Results in Engineering 20 (2023) 101537

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Results in Engineering
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Magnetic hyperthermia cancer therapy using rare earth metal-based

nanoparticles: An investigation of Lanthanum strontium Manganite’s
hyperthermic properties
Amit B. Tewari, Ritu Sharma, Deepika Sharma *
Institute of Nano Science and Technology (INST), Knowledge City, Sector 81, Mohali, 140306, Punjab, India

A B S T R A C T

Magnetic hyperthermia cancer therapy has emerged as a promising approach for targeted and localized treatment of cancer. This innovative technique utilizes
magnetic nanoparticles to generate localized heat within tumor cells, leading to their selective destruction. This study explores the hyperthermic potential of
Lanthanum Strontium Manganite (LSMO), which are rare earth metal-based magnetic nanoparticles, for their application in magnetic hyperthermia cancer therapy. A
modified citrate sol-gel technique was utilized to create LSMO (La0⋅7Sr0⋅3MnO3) nanoparticles, which were then modified by coating with silica. Comprehensive
physical characterization of the nanoparticles was performed, and their hyperthermic potential was evaluated in vitro. The biocompatibility and selective cyto­
toxicity of LSMO nanoparticles were investigated, and the results demonstrated promising outcomes. With its controlled and localized heat generation and enhanced
biocompatibility, LSMO offers an encouraging avenue for advancing targeted and effective cancer treatments. Future research in this field may pave the way for
transformative improvements in cancer therapy outcomes.

1. Introduction
Magnetic hyperthermia cancer therapy presents a promising
approach for selectively treating cancer cells by utilizing magnetic
nanoparticles and localized heat generation [1]. The technique involves
injecting biocompatible magnetic nanoparticles into the body, which
accumulates at the tumor site [2]. These nanoparticles are typically
composed of materials like iron oxide with soft magnetism characterized
by narrow hysteresis curve [3–5].Further these nanoparticles can be
functionalized with specific molecules to enhance targeting to cancer
cells [6,7]. Upon accumulation in the tumor, an alternating magnetic
field (AMF) exposure induces rapid oscillations in the nanoparticles,
generating heat through processes like Néel relaxation, Brownian
relaxation, and hysteresis loss [8]. Hysteresis loss occurs when magnetic
materials exhibit a lag in their response to changes in the applied
magnetic field, resulting in energy dissipation in the form of heat. The
generation of heat by the magnetic nanoparticles raises the temperature
in the tumor region, leading to localized hyperthermia [9]. This local­
ized hyperthermia aims to achieve temperatures between 42 ◦ C and
45 ◦ C, leading to apoptotic cell death [10]. Additionally, hyperthermia
can augment the efficacy of other cancer treatments, such as radiation
therapy or chemotherapy, by increasing cancer cells sensitivity [11–13].
A key advantage of magnetic hyperthermia therapy is its ability to
selectively target tumor cells while minimizing damage to healthy sur­
rounding tissues [14,15]. Functionalizing the nanoparticles with spe­
cific ligands enables recognition and binding to cancer cells, further
reducing off-target effects [16]. Moreover, the precise control and focus
of the magnetic field allow for localized heat generation within the
tumor region, making it a non-invasive and targeted therapeutic
approach that can be combined with other treatments for improved
outcomes [17–19].
Magnetic nanoparticles which act as transducers for heat generation
are a vital component of hyperthermia therapy and have been synthe­
sized using a variety of techniques and functionalized to make them
suitable for biomedical applications [20,21].Iron oxide-based magnetic
nanoparticles have been widely used in hyperthermia applications
[22–24],but rare earth metal-based magnetic perovskite, La1- xSrxMnO3,
has emerged as a promising alternative [25,26]. The curie temperature
of the nanoparticles can be optimized for medical hyperthermia appli­
cations by adjusting the doping ratio, making them a viable choice [26].
Specific substitution of La in LaMnO3 which is an antiferromagnetic
compound containing Mn3+ ions with Sr changes an equivalent amount
of Mn3+ ions into Mn4+ ions. Depending upon the amount of substitution
a transition into paramagnetic state also occurs [27,28].Of all the
possible ratio of Sr substitution possible, La0⋅7Sr0⋅3MnO3 have been
found to be optimal for magnetic hyperthermia applications due to their

* Corresponding author
E-mail address: deepika@inst.ac.in (D. Sharma).

