Alexandria Engineering Journal (2021) 60, 733–747

H O S T E D BY
Alexandria University

Alexandria Engineering Journal

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Drug delivery system based on magnetic iron oxide

nanoparticles coated with (polyvinyl alcohol-zinc/
aluminium-layered double hydroxide-sorafenib)
Mona Ebadi a, Kalaivani Buskaran b, Saifullah Bullo a,c, Mohd Zobir Hussein a,*,
Sharida Fakurazi b,d, Giorgia Pastorin e

a
Materials Synthesis and Characterization Laboratory, Institute of Advanced Technology (ITMA), Universiti Putra
Malaysia, 43400 UPM, Serdang, Selangor, Malaysia
b
Laboratory for Vaccine and Immunotherapeutic, Institute of Biosciences, Universiti Putra Malaysia, 43400UPM, Sedang,
Selangor, Malaysia
c
Institute of Advanced Research Studies in Chemical Sciences, University of Sindh, Hosho Raod Jamshoro, Sindh, Jamshoro
76080, Pakistan
d
Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM,
Serdang, Selangor, Malaysia
e
Department of Pharmacy, National University of Singapore, Singapore

Received 30 June 2020; revised 25 August 2020; accepted 17 September 2020

Available online 21 October 2020

KEYWORDS Abstract The structural, physicochemical, morphological, and magnetic properties of magnetic
Magnetic iron oxide drug nanoparticles prepared using polymer, layered double hydroxide (LDHs) and drug as the coat-
nanoparticles; ing agent and magnetic iron oxide nanoparticles (MNPs) as the core were systematically studied.
Nanoparticle toxicity; Firstly, a co-precipitation method was employed to synthesize the Fe3O4 nanoparticles. Then, the
Nanoparticle coating; surface was coated with polyvinyl alcohol, Zn/Al-LDH and sorafenib (SO). XRD and FTIR studies
Cancer; indicate that the core has the crystal structure of the iron oxide. The TGA results supported the
Drug delivery; existence of both the core and the shell. The saturation magnetization of the as-synthesized
Layer-doubled Hydroxide Fe3O4 nanoparticles was found to be reduced from 80 to57 emu/g when the nanoparticles were
coated with polyvinyl alcohol, Zn/Al-LDH and the drug sorafenib. HRTEM images revealed that
the mean dimension of the naked Fe3O4 nanoparticles is around 30 nm. Further structural charac-
terizations showed that the addition of the shell led to the formation of uniform particles with a
particle size distribution of about 95 nm. The kinetics of drug release from the nanoparticles was
found to be governed by the pseudo-second-order equation. Cell viability assays clearly showed that
the magnetic iron oxide nanoparticles coated with polyvinyl alcohol-sorafenib-Zn/Al-layered dou-
ble hydroxide were found to be more potent than sorafenib alone against HepG2 liver cancer cells,
while displayed no cytotoxicity against 3T3 fibroblasts. These results show that the coated Fe3O4

