To grapple with cancer, implementation of differentially cytotoxic nanomedicines have gained prime attention of the researchers across the globe. Now, ceria (CeO2) at nanoscale has emerged as a cut out therapeutic agent for malignancy treatment. Keeping this in view, we have fabricated SnxCe1-xO2 nanostructures by facile, eco-friendly, and biocompatible hydrothermal method. Structural examinations via XRD and FT-IR spectroscopy have revealed single phase cubic-fluorite morphology while SEM analysis has depicted particle size ranging 30-50nm for pristine and doped nanostructures. UV-Vis spectroscopy investigation explored that Sn doping significantly tuned the band gap (eV) energies of SnxCe1-xO2 nanostructures which set up the base for tremendous cellular reactive oxygen species (ROS) generations involved in cancer cells’ death. To observe cytotoxicity, synthesized nanostructures were found selectively more toxic to neuroblastoma cell lines as compared to HEK-293 healthy cells. This study anticipates that SnxCe1-xO2 nanostructures, in future, might be used as nanomedicine for safer cancer therapy.

Neuroblastoma, at pediatric stage malignancy, under the age of 10 years, contributed high mortality rate worldwide. In comparison to other neural disorders, neuroblastoma is highly progressive lethal disorder with heterogeneous developmental phases. Primary stage diagnosis may augment the survival rate up to 80%, whereas late phase diagnosis due metastasis of neuroblastoma reduces this rate up to 30%. Moreover, increase in the development of this disorder is so irregular and spontaneous that patients’ recuperation chances often decrease at later stage.1,2 In order to cure the various abnormalities of this malignancy, several therapeutic routes have been adopted in the recent past. Among these chemotherapy, radiotherapy, surgical intercessions and other conventional methods are very common.3,4 All these conventional approaches often exhibit temporary remission of the disorder, however, reoccurrence of disease is common later on.

Nanotechnology and nanoscience is an emerging science having an immense potential in all fields of science and engineering especially in the bio-medical research. Nanomaterials (NMs) because of their novel characteristics like lesser size, structure, chemical composition, higher specific surface area and optimum surface energy made them an ideal candidate to be used in plenty of applications in the fields of nanomedicine, medical engineering, drug delivery systems, nano bio-sensors, luminescent biomarkers and tissue culture technology, etc.5–7 However, NMs based targeted drug delivery systems require the optimization of their various factors, like cytotoxicity towards healthy cells, interaction route with tissues, cellular absorption, dosage, mode of action, morphology, chemical stability, reactivity and aspect ratio, etc., for their greater bio-compatibility.8,9

It is a proven-fact that reactive oxygen species (ROS) play a vital role in cancer cell proliferation, cellular damage due to excess production of oxygen radicals and hydroxyl ions. Malfunctioning of cellular enzymes in cancer cells to deal with ROS normally induced apoptosis.10 It is found that cellular ROS level is well controlled in human healthy cells due to proper functioning of ROS regulating cellular enzymes.11 Amongst various type of NMs, metal oxide based NMs are very handy to have higher anti-cancer activates with safe nature.12 Several metals oxide NMs (Fe3O4, Fe2O3, SnO2, ZnO, CuO, CoPt etc.) have been reported for cancer therapy and diagnostics.12–15 In the recent past, it has also been studied that higher concentration of these NMs strongly effect the viability of normal cells, which limits their applications.16,17 On the contrary, CeO2 NMs are considered a potential biomedical therapeutic agents as they have a natural tendency to generate ROS at cellular level due to their redox cycle with innate cytotoxic behavior to cancer cells, anti-invasive features and low-hypersensitivity to somatic cells.11,18–21 Furthermore, it is observed that the catalytic behavior of CeO2 based NMs can be tuned via selective metal ion doping (Mn, Cu, Fe, Ni, Co etc.).22,23 Tin (Sn) is believed to be more promising candidate in this regard as it owns the same ionic state and almost compatible ionic radii values to Ce ions. This makes it potential in providing characteristics like higher thermal stability, solubility and a tendency to give rise the defect chemistry in the host matrix.24,25 Consequently, we have fabricated CeO2 based NMs with differing molar concentration of Sn as dopant. The synthesized SnxCe1-xO2 nanostructures have been characterized for structural, morphological, compositional, optical and anti-cancer activity against hazardous Neuroblastoma cell line in comparison with HEK-293 cell line. So for, to the best of our knowledge, there is no anti-cancer study has been reported worldwide regarding SnxCe1-xO2 nanostructures. We presumably believe that our study will explore new strategies in combating neuroblastoma.

