Cerium oxide nanoparticles: properties, biosynthesis and biomedical application

Abstract

Nanotechnology is the branch of science which deals with particles ranging between 1–100 nm. These particles are called nanoparticles, and they exhibit unique electronic, optical, magnetic, and mechanical properties, which make them different from the bulk material. These properties of nanomaterials help them to find a variety of applications in the biomedical, agricultural, and environmental domains. Cerium oxide nanoparticles have gained a lot of attention as a potential future candidate for ending various kinds of problems by exhibiting redox activity, free radical scavenging property, biofilm inhibition, etc. Synthesis of these nanoparticles can be performed very easily by utilizing chemical or biological methods. But in this review, the focus is laid on the biosynthesis of these nanoparticles; as the biosynthesis method makes the cerium oxide nanoparticle less toxic and compatible with the living tissues, which helps them to find their path as an anticancer, anti-inflammatory and antibacterial agents. The pre-existing reviews have only focused on details relating to properties/applications/synthesis; whereas this review draws attention towards all the aspects in single review covering all the details in depth such as biosynthesis methods and its effect on the living tissues, along with properties, biomedical applications (diagnostic and therapeutic) and future outlook of the cerium oxide nanoparticle.

Full text

Cerium oxide nanoparticles: properties,
biosynthesis and biomedical application
Kshitij RB Singh, †Vanya Nayak, †Tanushri Sarkar
and Ravindra Pratap Singh *
Nanotechnology is the branch of science which deals with particles ranging between 1–100 nm. These
particles are called nanoparticles, and they exhibit unique electronic, optical, magnetic, and mechanical
properties, which make them different from the bulk material. These properties of nanomaterials help
them to find a variety of applications in the biomedical, agricultural, and environmental domains. Cerium
oxide nanoparticles have gained a lot of attention as a potential future candidate for ending various kinds
of problems by exhibiting redox activity, free radical scavenging property, biofilm inhibition, etc.
Synthesis of these nanoparticles can be performed very easily by utilizing chemical or biological
methods. But in this review, the focus is laid on the biosynthesis of these nanoparticles; as the
biosynthesis method makes the cerium oxide nanoparticle less toxic and compatible with the living
tissues, which helps them to find their path as an anticancer, anti-inflammatory and antibacterial agents.
The pre-existing reviews have only focused on details relating to properties/applications/synthesis;
whereas this review draws attention towards all the aspects in single review covering all the details in
depth such as biosynthesis methods and its effect on the living tissues, along with properties, biomedical
applications (diagnostic and therapeutic) and future outlook of the cerium oxide nanoparticle.
1 Introduction
Nanotechnology in the past decade has shown a momentous
growth and revolutionized the biomedical, industrial,
environmental, and material sciences domains.
1–7
It is the study
of extremely small things and its applications in various elds.
Particles of size ranging from 1 to 100 nm are considered
nanoparticles, and they exhibit higher surface to volume ratio.
8
Nanoparticles exhibit unique properties like electronic, optical,
magnetic, and mechanical properties due to their size, which
makes them different from the bulk material. There are various
types of nanoparticles: carbon nanotubes (multiwalled & single-
walled), fullerenes, metals (Au, Ag, etc.), metal oxides (zinc oxide
Mr Singh is nal year post-
graduate student of M.Sc.
Biotechnology at the Depart-
ment of Biotechnology, Indira
Gandhi National Tribal Univer-
sity, Amarkantak, Madhya Pra-
desh, India. He has good
number of publications to his
credit and has authored more
than 3 book chapters, which are
in internationally reputed press
for publications namely Elsev-
ier, Springer Nature, and CRC
Press. His research interest is in the eld of biotechnology,
biochemistry, epidemiology, nanotechnology, biosensors, and
material sciences.
Miss Vanya has completed her
B.Sc. Biotechnology from Vikram
University, Ujjain, Madhya Pra-
desh and is pursuing her M.Sc.
Biotechnology from Indira Gan-
dhi National Tribal University.
Her research interest areas are
biochemistry, biotechnology and
nanobiotechnology.
Department of Biotechnology, Faculty of Science, Indira Gandhi National Tribal
University, Amarkantak, Madhya Pradesh, 484887, India. E-mail: rpsnpl69@gmail.
com; ravindra.singh@igntu.ac.in; Tel: +91-91-0934-6565
†These authors have contributed equally to this work.
Cite this: RSC Adv., 2020, 10,27194
Received 29th May 2020
Accepted 11th July 2020
DOI: 10.1039/d0ra04736h
rsc.li/rsc-advances
27194 |RSC Adv.,2020,10, 27194–27214 This journal is © The Royal Society of Chemistry 2020
RSC Advances
REVIEW

(ZnO), cerium oxide (CeO
2
), titanium oxide (TiO), etc.),
liposome-bound, dendrimer-bound, albumin-bound, poly-
meric, quantum dots (CdSe, CdTe), magnetic nanoparticles,
etc.
9–12
Further, these nanoparticles play a very crucial role in
pollution reduction from the environment, as these nano-
particles have a large surface area, which also enables them to
be used in wastewater treatment.
13
Cerium is a member of the lanthanide group and is the most
abundant rare metal, with an atomic number of 58; it shows
3.19 eV wide-bandgap along with high excitation energy.
2
It
exhibits catalytic properties due to shielding of 5p and 4d
electrons in the 4f orbital.
14
Cerium oxide in the bulk state exists
in both +3 and +4 state, which helps them to form CeO
2
(Fig. 1)
and CeO
2x
and therefore exhibits antioxidant properties.
15,16
Free radicals are produced in a very minute amount during
normal metabolism and contain an electron in the outermost
shell. They are produced within a cell and incorporates:
superoxide (O
2+
), hydrogen radicals, lipid hydroperoxides, etc.
17
Normal oxygen metabolism yields reactive oxygen species (ROS)
as a by-product, and plays a major role in inammation which
affects normal cellular function, and further leads to pathoge-
nicity by damaging cell membranes, protein, and DNA; thus
triggering apoptosis. Further, from the investigation, it is well
known that cerium oxide nanoparticle act as a catalyst, which
mimics the feature of antioxidant enzyme superoxide dis-
mutase (SOD) and scavenges ROS or free radicals.
15,18
Due to the
high reactive surface area provided by the uorite crystalline
lattice structure of cerium oxide, it helps them in the
Fig. 1 General structure: face centered cubic structure of cerium oxide (CeO
2
) nanoparticles.
Miss Sarkar has accomplished
her B.Sc. from Indira Gandhi
National Tribal University,
Amarkantak, India and is
pursuing her M.Sc. in biotech-
nology from the same. Her
research interest areas are
nanotechnology, electrochem-
istry and material sciences. She
also holds an experience of
working in well-established
Indian Laboratories, namely
BARC and JNU. She has been
a scholar throughout and also has publications in internationally
reputed journals.
Dr Singh did his B.Sc. from
Allahabad University India and
his M.Sc and Ph.D in Biochem-
istry from Lucknow University,
India. Currently, he is working
as an Assistant Professor in the
Department of Biotechnology,
Indira Gandhi National Tribal
University, Amarkantak M.P.
India. He has previously worked
as a scientist at various
esteemed laboratories globally,
namely Sogang University, IGR,
Paris, etc. His work and research interests include biochemistry,
biosensors, nanobiotechnology, electrochemistry, material
sciences and applications of biosensors in biomedical, environ-
mental, agricultural and forensics. He has to his credit several
reputed national and international honours/awards. Dr Singh
authored over 30 articles in international peer reviewed journals
and more than 18 book chapters of international repute, and he
serves as reviewer of many reputed international journals, and is
also member of many international society.
This journal is © The Royal Society of Chemistry 2020 RSC Adv.,2020,10, 27194–27214 | 27195
Review RSC Advances