* Corresponding author.
E-mail address: mzobir@upm.edu.my (M.Z. Hussein).
Peer review under responsibility of Faculty of Engineering, Alexandria
University.
https://doi.org/10.1016/j.aej.2020.09.061
1110-0168 Ó 2020 The Authors. Published by Elsevier B.V. on behalf of Faculty of Engineering, Alexandria University.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
734
magnetite nanoparticles are a good candidate as a drug delivery carrier to be further explored for
biomedical applications.
Ó 2020 The Authors. Published by Elsevier B.V. on behalf of Faculty of Engineering, Alexandria
University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
1. Introduction
Cancer is the second leading cause of death in the world and
one of the diseases that will soon undergo significant changes
in their methods of identifying and treating with the applica-
tion of nanotechnology or the so-called nanomedicine. One
of the conventional methods of cancer treatment is chemother-
apy [1–3]. Sorafenib is one of the most popular anti-cancer
drugs, but its clinical efficacy is limited because of disadvan-
tages such as serious damage to the liver, hypertension,
decreased platelet count and drug resistance [4,5]. Various
methods have been used to reduce side effects and increase
treatment efficacy. One of them includes the use of nanotech-
nology, which has revolutionized the diagnosis and treatment
of cancer [6,7].
In the last two decades, much research has been done in the
field of nanotechnology applied to medicine (i.e. nanomedi-
cine), especially in developing efficient methods for the diagno-
sis and treatment based on magnetic nanoparticles in cancer
and other diseases [8,9]. Targeted nanomedicine through mag-
netic nanoparticles has thus become one of the most powerful
diagnostic and treatment tools [10–13]. One additional advan-
tage is that the core magnetic nanoparticle can be used to deli-
ver the drugs to target organs using an outside magnet. This
could overcome several problems including off-target side
effects, low drug solubility, short life cycle, etc. [14]. Drug
delivery systems based on nanotechnology have improved dra-
matically the therapeutic outcomes due to the pharmacokinetic
change of the drug, increase of the half-life of the drug cycle,
the release of the drug at a steady rate and reduced drug-
associated toxicity [15–17].
Inorganic magnetic iron oxide nanoparticles (MNPs) with
the general chemical formula of Fe3O4 have been used for var-
ious imaging applications such as fluorescence and MRI, as
well as cell separation, immunoassay, tissue repair, hyperther-
mia, tumor targeting and drug delivery. MNPs have become
the focus of novel materials science along with their attributes,
especially in targeted drug delivery, which stems from their
unique properties including small particle size, superparamag-
netic and specific magnetic characters, low toxicity, high half-
life and catalytic properties [18–20].
Magnetic nanoparticles are synthesized in a variety of ways:
co-precipitation, hydrothermal, sol-gel, etc [21]. Magnetite
nanoparticles with narrow size distribution and a particle size
range between 5 and 100 nm can be produced using the co-
precipitation method and their magnetization can be increased
by clustering the nanoparticles [22,23]. Furthermore, if a layer
is created onto the nanoparticle using polymer or layered dou-
ble hydroxide (LDH) to protect the core, then stabilization,
prevention of agglomeration, reduced toxicity and increased
biocompatibility can be achieved. The adsorption of coating
agents on the MNPs surface is due to a combination of various
chemical and electrostatic interactions, hydrogen bonding and
van der Waals forces [24–26].
M. Ebadi et al.
licenses/by-nc-nd/4.0/).
Recently surface modification or coating of MNPs using
biocompatible molecules such as polyethylene glycol (PEG),
dextran, polyvinylpyrrolidone (PVP) and polyvinyl alcohol
(PVA) have been explored to tune their properties. The poly-
mer used on the surface of iron oxide nanoparticles must be
non-antigenic, protein-resistant and increase the spin time in
the blood. Several studies have been conducted to investigate
the effects of adsorption of coating agents on the behavior
of magnetic iron oxide [27].
Polyvinyl alcohol is one of the synthetic polymers. Its tox-
icity is low and it is flexible and could bind to the magnetic iron
oxide nanoparticles and prevents attraction or agglomeration
of the iron oxide particles to each other. Several methods have
been developed to synthesize polymeric magnetic nanoparti-
cles, one of them is by the co-precipitation technique [28,29].
Lately, anionic clays are subjected to intense research due
to their great potential to be used in various applications.
Anionic clays or layered double hydroxide (LDH) have unique
physical and chemical properties. The history of the use of
LDH in therapeutic applications goes back to a long time
ago [30,31]. LDHs due to their high anion exchange capacity
can act as a host system for various guests. Besides, good bio-
compatibility, chemical stability, easy and inexpensive to pro-
duce are the main attraction for LDH to be used for various
technological developments [32].
In the present study, zinc/aluminum layered double hydrox-
ides (Zn/Al-LDH) with the chemical formula [Zn3Al
(OH)8]2+[(CO3)2]
nH2O was used as the host material. The
basic structure of ZLDH is based on the structure of the zinc
hydroxide Zn(OH)2 and it is created by replacing some of the
divalent cations by trivalent cations that cause the creation of a
positive charge on the layered structure. This positive charge is
counteracted by the negative anions located between the inter-
layers. The ZLDHs structure is shown in Fig. 1.
Fig. 1 Structure of Zn/Al-LDH [33].
Drug delivery system based on magnetic iron oxide
Multifunctional nanoparticles can be produced by combin-
ing the nanocarriers [34], for example, magnetic iron oxide
nanoparticle structures with multiple abilities could achieve
desirable properties upon modification of their surfaces with
functional groups. For instance, magnetic iron oxide nanopar-
ticles can be coated with more than one active drug together
with other active agents, resulting in considerable potential
applications in nanomedicine, like targeted drug delivery, etc.
These nanoparticles can move toward magnet and are being
studied as agents for drug delivery.
Previous studies have shown that the coated magnetic iron
oxide nanoparticles have a maximum drug release of only 60%
[35]. Also, no toxicity studies were reported, either in vivo or
in vitro.
In this article, a novel nano-drug delivery system consisting
of core-shell nanoparticles based on magnetite as a core coated
with sorafenib which was loaded into layered double hydrox-
ide and co-coated with polyvinyl alcohol was prepared to pro-
vide a suitable structure for drug loading and release. The
physicochemical, drug-release and toxicity properties of these
coated magnetic nanoparticles were perused. We believe that
the magnetic core in these nanostructures improves the move-
ment of the nanoparticles towards the target, therefore provide
lower doses of drugs required. In addition, the coating agent
will be able to tune the drug release rates.
2. Materials and methods
2.1. Materials
All the chemicals were used as received without any pretreat-
ment. Iron chloride 6-hydrate (FeCl3
6H2O, 99%), iron chlo-
ride 4-hydrate (FeCl2
4H2O, 99%) and NH3 25% were
purchased from Merck company, polyvinyl alcohol (PVA,
average M.W. 6000) from Acros Organics, aluminum nitrate
(Al(NO3)3
9H2O, 99%) and zinc nitrate hexahydrate (Zn
(NO3)2
6H2O, 99%) from ChemAR (Kielce, Poland), an
anti-cancer drug (Sorafenib, C21H16ClF3N4O3, 98.5%)) from
Xi’an Yiyang Bio-Tech (China) and dimethylsulfoxide
((CH3)2SO) was obtained from Sigma Aldrich (St. Louis,
MA, USA).
2.2. Preparation of samples
The sample, magnetic iron oxide nanoparticles-polyvinyl
alcohol-sorafenib-zinc/aluminum-layered double hydroxide
(MPVASO-Zn/Al-LDH) have been prepared by the co-
precipitation method. The synthesis process was initiated by
adding the precursors, ferric oxide (0.99 g), ferrous oxide
(2.43 g) as well as distilled water to a beaker stirred using a
magnetic stirrer at room temperature. After a while, an ammo-
nia solution (6 mL) was added to the above solution and con-
tinued to stir for about 15 min. The resulting particles formed
(Fe3O4 magnetite nanoparticles) were washed three times. The
prepared sample was then coated with a 2% polyvinyl alcohol
aqueous solution (2 g of PVA in 100 mL deionized water) and
placed in an autoclave at 150 °C for 24 h. To remove the
uncoated particles, the coated magnetite nanoparticles were
separated with a magnet and washed with deionized water.
Then MPVA dried in an oven at 70 °C for 8 h. After drying,
a solution of 3 g of an anticancer drug, sorafenib dissolved
735
in dimethyl sulfoxide, was added to the magnetic iron oxide
nanoparticles-polyvinyl alcohol (MPVA) powder via stirring
with a stirrer at medium speed for 24 hrs, to give the sample,
magnetic iron oxide nanoparticles-polyvinyl alcohol-
sorafenib (MPVASO). Then, zinc nitrate and aluminum
nitrate with zinc(II)/aluminum(III) molar ratio of 4:1 were dis-
solved in distilled water under the nitrogen gas environment.
Then sodium hydroxide was added dropwise until a pH of 7
was reached. Finally, 3 g of MPVASO were mixed with
thebZLDH at room temperature. The resulting sample,
MPVASO-ZLDH was then washed 3 times and dried in an
oven at 40 °C [36,37].
2.3. Characterization techniques
The structure and phase-type that are present in the sample
were analyzed using the XRD technique, a Shimadzu PW-
6000, Japan instrument with monochromatic CuKa radiation
(k = 1.5406 Å) in the range of 2–80° at 40 kV-30 mA. The
aggregation and the surface morphology of the samples were
recorded through a field emission scanning electron micro-
scope (FESEM), NOVA NANOSEM 230 model, California,
USA, and their elemental compositions were estimated using
the energy-dispersive X-ray spectroscopy (EDS). The particle
size and its distribution of the magnetic drug nanoparticles
were measured by the Dynamic Light Scattering (DLS, MAL-
VERN, NanoS, UK). FTIR analysis was carried out using the
Fourier transformed infrared spectroscopy at a resolution of
0.09 cm1 from 500 to 4000 cm1 (ThermoNicolet 6700,
AEM, Madison WI, USA). The thermal behavior of the sam-
ples was investigated using the thermogravimetric analysis and
differential thermogravimetric (Mettler-Toledo model TGA/
DTG, Greifensee, Switzerland) at a heating rate of 10 °C/
min in the range of 20–1000 °C. A vibrating sample magne-
tometer (VSM, model Lakeshore 4704, Westerville, OH,
USA) was used to measure the magnetic quantities and prop-
erties like remanent magnetization, saturation magnetization
and coercivity for the prepared magnetic drug nanoparticles,
in the range of 10000 to 10,000 Oe. The size distribution,
morphology and estimation of the synthesized magnetic drug
nanoparticles size were evaluated using the high-resolution
scanning transmission electron microscopy (HRTEM), a Hita-
chi H-7100 (Tokyo, Japan). The particle size was calculated by
Image J software from various images and based on the mea-
surements of at least 100 particles. To identify the Mg, Al and
Fe elements in the sample and their concentration, an induc-
tively coupled plasma optical emission spectrometry (ICP-
OES), using an Optima 8300 (Perkin Elmer, Wellesley, MA,
USA) was used. The percentage of N, H and C elements were
determined using the CHN analyzer (LECO, TruSpec, Stock-
port, UK). UV–Vis spectroscopy (a Perkin Elmer, Lambda 35,
UV–Visible spectrometer) was used to determine the show
release behavior of the drug from the sample.
2.4. MTT cell viability assay
Cell viability assay was conducted to analyze the toxicity
level of the nanoparticle to cell lines. Two types of cells were
used for the cytotoxicity assays; normal human fibroblast
(3T3) and human hepatocellular carcinoma cells (HepG2),
which were purchased from ATCC (Manassas, USA). All
736 M. Ebadi et al.