https://doi.org/10.1016/j.rineng.2023.101537
Received 31 July 2023; Received in revised form 19 October 2023; Accepted 22 October 2023
Available online 27 October 2023
2590-1230/© 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
A.B. Tewari et al.
magnetic properties and optimal curie temperature. However, achieving
biocompatibility is equally important, and surface modification with
silica offers an attractive solution due to its biocompatibility and po­
tential for further functionalization [25,29].
In this paper, we present an optimized synthesis route for LSMO
magnetic cores, which are subsequently coated with silica to enhance
biocompatibility and suitability for magnetic hyperthermia therapy. Our
synthesized nanosystem has shown very low value of coercivity and
remanence when compared to previously reported LSMO nanosystems.
We have also shown for the first time the effect of silica coating upon the
surface chemistry of the bare LSMO nanoparticles for hyperthermia
therapy using in depth XPS analysis. This could pave the way for further
work when the surface chemistry of the nanosystems needs to be
investigated for example while exploring ligand functionalization for
specific applications. By exploring this innovative approach, we aim to
contribute to the advancement of targeted and effective cancer
treatments.
2. Experimental section
2.1. Materials
Ethylene glycol(C₂H₆O₂,99%),Lanthanum nitrate(La(NO3)3⋅6H2O,
99%), Tetraethyl orthosilicate(TEOS)(SiC8H20O4,99%), Strontium ni­
trate(Sr(NO3)2,99%), Ammonium hydroxide (NH4OH,25%), Absolute
ethanol(C₂H₆O,99.9%), manganese(II) Nitrate Hydrate (Mn
(NO3)2⋅xH2O,98%), Hydrochloric acid(HCl,37 %), and Citric acid
(C₆H₈O₇,99%) were purchased from CDH chemicals. Dulbecco’s Modi­
fied Eagle’s Medium(Lonza), 0.25% trypsin, antibiotic antimycotic
cocktail, Phosphate buffer saline(PBS), Triton X-100, Paraformaldehyde
(4%), Foetal bovine serum (FBS), Dimethyl sulphoxide (DMSO(cell
culture grade)), Bovine serum Albumin(BSA), and MTT [(3-(4,5-dime­
thylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide] were procured
from HiMedia, unless otherwise specified. Anti-cleaved caspase-3 anti­
body was purchased from Cell signaling technology. Anti-rabbit FITC
was purchased from ABclonal, and phalloidin Alexa Fluor 594 were
purchased from ThermoFisher. Hoescht-33342 was purchased from
Invitrogen. 2′,7′-Dichlorofluorescin diacetate (DCFH-DA) was purchased
from Sigma-Aldrich. Mouse fibroblast cell line L929 and Human osteo­
sarcoma cell line MG-63 were obtained from National Centre for Cell
Science (Pune, India).
2.2. Preparation of LSMO (La0⋅7Sr0⋅3MnO3) core
A modified citrate sol gel protocol was used to synthesize the mag­
netic core. Stoichiometrically appropriate amounts of precursor salts, La
(NO3)3⋅6H2O, Sr(NO3)2 and Mn(NO3).xH20 were weighed and dissolved
in 10 ml of type 2 deionized water (DI) under constant stirring at 500
rpm. After that 5 g citric acid as fuel and 15 ml ethylene glycol as
capping agent were added dropwise [26]. The solution was then stirred
at 700 rpm and heated in an oil bath at 120 ◦ C till slight gelation began
to occur. The temperature was then increased to 180 ◦ C till combustion
occurred and a dried gel was obtained. The dried gel so obtained was
crushed finely in a mortar and then subjected to thermal treatment in a
tube furnace. Heat was provided in two stages: the first cycle constituted
raising temperature to 450 ◦ C for 3 h, then in the second stage the
temperature was further elevated to 800 ◦ C for 3.5 h for calcination
[30]. The black powder obtained was washed in DI water thrice and
separated magnetically.
2.3. Synthesis of silica coated LSMO (Si-LSMO)
The modified Stober method was utilized for the silica coating. The
dried LSMO(200 mg) nanoparticles were added to pure ethanol (200 ml)
and then ammonium hydroxide (25 % NH3 in H2O) solution was added
dropwise under repeated sonication in a bath sonicator at high intensity
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Results in Engineering 20 (2023) 101537
and stirring for 1 h 10 ml TEOS was then added and the solution further
sonicated in a bath sonicator at high intensity for 30 min. The mixture
was then left to stand for 12 h [29]. The obtained nanoparticles
(Si-LSMO) were magnetically separated and washed in ethanol thrice
before drying.
2.4. Characterization of nanoparticles
The crystallographic structure and chemical composition was
investigated using a Bruker D8 Advanced X-ray diffraction (XRD) system