Facile hydrothermal technique has been employed to synthesize SnxCe1-xO2 (where x = 0, 0.03, 0.055 and 0.07) nanostructures. Precursors utilized in this synthesis process were Cerium nitrate (CeNO3·6H2O) and Tin chloride (SnCl2·2H2O). An appropriate ratio (0.1M) of CeNO3·6H2O was dissolved in distilled water and put into fume hood on magnetic stirring (500rpm) hot plate (80o C) for 20 minutes. Polyethylene glycol (PEG), as a capping agent, was added to control the particle size and morphology of the synthesized samples. After a vigorous stirring for 20 minutes, an aqueous NaOH solution (1M) was supplemented to the parent solution drop by drop to adjust its pH value up to 8-9. After 1h further stirring, the solution was shifted into sealed glass bottle and was put into preheated oven at 95o C for 12h. After the prescribed time of 12h, the solution was cooled down to room temperature, precipitates was collected, washed in distilled water via centrifugation and dried at 60o C for overnight in electric oven. Similar method was implemented to synthesize Sn doped CeO2 nanostructures except the introduction of SnCl2·2H2O with different molar concentrations. Finally, to obtain a highly crystallinity, SnxCe1-xO2 nanostructures were annealed for 2h in an electric furnace at 300° C.

XRD technique was used for the structural analysis of synthesized SnxCe1-xO2 samples using PANalytical X-ray diffractometer (Model: 3040/60 X’Pert PRO, Netherlands). This analysis of the prepared samples were carried out in 2θ ranging 20o to 80o using CuKα X-rays owing a wavelength of 1.54 A°. SEM, model (JEOL, SEM, JSM6490LA), was employed to investigate the surface morphologies of the synthesized samples. The surface chemistry of the SnxCe1-xO2 samples was investigated using FTIR spectroscopy, model (NICOLET 6700 FTIR spectrometer made by THERMO SCIENTIFIC, USA) via KBr technique. A hydraulic presser was used to obtain the Pellets of the KBr and synthesized SnxCe1-xO2 nanostructures. Moreover, KBr pellets spectra was also recorded in order to made background corrections. Optical bandgap energy of the synthesized SnxCe1-xO2 samples was calculated using Tauc relation deploying UV-visible absorption spectroscopy (PerkinElmer Lambda 200 UV/VIS/NIR). In this method, the solution of the powder SnxCe1-xO2 samples was prepared in distilled water in a certain amount, and their absorption spectra was recorded. In order to investigate electrical properties, pellets of SnxCe1-xO2 nanostructures were again made with the assistance of a hydraulic presser and these prepared pellets were then sintered at 180o C in an electric oven for 2h. Silver paste coating was done on both sides of these pellets to obtain electrical contacts. The AC conductivity measurements of the synthesized SnxCe1-xO2 samples were carried out by using a LCR meter (Wayne Kerr 6500 B Impedance analyzer) in the range of 1 kHz to 5 MHz under ambient conditions.

For anticancer studies and ROS determination, SH_SY5Y and HEK_293 cell lines (Manassas, VA, USA) were seeded in a 96 well plate at a concentration of 105 cells per well. The cells were allowed to attach the surface and for this, they were kept in the incubator at 37°C, 5% CO2 for 24 hours. Later both cell lines were exposed to SnxCe1-xO2 nanoparticles (20μg/ml) for 24 hours and kept at the same conditions in the incubator. The cell viability assay was performed by using fluorescence microscopy (Hitachi, Tokyo, Japan). Images were taken through phase contrast microscopy (at 10X magnification).

ROS detection in both types of cell lines was carried out by flow cytometry in which the level of produced oxidative stress was examined with the help of 2′, 7′-Dichlorodihydrofluorescein diacetate (DCFH-DA) assay. (DCFH-DA) assay can easily be oxidatively tuned into a fluorescent derivative because it is highly sensitive to ROS variation especially in an atmosphere containing the different factors like hydrogen peroxide, superoxide anion with other co-factors. Cell permeable DCFH-DA dye in fact measures the levels of oxidative stress within the cell. This dye can further be diffused within the cell and can be oxidatively modified into a fluorescent derivative by different ROS, in particular hydrogen peroxide and superoxide anion in the presence of certain co-factors. For the detection of levels of ROS production in both type of cell lines and their morphology, flow cytometry was used. The electronic and semiconducting properties of a material are assumed to be responsible for the ROS production at particle surface.

Fig. 1 depicts the typical XRD spectra for the synthesized SnxCe1-xO2 samples. All peaks are well indexed according to prescribed JCPDS-Card No. (Fig. 1) which clearly confirmed the single phase cubic fluorite structure of CeO2 as no peak regarding Sn, SnO or other impurities is found. Magnified portion of the Fig. 1 manifests the systematic peak (111) shift towards higher angle with Sn content which endorsed the successful substitution of Sn on the site of Ce ion in the host CeO2 matrix. Furthermore, this peak shift may be attributed to the possible lattice contraction induced due to dopant ions.26 The microstructural parameters crystallite size ‘t’ and lattice constant a=b=c are found using the formulae,

t=0.89λβcosθ
(1)
1d2=h2+k2+l2a2
(2)

Where β is the full width half maxima (FWHM) in radians, λ is the wavelength of incident CuKα X-Rays (1.54Å) used in the experiment, d is the inter-planer spacing, θ is the angle of diffraction and h,k,l are Miller indices. It is found that lattice constant as well as crystallite size both mildly decrease with Sn content (Table I) which may be attributed to the fact that ionic radii of Sn (0.69Å) is smaller than that of Ce (1.01Å).