the cells were grown using the Roswell Park Memorial Insti-
tute (RPMI) of 1640 medium (Nacalai Tesque, Kyoto, Japan)
supplemented with 10% fetal bovine albumin (Sigma-Aldrich,
MO, USA), 1% antibiotics containing 10,000 units/mL peni-
cillin and 10,000 lg/ mL streptomycin (Nacalai Tesque,
Kyoto, Japan). Cells were maintained and incubated in
humidified 5% carbon dioxide at 37 °C. Cell layers were har-
vested using 0.25% trypsin/1mM-EDTA (Nacalai Tesque,
Kyoto, Japan). This was followed by seeded in 96-well tissue
culture plates at 1.0  104 cells/well for 24 hrs in an incubator
to attach and 80% confluence attained for treatment.
Methylthiazol tetrazolium (MTT)-based assay was carried
out to determine the cell viability and cytotoxicity. Cells were
treated with MPVA, MPVA-ZLDH (nanocarriers), pristine
sorafenib, and MPVASO-ZLDH (nanoparticles), where stock
solutions were prepared by dissolving the compound in 1:1 of
dimethyl sulfoxide (0.1%) and RPMI. Then, the mixture was
further diluted in the same media to produce various final
concentrations ranging from 1.25 to 100 lg/mL. Once the
cells were attached to the respective wells after 24 hrs, the
tested compounds were added until the final volume of
100 lL well was obtained. After 72 hrs of incubation,
10 lL of MTT solutions (5 mg/mL in PBS) was added in
each well and further incubated for 3 hrs before being aspi-
rated. Then100 lL of dimethyl sulfoxide was added per well
in the dark and room temperature to dissolve the purple for-
mazan salt. The intensity of the purple formazan solution,
which reflects cell growth was subsequently measured at a
wavelength of 570 nm using a microplate reader (Biotek
LE800, Winooski, Vermont, USA).

3. Result and discussion Fig. 2 X-ray powder diffraction patterns of magnetic iron oxide
nanoparticles (A), MPVASO-ZLDH (E). The inset displays the
3.1. Crystal structure XRD pattern of PVA (B), pure ZLDH (C), pure sorafenib (D).