using a Cu Kα radiation source at a scan rate of 2◦ min − 1. A Bruker
Vertex 70 FTIR spectrophotometer was used to confirm the silica
coating. The particle morphology and size of the magnetic nanoparticles
were determined using a JEOL JEM 2100 transmission electron micro­
scope (TEM) operating at 200 kV acceleration voltage. The magnetic
properties were determined using a Quantum Design DynaCool PPMS
magnetometer. A Thermo Fisher Scientific X-ray Photoelectron Spec­
trometer (XPS) System (K-Alpha) using an Al K-Alpha X-ray source was
used to evaluate the elemental composition and the surface chemistry of
the nanoparticles. A field emission scanning electron microscope
(FESEM, Jeol JSM-7610FPlus) was used to obtain micrographs of the
nanoparticles. Dynamic light scattering (DLS) measurements were
conducted using a Malvern Zetasizer Nano-ZS to investigate the hy­
drodynamic size of the particles. The Zeta potential of the synthesized
nanosystem was also evaluated using Malvern Zetasizer Nano-ZS.
2.5. Magnetic hyperthermia measurements
The hyperthermic efficiency of the nanoparticles were evaluated
using the magnetic hyperthermia system from MSI automation (Wichita,
KS).The nanoparticle dispersions at different concentration were sub­
jected to AMF of fixed frequency and different magnetic fields namely at
335 KHz and and 150 and 163 Oe. A fiber optic probe was used to
evaluate the temperature rise. The Box Lucas method was used to fit the
curve and calculate the specific absorption rate(SAR) [31].The magnetic
hyperthermia system from the nB D5 series (nB nanoscale Biomagnetics,
Spain) was used for the cellular experiments.
2.6. Cell culture
Dulbecco’s modified Eagle’s medium supplemented with 10 % FBS
and 1 % antibiotic cocktail was used to culture murine fibroblast cell line
L929 and human osteosarcoma cell line MG-63 in a humid environment
at 37 ◦ C with 5 % CO2. For invitro experiments, the cells were seeded
onto the desired culture vessel and then treated with Si-LSMO followed
by the AMF exposure. The cells were exposed to an AMF for a 30 min
duration. MTT assay was performed to evaluate biocompatibility and
cell proliferation. The biocompatibility of the nanoparticles was evalu­
ated on the L929 cell line at different concentrations. The experimental
groups for the hyperthermia exposure were: (a) cells only; (b) cells
treated with Si-LSMO and (c) cells with Si-LSMO and AMF exposure for
both (t = 0 h) and (t = 4 h), t being the time between hyperthermia
treatment and cell viability evaluation. Reactive oxygen species(ROS)
production was qualitatively seen via DCFH-DA staining. The cells were
cultured using 6 well plates and post treatment the DCFH-DA dye was
added after media was removed and the cells washed with PBS. The cells
were then incubated for 30 min with the dye. Thereafter the cells were
washed with PBS thrice and observed under the microscope.
2.6.1. Immunocytochemistry
The effect of the hyperthermia treatment upon the cells was inves­
tigated by immunocytochemistry.MG-63 cells were seeded on sterilized
coverslips for a period of 24 h and then treated with Si-LSMO overnight.
The cells were then subjected to AMF treatment as given in 2.6.There­
after the cells were washed with PBS and fixed using 4 % para­
formaldehyde for 5 min at room temperature. Cells were then
A.B. Tewari et al.
permeabilized using 0.5 % Triton X-100 in PBS at room temperature for
5 min and washed with PBS. To reduce background noise blocking was
then done using BSA prepared in PBS at room temperature. Primary
antibody against caspase 3 diluted in BSA was then added and incubated
overnight at 4 ◦ C. PBS wash was then given and the secondary antibody
tagged with fluorescent dye was added and incubated at room temper­
ature for 1 h in the dark. Cells were then washed with PBS. Cells were
then incubated with the nuclear stain Hoescht-33342 for 5 min followed
by staining of the cytoskeletal elements with phalloidin Alexa Fluor 594
for 20 min. Multiple washings with PBS were given in between each
step. The coverslip was then mounted onto a glass slide and observed
under a confocal microscope(Zeiss LSM880,Carl Zeiss).
3. Results and discussion
3.1. X-ray diffraction (XRD) analysis
X-ray diffraction (XRD) was performed to assess the phase and
crystal structure of the synthesized Lanthanum Strontium Manganite
(LSMO) nanoparticles. The XRD spectra, presented in Fig. 1(a),
confirmed the successful formation of the desired polycrystalline
perovskite structure with high purity. Notably, no peaks corresponding