neutralization of the free radicals.
19
This nanoparticle is utilized
for making solar cells,
20
as a catalyst for fuel oxidation,
21
chemical–mechanical polarization,
22
and corrosion protec-
tion;
23
they also exhibit biorelevant activities and are considered
as potential pharmacological agents.
24
Further, the lattice
structure of cerium oxide nanoparticles forms oxygen vacancies,
which make them act as a scavenger of free radicals in the
physiological conditions.
25,26
Prior reviews
27–30
have laid focus on single aspects, namely
properties/synthesis/applications of cerium oxide nano-
particles. But this review presents the updated and detailed
development of cerium oxide (metal oxide) nanoparticle appli-
cations in the biomedical domain by considering the diagnostic
and therapeutic aspect of this nanoparticle; these nanoparticles
have gained a lot of attention in the biomedical eld in the
recent years and is still developing at a faster pace. Apart from
the biomedical application of cerium oxide nanoparticles, this
review also highlights some glimpse of cerium oxide nano-
particles application in the environmental and agricultural
elds and further elaborates its physicobiochemical properties,
various biological methods and protocols for synthesis
(biosynthesis). Biosynthesized nanoparticles have gained a lot
of attention in recent years for application in diagnosis and
therapeutics, as they are simple, efficient, and cost-effective.
6
But comprehensive review based on the biosynthesis of cerium
nanoparticles is not yet present. Thus, this review emphasizes
the biosynthesis of cerium oxide nanoparticles in detail. Hence,
this review analyzes the current status of the cerium oxide
nanoparticles in the biomedical domain along with its
prospects.
2 Physicobiochemical properties
2.1 Physicochemical properties
Cerium is the most abundant rare earth alkali element which is
listed in the F block of the periodic table, and they are found in
minerals, namely synchysite, hydroxyl bastnasite, monazite,
zircon, rhabdophane, sallanite, and bastnasite. Cerium exhibits
exceptional character of cycling between the two ionic states,
which is Ce
3+
and Ce
4+
, and this is possible due to the presence
of ground-state electron in the 4f (Xe 4f
1
5d
1
6s
2
) orbital which
enables it to exhibit redox properties. Further, the cerium oxide
nanoparticle (Ce
4
O
8
) is a face-centered cubic (fcc) uorite lattice
comprising of eight oxygen atoms bonded to the cerium atom
(Fig. 2), and the complete unit cell (Ce
4
O
8
) measures 5.1 ˚
Aonan
edge.
31
The building blocks of nanoparticles are the crystallite
nature of the particle, and in the cerium oxide nanoparticle,
polycrystallinity is more common. Generally, the crystallite unit
depends on the synthesis method, and the crystallites are
analyzed through the X-ray diffraction technique.
32
Moreover,
hierarchal assembly of the unit's cells into crystallites and
crystallites to particles can be done by self-assembly of particles
into sheets, rods, hollow variants, etc. which are larger
structures.
33
Density and molar mass of cerium is 6.770 gm cm
3
(approximately) and 140.12 g mol
1
respectively; it is malleable
and at room temperature oxidizes very readily. It also shows
excellent thermal properties with melting and boiling temper-
ature of 798 C and 3424 C respectively.
34
Cerium in its oxide
form represents the cubic uorite structure, and at the nano-
scale range, it maintains the same structure along with oxygen
deciencies, which provide it with redox reaction sites. Further,
the cubic uorite structure shows three low-index planes (100),
(110), and (111), and the dipole moments perpendicular to the
surface shows charged plane, neutral, and none respectively.
Interactions between the adsorbed molecules with the cerium's
surface are dependent on the crystal surfaces and plane prop-
erties exhibited by the cerium nanoparticles. The structure also
enhances the catalytic property. Unlike the (100) and (111),
(110) does not present the o-terminal endings, rather it has a Ce
center with O-ions (C1, C2). The ability of cerium oxide nano-
particles to exists in +3 and +4 valence states helps them to
exhibit two oxidation states, which are Ce
3+
and Ce
4+
.
35,36
Cerium oxide is highly unsaturated, which contributes to the
instability and promotes restructuring of the surface. Further,
this also affects the microstructure and physicochemical envi-
ronment, which affects their chemical reactivity. They can also
switch between two oxidation states that are from trivalent +3 to
tetravalent +4, giving them the capability to show redox reac-
tions.
37–40
The elimination of the oxygen ions by cerium oxide
Fig. 2 Structurally analyzed ceria crystals Ce
4
O
8
(unit cell); in (a) and (b) yellow color represents eight-folds of cerium atoms and red represents
four-fold oxygen atoms in ceria crystal structure; (c) is the basic fcc fluorite lattice structure of Ce
4
O
8
(reproduced from K. Reed et al.,Environ.
Sci.: Nano, The Royal Society of Chemistry, 2014 (ref. 22)).
27196 |RSC Adv.,2020,10, 27194–27214 This journal is © The Royal Society of Chemistry 2020
RSC Advances Review

leads to the non-stoichiometric and reduced metal oxide, which
clears the presence of certain binding energy between Ce
3+
and
oxygen atoms.
41
2.1.1 Oxygen vacancy. Esch and co-workers
40
utilized
scanning tunneling microscope to determine the oxygen
vacancy, and clustering of oxygen on the (111) surface of CeO
2
and further, this study revealed a better understanding of rare-
earth oxides reduction by oxidation. The absence of one or more
oxygen atom from the eight octants found in the ceria unit cell
is the concept of oxygen vacancy (Fig. 3).
31,42,43
The debate on the
charge which cerium atom has and their link with oxygen
vacancies, till date, is unanswered but many researchers have
made some assumptions like the single oxygen vacancy is due to
the reduction of the Ce
4+
atoms, and the location of resulting
Ce
3+
atom will be adjacent called as a triplet, and the reason
behind this is size and the method utilized to synthesize crystals
of ceria. Further, many researchers have tried to determine the
Ce
3+
concentration value, but all the results were contradicting
and varying.
44–46
Hence, it can be considered that particle size
decides the percentage of cerium atoms; the particle size when
decreases, the percentage of cerium atom increases and vice
versa.
Measurement of the Ce
3+
/Ce
4+
ratio can be useful to under-
stand the concentration of oxygen vacancy. Oxygen vacancy can
construct itself, and they can also be quantied by a numeral
called oxygen storage capacity (OSC). This numeral can be
expressed as oxygen micromoles released per-gram of starting
material. The OSC value of cerium dioxide in the gas phase is
1452.47 mmol per O
2
per g and can be explained from the below-
mentioned equilibrium reaction:
CeO
2
4CeO
2x
+x/2O
2
for x¼0.5 then CeO
1.5
(Ce
2
O
3
)(1)
Further, commonly used cerium oxide is prepared as micro-
or nano-scale crystals but not as a gas phase molecule. The
entirely reduced commercial cerium oxide can be just a fraction
of the OSC value calculated theoretically in eqn (1). OSC equi-
librium equation signies a reversible reaction and it justies
that this material can act as a catalyst, as it’s an idea that is
fundamental. Indeed, solid cerium oxide particles can be
assumed as oxygen buffer;
31
this provides/removes oxygen from
the surrounding environment by reacting to lack/excess of
oxygen in the existing environment. This ability to extract
oxygen atoms reversibly from the lattice can be utilized for
catalytic oxidation of various materials, namely CO and other
exhaust gases which are partially oxidized (Fig. 4).
There are two different thoughts for the mechanism of
cerium oxide on the SOD-mimetic and hydrogen peroxide
catalase. The initial thought is that the Ce
3+
/Ce
4+
ions, interact
directly to neutralize superoxide and destroy peroxide, and this
is known as the ionic mechanism. The other thought is that
SOD-mimetic and hydrogen peroxide catalase reactions proceed
by annihilation and oxygen vacancy creation with the cerium
ionic states by interchanging between +3 and +4 to support the
oxygen vacancy state. Further, referring to the ionic mechanism,
the SOD mimetic component is favored by an increase in the
Ce
3+
/Ce
4+
ratio,
47
and on the other hand, catalase reaction is
favored by a decrease in this ratio.
48
Apart from focusing on
ratios of ions, let's explore the thermodynamic aspect of the
Ce
3+
/Ce
4+
in detail by investigative dynamic reaction chemistry.
The unique and complete balanced reaction is embodied in the
eqn (2) and (3), which represents the SOD-catalytic like dis-
mutation reaction.
3Ce
4+
+3O
2