FIG. 1.

XRD patterns of the (a) as prepared (b) 3% Sn (c) 5% Sn (d) 7% Sn doped CeO2 samples while magnified portion depicting Sn doping induced shift in the (111) peak.

FIG. 1.

XRD patterns of the (a) as prepared (b) 3% Sn (c) 5% Sn (d) 7% Sn doped CeO2 samples while magnified portion depicting Sn doping induced shift in the (111) peak.

Close modal
TABLE I.

Physical Characteristics of SnxCe1-xO2 nanostructures.

LatticeFT-IRAC ConductivityOptical
CrystalliteParameterParticleCharacteristics(σac)Energy
SampleSize (t)a=b=cMorphologyCe-O Stretching1MHz3MHz5MHzBandgap (Eg)
SnxCe1-xO2
Nanostructures(nm)(Å)Shape/(nm)(cm-1)(s/m)* 10-4eV
X=0 5.415 Spherical/20-30 466 0.7 1.1 1.5 2.8 
X=0.03 5.363 Spherical/20-30 466 1.6 3.0 3.9 3.1 
X=0.05 5.364 Beads Like/30-60 466 2.7 4.9 6.3 2.9 
X=0.07 5.5 5.387 Heterogeneous 466 1.3 2.5 3.1 3.3 
   Nanowires-      
   Nanosheets      
   /Diameter      
   =15-30      
LatticeFT-IRAC ConductivityOptical
CrystalliteParameterParticleCharacteristics(σac)Energy
SampleSize (t)a=b=cMorphologyCe-O Stretching1MHz3MHz5MHzBandgap (Eg)
SnxCe1-xO2
Nanostructures(nm)(Å)Shape/(nm)(cm-1)(s/m)* 10-4eV
X=0 5.415 Spherical/20-30 466 0.7 1.1 1.5 2.8 
X=0.03 5.363 Spherical/20-30 466 1.6 3.0 3.9 3.1 
X=0.05 5.364 Beads Like/30-60 466 2.7 4.9 6.3 2.9 
X=0.07 5.5 5.387 Heterogeneous 466 1.3 2.5 3.1 3.3 
   Nanowires-      
   Nanosheets      
   /Diameter      
   =15-30      

Fig. 2 elaborates the morphological analysis of SnxCe1-xO2 samples using SEM. SEM micrograph illuminates the formation of spherical nanoparticles with average particle size of 20-50nm for pristine and 3% Sn content CeO2 samples. It is very interesting to observe that at 5 and 7% Sn loading, the morphology of the synthesized sample is dramatically changed to heterogeneous beed and nanowires-nanosheets like structure respectively. The observed morphological transformation probably linked to the successful incorporation of Sn ions into the host CeO2 matrix. Moreover, it is a well-established reality that the introduction of Sn in CeO2 lattice tailored the Pauling electronegativity (χ) of the crystal which in turns alters the chemical reactivity of the material.27,28 This alteration in morphology is due to the fact that vale of χ of Sn (1.96) is too higher than that of Ce element (1.1). Thus, introduction of Sn as dopant in CeO2 lattice may boost up the growth rate of SnxCe1-xO2 samples towards heterogeneous beads and nanowires-nanosheets like structure.

FIG. 2.

SEM micrographs of (a) Undoped (b) 3% Sn (c) 5% Sn (d) 7% Sn doped CeO2 samples.

FIG. 2.

SEM micrographs of (a) Undoped (b) 3% Sn (c) 5% Sn (d) 7% Sn doped CeO2 samples.

Close modal

Comparative FT-IR study has been used to investigate the vibrational modes of chemical bonds and surface chemistry of the synthesized SnxCe1-xO2 nanostructures. Fig. 3 shows prominent absorption peaks in the range 400 to 4000 cm-1 for the prepared nanostructures. The spectrum values between 2357 to 3642 cm-1 corresponds to O-H and C-H bond stretching which are supposed to be arises due to surface attraction of water molecules from environment.29 Typical Ce-O stretching bond peaks in undoped, 3% Sn doped and 5% Sn doped CeO2 NPs samples can be observed at 466 cm-1, the Ce-O spectrum with characteristics peaks around 450 to 470 cm-1 were also reported previously.30,31 In our studies, all of the samples reflects high similarity index in FT-IR spectrum peak values, presenting the masked effect of Sn doping in the synthesized CeO2 nanostructures.

FIG. 3.

FTIR spectra of the synthesized SnxCe1-xO2 nanostructures.

FIG. 3.

FTIR spectra of the synthesized SnxCe1-xO2 nanostructures.

Close modal

The frequency dependent electrical behavior of prepared SnxCe1-xO2 nanostructures has been investigated using LCR meter in the frequency range of 1 kHz to 5 MHz under ambient conditions. The frequency dependent AC conductivity (σac) was found by the relation (3) and is shown in Fig. 4,

σac=2πεoέtanδ
(3)

Where, tanδ=ε/ε

FIG. 4.

AC conductivity as a function of AC frequency for (a) as prepared (b) 3% (c) 5% (d) 7% Sn doped CeO2 nanostructures.