to any secondary impurities were detected, signifying the excellent
quality of the synthesized nanoparticles. The match with JCPDS card no.
00-051-0409 further confirmed the formation of desired crystal struc­
ture, demonstrating rhombohedral pseudo-cubic symmetry [32].
The XRD pattern exhibited distinct peaks, with the most prominent
ones observed at Bragg’s angles 2θ of 23.10◦ , 32.70◦ , 40.3◦ , 46.9◦ , 58.3◦ ,
68.7◦ , 78.1◦ , corresponding to lattice planes (012), (110), (202), (024),
(214), (208), and (128), respectively. The crystallite size of the uncoated
LSMO nanoparticles was determined to be 25.71 nm using the standard
Debye-Scherrer equation based on the full width half maxima of the
most prominent peak.
Upon silica coating (Si-LSMO) the XRD pattern exhibited similar
peaks characteristic of the rhombohedral perovskite structure. However,
a noticeable suppression of all the peak intensities was observed, indi­
cating the presence of silica in an amorphous form, likely due to its
coating around the LSMO nanoparticles [29]. The crystallite size for the
Si-LSMO samples was found to be 26.79 nm, slightly higher than that of
the uncoated sample.
Overall, the XRD analysis confirms the successful synthesis of LSMO
nanoparticles with the desired perovskite crystal structure. The coating
of silica, while affecting peak intensities, did not compromise the crys­
talline nature of the nanoparticles. These findings contribute to the
understanding of the structural characteristics of LSMO nanoparticles
and their potential applications in various fields, including magnetic
Fig. 1. (a) XRD spectra and (b) FTIR spectra for uncoated LSMO and silica coated Si-LSMO.
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Results in Engineering 20 (2023) 101537
hyperthermia cancer therapy.
3.2. Fourier transform infrared (FTIR) analysis and silica coating
confirmation
The FTIR spectra of both uncoated LSMO and the silica coated (Si-
LSMO) are presented in Fig. 1(b). In both samples, the band observed
around 570 cm− 1 corresponds to the characteristic Mn–O vibrations of
perovskite structure [29]. Additionally, traces of unburnt citric acid fuel
may contribute to the presence of carbon-related groups, particularly
carboxyl groups, in the 1000-2500 cm− 1 region [29].
The appearance of peak at around 851 cm− 1 and 1440 cm− 1 is
attributed to strontium carbonate. Notably, all significant vibrations
related to silica are evident in the spectrum corresponding to Si-LSMO
(25,28). Specifically, the vibrations observed at 1047 cm− 1 correspond
to Si–O–Si stretching [33].
Overall, the FTIR spectra demonstrates that silica was successfully
coated onto the bare LSMO core. The presence of characteristic vibra­
tions relevant to both the perovskite structure and silica coating vali­
dates the successful synthesis of the Si-LSMO nanoparticles.
3.3. Microstructural analysis: TEM and FE-SEM results
Transmission Electron Microscopy (TEM) was employed to investi­
gate the structure and morphology of the nanoparticles. Images obtained
from TEM allowed the calculation of the average particle size. The TEM
images clearly reveal a core-shell structure for Si-LSMO nanoparticles,
where a magnetic core is surrounded by a distinct silica layer (Fig. 2(b)
and (c)) The thickness of the silica coating was found to be approxi­
mately 5–10 nm, forming a continuous layer around the magnetic core,
as shown in Fig. 2(c).
The average particle size distribution of the Si-LSMO ranged from 25
nm to 35 nm, as depicted in the histogram shown in Fig. 2(f). It is worth
noting that during the synthesis protocol, the high annealing tempera­
ture resulted in the formation of connecting bridges between individual
particles. These bridge-like structures are evident in the TEM images of
both the uncoated and coated nanoparticles (Fig. 2(a) and (b&c)),
confirming a similar morphology for both. Additionally, Field Emission
Scanning Electron Microscopy (FE-SEM) images further support the
observation of individual nanoparticles connected by these bridge-like
structures in both uncoated and coated samples (Fig. 2(d) and (e)).
The FE-SEM analysis complements the TEM findings, providing addi­
tional evidence of the particle morphology and structural features.
The TEM and FE-SEM results collectively demonstrate the successful
formation of Si-LSMO nanoparticles with a core-shell structure and
interconnected morphology [28]. These findings contribute to our
A.B. Tewari et al. Results in Engineering 20 (2023) 101537