/3Ce
3+
+3O
2
(Ce
4+
reduction) (2)
Ce
3+
+O
2

+2H
+
/Ce
4+
+H
2
O
2
(Ce
3+
oxidation) (3)
2.1.2 Size and reactivity. The size of the nanoparticle does
matter in case of the reactivity, and if the cerium oxide nano-
particle size is small, it shows a greater lattice expansion which
further leads to reabsorption and decline in oxygen release; this
was explained using a comparison between lattice expansion of
bulk ceria with cerium oxide nanoparticle.
34,49,50
2.1.3 Lattice doping. The doping of transition metal and
lanthanide in the cerium oxide nanoparticle's sub-lattice helps
in the prediction of oxygen vacancy defect concentration and
particle reactivity in cerium. When the La ion was doped with
the cerium oxide, the oxygen vacancy increased with the
increase in the surface area.
51
Interestingly, another study
Fig. 3 (a) Represents the unit cell structure of cerium oxide nano-
particles and (b) represents single oxygen vacancy of cerium oxide unit
cell, where absence of one oxygen atom in left side (uppermost) and
forward octant position can be seen (reproduced from K. Reed et al.,
Environ. Sci.: Nano, The Royal Society of Chemistry, 2014 (ref. 22)).
Fig. 4 Oxygen vacancy created by CeO
2
particle while oxidizing CO
to CO
2
, and two Ce
4+
atoms were reduced simultaneously (adapted
from K. Reed et al.,Environ. Sci.: Nano, The Royal Society of Chemistry,
2014 (ref. 22)).
This journal is © The Royal Society of Chemistry 2020 RSC Adv.,2020,10, 27194–27214 | 27197
Review RSC Advances

showed a decrease in the oxygen vacancy concentration when
doped with the smallest atomic radii ion (Yb).
52
Considering a point that which type of cations can be doped
in cerium lattice, for the same, it can be assumed that cations
with low ionic radii than cerium ion can be the ideal candidate
for doping, but this is not always true. The thermodynamic
aspect specially enthalpy of incorporated dopant must be taken
into consideration, in this regard modern computational
quantum mechanical methods can be useful. Further, K. Reed
et al.
22
investigated and found that substitution of the small iron
atom of 78 pm to 97 pm cerium was endothermic by 4.3 eV per
Fe
2
O
3
unit, but in the case of 116 pm lanthanum, the substi-
tution was exothermic by 3.3 eV per La
2
O
3
unit. Hence, from the
studies, its well understood that approx. 2–4% of iron is doped
into cerium lattice in low-temperature conditions, and the iron
associated was in amorphous form.
2.1.4 Catalytic activity. Cerium oxide nanoparticles are very
capable of maintaining their catalytic behavior in harsh envi-
ronments; they can also decompose ROS by the action of cata-
lysation. Cerium oxide nanoparticles have low 3
+
/4
+
ion ratios
and thus show high catalyse mimetic activity, which is
responsible for the decomposition of a potentially harmful
oxidizing agent known as H
2
O
2
and produces H
2
O and O
2
.H
2
O
2
is the product generated from the superoxide, which is
produced in the mitochondria during the NADPH
oxidases.
48,53–55
From the earlier experiments, it is well known
that cerium oxide nanoparticles depend on the size,
morphology, etc. of the particle to show catalytic effects.
Researchers revealed that the Ce
4+
reduced by H
2
O
2
accom-
plishes by the initial reduction of Ce
4+
into Ce
3+
.
56–59
The
catalyse type activity is supposed to rely on the Ce
4+
fraction,
and further studies have shown that the smaller surface area of
large Ce
3+
fraction enhances the enzyme-like catalytic
activity.
30,48,60
An investigation was performed to identify the key
factors which affect the catalytic activity of cerium oxide nano-
particles, and this study also showed adsorption of H
2
O
2
on
cerium oxide nanoparticles surface. The observation of this
study shows that the efficacy of the disproportionation process
is modulated by adsorption of the H
2
O
2
molecules on cerium
oxide nanoparticles surface and this depends on the particle
size.
47
Hence, cerium oxide nanoparticles depend on the surface
area to the volume ration, giving them the capability to act as
a catalyst. The increase in the surface area to volume ration is
considered as the major reason behind the extraordinary cata-
lytic activity of the cerium oxide nanoparticles.
2.1.5 Optical properties. One of the most captivating and
useful properties of nanomaterials is their optical properties
and these properties usually depend on factors like size, shape,
surface, characteristics, interaction with the outer environment,
etc. There are many applications based on optical properties like
sensors, imaging, display, photocatalysis, photo-
electrochemistry, etc.
61,62
Further, variation in the nano-
materials optical, magnetic and electrical properties are caused
due to the differences in the band-gap, electrical conductivity,
and saturation magnetization. Thus, these variations make
them suitable for optoelectronic and opto-magnetic devices. To
explore the optical properties of the nanoparticles, the absor-
bance and uorescence spectroscopy is widely used.
63,64
Many investigators
65–70
have studied the optical character-
istic of cerium oxide thin lms by utilizing UV-vis transmittance
measurements. The deposition of material on the substrate to
form thin lm generates interference effects and creates oscil-
lations, which determine the spectra.
71
Hence, the amplitude of
the oscillations provides a refractive index. Higher the ampli-
tude, higher is the refractive index of the lm; an increase in the
thickness of the lm, higher is the number of oscillations.
72
Films of cerium oxide show excellent optical properties thus
offering them applications as electro-optical and optoelectronic
devices.
65,66,73–77
These lms have a high refractive index, dc
permittivity, and transparency in visible and IR (near- and mid-)
region. In every study, the values of the refractive index were
different and fall in the range of 1.6–2.4.
76,78–80
Further, the
direct band-gap falls in the range of 3.2–3.6 eV, while the indi-
rect band-gap is ranged between 2.9–3.3 eV. Cerium oxide
nanoparticles prepared by hydroxide mediated method was
having a particle size of 6.4 nm and further, studies related to
optical property was performed by utilizing UV-visible absorp-
tion and uorescence spectroscopy, which revealed that the
prepared cerium oxide nanoparticle recorded the absorbance
peak at 349 nm, and band-gap of 3.1 eV; photoluminescence
spectra (PL) showed violet emission peak at 477 nm, due to
interface traps at boundaries of grain, and PL has shown slight
emission peak at 508 nm which might have resulted due to
surface defect or oxygen defects.
81
2.1.6 Electrochemical properties. Transition metal oxides
show outstanding electrochemical properties, and this offers
them to be used as an electrode material for a variety of appli-
cations, such an example is for lithium-ion batteries, electro-
chemical sensors, electrocatalysis, and supercapacitors. Amid
all these transitional metal oxides, cerium oxide is considered
as one of the most suitable candidates for electrode material
due to its unique properties, namely higher thermal stability,
excellent oxygen storage capacity, supercial electrical diffu-
sivity, and conductivity.
82
Spherical crystalline cerium oxide
nanoparticles of diameter range 5–10 nm, synthesized from the
hydrothermal method was studied for its electrochemical
properties using galvanostatic methods, and the result signies
that the initial discharge capacity of cerium oxide fabricated
electrode was 460 mA h g
1
, which is higher than the pre-
existing carbonaceous electrode. Aer 50 cycles only 7% loss
was observed in the discharge capacity, which means it has
better cyclability.
83
Further, hexagonal cerium oxide nano-
particle was synthesized by the hydrothermal method and was
studied for electrochemical properties using cyclic voltamme-
try, ac impedance spectroscopy, and charge–discharge in
various neutral electrolytes (NaCl, KCl, Na
2
SO
4
, and K
2
SO
4
). The
result demonstrated that maximum capacitance was observed
in NaCl electrolyte, which was around 523 F g
1
at 2 mV s
1
.
While checking for cyclability only an 18% decline in capaci-
tance was observed aer 2000 cycles. Hence, from this study, it
can be emphasized that NaCl is the best neutral electrolyte for
cerium oxide-based supercapacitor electrodes.
84
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RSC Advances Review