FIG. 4.

AC conductivity as a function of AC frequency for (a) as prepared (b) 3% (c) 5% (d) 7% Sn doped CeO2 nanostructures.

Close modal

It is obvious from Fig. 4 that σac increases both with frequency as well as dopant content except at 7% Sn doping content (Table I). Frequency dependence of σac is in good agreement with the powers law which states that σac is proportional to AC frequency. The enhancement of σac with Sn content may be attributed to the fact that with doping, Sn2+ ions replace the Ce4+ ions which induces more free electrons to the host system. Moreover, in order to attain charge neutrality some defects (structural defects, oxygen vacancies etc.) will produced which may enhance the σac of the prepared nanostructures.32 Moreover, at higher level of Sn doping, σac is found to be decreased. This may be attributed to the grain boundaries effect that extra amount of energy is required for the exchange of electrons at grain boundaries.33 

Optical properties of NMs are of immense significance in tuning the catalytic and biomedical activities. It is very important to have exact knowledge about optical features of NMs as these characteristics determined their photo-induced cytotoxicity. In order to investigate optical band gap energies of the synthesized SnxCe1-xO2 nanostructures, UV-visible spectroscopy has been utilized. Fig. 5(a) depicts the UV- visible absorption spectra of the synthesized SnxCe1-xO2 nanostructures which clearly shows the existence of sharp absorption peaks in the range of 299nm-331nm. The existence of these peaks confirms the formation of single phase cubic fluorite structure as these peaks are originated from electronic transition between 2d and 4f states of O and Ce respectively34 these results are inconsistent with XRD and FT-IR findings. Moreover, this spectra also reveals the Sn induced substantial variations in the absorption and shift in absorption band edge of the synthesized SnxCe1-xO2 nanostructures. Bandgap energies of the synthesized SnxCe1-xO2 nanostructures are estimated by the famous Tauc relation for direct bandgap materials,

(αhν)2=A(hνEg)
(4)

Where hν is the photon energy, Eg stands for bandgap energy, α is the absorption coefficient and A is the constant. The linear exploration of the (αhν)2 curves up to energy axis give the bandgap energy of SnxCe1-xO2 nanostructures as shown in Fig. 5(b).35 The observed Eg value for pristine CeO2 is found to be 2.8eV which has a blue shift with Sn doping up to maximum value of 0.5 eV. This shift in energy band gap exhibits the size dependent quantum confinement of the SnxCe1-xO2 nanostructures.36 Moreover this blue shift in the Eg also indicates electron-hole confinement at very large scale which in turns is due to replacement of Sn+2 at Ce+4 sites and providing excess number of oxygen vacancies.32 The existence of the structural defects make nano-materials highly potential for biomedical applications.

FIG. 5.

(a) UV- visible absorption spectra of the synthesized SnxCe1-xO2 nanostructures (b) Direct band gap energy estimation of the synthesized SnxCe1-xO2 nanostructures.

FIG. 5.

(a) UV- visible absorption spectra of the synthesized SnxCe1-xO2 nanostructures (b) Direct band gap energy estimation of the synthesized SnxCe1-xO2 nanostructures.

Close modal

Combating cancer, one of the most lethal disease around the globe, inorganic nanoparticles have been extensively examined.37 It has been reported in prior observations that doping phenomenon will results in condensation of band gap along with photo-excitation of CeO2 nanoparticles at visible spectrum under room temperature,38 these tuned properties may be helpful in targeting cancer cells. Thus, cytotoxic behavior of SnxCe1-xO2 nanostructures have been studied against SH_SY5Y and HEK_293 cell lines. Fig. 6 reflects the differential cytotoxicity against both type of cell lines after being incubated at 37°C with different concentration of Sn. It is clearly observed from fig. 6 that with great biocompatibility to healthy cells (up to 5% doping), cell viability of cancer cells inhibited to almost 40%. These observed values of cytotoxicity of synthesized SnxCe1-xO2 nanostructures are found to be higher than the reported values for other metal oxides (CuO, ZnO and WO3) nanostructures performed under the similar parameters (Exposure time, methodology, nanostructures type and concentrations etc.) and against the similar cancer cell lines.34,39–41 Moreover, results from fig. 6 depict selective cytotoxicity of 0, 3 and 5% Sn doped CeO2 nanoparticles towards SH_SY5Y and HEK_293 cell lines, while 7% Sn doped CeO2 nanoparticles were observed relatively equally toxic for both healthy and cancer cells. This toxic behavior of NPs towards healthy cells may be due to decrease in surface area because of agglomeration of 7% Sn doped CeO2 NPs (Fig. 2d), resulting in bulk deposition inside the healthy cells cytosol which ultimately produces lethality. Results from phase contrast microscopy, Fig. 7 and 8, clearly shows apoptotic bodies of targeted cancer cells while healthy cells are least effected up to 5% doping.

FIG. 6.

Effect of synthesized SnxCe1-xO2 nanostructures on Neuroblastoma & HEK-293 Cells.

FIG. 6.