Fig. 2. (a) TEM image of LSMO; (b&c) TEM image of Si-LSMO; (d&e) FESEM images of LSMO and Si-LSMO respectively and (f) average particle size.

understanding of the nanoparticles’ physical characteristics and support
their potential application in magnetic hyperthermia cancer therapy.
3.4. XPS analysis: elemental composition and surface chemistry
X-ray Photoelectron Spectroscopy (XPS) was utilized to investigate
the elemental composition and the surface chemistry of the particles.
Narrow scan high-resolution spectra of the detected elements for both
uncoated and the silica coated nanoparticles were carefully analyzed
and are presented in Figs. 3 and 4, respectively.
For the uncoated LSMO sample, the narrow scan spectra of La
exhibited peaks at 854.3 eV and 850.6 eV, corresponding to the La3d3/2
state, and peaks at 837.5 eV and 833.8 eV, corresponding to La3d5/2
state [34]. Notably, two doublets were observed for strontium, con­
firming its substitution in the La sites (Fig. 3(b)). Peaks at 135.2, 134.3,
133,5 and 132 correspond to Sr3d3/2 and Sr3d5/2 [34,35]. The O1s
spectra showed three major peaks: the peak at 528.8 eV corresponds to
oxygen in the LSMO lattice, while the peaks at 530 eV and 531 eV