Fig. 2 shows the X-ray diffraction patterns of the MNPs, PVA,

sorafenib, ZLDH and the drug nanoparticles. The XRD pat-
tern of the synthesized magnetic iron oxide nanoparticles
(Fig. 2A), shows reflection peaks at 2h = 35°, 41.3°, 50.4°,
62.9°, 67.2° and 74.1°, corresponding to the (2 2 0), (3 1 1),
(4 0 0), (4 2 2), (5 1 1), and (4 4 0), respectively [37,38]. The posi-
tion of these peaks was indicative of a single-phase of the cubic
structure of MNPs, which corresponds with the JCPDS refer-
ence number of 19–629. The intensity of the peaks indicates
that the iron oxide nanoparticles are of crystalline structure,
without the presence of any impurities. Similar previous work
has also shown that the synthesis of iron oxide nanoparticles
using the co-precipitation method faced no problem with the
impurities.
The X-ray diffraction patterns of the synthesized nano-drug
are shown in Fig. 2E, which shows that some new peaks have
been added, especially at 2h = 19.5° corresponding to the
(1 0 1), which is due to the polymer (JCPDS 65–2870). The
XRD diffractogram in Fig. ures 2C and 2D illustrate two main
peaks at 2h = 11° and 22° and another sharp peak at 23.4°
using the standard JCPDS card no 48-1022 [36]. The first
two are due to ZLDH and the third one is due to the anti-
cancer drug, sorafenib (SO).
The X-ray analysis result of the sample indicates that the
peaks attributed to MNPs are observed. These XRD patterns
indicate that iron oxide is the dominant phase in the sample.
This pattern matched nicely with the previously reported
results of iron oxide nanoparticles coated with outer layers
[39,40]. In addition, partial displacement of some peaks
towards lower angles and a decrease in the width of the peaks
in the synthesized sample compared to the pure samples are
evident. When the drug was replaced with nitrate anion in
the interlayer of the LDH, the peaks shifted to lower angles
due to the intercalation of the drug moieties, as shown in
Fig. 2C, D and E. Moreover, the small width of the peaks
demonstrated the small size of the particles, which may be
due to the successful presence of the coatings that prevent
the agglomeration of the particles. Finally, looking at the
XRD spectra of the drug nanoparticles, it seems that the sam-
ple has some impurity, presumably due to the a-Fe2O3 phase.
Such observation was also indicated by Naseri et al. [41]
3.2. Ftir
The FTIR spectrum of pure PVA, ZLDH, MNPs and SO are
shown in Fig. 3. The FTIR spectra give the qualitative infor-
mation about the functional groups that are present in a mate-
rial, which can be indirectly used to indicate the presence of a
compound in a material or the adsorbed coated molecules are
bonded to the surface and the interaction between them and
also identify the coating layers on the MNPs nanoparticles.
Drug delivery system based on magnetic iron oxide
Fig. 3 FTIR spectra of the magnetic iron oxide nanoparticles
(A), pure PVA (B), ZLDH (C), pure sorafenib (D), MPVASO-
ZLDH (E).
For the MPVASO–ZLDH, the FTIR absorption bands of
525 cm1, 866 cm1, 1090 cm1, 1246 cm1, 1466 cm1,
1619 cm1 and near 2925 cm1 are assigned to the vibrations
of the following bonds; OAFe stretching, CAH rocking,
CAO bonds, NAH group, HACAH bending, asymmetric
stretch at C‚O bond and CAH bending. As shown in
Fig. 3A and Fig. 5E, the broad peaks at about 3200–
3400 cm1 are attributed to the stretching of OAH vibrations
[42]. There is a peak located at 1166 cm1 (Fig. 3D) which was
assigned to the characteristic absorption of the NACAH
group. The intensity of the band at 2906 cm1 is usually
ascribed to CH2 stretching vibration of the polymer linkage
chains [43,44]. In addition, two sharp and weak bands at
1415 cm1 and 1638 cm1 can be assigned to the CH3 symmet-
rical deformation and bending vibration mode and the H2O
bending vibration of the interlayer water, respectively
(Fig. 3B and C).
Generally, these FTIR results confirmed that the magnetic
iron oxide nanoparticles have been coated by a layer of poly-
vinyl alcohol, ZLDH and anti-cancer drug. These absorptions
are also characteristics of the hydrogen bonds that have been
formed between the PVA particles and MNPs nanoparticles.
Moreover, a shift to lower wavenumbers of some bands is
another indication that some interactions exist. Based on
Fig. 3E, the band at 3555 cm1 shows the presence of the
737
hydroxyl (CAOAH) group, which was shifted towards the
lower wavenumbers in comparison with the band of the hydro-
xyl group in the MNPs nanoparticles (3737 cm1).
3.3. Thermal analysis
The thermogravimetric/differential analyses (TGA/DTG) are
to determine the mass reduction due to thermal treatment
under a controlled environment. This can indirectly indicate
the presence of the coating layers on the surface of MNP.
TGA profiles of PVA, MNPs, sorafenib, ZLDH and
MPVASO-ZLDH are shown in Fig. 4 in the range of 25–
1000 °C. The mass reduction is given in Table 1. As shown
in the diffractogram, all the synthesized samples showed a
weight reduction upon temperature treatment. TGA/DTG
results of the magnetic iron oxide nanoparticles shown at tem-
peratures below 600 °C indicate that a total of 4.4% of the
weight of the particles has been reduced (Fig. 4A). Since the
weight loss up to a temperature of 200 °C is related to the
evaporation of the water absorbed onto the surface, this indi-
cates that approximately 2.7% of this weight loss was due to
the moisture. Fig. 4C shows the thermal behavior of pure
ZLDH, the first event near to 48 °C is due to the vaporization
of water on the surface of the nanoparticles. The peak at 250–
290 °C is due to the elimination of the hydroxyl groups. N2 gas
release arising from thermal decomposition of anion nitrate
occurred at a temperature range of 450–500 °C. At tempera-
tures above 600 °C, a slight decrease in temperature can be
attributed to the decomposition of metal oxides like MgO
and AlO. Generally, the decomposition of ZLDH particles
can be divided into three stages [45,46]:
Mg1x Alx ðOHÞ2 ðNO3 Þx:nH2 O
! Mg1x Alx ðOHÞ2 ðNO3 Þx þ nH2 O ð3:1Þ
Mg1x Alx ðOHÞ2 ðNO3 Þx ! Mg1x Alx OðNO3 Þx þ H2 O ð3:2Þ
b
Mg1x Alx OðNO3 Þx ! Mg1x Alx O1þðx=2Þ þ xNO2 þ x=4O
ð3:3Þ
The thermogram of the nanoparticles is shown in Fig. 4E. It
is expected that for each step a weight loss will be observed. As
can be seen, the thermal stability of the nanoparticles up to
200 °C was very high and there was no significant weight loss
at this temperature range. At 200–450 °C, the sample shows
high weight changes, with a weight loss of 24.3%. This is
due to two reasons: the loss of physisorbed and structural
water and the loss of surface-active agent (the organic group)
that conjugated to the surface. Therefore, the 11.2% weight
loss is attributed to the moisture and water in the sample [43].
A sharp weight loss of around 6% at 380–500 °C is attrib-
uted to the PVA decomposition, which is consistent with pre-
vious studies. The weight loss between 550 °C and 600 °C was
due to the decomposition of nitrate anions, due to the com-
plete removal of the NO2. At temperatures above 800 °C, only
slight weight changes can be observed. The TGA/DTG ther-
mogram shows that the coated nanoparticles have higher ther-
mal stability compared to the uncoated nanoparticles.
Additionally, it demonstrates that in addition to the MNPs
nanoparticles, there are other particles in the composition that
similar to coating materials.
738 M. Ebadi et al.