Effect of synthesized SnxCe1-xO2 nanostructures on Neuroblastoma & HEK-293 Cells.

Close modal
FIG. 7.

Cell viability assay of HEK-293 Cells after treatment with SnxCe1-xO2 nanostructures. (a) DMEM++. (b) Undoped CeO2. (c) 5% Sn doped. (d) 7% Sn doped.

FIG. 7.

Cell viability assay of HEK-293 Cells after treatment with SnxCe1-xO2 nanostructures. (a) DMEM++. (b) Undoped CeO2. (c) 5% Sn doped. (d) 7% Sn doped.

Close modal
FIG. 8.

Cell viability assay of Neuroblastoma Cells after treatment with SnxCe1-xO2 nanostructures. (a) DMEM++. (b) Undoped CeO2. (c) 5% Sn doped. (d) 7% Sn doped.

FIG. 8.

Cell viability assay of Neuroblastoma Cells after treatment with SnxCe1-xO2 nanostructures. (a) DMEM++. (b) Undoped CeO2. (c) 5% Sn doped. (d) 7% Sn doped.

Close modal

Cytotoxicity of metallic NPs mainly depends upon fine particle size, electrostatic interaction between particle and cell envelope and reactive oxygen species (ROS) generations.9,42 Oxidative stress caused by CeO2 nanoparticles are well reported,43 in order to check the relation of selective ROS generation with selective cytotoxicity of undoped and Sn doped CeO2 nanostructures, we have conducted ROS generation studies. Fig. 9 shows ROS generation in both cancerous and healthy cell lines and is found that pristine and Sn doped CeO2 nanoparticles strictly followed the ROS generation format. Absorption of the synthesized SnxCe1-xO2 nanostructures inside the both type of cell lines has differential behavior due to different cell environmental conditions (pH and homeostasis) of cancer cells as compared to healthy cells.44 It has also been observed from Fig. 9 that cancer cells treated samples, with up to 5% of Sn doped CeO2 nanostructures, exhibit great intensity of damaging ROS as compared to healthy cells. This promising retardation in growth were prominently observed in cancer cells on all concentrations, while healthy cell only show ROS generation at 7% doping which is in good agreement with healthy cell viability at this concentrations. This malfunctioning of healthy cells (with 7% Sn loadings) may be linked with the various factors like, blue shift in the optical band gap from visible region (Fig. 5b), particle size variation (Fig. 2d) and crystallite size variation (Table I) etc. It is here further explained that normal somatic cells can tolerate ROS cycle at cellular level to overcome the cell apoptosis upon exposure to ROS inducers (like Undoped and Sn undoped CeO2 nanostructures), while comparatively due to high metabolic rate and acidic environment of cancer cells they fails to tolerate ROS disturbance inside the cell which results in cell necrosis, as elaborated in our previous study.45 As highlighted in Fig. 10, upon penetration of nanoparticles inside cancer cell through phagocytosis, ROS species like hydroxyl radical (OH), singlet oxygen (1O2) and least toxic superoxide anion radical (-*O2), contributing to the major oxidative stress46 in cellular environment. Increase in stress results in denaturation of plasma proteins, cell membrane, cellular DNA and also will induces apoptosis by damaging mitochondrial population inside the cancer cell. Metabolic machinery of host cell destroy which results in ROS induce cell death. From above analysis it is obvious that our engineered SnxCe1-xO2 nanostructures possess the capabilities of differentiating healthy cells from cancer cells which makes them highly potential for targeted anticancer drug treatment in future.

FIG. 9.

Reactive oxygen species (ROS) production in Neuroblastoma & HEK-293 Cells after incubation of SnxCe1-xO2 nanostructures.

FIG. 9.

Reactive oxygen species (ROS) production in Neuroblastoma & HEK-293 Cells after incubation of SnxCe1-xO2 nanostructures.

Close modal
FIG. 10.

A Schematic illustration of ROS induced death of Cancer cell.

FIG. 10.

A Schematic illustration of ROS induced death of Cancer cell.

Close modal

In present study, we have successfully synthesized the SnxCe1-xO2 nanostructures via soft hydrothermal route and achieved the following outcomes.

  • XRD analysis reveals the phase purity of undoped and Sn doped CeO2 nanostructures. It has also been observed that Sn doping has decreased the average crystallite sizes as well as the lattice parameters which make it potential for biomedical applications.

  • FT-IR spectra demonstrates the formation of a single phase cubic fluorite structure of the synthesized SnxCe1-xO2 samples which is inconsistent with the XRD results.

  • SEM micrographs depict the formation of homogeneous spherical nanoparticles with average particle size ranging 20-30nm for undoped and 3% Sn doped CeO2. While higher Sn concentrations (5% and 7%) has modified the morphology to heterogeneous beads and nanowires-nanosheets like structures. This growth in morphology is attributed to the difference of Pauling electronegativity values of dopant cation and host Ce ion.

  • AC conductivity of the prepared samples, overall, is found to be significantly enhanced with Sn doping content and with the AC frequency.

  • Optical band gap energies of the prepared SnxCe1-xO2 nanostructures are observed to increase with the Sn doping which may be linked to the quantum confinement effect.