2.1.7 Magnetic properties. Cerium oxide nanocrystals
exhibit physical properties that grab the attention of
researchers, such an example of this property is ferromagnetic
behavior. Collective interaction of atoms/ions that constitutes
the material for magnetic moments will help to determine the
magnetic behaviour of transition metal oxides. Long-range
magnetic ordering results from the arrangement of atoms/
ions in crystalline periodic lattice and their interaction
moment through the eld of molecular exchange. Further,
cerium oxide is a band insulator as in this cerium exists as Ce
4+
and behaves as diamagnetic.
85
Cerium oxide nanoparticle show
ferromagnetism and further magnetic analysis suggest that
Ce
3+
ions have their own magnetic moment, unlike Ce
4+
ions.
However, prepared cerium nanoparticle shows the insignicant
inuence of Ce
3+
ions on the ferromagnetism. But impurities of
iron in the prepared nanoparticles and their effect on ferro-
magnetic properties were well established by M}
ossbauer spec-
trometry. Since impurities of iron in cerium oxide and other
oxides are not well known, and their effects are also not iden-
tied. Hence, there is a need to investigate the ferromagnetic
behaviour of cerium oxide nanoparticles and other transition
metal-based oxides.
86
2.2 Biological properties
2.2.1 SOD activity. Normal aerobic metabolism in
mammalian cells produces some free radicals acting as the
signalling molecules, which are known as superoxide radicals;
these radicals play a crucial role in the pathogenesis by the
oxidation process. In mammalian cells, these superoxide radi-
cals are abundant, but if their concentration increases, it can
further lead to certain disorders. The increase in the number of
superoxide radicals is generally controlled by the SOD, which
eventually destroys the surfeit of radicals. Cerium oxide
nanoparticles possessing the high +3 and +4 ratio are known to
affect the SOD-mimetic activity; they show the SOD-like activity
in the Ce
3+
fraction.
25
I. Celardo et al.
24
proposed a comprehen-
sive molecular mode of the mechanism of cerium oxide nano-
particle by SOD in his review. This mode of mechanism is
described in Fig. 5, in this (4) is considered as original state, and
at (5) there are two Ce
3+
ions that have oxygen vacancy sites to
which the superoxide can bind. Aer this, the oxygen atom
gains an electron from one Ce
3+
. At (6) the binding of two
protons present in the solution with the two electronegative
oxygen atoms, which form an H
2
O
2
molecule and gets released.
Further, the second superoxide molecule at (7), will bind to the
binding site of the remaining oxygen vacancy. At (1) the 2Ce
3+
is
oxidized to the 2Ce
4+
by the liberation of a second H
2
O
2
mole-
cule aer the oxidization reaction. Though the reaction didn't
stop, as at the surface of (1) it has a site for oxygen vacancy,
which contains 2Ce
4+
binding site and to this one H
2
O
2
mole-
cule bind (2); thus, offering H
2
O
2
application as a reducing
agent. Following the previous reactions, protons are released, at
(3) the 2Ce
3+
is reduced by the transfer of two electrons to the
two cerium ions. Finally, the fully reduced oxygen vacancy site is
returned to its initial state (4) by the liberation of the oxygen.
Paradoxical effect is shown by H
2
O
2
on cerium oxide nano-
particles for oxidation and reduction processes. However, the
structural properties of cerium oxide nanoparticles enable it to
restore its initial state.
44
Seal et al.
25
measured the kinetics and
revealed that cerium oxide nanoparticles (3–5 nm) show excel-
lent activity by demonstrating a constant catalytic rate, which is
much higher than that determined for the SOD enzyme.
2.2.2 Phosphatase mimetic activity. The phosphate group
provides stability to the genetic material (DNA and RNA),
regulates protein, and energy transfer (ATP), etc. This group can
be hydrolyzed at the ester bonds, which can be removed by
Fig. 5 Schematic representation of SOD reaction mechanism by cerium oxide nanoparticle (reproduced from I. Celardo et al.,Nanoscale, The
Royal Society of Chemistry, 2011 (ref. 24)).
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enzymes known as phosphatases.
87
Initially, cerium(IV)
complexes were held responsible for the high catalytic reac-
tivity: as they hydrolyze the phosphorous–oxygen bonds present
in the DNA & RNA; but later on it was observed that Ce(III)
complexes are responsible, as the negative charge of the phos-
phate group interacts with the cerium oxide nanoparticle due to
the Lewis acidity of the metal.
88–96
It was investigated that
cerium oxide nanoparticles have the capacity to break the
phosphate bond of para-nitrophenylphosphate and O-phospho-
L-tyrosine due to the presence of Ce(III) sites. It is also known
that cerium oxide nanoparticles bind with the plasmid DNA,
but no hydrolysis product was observed. Hence, it can be
concluded that without damaging the DNA; ATP and proteins
can be phosphorylated.
97
It's also explored that cerium oxide
nanoparticle along with anions of phosphate, inuences the
mimetic activity of catalase and SOD by increasing and
decreasing their effectiveness respectively.
98,99
Catalase mimetic
activity is different from the phosphate mimetic activity; the
mimetic activity of phosphatases particular active sites, but it
follows catalase mimetic activity trends.
100
2.2.3 Destruction of hydroxyl radical, peroxynitrite, and
nitric oxide. Among all metallic oxide nanoparticles, the cerium
oxide nanoparticles are found to be the most potential in
catalytic scavenging of ROS, in which the hydroxyl radical is
known to be the active free radical in the biology.
101
A series of
experiments were performed to eradicate hydroxyl radicals from
the plant under abiotic stresses.
102,103
The size of the cerium
oxide nanoparticle plays a crucial role in the elimination of
hydroxyl radicals.
104
Nano-ranged cerium oxide nanoparticles
ranged between 2–5 nm exhibit neuroprotective effects when
treated with H
2
O
2
in the adult spinal cord model, which was
designed to avoid oxidative damage. It is well known that H
2
O
2
is a source of hydroxyl radicals and plays a key role in oxidative
damage. Further, keeping the above view M. Das et al.
105
investigated the auto-catalytic anti-oxidant conduct and
biocompatibility for the treatment of neurological complica-
tions, and they found that these nanoparticles show a protective
effect on the spinal cord and exhibited scavenging effect for
free-radicals. They utilized H
2
O
2
to treat cerium oxide nano-
particles directly and noticed (Fig. 6) change in color from light
yellow to orange, which species that Ce
3+
acted as an antioxi-
dant in response to the free-radicals generated from H
2
O
2
and
as a result, was oxidized to yield Ce
4+
.Aer 30 days of incuba-
tion, the color again turned to its initial state, which signies
that cerium oxide nanoparticle has auto-regenerative properties
and can play a key role in neuroprotective action by acting as an
antioxidant.
105
Later in another study,
106
it was found that auto-
regenerative property of cerium oxide nanoparticle is pH-
dependent (Fig. 7); as in basic pH environment of 7.4, this
property was attained, but in acidic it was not observed. Hence,
they revised the chemical reaction to make it more appropriate.
Cerium oxide is capable of scavenging gaseous free radicals
that is nitric oxide, which is found in the living cells and these
nanoparticles have the ability to interchange between the Ce
3+
and Ce
4+
redox states which is provided by the substantial
oxygen storage capacity in their structure.
107
The scavenging of
the reactive nitrogen species (RNS) is important as they cause
damage to the biomolecules like DNA, RNA, etc. by forming
toxic products that cause mutations in them. However, the RNS
Fig. 6 Top: Observation of change in color when, cerium oxide
nanoparticle coated with dextran was treated with H
2
O
2
at different
time intervals. Bottom: Schema of chemical reaction showing auto-
regenerative properties cerium oxide nanoparticles and possible mode
of mechanism data of the cerium oxide nanoparticle autocatalytic
behavior and free-radical scavenging property (reproduced from M.
Das et al.,Biomaterials, Elsevier, 2007 (ref. 105)).
Fig. 7 Top: Color change in solutions of cerium oxide nanoparticle
coated with dextran at basic and acidic pH environment on addition of
H
2
O
2
. Bottom: Detailed probable revised mode of mechanism data
cerium oxide nanoparticle auto-regenerative attribute and free-radical
scavenging property (reproduced from J. M. Perez et al.,Small, John
Wiley and Sons, 2008 (ref. 106)).
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helps in cell signaling, vasodilation, and immune response.
108
Cerium oxide nanoparticles interact with peroxynitrite
(ONOO