Fig. 3. XPS Spectra of uncoated LSMO and SNAPMAP images to check elemental composition: High resolution spectra for(a)La3d; (b)Sr3d; (c)Mn2p; (d)O1s and
SNAPMAP images (e)La3d; (f)Sr3d; (g)Mn2p & (h)O1s.

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A.B. Tewari et al.
Fig. 4. XPS Spectra of Si-LSMO and SNAPMAP images to check elemental composition: High resolution spectra for (a)La3d; (b)Sr3d; (c)Mn2p; (d)O1s; (e)Si2p and
SNAPMAP images (f)La3d; (g)Sr3d; (h)Mn2p; (i)O1s &(j)Si2p.
corresponded to adsorbed oxygen and oxygen in the adsorbed molecular
water on the surface, respectively [34]. Integration of manganese was
confirmed with peaks at 655.4 eV and 653.2 eV for Mn2p1/2 and the
peaks at 643.2 eV and 641.3 eV for Mn2p3/2, respectively [34].
In the spectra of silica-coated samples (Fig. 4), observable changes
were noticed. Peaks corresponding to silica were evident, and corre­
sponding changes were observed in the oxygen narrow spectra. Addi­
tionally, the resolution for peaks corresponding to Sr and Mn decreased
due to the presence of the silica layer coating over them. The O1s narrow
spectra exhibited peaks at 529eV, 532.5eV and 533 eV, corresponding to
oxygen in the LSMO lattice, Si–O–Si and Si–OH, respectively [36].The
Si2p spectra showed peaks at 102 eV and 103.5 eV, corresponding to
Si–O–Si and SiO2, respectively [36,37]. SnapMap graphs for the un­
coated LSMO (Fig. 3(e–h)) and silica-coated Si-LSMO (Fig. 4(f–j)) were
generated to visually confirm the presence of all expected elements.
The XPS analysis provides valuable insights into the elemental
composition of the nanoparticles, shedding light on their structural
characteristics and potential applications in magnetic hyperthermia
cancer therapy.
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Results in Engineering 20 (2023) 101537
3.5. Magnetic characterization: VSM studies
Vibrating Sample Magnetometer (VSM) studies were conducted to
investigate the magnetism of both LSMO and Si-LSMO. The magneti­
zation measurements were carried out at room temperature (300K). As
shown in Fig. 5, the M − H hysteresis loop at 300K were obtained for
both samples. For LSMO and Si-LSMO, the saturation magnetization
(Ms) was observed to be 38.9 emu/g and 29 emu/g, respectively. It was
observed that the coated sample (Si-LSMO) exhibited a lower saturation
magnetization, which can be attributed to the non-magnetic nature of
the silica coating, thus reducing the overall magnetization [32,38,39].
The hysteresis curve of the particles were narrow, indicating their
suitability for further biological application [40,41].A narrow hysteresis
curve is indicative of soft magnetism which is highly desirable for bio­
logical applications due to low coercivity and low remanence. A very
low remanence (Mr) of 1.37 Oersted was observed for the uncoated
sample, while the coated sample showed a remanence of 1.47 Oersted.
Coercivity(Hc) was measured to be 0.12 emu/g for the uncoated sample
and 0.22 emu/g for the coated sample.
In summary, the VSM studies revealed the magnetic properties of
A.B. Tewari et al. Results in Engineering 20 (2023) 101537