  • Prepared SnxCe1-xO2 nanostructures upon installation to Neuroblastoma cell lines, in order to observe cytotoxic behavior, resulted into ROS activated necrosis of these cells with complete inhibition in growth and metastasis, meanwhile, it shows great bio-compatibility for healthy cells.

1.
D. A.
Oldridge
,
A. C.
Wood
,
N.
Weichert-Leahey
,
I.
Crimmins
,
R.
Sussman
,
C.
Winter
,
L. D.
McDaniel
,
M.
Diamond
,
L. S.
Hart
,
S.
Zhu
, and
A. D.
Durbin
, “
Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism
,”
Nature
(
2015
).
2.
L. M.
Wagner
and
M. K.
Danks
, “
New therapeutic targets for the treatment of high-risk neuroblastoma
,”
Journal of Cellular Biochemistry
107
(
1
),
46
57
(
2009
).
3.
G.
Zhao
and
B. L.
Rodriguez
, “
Molecular targeting of liposomal nanoparticles to tumor microenvironment
,”
International Journal of Nanomedicine
8
,
61
(
2013
).
4.
Y.
Wang
,
F.
Yang
,
H. X.
Zhang
,
X. Y.
Zi
,
X. H.
Pan
,
F.
Chen
,
W. D.
Luo
,
J. X.
Li
,
H. Y.
Zhu
, and
Y. P.
Hu
, “
Cuprous oxide nanoparticles inhibit the growth and metastasis of melanoma by targeting mitochondria
,”
Cell Death & Disease
4
(
8
),
e783
(
2013
).
5.
M. S.
Wason
and
J.
Zhao
, “
Cerium oxide nanoparticles: Potential applications for cancer and other diseases
,”
Am J Transl Res
5
(
2
),
126
131
(
2013
).
6.
S.
Milo
,
N. T.
Thet
,
D.
Liu
,
J.
Nzakizwanayo
,
B. V.
Jones
, and
A. T. A.
Jenkins
, “
An in-situ infection detection sensor coating for urinary catheters
,”
Biosensors and Bioelectronics
81
,
166
172
(
2016
).
7.
A. B.
Chinen
,
C. M.
Guan
,
J. R.
Ferrer
,
S. N.
Barnaby
,
T. J.
Merkel
, and
C. A.
Mirkin
, “
Nanoparticle probes for the detection of cancer biomarkers, cells, and tissues by fluorescence
,”
Chemical Reviews
115
(
19
),
10530
10574
(
2015
).
8.
A.
Rodzinski
,
R.
Guduru
,
P.
Liang
,
A.
Hadjikhani
,
T.
Stewart
,
E.
Stimphil
,
C.
Runowicz
,
R.
Cote
,
N.
Altman
,
R.
Datar
, and
S.
Khizroev
, “
Targeted and controlled anticancer drug delivery and release with magnetoelectric nanoparticles
,”
Scientific Reports
6
(
2016
).
9.
F.
Abbas
,
T.
Jan
,
J.
Iqbal
,
I.
Ahmad
,
M. S. H.
Naqvi
, and
M.
Malik
, “
Facile synthesis of ferromagnetic Ni doped CeO2 nanoparticles with enhanced anticancer activity
,”
Applied Surface Science
357
,
931
936
(
2015
).
10.
E.
Panieri
and
M. M.
Santoro
, “
ROS homeostasis and metabolism: A dangerous liason in cancer cells
,”
Cell Death & Disease
7
(
6
),
e2253
(
2016
).
11.
P. D.
Ray
,
B. W.
Huang
, and
Y.
Tsuji
, “
Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling
,”
Cellular Signalling
24
(
5
),
981
990
(
2012
).
12.
M. P.
Vinardell
and
M.
Mitjans
, “
Antitumor activities of metal oxide nanoparticles
,”
Nanomaterials
5
(
2
),
1004
1021
(
2015
).
13.
M.
Ahamed
,
H. A.
Alhadlaq
,
M. M.
Khan
, and
M. J.
Akhtar
, “
Selective killing of cancer cells by iron oxide nanoparticles mediated through reactive oxygen species via p53 pathway
,”
Journal of Nanoparticle Research
15
(
1
),
1
11
(
2013
).
14.
S.
Alarifi
,
D.
Ali
,
S.
Alkahtani
, and
M. S.
Alhader
, “
Iron oxide nanoparticles induce oxidative stress, DNA damage, and caspase activation in the human breast cancer cell line
,”
Biological Trace Element Research
159
(
1–3
),
416
424
(
2014
).
15.
X.
Meng
,
H. C.
Seton
,
L. T.
Lu
,
I. A.
Prior
,
N. T.
Thanh
, and
B.
Song
, “
Magnetic CoPt nanoparticles as MRI contrast agent for transplanted neural stem cells detection
,”
Nanoscale
3
(
3
),
977
984
(
2011
).
16.
J. E.
Kim
,
J. Y.
Shin
, and
M. H.
Cho
, “