) which are formed due to the interaction of the
superoxide radicals with the nitric oxides.
22
The cerium oxide
nanoparticles +3 and +4 ratios are inversely proportional to the
scavenging property of the nitric oxide radicals; that means if
the ratio is low the scavenging action will be high and vice
versa.
109,110
3 Biosynthesis
The various method of synthesis of nanoparticles determines its
physiochemical properties (morphology, varying size, etc.). To
obtain physiochemical properties which are benecial;
synthesis parameters are carefully administered.
15
There are
mainly two approaches applied in the synthesis of nano-
particles which are demonstrated in the Fig. 8. Further,
explaining these approaches of nanoparticle synthesis, the rst
one is top-down, in this approach large molecules are decom-
posed into smaller form known as nanoparticles; this method is
also known as destructive approach. Second approach of
nanoparticle synthesis is bottom-up, in this process the nano-
particles are prepared from elementary substances (atoms); this
approach is also called as building-up.
109
Numerous preparation techniques (Table 1) have been
implied to produce cerium oxide nanoparticles, involving
chemical and biological synthesis.
111–115
Nowadays, researchers
are adapting the fundamentals of green chemistry for the
synthesis of nanoparticles as they are nontoxic and environ-
ment friendly, and this eco-friendly process is termed as
biosynthesis; it is cost-effective and simpler alternative to
chemical method of synthesis. Synthesis of cerium oxide
nanoparticle using natural matrices as stabilizing agents
decreases the bio-compatibility concerns. Cerium oxide nano-
particles biosynthesis method is mediated by polymers, plants
and nutrient. Synthesis of cerium oxide nanoparticle is gener-
ally preferred by chemical methods because it helps to deter-
mine size and shape of these nanoparticles. But the problem
still persist with the chemical method of synthesis that it has
low biocompatibility and for synthesis using this method they
require higher energy consumption to maintain high pressure
and temperature; due to these problems the interest in mini-
mizing wastage of energy resources, implementation of
sustainable process is the need of present, and for the same
adapting the fundamentals of green chemistry is increasing.
Table 2 emphasize biosynthesis along with the laboratory
protocol for synthesis of cerium oxide nanoparticle.
110,116–125
Fig. 8 Method of nanoparticle synthesis; (A) top-down approach and (B) bottom-up approach of nanoparticle synthesis with examples.
Table 1 List of methods for synthesis from chemical and biological
processes
Synthesis methods Reference
Chemical synthesis
1 Sol–gel 111
2 Pyrolysis 112
3 Sono-chemical 113
4 Mechanochemical 114
5 Co-precipitation 115
Biosynthesis
1 Plant mediated 110 and 116–121
2 Natural polymer
mediated
123
3 Nutrient mediated 122–124
4 Fungus mediated 125
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Table 2 Different types of biosynthesis along with detailed protocol for in lab biosynthesis of cerium oxide nanoparticles; (A) plant-mediated
biological synthesis, (B) nutrient-mediated biological synthesis, and (C) fungal-mediated biological synthesis of cerium oxide nanoparticles
(A) Plant mediated synthesis
S. no. Plant name Synthesis procedure Reference
1Acalypha indica 110
2Petroselinum crispum 116
3Gloriosa superba 117
4Aloe barbadensis 118
5Olea europaea 119
6Hibiscus sabdariffa120
7Azadirachta indica 121
(B) Nutrient mediated synthesis
S. no.
Nutrient
name Synthesis procedure Reference
1 Starch 122
2 Honey 123
3 Pectin 124
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Plant mediated metal oxide synthesis is a part of biosyn-
thesis method, in this method extract of plants act as an agent
for capping and stabilizing; thus, resulting in relatively higher
yield of nanoparticles when compared to chemical synthesis
method.
126–130
From Acalypha indica leaf extract in the aqueous
form, pure and stable cerium oxide nanoparticles can be
synthesized and this method was found to be simple, cost
effective and efficient.
110,131
Another approach for biosynthesis
of stable and well-dispersed cerium oxide nanoparticle was
successfully accomplished by the plant extract of Petroselinum
crispum, as they were capable of reducing the cerium ammo-
nium nitrate [(NH
4
)
2
Ce(NO
3
)
6
] salt.
116
Gloriosa superba plant
extract were able to reduce the cerium salt and synthesized 5 nm
spherical shaped small crystals of cerium oxide nanoparticles
with a higher surface area.
117
Aloe barbadensis miller plant,
commonly known as Aloe vera along with the cerium(III) nitrate
hexahydrate was used for the biosynthesis of spherical cerium
oxide nanoparticles with a mean diameter of 63.3 nm.
118
Olea
europaea leaf extract act as a reducing agent by chelating cerium
nitrate and thus produces the 24 nm pure single-face cubic
structure of cerium oxide nanoparticles, which can be effec-
tively used for biomedical applications.
119
By using Hibiscus
sabdariffaower extract, the rst entire green synthesis protocol
was designed to synthesize pure cerium nanoparticles without
the use of any additional standard components (reduction or
oxidization agent); the synthesized cerium oxide nanoparticles
exhibited an average particle size of 3.9 nm and were spherical
in shape.
120
Another plant-based approach for the synthesis of
cerium oxide nanoparticles was from Azadirachta indica, which
is also known as neem (a native plant of India); extract of this
plant was able to reduce cerium nitrate [Ce(NO
3
)
2
$6H
2
O],
resulting into cerium oxide nanoparticles with higher quality
yield and cubic crystalline structure.
121
Natural polymers like starch which act as stabilizers can be
utilized for synthesis of cerium oxide nanoparticles; the
synthesized particle from this method are smaller in size.
Cerium oxide nanoparticle can be synthesized by sol–gel
method mediated by starch in aqueous solution from cerium
nitrate salt; the resulting nanoparticles will be cubic uoride in
shape with a mean diameter of 6 nm.
122
A simple, cost-effective
method to synthesize cerium oxide nanoparticles is by using
honey which can act as the stabilizing agent when dissolved
with the cerium(III) nitrate hexahydrate [Ce(NO
3
)
3
$6H
2
O].
123
Nutrient mediated synthesis is extremely cost effective and by
utilizing egg white (nutrient substrate), as a stabilizing agent
result in the controlled isotropic synthesis of cerium oxide
nanoparticles.
132
Pectin a non-toxic biopolymer which can be
obtained by extracting Indian red Citrus maxima peels, can be
utilized for biosynthesis of cerium oxide nanoparticles and the
resulting nanoparticles exhibited size of #40 nm (average); were
cubic uorite structure and spherical in shape.
124,133
Synthesis of
these nanoparticle can also be achieved by the help of nontoxic
and renewable degraded agarose, as it has capping capabil-
ities.
134
The cerium oxide nanoparticle synthesized from
different method will have varying particle size, crystallization
temperature, thermal stability, morphology, uorescence
properties, luminescence, etc. and these attributes offer the
synthesized material applications in various domains; in Table
3, few most commonly synthesized nanoparticles from different
method are demonstrated with striking difference in its prop-
erties (physicobiochemical). Hence, the above discussed
methods give an overview of biosynthesis methods for the
synthesis of the cerium oxide nanoparticles giving a reference of
well-characterized properties.
4 Biomedical applications
One of the most potential metal oxide nanoparticles aer the
silver oxide nanoparticles, which gained attention in past few
decades are cerium oxide nanoparticles; they exhibit enor-
mous range of applications in different domains like agricul-
ture, environmental and biomedical. Application of cerium
oxide nanoparticle in the biomedical domain are enormous.
From an investigation
135
performedbyscientistsitisfound
that cerium oxide nanoparticles should have either pro-
oxidant or anti-oxidant properties to be nontoxic to humans;
as cerium oxide nanoparticles are not found in humans and
till date no clearing mechanism is known, which will lead to
systemic toxicity in humans. From the above investigation it
can be highlighted that nanoparticle interaction with micro-
environment should be considered while designing effective
nanocarriers. At present, use of these nanoparticles have good
grip in industrial applications, but biomedical applications
are still developing. Till date lot of biomedical study related
with diagnosis and treatment of life-threatening diseases by
utilizing cerium oxide nanoparticles are performed and result
Table 2 (Contd. )
(C) Fungal mediated synthesis
S. no. Fungus name Synthesis procedure Reference
1Humicola sp. 125
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obtained from these studies have shown good sign. Cerium
oxide nanoparticles have enormous application in this eld
which are elaborated below and in Fig. 9.
4.1 Anti-cancer
Cancer is the leading cause of death worldwide and cerium
oxide nanoparticles exhibit cytoprotectant property, this make
Table 3 Few most commonly biologically synthesized cerium oxide nanoparticle by using different biological sources and its comparative
analysis
S.
no. Source
Particle
size
Crystallization
temperature Morphology Others Ref.
1Acalypha indica 25–30 nm 800 C Spherical-fcc
(face centered
cubic) shaped
structure.
Thermal stability temperature
was 998 C
110
2Gloriosa superba 5 nm 400 C Spherical-fcc
structure
Showed bioluminescence at
486 nm, and exhibits
antibacterial activity
117
3Olea europa 24 nm 500 C Spherical and
homogenous
Thermal stability at 50–600 C,
and exhibits antibacterial and
antifungal activity
119
4Azadirachta
indica
10–15 nm 240–250 C Fcc-structure It showed thermal
decomposition between 329–
434 C
121
5 Starch 6 nm 200–400 C Spherical-fcc
structure
Showed low toxicity to N2a cell
lines
122
6 Food-mediated
(honey)
23 nm 200–800 C Uniform
spherical
structure
Thermal stability at 400–800
C
123
7 Pectin 5–40 nm 400 C Spherical Showed antioxidant,
antibacterial, and bio–
luminescence activity
124
8 Fungal-mediated 12–20 nm 300 C Spherical Showed bioluminescence
activity
125
9 Egg-white 25 nm 200–800 C Fluorite cubic
structure
Thermal stability at 20–
1000 C, and showed non-toxic
effect on periodontal broblast
cells
132
10 Degraded
agarose
10 nm 200–800 C Fcc-structure Thermal stability at 20–1000
C
134
Fig. 9 Potential applications of cerium oxide nanoparticles in the biomedical, environmental, and agricultural domains.
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them induce ROS formation in the cancer cells which make
these nanoparticles a good anticancer agent; this is due to
deregulation of antioxidant enzyme expression and acidic
environment in the cancer cells which develops ROS, further
leading to the generation of RNS interfering with intracellular
activities.
106,136
The anti-invasive property of cerium oxide
nanoparticle leads to regulation of antioxidant enzymes by
inducing radio-sensations; this regulates the quantity of ROS
and provides radioprotection to normal cells. Thus, this can be
used as the potential radiation sensitizers for cancer therapy by
protecting normal cells surrounded by radiation damage.
137–140
As these nanoparticle exhibit redox-activity due to which it can
become new prototype for the treatment of cancer.
141
Recent
investigations have revealed that cerium oxide nanoparticles are
nontoxic to normal cell lines and can be successfully used for
the treatment of cancer; but this nanoparticle can't be used for
prostate cancer care as analyzed by the MTT colorimetric
assay.
142,143
In in vivo and in vitro study by L. Alili et al.,
144
they
demonstrated effect of cerium oxide nanoparticles coated with
polymer in human melanoma cells, and result of their study
suggest, that these nanoparticle which were non-toxic to
stromal cells showed cytotoxic, pro-apoptotic, and anti-invasive
activity to melanoma cells; further this study was rst to
conrm that cerium oxide nanoparticle exhibit tumor sup-
pressing properties in vivo and opens avenue for future cancer
therapeutic development. In another study, the investigators
prepared cerium oxide nanoparticles for different concentra-
tions by utilizing two different methods that are hydrolysis (for
+3 oxidation state) and hydrothermal (for +4 oxidation state);
when these prepared nanoparticles by different method where
tested on the human lung cancer cells in time dependent
manner for 24, 48 and 72 hours. The cancer cells at nanoparticle
concentration between 3.5–23.3 mg showed dose- and time-
dependent cytotoxicity by inducing ROS, and it also demon-
strated that the different oxidation states lead to the different
cytotoxic levels, as the hydrothermal-cerium oxide nanoparticle
showed more cytotoxicity when compared to the hydrolysis-
cerium oxide nanoparticles, due to their higher cellular
uptake.
145
Further, on colon cancer cells of human these
nanoparticles exhibit cytotoxicity that resulted in production of
ROS, which causes depolarization of mitochondrial membrane
leading to apoptosis.
146
An in vivo study,
147,148
on ovarian cancer
cells was performed to check the inhibitory effect of cerium
oxide nanoparticles for metastasis and angiogenesis; results
suggest that they are better candidate for ovarian cancer treat-
ment as it shows signicant decrease in viability of cancer cells
and increased cancer cell death. In other study, related with
anti-cancer effect of cerium oxide nanoparticle in brosarcoma
(cancer cells) cell lines, these nanoparticles generate ROS and as
a result of ROS generation it lead to apoptosis.
149
Doxorubicin
loaded cerium oxide nanoparticles avert tumor cell-released
growth factor (GF)-dependent modulation of stromal cells,
namely neoangiogenesis and transdifferentiation. Thus,
mediate their protection from apoptotic cell death initiated by
doxorubicin. Beside this, in in vivo cerium oxide nanoparticles
also decreases tumor invasion and tumor growth. In contrast,
cerium oxide nanoparticles generate ROS, which causes cell
death and doxorubicin loaded with this nanoparticle (combi-
national approach of treatment) help to enhance rate of
apoptosis in the desired tumor cells (Fig. 10).
150
Hence, it can be
concluded that the cerium oxide nanoparticle are best anti-
cancer agent as it has excellent tumor suppressing properties
in vitro, as well as in in vivo for various type of cancers such as
lung, colon, ovarian, etc.
4.2 Antibacterial
Cerium oxide nanoparticles when interact with bacterial cell by
electrostatic attraction it generates ROS, which leads to bacte-
rial cell death; this determines its antibacterial efficiency.
151–153
The mechanism behind a decrease in the membrane perme-
ability and bacterial cell death by cerium oxide nanoparticle
may be due to the release of some ions, which particularly react
with the thiol (SH) group found in the proteins of the bacterial
cell membrane. These nanoparticles in bacterial cells cause
a disturbance in intracellular functions (DNA replications, cell
division, and cellular respiration), which induces ROS.
154
Further, cerium oxide nanoparticle synthesized by the green
method was utilized to study antibacterial activity by using
Gram-negative bacteria Escherichia coli and Gram-positive
bacteria Staphylococcus aureus, and the result of this study
suggest Gram-positive bacteria were more susceptible to this
nanoparticles as compared to the Gram-negative bacteria.
117
The concentration of cerium oxide nanoparticle also deter-
mines the antibacterial efficiency, to prove this an experiment
was designed to determine the antibacterial efficiency at
Fig. 10 Schematic illustration of cerium oxide nanoparticles loaded
doxorubicin mode of mechanism interaction data of stromal-tumor
for cancer treatment by combinational approach (reproduced from P.
Brenneisen and A. Reichert, Antioxidants, MDPI, 2018 (ref. 150)).
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different concentrations of nanoparticles, and this revealed that
for the binding of metal oxide with the bacterial cell wall,
electrostatic forces are required which will result into bacterial
growth inhibition. Thus, a high concentration of these nano-
particles will exhibit excellent antibacterial efficacy.
155
On the
contrary, differences in membrane surface, surface charge
density, and the metabolic processes are also responsible for
the variation in the inhibitory effect of cerium oxide nano-
particles on Gram-negative and Gram-positive bacteria.
156
Moreover, when E. coli bacterial cells are exposed to cerium
oxide nanoparticles, these nanoparticles are directly taken up
by the bacterial cell surface, which causes oxidative stress and
leads to bacterial cell death.
156,157
In cyanobacteria, oxygenic
photosynthesis induces ROS production, and cerium oxide
nanoparticle's Ce
3+
site reacts with the produced ROS, which
results in an oxidative reaction. This reaction further produces
anions and radicals, which impairs membrane integrity and
causes bacterial cell death.
158
Besides cerium oxide nano-
particles, hybrid chitosan-cerium oxide nanoparticles also
exhibit extraordinary antibacterial properties by disrupting
bacterial cell membranes, which causes cell death; but it is only
possible at a high concentration of this hybrid nanoparticles.
159
The major problem with polysaccharide encapsulated bacteria
is that it prevents direct contact of nanoparticles with the cell
wall, which will lead to hindering antibacterial activity, and to
overcome this problem indirect interaction or contact mecha-
nism can be used. For this, ROS is produced outside the cell and
then transferred to the cell via cell membrane; this results in the
degradation of bacterial protein and nucleic acids, which nally
causes cell death.
160
4.3 Anti-oxidant potential
An imbalance between ROS, production of nitrogen species,
and anti-oxidant level cause oxygen stress, as nitrogen species
and ROS, is a potent oxidizing and nitrating agent.
161
These
nanoparticles show remarkable antioxidant properties by scav-
enging the free radical's; thus, offering them potential medical
application. Further, when cerium oxide nanoparticles were
exposed with brain tissue of rat to analyze the antioxidant
activity, it was observed that these nanoparticles increase thiol
content and initiate caspase-3 activity, which declines the
oxidative DNA damage and lipid peroxidation; resulting in
enhanced antioxidant activity and also act as a neuroprotective
agent.
162
From another study, it was well established that these
nanoparticles have free radical scavenging properties and
radioprotective effects, which will protect it from induced
oxidative damage, thus providing it anti-oxidative potential.
139
Later it was determined that the Levan polysaccharide coated
cerium oxide nanoparticles showed synergistic anti-oxidation
property against H
2
O
2
in the NIH3T3 cells. Thus, Levan poly-
saccharide coating offers stability and water solubility to the
cerium oxide nanoparticles; as Levan and its derivatives show
anti-oxidants, anti-inammatory, and anti-tumor properties.
163
In the human epithelial cell line (BEAS-2B), these nanoparticles
exhibit oxidative stress against KBrO
3
.
164
And further in
epithelial cells, these nanoparticles hinder H
2
O
2
and stops
overproduction of ROS, which leads to a decrease in cell death
and helps prevent cardiovascular diseases.
165
Hence, these
nanoparticles have the potential anti-oxidant ability and exhibit
enormous biomedical applications.
4.4 Anti-inammation
Cerium oxide nanoparticles as mentioned earlier in this review
has radical scavenging and auto regeneration mechanisms,
which offer them the unique potential to be considered as an
anti-inammatory agent.
166
Pro-inammatory enzymes like
iNOS expression cause rapid generation of free radicals in the
body; protein in the iNOS gets activated by ROS, and macro-
phages produce NO. ROS production should not be stopped,
and its level should also be not declined, but it can be reduced.
As ROS depletion can result in pathological consequences, and
they are essential for normal cellular functions. When the
cerium oxide nanoparticles were tested on J774A.1 cell, it
suppresses iNOS and ROS production; thus, acting as an anti-
Fig. 11 Combination therapy for non-small-cell lung cancer (NSCLC) by using NC (cerium oxide nanoparticles), which results as an excellent
tool for targeted drug delivery system. In this illustration, FNC is folate decorated cerium oxide nanoparticles, GT is ganetespib, Dox is doxo-
rubicin, and nanoceria is cerium oxide nanoparticles (reproduced from S. Sulthana et al.,Mol. Pharm., American Chemical Society, 2017 (ref. 172)).
27206 |RSC Adv.,2020,10, 27194–27214 This journal is © The Royal Society of Chemistry 2020
RSC Advances Review