Fig. 4 TGA/DTG thermograms for the bare magnetic iron oxide nanoparticles (A), pure PVA (B), ZLDH (C), sorafenib (D), and
MPVASO-ZLDH (E). The arrows indicate weight loss.
Drug delivery system based on magnetic iron oxide 739

Table 1 The thermal behavior of the samples.

Samples T1–T2 (°C) Tmax (°C) Dm (mg) weight loss (%)
MNPs 25–74 25 0.11 0.8
161–365 191 0.2 1.9
355–456 365 0.18 1.7
PVA 212–368 265 7.5 76.7
368–443 419 0.9 9
ZLDH 25–73 48 0.2 2
162–366 264 1.6 15.5
366–641 453 1.2 12
666–740 691 5.2 4.9
SO 223–304 262 5.8 67.9
304–524 424 1.8 32.1
MPVASO-ZLDH 27–76 46 0.12 0.5
76–245 219 0.13 11.2
245–320 269 0.6 13.1
320–505 453 0.4 6
505–660 543 8.9 4.1

3.4. Magnetic evaluation

Vibrating sample magnetometer (VSM) analysis of the samples

at room temperature is shown in Fig. 5. VSM measurements
were used to investigate and identify the magnetic properties
of the samples by recording the M-H loops at the magnetic
field in the range 20000 to 20,000 G. From the hysteresis
loops, saturation magnetization (Ms), remanent magnetization
(Mr), positive Mr, negative Mr and coercivity (Hci) values are
extracted. The obtained magnetic values are listed in Table 2.
The VSM curves of magnetic iron oxide nanoparticles and
PVA/ZLDH-coated MNPs are presented in Fig. 5A and 5B.
In both samples, there is the S-like form with no hysteresis
and the completely reversible hysteresis loop was observed,
which verified the superparamagnetic behavior of the sample
and suggested that the MNPs surface modified with polymer
and LDH preserved the superparamagnetic property. As listed
Table 2 Magnetic properties of the nanoparticles.
Samples Ms (emu/g) Mr (emu/g) Hci (G)
FNPs 80 1.448 11.53
MPVASO-ZLDH 57 2.706 19.3
in Table 2, the saturation magnetization values of 80 and 57
emu.g1 were observed for the fabricated MNPs and
MPVASO-ZLDH samples, respectively. Furthermore, the
bare MNPs and MPVASO-ZLDH show the remaining magne-
tization values of 1.448 and 2.706 emu/g, respectively. The
results are very close to the one previously reported using
the same method.
This confirms that the decreasing Ms, Mr, and Hci of the
modified nanoparticles in comparison to that of the pure mag-
netic iron oxide nanoparticles. It was previously reported that
PEG coating on the surface of NPs caused the reduction of
magnetic saturation [47]. The decline in values is due to the
non-magnetic coated layer on the surface of MNPs nanoparti-
cles, which decreases the exchange coupling energy and mag-
netic particle interactions [48]. It noteworthy that the
decrease in the size of the particle plays a crucial role in
decreasing the value of the coercivity in MPVASO-ZLDH.
Moreover, the presence of polymer has resulted in the reduc-
tion of the magnetic anisotropy, and very low Mr and Hci val-
ues indicate that the nanoparticles are suitable to be used with
an external magnetic field, for uses in biomedical applications
[49].

3.5. Surface morphology

Fig. 5 Hysteresis loops for the prepared iron oxide nanoparticles Fig. 6 displays the surface morphology of the synthesized
(A) and MPVASO-ZLDH (B). Notes: The data is presented in nanoparticles and their energy dispersive spectroscopy (EDS)
terms of Ms, mass magnetization (emu/g), versus H, applied analysis data is given in Fig. 6 and Table 3. The particle mor-
magnetic field (Oe). phology is dominated by spherical shape but with random
740 M. Ebadi et al.

Fig. 6 FESEM images of the samples; MNPs (A), MPVASO-ZLDH (B) and EDS data of the prepared samples (C). *The sample holder
is made of aluminum, therefore resulting in a high percentage of aluminum, and therefore it is not reliable to represent the aluminum
content of the sample.

Table 3 Elemental analysis of the sample obtained by the ICP-AES and CHNS analyses.
Sample *C% *H% *N% Zn% Al% Fe%
MNPs 0.02 0.54 1.02 – – 47
ZLDH – 2.37 4.45 6.8 5.2 –
SO 52.9 5.01 19.84 – – –
PVA 52.05 8.68 1 – – –
MPVASO-ZLDH 6.42 1.64 0.06 2.8 2.5 24.8