Magnetic nanoparticles: An update of application for drug delivery and possible toxic effects
,”
Archives of Toxicology
86
(
5
),
685
700
(
2012
).
17.
U. O.
Häfeli
,
J. S.
Riffle
,
L.
Harris-Shekhawat
,
A.
Carmichael-Baranauskas
,
F.
Mark
,
J. P.
Dailey
, and
D.
Bardenstein
, “
Cell uptake and in vitro toxicity of magnetic nanoparticles suitable for drug delivery
,”
Molecular Pharmaceutics
6
(
5
),
1417
1428
(
2009
).
18.
A.
Asati
,
S.
Santra
,
C.
Kaittanis
, and
J. M.
Perez
, “
Surface-charge-dependent cell localization and cytotoxicity of cerium oxide nanoparticles
,”
ACS Nano
4
(
9
),
5321
5331
(
2010
).
19.
M. S.
Wason
,
J.
Colon
,
S.
Das
,
S.
Seal
,
J.
Turkson
,
J.
Zhao
, and
C. H.
Baker
, “
Sensitization of pancreatic cancer cells to radiation by cerium oxide nanoparticle-induced ROS production
,”
Nanomedicine: Nanotechnology, Biology and Medicine
9
(
4
),
558
569
(
2013
).
20.
G.
Waris
and
H.
Ahsan
, “
Reactive oxygen species: Role in the development of cancer and various chronic conditions
,”
Journal of Carcinogenesis
5
(
1
),
14
(
2006
).
21.
H. M.
Shen
and
Z. G.
Liu
, “
JNK signaling pathway is a key modulator in cell death mediated by reactive oxygen and nitrogen species
,”
Free Radical Biology and Medicine
40
(
6
),
928
939
(
2006
).
22.
X.
Zhang
,
J.
Wei
,
H.
Yang
,
X.
Liu
,
W.
Liu
,
C.
Zhang
, and
Y.
Yang
, “
One-pot synthesis of Mn-doped CeO2 nanospheres for CO oxidation
,”
European Journal of Inorganic Chemistry
2013
(
25
),
4443
4449
(
2013
).
23.
L.
Zhou
,
X.
Li
,
Z.
Yao
,
Z.
Chen
,
M.
Hong
,
R.
Zhu
,
Y.
Liang
, and
J.
Zhao
, “
Transition-metal doped ceria microspheres with nanoporous structures for CO oxidation
,”
Scientific Reports
6
(
2016
).
24.
G.
Xiao
,
S.
Li
,
H.
Li
, and
L.
Chen
, “
Synthesis of doped ceria with mesoporous flowerlike morphology and its catalytic performance for CO oxidation
,”
Microporous and Mesoporous Materials
120
(
3
),
426
431
(
2009
).
25.
J. L.
Ayastuy
,
A.
Iglesias-González
, and
M. A.
Gutiérrez-Ortiz
, “
Synthesis and characterization of low amount tin-doped ceria (CeX Sn1−X O2−δ) for catalytic CO oxidation
,”
Chemical Engineering Journal
244
,
372
381
(
2014
).
26.
T.
Ahmad
,
S.
Khatoon
, and
K.
Coolahan
, “
Structural, optical, and magnetic properties of nickel-doped tin dioxide nanoparticles synthesized by solvothermal method
,”
Journal of the American Ceramic Society
(
2016
).
27.
S. H.
Yang
,
S. Y.
Hong
, and
C. H.
Tsai
, “
Growth mechanisms and characteristics of ZnO nanostructures doped with In and Ga
,”
Japanese Journal of Applied Physics
49
(
6S
),
06GJ06
(
2010
).
28.
T.
Jan
,
J.
Iqbal
,
Q.
Mansoor
,
M.
Ismail
,
M. S. H.
Naqvi
,
A.
Gul
,
S. F. U. H.
Naqvi
, and
F.
Abbas
, “
Synthesis, physical properties and antibacterial activity of Ce doped CuO: A novel nanomaterial
,”
Journal of Physics D: Applied Physics
47
(
35
),
355301
(
2014
).
29.
J.
Gao
,
Y.
Zhao
,
W.
Yang
,
J.
Tian
,
F.
Guan
,
Y.
Ma
,
J.
Hou
,
J.
Kang
, and
Y.
Wang
, “
Preparation of samarium oxide nanoparticles and its catalytic activity on the esterification
,”
Materials Chemistry and Physics
77
(
1
),
65
69
(
2003
).
30.
E. K.
Goharshadi
,
S.
Samiee
, and
P.
Nancarrow
, “
Fabrication of cerium oxide nanoparticles: Characterization and optical properties
,”
Journal of Colloid and Interface Science
356
(
2
),
473
480
(
2011
).
31.
A.
Arumugam
,
C.
Karthikeyan
,
A. S. H.
Hameed
,
K.
Gopinath
,
S.
Gowri
, and
V.
Karthika
, “
Synthesis of cerium oxide nanoparticles using Gloriosa superba L. leaf extract and their structural, optical and antibacterial properties
,”