inammatory agent.
18
Further, cerium oxide nanoparticles
when injected in the murine model of cardiomyopathy it
suppresses pro-inammatory markers like monocytes chemo-
attractant protein-1 (MCP-1), interleukin-6 and also decreased
oxidative stress. Thus, these nanoparticles in mice improved
cardiac dysfunction and can play a key role as an agent for the
treatment of ischemic heart disease.
167
4.5 Drug delivery
Cerium oxide nanoparticles are well known for their cytotoxic
properties towards cancer cells, thus offering them anticancer
activity. Further, these nanoparticles can also be utilized as
a vector to deliver drugs.
168
A study was conducted by a group of
investigators to develop drugs for targeted photodynamic
therapy of drug-resistant human breast cancer; they synthesized
multifunctional nanocomposite chlorin e6 (Ce6)–folic acid
(FA)–polyethylenimine–PEGylation cerium nanoparticles
(PPCNPs) [Ce6–FA–PPCNPs], and these nanocarriers promoted
cellular uptake. Hence, the result of this study suggests that
these nanocomposites formed by cerium oxide nanoparticles
are multifaceted and effective drug delivery systems.
169
Further,
carboxybenzenesulfonamide (an hCAII (human carbonic anhy-
drase) enzyme inhibitor) and carboxyuorescein (a uorophore
for tracking nanoparticle in vivo and in vitro), when attached
with cerium oxide nanoparticles via intermediate linker
epichlorohydrin, can be used as a potential drug delivery system
for the treatment of glaucoma.
170
Moreover, from other inves-
tigations, it was suggested that cerium oxide nanoparticles due
to their redox properties can be utilized to develop a very
responsive drug delivery system.
171
Cerium oxide nanoparticles coated with polyacrylic acid can
be used as a vector to carry drugs; it was synthesized and loaded
with drug combination (doxorubicin and ganetespib) for effec-
tive treatment of NSCLC (non-small-cell lung cancer). The result
of this study (Fig. 11) signies that cerium oxide-based multi-
functional nanoparticles can be used for targeted drug delivery
treatment for this type of lung cancer by utilizing combination
therapy.
172
In the case of ovarian cancer cells, cerium oxide
nanoparticles loaded with drug doxorubicin (CeO
2
–Dox)
showed increased cell proliferation, cellular uptake, and
apoptosis. Further, considering the drug release mechanism by
carrier nanoparticle, it is released when it gets an acidic envi-
ronment.
173
Cerium oxide nanoparticles coated with dextran
loaded curcumin as a drug was utilized for the treatment of
childhood neuroblastoma, and the result signies that cerium
oxide nanoparticles coated with drug dextran loaded curcumin,
induced cytotoxicity in the neuroblastoma cells. On the
contrary, it was not harming the normal cells.
174
Hence, it can
be emphasized that multifunctional nanoparticles based on
cerium oxide nanoparticles are best suitable to be utilized as
a vector for synergistic and targeted drug delivery.
175
4.6 Gene-delivery
Cerium oxide nanoparticles in 2016 were reported as a carrier
for gene delivery, as the investigators of the study have
synthesized hybrid cerium oxide–
dimethyldioctadecylammonium bromide (DODAB) multifunc-
tional nanoparticles, which replaced viral vector and was used
to transfect plasma DNA (pEGFPN1) in different cell lines.
Further, the transfection efficiency of nanovector (CeO
2
/
DODAB) was analyzed in vivo by injecting it into the muscle of
tibialis mice, and result signies that it shows 3.5 folds higher
uorescence intensity then naked DNA treatment and it also
didn't exhibit any toxic effect to the cells, but this nanovector
showed approx. 17% less transfection efficiency than commer-
cially available in vivo-jetPEI transfection reagents. Hence, it can
be concluded that cerium oxide nanoparticles can be efficiently
utilized as a transporter in the gene delivery method and can be
the best alternative for viral vector gene delivery methods.
176
4.7 Bioscaffolds
Cerium oxide nanoparticle exhibits excellent pharmacological
potential, which offers them applicability as a scaffold and
makes them an extraordinary therapeutic agent. Porous bioac-
tive glass scaffolds with cerium oxide nanoparticles were used
for regeneration, and the result suggests that cerium oxide
nanoparticles were nontoxic to cells, and they enhanced oste-
oblastic differentiation without the use of osteogenic supple-
ments, namely dexamethasone, ascorbic acid, etc. They also
found enhanced collagen production by bone-marrow-derived
human mesenchymal stem cells (HMSCs). Thus, this study
suggests that cerium oxide nanoparticles due to their oxygen
buffering properties can be used as excellent bioscaffolds.
177
Further, C. Mandoli et al.
178
suggested that cerium oxide and
poly(D,L-lactic-co-glycolic acid) powders when mixed at specic
concentrations by solvent castings on pre-patterned molds; they
can be used as a 2-dimensional polymeric ceramic bio-supports
for in vitro stem cell culturing (Fig. 12). The ndings of this
study highlight that hybrid polymer ceramic bioactive scaffolds
of cerium oxide nanoparticles can have potentiality as a tool for
tissue engineering applications. Hence, these studies suggest
that cerium oxide nanoparticle can be effectively used as a bio-
scaffold due to its unique anti-oxidant property; it also has
virtuous hold to be a possible material for tissue engineering.
4.8 Treatment of diseases
The unique pharmacological properties to treat diseases shown
by the cerium have been used for more than a century ago.
179
The root causes of neurodegenerative diseases (Parkinson's
disease, ischemic strokes, etc.) are proved to be due to an
increase in oxidative stress and free radical production.
180
Cerium oxide nanoparticles show neutron shielding effects by
damaging the formation of free radicals, and it also affects the
signal transduction pathways, which causes neuronal cell
death; hence, these nanoparticles are considered as a potential
element in treating the neurodegenerative diseases particularly
Alzheimer's disease. These nanoparticles because of their
antioxidant property, inuence the signal transduction pathway
when they are exposed to antibody-treated cells, and can be
used as therapeutic material in the treatment of neurological
diseases.
17,105,181–184
The third common cause of death on the list
globally is the ischemic stroke/cerebral stroke, in which clot/
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Review RSC Advances