aggregation. Also, the presence of coated agents on the
nanoparticles can be seen as homogeneous and uniform
(Fig. 6B). This is presumably due to the result of the coating
which plays a role as a surface stabilizer, growth modifier
and nanoparticle dispersant. It worth noting that sometimes,
some of the drugs are absorbed onto the LDHs surfaces, which
created the surface attractive forces and caused the agglomer-
ation of the nanoparticles together. These observations sug-
gested that the surfaces of magnetic iron oxide nanoparticles
are fully coated with the coating agent. According to the pre-
vious report, a few aggregates were found in Fe3O4 after sur-
face modification [42]. As shown in Fig. 6B, the magnetic
Drug delivery system based on magnetic iron oxide
iron oxide nanoparticles are more agglomerated and non-
spherical compared to the MPVASO-ZLDH nanoparticles.
The EDS diagram and the result for MPVASO-ZLDH are
given in Fig. 6C. Based on the EDS analysis, the weight per-
centage of oxygen, carbon, aluminum, iron and zinc was found
to be 23.1%wt, 7.13%wt, 3.5%wt, 46.2%wt and 19.1%wt,
respectively. Also, the result shows that the sample contains
C and Fe, and the presence of these elements indicates that
the polymer is also a presence in the resulting magnetic iron
oxide nanoparticles in the fabricated sample. Furthermore,
the presence of aluminum and magnesium in the chemical
composition of the sample confirmed the presence of Mg/Al-
LDH. Generally, the FESEM and the EDS data show the for-
mation of the coating layers onto the surface of the iron oxide
nanoparticles. The EDS analysis indicates that the product is
relatively pure without significant residual impurity.
Results of the hydrodynamic diameters of the relative and
cumulative particle size distribution of the dispersed magnetic
iron oxide nanoparticles in phosphate buffer saline (simulated
body fluid) by the dynamic light scattering (DLS) instrument
are shown in Fig. 7, showing a peak at 198 nm with a mono-
modal particle size distribution (Fig. 7A). After the surface
of the magnetic nanoparticles was coated with the coating
agents, the particle size distribution was decreased and dis-
played a monomodal pattern with the maximum at 95 nm with
a narrow size distribution (Fig. 7B). MPVASO-ZLDH
nanoparticles appeared more well-dispersed than the pure
MNPs. The synthesis of iron oxide magnetite nanoparticles
through the co-precipitation method yielded the most stable
particles. Thus, the surface modification using different coat-
ing agents did not compromise the stability. In other words,
the stability of the solution was improved by altering the sur-
face of the magnetite nanoparticle through coating by suitable
agents. This was further confirmed by DLS analysis [10].
According to a previous study, coated-Fe3O4 magnetic
nanoparticles have been used to improve the solubility of the
solution [50].
Based on the particle size distributions calculated by DLS
for the synthesized samples, two possibilities can be consid-
ered. First, the nanoparticles are small enough that they have
nanometer dimensions despite being agglomerated in the PBS
environment. The second possibility is the proper spatial
Fig. 7 The cumulative particle size distribution of bare MNPs (A) and the MPVASO-ZLDH (B).
741
interdiction that polymer and LDH coating exerted on the
MNPs surface and that causes repulsion between the magnetic
iron oxide nanoparticles, thereby prevented agglomeration and
size enhancement of the MNPs particles. This size decrease
completely indicates that agglomeration of MNPs can be
avoided by the presence of coating agents.
3.6. HRTEM of sample
The detailed morphology, structures, size, and distribution of
the nanoparticles were determined using a high- resolution
transmission electron microscope (HRTEM). As it is seen,
the transmission electron microscopy image clearly illustrates
that the synthesized nanoparticles are spherical (Fig. 8). As a
result, the calculated mean size and the particle size distribu-
tions of the samples were obtained by measuring more than
100 particles randomly via ImageJ software. The result shows
that the mean diameter of the magnetic nanoparticles is 9 nm.
Based on the HRTEM image, the nanoparticles are gener-
ally well dispersed and relatively uniform. Further, the organic
molecules were adsorbed on the magnetic nanoparticles as the
core and due to interfacial energy reduction, the particle
growth slows down or stops, preventing them from agglomer-
ation. Although most of the nanoparticles are well separated
from each other, some agglomerated particles still can be
observed, presumably due to the dipole-dipole interaction of
the magnetic iron oxide nanoparticles. The free surface energy
and magnetic character could be responsible for the agglomer-
ation of the large particles. Using the nanoparticles in this size
regime will increase their life span in the bloodstream.
3.7. Elemental analyses
Elemental analyses are used to determine the chemical compo-
sition of the sample. In this study, the elemental content was
obtained by ICP-OES and CHN methods. Inductively coupled
plasma - optical emission spectrometry (ICP-OES) is a device
used for rapid and accurate analysis of a wide range of the
composition of elements in the sample at a low concentration
range of ppm scale. Metal contents of Al, Fe, Mg and Zn were
analyzed by ICP-OES. The CHNS analyzer, on the other
742
Fig. 8 HRTEM photographs of uncoated and coated samples (A) MPNs (50 nm bar), (C) MPVASO-ZLDH (50 nm bar) and (B and D)
their particle size distribution, respectively.
hand, was used to measure the carbon, hydrogen, nitrogen and
sulfur composition of the sample. The results of the ICP-OES
and CHN analyses are shown in Table 4. The elemental com-
position showed 2.5%, 2.8% and 24.8% for aluminum, zinc
and iron, respectively. This confirms the presence of ZLDH
and magnetic core in the sample. The presence of C, H and
N indicate the presence of polymer as the coating layer and
the drug, sorafenib. These results were well in good agreement
with the data obtained by the EDX analysis. The percentages
of the elements are summarized in Table 5.
3.8. In vitro release of sorafenib from the magnetic nanoparticles
The release profiles of a physical mixture of the drug and the
prepared nanoparticles at pH 7.4 and 4.8 of PBS
(phosphate-buffered saline) solutions are depicted in Fig. 9
and the percentage of drug released was calculated and given
in Table 5. These pH 7.4 and 4.8 buffer solutions were used
M. Ebadi et al.
to simulate the pH of blood (extracellular lysosomal environ-
ment) and cancer cells (intracellular lysosomal environment),
respectively, and to determine the extent of the drug release
in these two media. It was revealed that sorafenib released
from the in the first 10 min in both pHs followed different pro-
files. The release of the drug shows a very steep slope and fast
release, about 86% and 81% under the PBS at pH 4.8 and 7.4,
respectively, and was completed in only 7 and 9 min,
respectively.
Overall, the release at pH 7.4 was slower than at pH 4.8.
This is because under acidic environments the drug can be
released more easily. After about 10 min, the drug release rate
did not change so much and was slower and sustained.
Fig. 10 displays the release profiles of sorafenib from the
synthesized nanoparticles for 7 days. Standard solutions of
phosphate-buffered saline with different pH, at 4.8 and 7.4,
were used as the media and the release was measured from
the media solutions at different times. As can be seen from
Drug delivery system based on magnetic iron oxide 743

Table 4 Percentage of elements of the sample obtained by EDX analyses.