Materials Science and Engineering: C
49
,
408
415
(
2015
).
32.
K. S.
Kumar
and
N. V.
Jaya
, “
Synthesis and characterization of pure and Sn-doped CeO2 nanoparticles
,”
Asian Journal of Chemistry
25
(
11
),
6095
(
2013
).
33.
J.
Kaur
,
V.
Gupta
,
R. K.
Kotnala
, and
K. C.
Verma
, “
Size dependent dielectric properties of Co and Fe doped SnO2 nanoparticles and their nanorods by Ce co-doping
,”
Indian J. Pure Appl. Phys.
50
,
57
63
(
2012
).
34.
J.
Iqbal
,
T.
Jan
,
M. S.
Awan
,
S. H.
Naqvi
,
N.
Badshah
, and
F.
Abbas
, “
Mg doping induced effects on structural, optical, and electrical properties as well as cytotoxicity of CeO2 nanostructures
,”
Metallurgical and Materials Transactions B
47
(
2
),
1363
1368
(
2016
).
35.
D.
Channei
,
B.
Inceesungvorn
,
N.
Wetchakun
,
S.
Ukritnukun
,
A.
Nattestad
,
J.
Chen
, and
S.
Phanichphant
, “
Photocatalytic degradation of methyl orange by CeO2 and Fe–doped CeO2 films under visible light irradiation
,”
Scientific Reports
4
(
2014
).
36.
H.
Wang
,
J. J.
Zhu
,
J. M.
Zhu
,
X. H.
Liao
,
S.
Xu
,
T.
Ding
, and
H. Y.
Chen
, “
Preparation of nanocrystalline ceria particles by sonochemical and microwave assisted heating methods
,”
Physical Chemistry Chemical Physics
4
(
15
),
3794
3799
(
2002
).
37.
H. S.
Choi
,
W.
Liu
,
F.
Liu
,
K.
Nasr
,
P.
Misra
,
M. G.
Bawendi
, and
J. V.
Frangioni
, “
Design considerations for tumour-targeted nanoparticles
,”
Nature Nanotechnology
5
(
1
),
42
47
(
2010
).
38.
F.
Abbas
,
T.
Jan
,
J.
Iqbal
,
M. S. H.
Naqvi
, and
I.
Ahmad
, “
Inhibition of Neuroblastoma cancer cells viability by ferromagnetic Mn doped CeO2 monodisperse nanoparticles mediated through reactive oxygen species
,”
Materials Chemistry and Physics
173
,
146
151
(
2016
).
39.
T.
Jan
,
J.
Iqbal
,
M.
Ismail
,
M.
Zakaullah
,
S. H.
Naqvi
, and
N.
Badshah
, “
Sn doping induced enhancement in the activity of ZnO nanostructures against antibiotic resistant S. aureus bacteria
,”
International Journal of Nanomedicine
8
,
3679
(
2013
).
40.
T.
Jan
,
J.
Iqbal
,
U.
Farooq
,
A.
Gul
,
R.
Abbasi
,
I.
Ahmad
, and
M.
Malik
, “
Structural, Raman and optical characteristics of Sn doped CuO nanostructures: A novel anticancer agent
,”
Ceramics International
41
(
10
),
13074
13079
(
2015
).
41.
F.
Mehmood
,
J.
Iqbal
,
T.
Jan
,
W.
Ahmed
,
W.
Ahmed
,
A.
Arshad
, and
I.
Ahmad
, “
Effect of Sn doping on the structural, optical, electrical and anticancer properties of WO 3 nanoplates
,”
Ceramics International
42
(
13
),
14334
14341
(
2016
).
42.
X.
Fang
,
R.
Yu
,
B.
Li
,
P.
Somasundaran
, and
K.
Chandran
, “
Stresses exerted by ZnO, CeO2 and anatase TiO2 nanoparticles on the Nitrosomonas europaea
,”
Journal of Colloid and Interface Science
348
(
2
),
329
334
(
2010
).
43.
E. J.
Park
,
J.
Choi
,
Y. K.
Park
, and
K.
Park
, “
Oxidative stress induced by cerium oxide nanoparticles in cultured BEAS-2B cells
,”
Toxicology
245
(
1
),
90
100
(
2008
).
44.
C. L.
Chaffer
and
R. A.
Weinberg
, “
A perspective on cancer cell metastasis
,”
Science
331
(
6024
),
1559
1564
(
2011
).
45.
F.
Abbas
,
J.
Iqbal
,
T.
Jan
,
M. S. H.
Naqvi
,
A.
Gul
,
R.
Abbasi
,
A.
Mahmood
,
I.
Ahmad
, and
M.
Ismail
, “
Differential cytotoxicity of ferromagnetic Co doped CeO2 nanoparticles against human neuroblastoma cancer cells
,”
Journal of Alloys and Compounds
648
,
1060
1066
(
2015
).
46.
Y.
Li
,
W.
Zhang
,
J.
Niu
, and
Y.
Chen
, “
Mechanism of photogenerated reactive oxygen species and correlation with the antibacterial properties of engineered metal-oxide nanoparticles
,”
ACS Nano
6
(
6
),
5164
5173
(
2012
).