hemorrhage is formed in the blood due to the lack of blood ow
in the brain, and cerium oxide nanoparticles encapsulated with
phospholipid-polyethylene glycol can play a very important role
to protect from the ischemic stroke.
185
The insufficient secretion
of endogenous insulin caused by the increase in oxidative stress
leads to a metabolic disorder known as diabetes mellitus and
for the decrease in the low blood glucose levels the cerium oxide
nanoparticle when combined with the sodium selenium, leads
to a decrease in the ROS levels and increases the secretion of
insulin. Hence, cerium oxide nanoparticles can also be used for
the treatment of a lifestyle-related major disorder that is
diabetes.
186–188
Further, cerium oxide nanoparticles have been studied for
the treatment of the retinal diseases, as ROS damages the
sensitive cells of the retina, which leads to retinal diseases
(retinal degeneration, diabetic retinopathy, etc.) which can
cause partial/total loss of vision.
189
Moreover, cerium oxide
nanoparticles when studied in in vitro cell culture and in vivo for
the treatment of retinal diseases, it was found that these
nanoparticles induce intracellular peroxides, which prevents
retinal degeneration. Further, it can be concluded from this
study, that cerium oxide nanoparticles decrease the ROS,
upregulates the expression of neuroprotection-associated
genes, and downregulates apoptosis signaling pathway (it
slows photoreceptor degeneration).
190–192
In another study, it
was found that these nanoparticles can induce the regression of
pre-existing pathologic retinal neovasculature and can also
inhibit the rise in ROS.
193
Hence, these properties and mode of
mechanism data of cerium oxide nanoparticles suggest their
potential role as a therapeutic agent for the treatment of life-
threatening diseases.
4.9 Cerium oxide based biosensors
Biosensors are an analytical device that recognizes, analyses,
and converts the biological/physical/chemical signals into
measurable signals (electrochemical, an optical signal, etc.).
These analytical devices consist of sensing elements, trans-
ducers, and signal processors; its working mechanism is as
follows: sensing element detects an analyte and is passed to the
transducer to produce a signal, which is amplied by the signal
processor.
194–198
From all the metal oxide nanoparticles, cerium
oxide nanoparticle is mostly considered to be used for the
development of biosensor as they exhibit distinctive properties,
namely high mechanical strength, oxygen ion conductivity,
biocompatibility, high storage capacity, large surface area, and
are nontoxic to the living cells.
Biosensor based on sol–gel derived cerium oxide nano-
particles was developed for the detection of cholesterol; this is
a cost-effective approach for clinical diagnosis of coronary
diseases. As sol–gel derived cerium oxide nanoparticles lm was
considered and it resulted in many advantages like optical
transparency, thermal stability, and low processing tempera-
ture. In this experiment by using electrophoretic deposition,
cerium oxide nanoparticle was deposited on the indium-tin-
oxide (ITO) coated glass substrate to form a lm, and further
cholesterol oxidase (ChOx) was immobilized for the detection of
cholesterol. Hence, the result of this study showed higher
sensitivity, selectivity and suggested that these nanoparticles
can be a potential material, which can be used in the form of
alm for fabricating efficient biosensor, as they are highly
chemically stable which helps them to immobilize biomole-
cules.
199
Another biosensor was fabricated for the estimation of
hydrogen peroxide (H
2
O
2
) based on cerium oxide nanoparticle
lm deposited on indium-tin-oxide (ITO) glass substrate
Fig. 12 Immunofluorescence monitoring of in vitro culture of adult murine resident cardiac stem cell incubated by different concentration of
cerium oxide nanoparticle-poly(D,L-lactic-co-glycolic acid) composite material for 6 days: (a) 5, (b) 10, and (c) 20% wt%, together with (d)
poly(D,L-lactic-co-glycolic acid) (PLGA) as a control (reproduced from C. Mandoli et al.,Adv. Funct. Mater., John Wiley and Sons, 2010 (ref. 178)).
27208 |RSC Adv.,2020,10, 27194–27214 This journal is © The Royal Society of Chemistry 2020
RSC Advances Review