Sample *C% *H% *N% Zn% Al% Fe%
MNPs – 0.54 0.07 – – 8.5
ZLDH – 2.37 0.4 0.1 0.2 –
SO 4.4 5.0 1.4 – – –
PVA 4.3 8.6 0.07 – – –
MPVASO-ZLDH 0.5 1.6 – 0.04 0.1 0.4

the Fig. ure, sorafenib was not released suddenly, i.e. no burst
release was observed and the release happened moderately for
Table 5 The release percentage of the loaded drug in PBS in the first 7 days. The release profiles indicate that the maximum
acidic and alkaline pH. amount of anticancer drug (sorafenib) released from the
Sample pH 4.8 pH 7.4 MPVASO-ZLDH nanoparticles occurred within 7 days was
(%) (%) 98% and 96% in the neutral (pH 7.4) and acidic (pH 4.8) buf-
fer solution, respectively. It is noteworthy that under acidic
Physical mixtures of SO and MPVASO- 86 81
ZLDH
conditions, the drug released from the sample was significantly
MPVASO-ZLDH 98 96 increased and higher drug release efficiency was achieved in
comparison to the neutral pH. Thus, the release process of
the drug from the synthesized nanoparticles proved to be
slower compared to the physical mixture. In the former, the
drug binds to the surface of the magnetic nanoparticles, there-
fore the amount of drug released from the nanocarriers is
slower because the rate of drug release depends on the forces
100
to detach the drug from the carrier.
90 It is known that one of the factors that control drug release
80 is the pH of the surrounding environment. In an acidic envi-
70
Release / %

ronment, the drug release was found to be less than 80% in

60 the first 360 min while in the alkaline and neutral environment,
50 pH 4.8
drug release reached a maximum value of 50%. The results in
40 pH 7.4 the present study showed that the release profiles of the anti-
30 cancer drug from the nanoparticles can be modulated accord-
20 ing to both environments’ pH and also to the interaction with
10 the nanoparticles.
0
0 2 4 6 8 10 12 14
Time / min 3.9. Kinetics release of sorafenib from the magnetic
nanoparticles
Fig. 9 Release of sorafenib from its physical mixtures and
MPVASO-ZLDH sample in phosphate-buffered solutions at pH The kinetics release profile of sorafenib from its magnetic
4.8 and pH 7.4. nanoparticles into the phosphate-buffered saline solution at
alkaline and acidic pHs was studied based on three models:
the first-order, the pseudo-second-order and the parabolic dif-
fusion. The data obtained from the 3 models were evaluated
100 based on the correlation coefficient, rate constant and half-
90 life. The release kinetics of these models are as follows:
80
Pseudo-first order:
70 lnðqe  qt Þ ¼ lnqt  kt ð3:4Þ
Release / %

60 Pseudo-second order:
50
pH 4.8 t=qt ¼ l=kq2e þ t=qe ð3:5Þ
40
pH 7.4 Parabolic diffusion:
30
20 ð1  Mt =Mo Þ=t ¼ kt0:5 þ b ð3:6Þ
10
where the amount of drug release at equilibrium is qe, the
0 amount of drug release at a time, t is qt, and k is the release
0 2000 4000 6000 8000 10000
Time/ min constant for all the equations, while the drug content remain-
ing at release time 0 and t, is Mo and Mt, respectively.
Fig. 10 The sorafenib release profiles from MPVASO-ZLDH in The parameters and kinetics models used to describe and
phosphate-buffered solutions at pH 4.8 and pH 7.4. investigate the drug-release kinetics from the synthesized
744
nanoparticles loaded with sorafenib are given in Table 6. As
shown in the table, the linear regression, the saturation release,
rate constant and t1/2 were obtained. The correlation coeffi-
cients are deduced from the plot of t/qt versus t and are pre-
sented in Fig. 11.
Based on the three mentioned kinetic models, it was found
that the pseudo-second-order plot has the highest values for
the correlation coefficients, with R2 of 0.999 for pH 4.8 and
0.989 for pH 7.4, compared to 0.726 (pH 7.4) and 0.771 (pH
4.8) for the first order and 0.839 (pH 7.4) and 0.821 (pH 4.8)
for the pseudo-second-order. Further, the rate constant
derived from the pseudo-second-order model is 3.1 and
1.8 mg/min for pH 7.4 and 4.8, respectively. Other parameters
are summarized in Table 6.
3.10. In vitro bioassay
All the cytotoxicity assays were carried out in triplicates and
the standard deviations were calculated and are incorporated
in the respective bar graphs. For the calculation of the half-
maximal inhibitory concentration value (IC50), we plotted
the x- against the y-axis and converted the x-axis values (conc.)
to their log values, followed by nonlinear regression (curve fit)
under the xy analysis to obtain a straight line equation fit,
y = ax + b, from which the regression line and then inhibition
IC50 was calculated.
3.10.1. Cytotoxicity studies on normal 3T3 fibroblast cells
Cytotoxicity studies were conducted by treating MPVA,
MPVA-ZLDH (empty nanoparticles), pristine sorafenib, and
MPVASO-ZLDH (sorafenib-loaded nanoparticles) with nor-
mal fibroblasts, 3T3 cells. Various gradient concentrations of
the samples were incubated for a maximum of 72 hrs with
the 3T3 cells. Fig. 12 shows the percentage of cell viability of
the 3T3 cells after 72 hrs incubation with all the samples. Sim-
ilar results were found in a previous study in which treatment
with the modified magnetite nanoparticles significantly inhib-
ited the Gram-positive bacteria [51]. All of the samples were
found to be biocompatible and non-toxic even at 72 hrs incu-
bation. This suggests that the designed anticancer nanoparticle
formulation is biocompatible with normal cells and would be
very useful for targeting cancer cells without damaging/harm-
ing the normal tissues. The statistics ANOVA revealed that no
significant difference was found among the sample groups at
an individual, from 1.25 mg to 50 mg concentrations using the
ANOVA and Duncan’s Multiple Range Test.
In a previous study, a gold-coated iron oxide nanoparticle
loaded with l-sulforaphane for the drug delivery system was
designed and the results revealed low cytotoxicity for both
Table 6 The correlation coefficient, rate constant and half-life obtained by fitting the sorafenib release data into the PBS solution at
pH 4.8 and pH 7.4.
Sample pH Saturation release/% R2
Pseudo first order Pseudo 2nd Order
4.8 99.56 0.794 0.999
7.4 98.66 0.864 0.989
M. Ebadi et al.
the bare and the drug-loaded nanoparticles on human breast
cancer cells [47]. In the in vitro study of drug-loaded PEGy-
lated Fe3O4@Au NPs on human breast adenocarcinoma cell
line showed enhanced cytotoxicity of the drug by loading the
drug on PEGylated Fe3O4@Au NPs [50]. In another report,
the anticancer activity of chrysin-loaded L-phenyl alanine
(Phe)-coated iron oxide magnetic nanoparticles on MCF-7
cell line was found good biocompatibility and non-toxicity
of the synthesized nanocarriers [52]. Also, GSH-conjugated
IONPs as a delivery vehicle showed the stability and non-
toxicity of the synthesized nanoparticles to different cell lines
[46].
3.10.2. Anticancer action against liver cancer cells, HepG2
The anticancer activity of MPVA, MPVA-ZLDH, the drug
sorafenib alone, and MPVASO-ZLDH was evaluated by treat-
ing the samples with liver cancer cells, HepG2, as shown in
Fig. 13. Different concentrations of the above samples were
incubated with HepG2 cells for 72 hrs. The empty carriers
MPVA and MPVA-ZLDH from concentrations 1.25–50 mg
did not show any inhibitory action against liver cancer cells,
HepG2. The IC50 of the pristine sorafenib against liver cancer
cells was found to be 32.73 lg/mL compared to 10.77 lg/mL
for the MPVASO-ZLDH nanoparticles. The 3-fold improve-
ment in the IC50 value could be attributed to a slower release
profile of the drug from the nanocarrier and more efficient cel-
lular uptake of the drug when loaded onto the MPVASO-
ZLDH nanoparticles. Although future studies will be needed
to confirm this hypothesis, it was found that the percentage
of drug loading is 87% for MPVASO-ZLDH, which was
determined using the HPLC analysis. Therefore. based on this
result, the MPVASO-ZLDH nanoparticle with an IC50 value
of 10.77 lg/mL has much better anticancer activity compared
to its counterpart, i.e. the pristine drug sorafenib.
Statistical analysis was determined using several Softwares;
SPSS and ANOVA and Duncan’s multiple range test. The sig-
nificant differences were found between the MPVA, MPVA-
ZLDH, pristine sorafenib, and MPVASO-ZLDH. The
MPVASO-ZLDH nanoparticles were found significantly dif-
ferent from all the other samples at concentrations of 3.125–
100 lg/mL with (P-values of less than 0.5). At a concentration
of 6.25–100 lg/mL, the sample, sorafenib was significantly dif-
ferent from the empty carrier. All the samples showed an anti-
cancer effect towards the cell line is in a dose-dependent
manner. The IC50 of all the samples is given in Table 6. The
IC50 values of the nanoparticles determined based on the per-
centage of drug loading indicate that the synthesized nanopar-
ticles have a better anticancer effect than the drug in their free
forms (see Table 7).
Pseudo second Order t ø
Rate constant (k(mg/min)
Parabolic Diffusion
0.533 1.81  10-5 170
0.552 3.10  10-5 90
Drug delivery system based on magnetic iron oxide 745