Fig. 5. Magnetization curve of LSMO and Si-LSMO with zoomed in figures.

LSMO and Si-LSMO nanoparticles, with the coated sample showing
slightly reduced magnetization due to the non-magnetic silica coating
[32,42]. The observed narrow hysteresis curves and low remanence
values indicate the potential suitability of these nanoparticles for mag­
netic hyperthermia applications.
3.6. Hydrodynamic size and zeta potential
The hydrodynamic size and the zeta potential of the Si-LSMO were
investigated to check their colloidal stability.A colloidally stable nano­
system is characterized by a high negative or positive value of zeta po­
tential [43]. As shown in Fig. 6 (b) the value of the zeta potential was
found to be − 28.2 mV which shows that the nanoparticles are

Fig. 6. (a) Hydrodynamic size of Si-LSMO and (b) Zeta potential of Si-LSMO.

6
A.B. Tewari et al.
moderately stable [43]. The hydrodynamic size of the nanoparticles was
found to be 283.3 nm as shown in Fig. 6(a). The increased diameter as
measured by DLS when compared to the electron micrographs could be
attributed to the hydrated adsorbed organic layers [31,44].The stable
nature of the nanosystem as evident from the Zeta measurements make
them suitable for biological applications. The negative zeta potential
also ensure that agglomeration of the magnetic nanoparticles is mini­
mized and the stability of the nanomagnetic fluid suspension enhanced.
3.7. Hyperthermia studies and specific absorption rate (SAR) analysis
The silica-coated nanoparticles (Si-LSMO) underwent thorough
sonication in a bath sonicator at high intensity for 15 min and were
exposed to an alternating magnetic field (AMF) after appropriate di­
lutions. The hyperthermic output of Si-LSMO was then investigated at a
frequency of 335 kHz under different amplitudes of 150 Oe, and 163 Oe.
Four different nanoparticle dilutions (1 mg/ml, 750ug/ml, 500ug/ml
and 250ug/ml) were employed for the study. The time-dependent hy­
perthermic output curves obtained upon AMF application are given in
Fig. 7.
To analyze the hyperthermia output curve of Si-LSMO, the Box-Lucas
model was applied. The model was represented by the equation:
( )
T(t) = A 1 − e− B(t− t0)
T(t) here is time dependent temperature, t is the time of exposure to
AMF, A is the maximum temperature of the heating curve, B represents
the fitting constant and t0 corrects the non-zero start in temperature. The
product of A and B at t = 0 gives the initial increase in heat rise change
[32].
To calculate the Specific Absorption Rate (SAR) value, the following
equation was utilized:
SAR = ( Ms / Mn) ∗ (C(A ∗ B))
Here, Ms is the mass of the magnetic nanoparticle + solvent, Mn is
the mass of the magnetic nanoparticle while C is the specific heat ca­
pacity of the solvent (Cwater = 4.185 J/g/K).
At a concentration of 1 mg/ml, the calculated SAR value for Si-LSMO
at 163 Oe and a frequency of 300 kHz was found to be 158.4 W/g.
Remarkably, at this concentration, the nanoparticles exhibited the
ability to achieve the hyperthermic window in less than 150 s. In recent
years a new parameter known as, Intrinsic Loss Power(ILP) has emerged
as a better alternative to SAR calculations which also takes into account
the external AMF applied to obtain a better picture of the heat pro­
duction capacity of the nanoparticles [45].ILP can be calculated by the
following equation:
Fig. 7. Time dependent heat rise curve (a) at 150 Oe and (b) 163 Oe amplitude at a frequency of 335 kHz.(The symbols show the data points while the straight line
shows the Box-Lucas fitted curve). The blue rectangle box depicts the hyperthermic window.
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Results in Engineering 20 (2023) 101537
/ ( )
ILP = SAR f ∗ H2
Where f is the applied frequency and H is the applied field amplitude.
At the concentration of 1 mg/ml and amplitude of 163 Oe and fre­
quency of 300 kHz the ILP was calculated to be 1.98 nHm2 Kg− 1.It is also
important to note that the field and frequency combination employed
also satisfy the Brezovich criterion that proposes that the product of the
magnetic field and frequency employed should be less than 4.85× 108
A/ms for biological applications to minimize damage to healthy tissues
[46,47].Hence it becomes evident that the nanosystem is capable of
generating sufficient heat within the currently recommended safety
limits.
These results demonstrate the potential of Si-LSMO nanoparticles for
effective hyperthermia applications and offer valuable insights for
optimizing their use in magnetic hyperthermia cancer therapy as the
heat rise obtained is satisfactory for hyperthermia applications and is
within the prescribed safety limits and also comparable with what has
been reported in the literature [26,31,46,48,49].
3.8. Biological evaluation and hyperthermia-induced apoptosis
3.8.1. Biocompatibility assessment and cell viability studies
The biocompatibility of the Si-LSMO nanoparticles was checked
using murine fibroblast cells (L929). Remarkably, excellent biocom­
patibility was demonstrated by the nanoparticles even at high concen­
trations of up to 1 mg/ml, with cell viability exceeding 70 % (Fig. 8(b)).
Notably, a progressive increase in cell viability was observed with
decreasing nanoparticle concentration, and the lowest concentration of
250 μg/ml exhibited the highest viability, exceeding 93 %. This dose-
dependence effect on cell viability with varying nanoparticle concen­
trations was expected.
The high cellular viability observed at the concentration of 250 μg/
ml suggests it to be an optimal dosage for further studies, as it is not only
biocompatible but also suitable for hyperthermia applications, as shown
in Fig. 7. The results indicate that Si-LSMO nanoparticles possess
favorable biocompatibility, making them a promising candidate for
potential use in magnetic hyperthermia cancer therapy. The concen­
tration of 250 μg/ml is particularly noteworthy as it strikes a balance
between high cell viability and effective hyperthermia performance,
warranting further investigation in subsequent studies.
3.8.2. In vitro hyperthermia application
Cultured MG-63 osteosarcoma cells were subjected to hyperthermia
treatment, as discussed in section 2.6. The experimental setup included
A.B. Tewari et al. Results in Engineering 20 (2023) 101537