immobilized with horseradish peroxidise (HRP). Their result
signies that biosensors based on cerium oxide nanoparticles
show excellent detection selectivity and sensitivity.
200
Further,
for blood glucose level monitoring, a sol–gel derived cerium
oxide nanoparticle, glucose biosensor was fabricated by
depositing this nanoparticle on the gold electrode, showing
a high affinity for glucose with enhanced sensitivity.
201
The lactate imbalance causes diseases like hypoxia/acute
heart disorders, so for the easy detection of lactate in blood,
an electrochemical biosensor was developed using hydroxide
mediated cerium oxide nanoparticles, fabricated on glassy
carbon electrode (GCE) and the cerium oxide nanoparticles act
as an interface to immobilizes nicotinamide adenine dinucle-
otide (NADH) and lactate dehydrogenase (LDH) on the GCE
surface.
202
Hence, it can be concluded that cerium oxide nano-
particles can be considered as a promising material for the
development of the biosensor, but further investigations are
required to reach the stage of commercialization for this type of
futuristic technology.
5 Conclusion and prospects
Nanotechnologies have revolutionized all the elds of science
and technology such as chemistry, biology, physics, material
sciences, etc. and it deals with the study and application of
extremely small things at the nanoscale (1–100 nm) range.
Cerium is an abundant rare earth metal that exhibits many
defects on the surface, mainly the oxygen vacancies, which leads
to the co-existence of two oxidation states: cerium(III) and cer-
ium(IV), enabling them to exhibit redox catalytic activity.
Biosynthesis of nanoparticles has gained a lot of attention due
to its environment-friendly procedure, as it utilizes plant
extracts, microbes, nutrients, etc. for the synthesis of nano-
particles. Thus, the biosynthesized cerium oxide nanoparticles
are non-toxic and bio-compatible to the living cells and tissues.
In this review, focus is laid on cerium oxide nanoparticles
physicobiochemical properties, their biomedical applications,
and prospects. This review also puts the reader's main focus on
the several biosynthesis methods of the cerium oxide nano-
particle highlighting the major green sources for synthesis such
as plant extracts, nutrient and natural mediated synthesis.
Due to an increase in the prevalence of lifestyle diseases,
203
development in the medical eld is the need of the current
scenario, and the urge to provide treatment for life-threatening
diseases like cancer, HIV, etc. increases. The cerium oxide
nanoparticle has been recognized in the eld of biomedicines
due to their unique redox properties, and are widely being used
for the treatment of cancer, as an antimicrobial agent, bio-
scaffold, and also for the fabrication of biosensor devices.
Apart from the biomedical elds, these nanoparticles are also
used in solar cells,
20
fuel oxidation catalysis,
21
chemical
mechanical polarization,
22
and corrosion protection.
23
These
nanoparticles have enormous properties, thus offering them
vast applications in the biomedical eld as well as in agriculture
and environmental domains.
Currently, we are experiencing the global viral (COVID-19)
pandemic, which is threatening to the human civilization,
and cerium oxide nanoparticle can be utilized for the produc-
tion and commercialization of antimicrobial PPE (personal
protective equipment), surgery suits, sanitizers, etc. because of
their great antimicrobial efficiency, about which we have
embellished in this review. Further, there has been no evidence
of cerium present in the human body naturally, and to date,
there is no known mode of mechanism data pertaining to the
clearing mechanism of these nanoparticles in the human body,
which can lead to systemic toxicity. Thus, the focus can be laid
on exploring the nanotoxicological data of the cerium oxide
nanoparticles. The multifunctional cerium oxide nanoparticles
based on natural biomaterials have shown promising applica-
tions in the biomedical eld and in the review, it's highlighted
in detail. Hence, from the detailed study of these nanoparticles,
we can suggest that researchers should lay their focus on
engineering the cerium oxide nanoparticles by functionalizing
them with synthetic materials (peptide nucleic acids, xeno-
nucleic acids, threose nucleic acid, morpholino, etc.)
204,205
for
more benecial applications. In addition to this, the cerium
oxide nanoparticles could have potential application potenti-
alities towards agriculture and environmental domain, data are
still lacking or in very infancy phase and need to be explored.
Funding
This review did not receive any specic grant from any funding
agencies in the public, commercial, or not-for-prot sectors.
Conflicts of interest
Author's declare no conict of interest for this work.
Acknowledgements
The authors would like to extend their gratitude of thanks to
Vice-chancellor, Indira Gandhi National Tribal University, for
providing facilities to prepare this review and we are also
thankful to all the faculty members of Department of Biotech-
nology, Indira Gandhi National Tribal University,
Amarkantak, M.P., India for their support. Special thanks to Dr
Parikipandla Sridevi, Department of Biotechnology, IGNTU,
Amarkantak for her unconditional support throughout this
work.
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