Fig. 11 Kinetic parameters for the release study of sorafenib from MPVASO-ZLDH dissolved in dimethyl sulfoxide into different
solutions to (A) the pseudo-first-order kinetic; (B) the pseudo-second-order kinetic; (C) the parabolic diffusion kinetic for pH 7.4; (D)
dissolved in dimethyl sulfoxide into different solutions to the pseudo-first-order kinetic; (E) the pseudo-second-order kinetic; (F) the
parabolic diffusion kinetic for pH 4.8.

Fig. 12 Cytotoxicity assay of MPVA, MPVA-ZLDH (the

nanocarriers), sorafenib, and MPVASO-ZLDH (the nanoparti- Fig. 13 Cytotoxicity assay of MPVA, MPVA-ZLDH (the
cles) against normal 3T3 cells at 72 hrs. nanocarriers), sorafenib, and MPVASO-ZLDH (the nanoparti-
cles) against HepG2 cells at 72 hrs of incubation.

4. Conclusion
This study aimed to investigate the effects of co-coating of
magnetic iron oxide nanoparticles with PVA, ZLDH and sor-
afenib, an anticancer drug using the co-precipitation method
and the resulting nanoparticles displayed a magnetite crystal
structure. The data showed that the coating of the 3 com-
pounds was successful on the surface of the magnetic iron
oxide nanoparticles. Furthermore, it was observed a much
better anticancer activity than the drug sorafenib alone against
liver cancer and HepG2 cells, while showing no cytotoxicity
towards normal fibroblast 3T3 cells. The superparamagnetic
nature of the prepared samples was found to have excellent
magnetic properties. It was also found that the coating resulted
in a decrease in particle size to around 40 nm and the size dis-
tribution became narrower, = with a uniform spherical shape.
Of note, the toxicity decreased significantly by the formation
746
Table 7 The half-maximal inhibitory concentration (IC50)
value for MPVA, MPVA-ZLDH (the nanocarriers), sorafenib,
and MPVASO-ZLDH (the nanoparticles) samples tested on
3 T3 and HepG2 cell lines.
Nanocomposites IC50 (lg/mL) 3 T3 Fibroblast cell HepG2 cells
MPVA N.C N.C
MPVA-ZLDH N.C N.C
Sorafenib (SO) N.C 32.73
MPVASO-ZLDH N.C 10.77
N.C. = no cytotoxicity.
of the magnetic nanoparticles of the drug compared to its pure
form. Based on these findings, this method can be used to syn-
thesize magnetic nanoparticles for drug delivery, where these
nanocarriers have all the essential requirements for promising
biomedical applications.
Funding
This work was funded by the Universiti Putra Malaysia and
the Ministry of Higher Education of Malaysia under Grant
Putra Berimpak, UPM/800-3/3/1/GPB/2019/9678800.
Acknowledgments
The authors would like to thank Universiti Putra Malaysia
and the Ministry of Higher Education of Malaysia for funding
this project.
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