigate the potential application in glaucoma therapy;
successful derivatization and therapeutic effects were
later observed both in vivo and vitro[56]. In another study,
transferrin-conjugated nanoceria were demonstrated to
improve selective uptake by cancer cells[57]. Furthermore,
in terms of neurodegenerative disorders, Li et al[58] de-
scribed the synergistic protective effects were obtained
when nanoceria capped H2O2-responsive controlled drug
release system was applied for the treatment of Alz-
heimer’s disease. Taken together, it is easy to get
nanoceria modified due to the ultra-small particle size
and unique chemical structure. Nanoceria exhibit better
biocompatibility, longer survival time in systemic circu-
lation and better permeability across microcirculation
after surface coating/modification with hydrophilic or
amphiphilic biodegradable polymers such as PEG and
PLGA. Additionally, when combined or incorporated
with other targeting agents that pose affinity to specific
protein, cell or tissue, nanoceria might exert more strik-
ing synergistic effects on enormous disease models. Un-
fortunately, there are only a handful studies concerning
nanoceria application in ischemic stroke, and more in-
vestigations are anticipated.
4 CONCLUSIONS AND PROSPECTS
CIS has been demonstrated to be associated with
multiple bizarre, poorly understandable pathological
mechanisms such as excitotoxic injury, inflammation,
oxidative stress, nitrative stress and apoptosis. Many of
these mechanisms are influenced by free radicals includ-
ing H2O2, O2
−, HO–, NO and ONOO−. Overwhelming
generation and accumulation of these free radicals during
the ischemia-reperfusion periods may further exacerbate
ischemic damage to cerebral tissues. Given that, target-
ing the deleterious free radicals may provide promising
advances in ameliorating insults and improving out-
comes in clinical research and therapy of CIS. Nanoceria
possess unique antioxidant features owing to coexistence
of Ce3+ (reduced) and Ce4+ (oxidized) ions, rapid shifting
between these two states and oxygen-vacancy defects.
Previous studies have also confirmed that nanoceria have
multiple free racial scavenging enzyme-like properties.
Furthermore, good biocompatibility, longer systemic
circulation, better BBB permeability are all vital factors
for any administered therapeutic agents to enter brain
and exert efficient functions in cerebral ischemia, which
could be easily achieved through surface modification
with biodegradable and non-toxic polymers, such as PEG,
PLGA. Utilizing polymermodified nanoparticles as drug
carriers has indicated enormous potential in the treatment
of CIS, whereas evidence concerning nanoceria is still
lacking.
Notwithstanding, a broad range of issues concerning
toxicological, biological and pharmacological profiles
still needs to be addressed. Contrary to the majority of
published literature, some presented toxicity and poor
biocompatibility of nanoceria in vivo or vitro, which
could possibly be explained by different synthetic proto-
cols, thus with distinct particle sizes, chemical or physi-
cal structures, surface modifications; all of these features
might exert undefined, equivocal effects on its pharma-
cokinetics including absorption, distribution, metabolism,
excretion and catalytic properties in biological systems.
In addition, methodological differences in administered
doses, routes or even individual skills might alter its be-
havior and therapeutic effect. It has been suggested that
nanoceria could exert pro-oxidant effects, thus increasing
the generation of ROS, or even inducing apoptosis. Al-
though explanation for this discrepancy from well-
known antioxidant features has not been fully elucidated
yet, environmental pH, especially an acidic milieu, is
likely to transform nanoceria into oxidants[4, 26]. More-
over, pro-oxidants might be provoked due to a series of
signal transduction cascades induced by possible interac-
tion between nanoceria and different cells. Therefore,
more detailed and systematic investigations based on
J Huazhong Univ Sci Technol［Med Sci］ 36(4):2016 485
standardized protocols of synthesis and utility, toxicol-
ogy and biocompatibility in experimental models which
mimic biological internal environment are required, es-
pecially if our definitive purpose is to put nanoceria onto
clinical application, such as in treatment of ischemic
stroke and other neurodegenerative diseases.
Preclinical evidence has clarified that some peptides
possess pivotal roles in the pathological cascades during
ischemia-reperfusion periods; and therefore inhibition or
promotion of one or more peptides might exert notable
efficacy in the therapy of cerebral ischemia, particularly
in the context of inflammation, edema and apoptosis.
Up-regulation of integrin alpha v beta 3 has been re-
ported in the context of cerebral ischemia, and selective
inhibition of this integrin showed significant improve-
ment after ischemic damage in vivo[59, 60]. Kim et al[8]
also concluded that PEG-coated nanoceria conferred
protection to the cerebral tissues. Therefore, continued
efforts will be needed in future research, intending to test
and analyze the neuroprotective effects of alpha v beta 3
inhibitor and nanoceria separately in acute ischemic
stroke models. Furthermore, we propose utilizing possi-
ble biological composite carrier alpha v beta 3 inhibitor-
CeO2-NPs to investigate its biocompatibility, bio-
distribution, stability, and the synergistic effect against
ischemic stroke in vivo, hoping that it could serve as a
potential new type of highly efficient, targeted control-
released carrier to deliver neural protective drugs for the
treatment of CIS.
Conflict of Interest Statement
The authors declare that there is no conflict of interest
with any financial organization or corporation or individual that
can inappropriately influence this work．
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(Received June 2, 2015; revised June 15, 2016)