Fig. 8. (a) Effect of Hyperthermia application upon MG-63 cell line (b) Biocompatibility on L929 and qualitative assessment of ROS production following hyper­
thermia treatment using DCFH-DA staining: (c) control and (d) hyperthermia treatment.

four groups for evaluation. The first group, comprising MG-63 cells, Moving forward, the third group was assessed immediately after
served as the control group. The second group which consisted of cells AMF application (332 KHz & 150 Oe) in the presence of nanoparticles. A
incubated with Si-LSMO nanoparticles, demonstrated an excellent drastic reduction in cellular viability was observed, with the cell
reduction in cell viability by 30 % as compared to the control. viability dropping to as low as 40 % (Fig. 8 a). To examine the extended

Fig. 9. Immunocytochemical analysis of the cleaved caspase-3 expression of cells exposed to magnetic hyperthermia depicting death via apoptosis: Control group
((a)Hoechst nuclear staining; (b)Phalloidin F-Actin Staining; (c)Caspase 3 expression & (d)merged images) and for the treatment group ((e)Hoechst nuclear staining;
(f)Phalloidin F-Actin Staining; (g)Caspase 3 expression & (h)merged images).

8
A.B. Tewari et al.
effect of the therapy, the last group’s cell viability was evaluated 4 h
after the hyperthermia exposure. Remarkably, an even greater reduction
in cell viability was observed, with the cellular survival rate being less
than 25 %. The results demonstrate the nanoparticles’ potential for
hyperthermia applications, effectively reducing the number of cancer
cells even after the treatment period.
Additionally, the production of reactive oxygen species(ROS) was
qualitatively evaluated using confocal microscopy using DCFH-DA
staining [50,51]. A marked increase in cellular ROS production were
evident in the hyperthermia-treated cells compared to the control group,
as depicted in Fig. 8 (c) and (d).The high ROS production indicates
cellular damage and suggests a propensity for apoptosis induced by the
hyperthermia treatment.
In conclusion, the results support the excellent potential of the
nanoparticles for hyperthermia applications, providing an effective
route to decrease tumor burden. The observed increase in ROS pro­
duction further indicates the cellular damage and apoptosis induction,
affirming the therapeutic efficacy of hyperthermia treatment for cancer
therapy.
3.8.3. Immunocytochemistry
The impact of the hyperthermia treatment on the MG-63 cells were
further investigated using immunocytochemistry to elucidate the un­
derlying mechanism behind cellular death. Hoechst 33342 was utilized
as a nuclear stain, and Alexa Fluor 594 phalloidin was employed to stain
F-Actin filaments. Caspase 3, when activated, triggers chromatin
condensation and DNA fragmentation, leading to cell death through an
apoptotic route.
As depicted in Fig. 9, the control group (Fig. 9(c)) exhibited only a
negligible amount of Caspase 3 expression. However, in the group
exposed to hyperthermia treatment, a significant increase in Caspase 3
expression was observed (Fig. 9(g)). This marked upregulation of Cas­
pase 3 expression strongly indicates that cell death occurred via an
apoptotic pathway following exposure to magnetic hyperthermia
treatment [32].
The immunocytochemistry results provide valuable insights into the
mechanism underlying cellular death after hyperthermia treatment. The
observed increase in Caspase 3 expression confirms the activation of an
apoptotic pathway, affirming the effectiveness of magnetic hyperther­
mia treatment in inducing cell death through apoptosis.
4. Conclusion
In conclusion, the comprehensive investigation of Lanthanum
Strontium Manganite (LSMO) nanoparticles and their silica-coated
counterparts (Si-LSMO) has revealed their promising potential for
magnetic hyperthermia cancer therapy. The successful synthesis and
characterization of the nanoparticles were confirmed through XRD,
TEM, and FE-SEM analyses, demonstrating their suitable structural and
morphological properties for therapeutic applications. Highly crystal­
line structure with no additional impurities were observed via XRD
analysis. The Electron microscopy images clearly showed the charac­
teristic LSMO morphology with a very clearly visible layer of silica
coating around the core structure. The VSM studies indicated favorable
magnetic profiles and a narrow hysteresis curve, making them suitable
candidates for hyperthermia treatment due to their good saturation
magnetization of 29 emu/g and low coercivity. The nanoparticle solu­
tion was also stable as evident by the zeta potential of − 28.2 mV which
makes it fit for biomedical applications. The hyperthermia output was
also optimal for biological applications with an obtained SAR value of
158.4 W/g at 163 Oe and a frequency of 300 kHz Moreover, the in vitro
evaluation showcased the excellent biocompatibility of Si-LSMO nano­
particles, ensuring minimal cytotoxicity(viability >70 %) even at higher
concentrations of up to 1 mg/ml. Further, hyperthermia studies
demonstrated significant reductions in cell viability post-treatment of up
to 40 %, confirming the nanoparticles’ efficiency in inducing localized
9
Results in Engineering 20 (2023) 101537
hyperthermia for cancer cell destruction. Notably, the therapy triggered
apoptotic pathways, as evidenced by Caspase 3 upregulation and ROS
production, providing a mechanistic understanding of cellular death.
This also showed that the treatment induced cell death via apoptosis as
opposed to a necrotic pathway which would be vital in a clinical setting.
Overall, these findings highlight the promising potential of LSMO-based
magnetic nanoparticles, particularly Si-LSMO, as an effective and
biocompatible approach for targeted and localized magnetic hyper­
thermia cancer therapy, offering a valuable avenue for advancing cancer
treatment outcomes.
Funding
The author would like to express gratitude to the Institute of Nano
Science and Technology for providing the appropriate funding and
fellowship to the student.
Author contributions
ABT was involved in the experimental design, conducted experi­
mental work, analyzed and interpreted the data, and drafted the
manuscript. RS also contributed to the experimental work, participated
in data analysis, and contributed to the drafting of the manuscript.
Furthermore, DS played a crucial role as the supervisor, providing
guidance and support throughout the research. DS made substantial
contributions to the data analysis and played a vital role in the final
editing of the manuscript.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Data availability
Data will be made available on request.
Acknowledgement
The authors wish to thank the Institute of Nanoscience and Tech­
nology for their support in successful completion of this work.
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