Journal of Superconductivity and Novel Magnetism

https://doi.org/10.1007/s10948-018-4841-2

REVIEW PAPER

A Review on Iron Oxide Nanoparticles and Their Biomedical

Applications
P. Sangaiya1 · R. Jayaprakash1

Received: 21 March 2018 / Accepted: 11 August 2018

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract
The iron oxide nanoparticles have a great attraction in biomedical applications due to their non-toxic role in the
biological systems. The iron oxide nanoparticles have both magnetic behaviour and semiconductor property which lead
to multifunctional biomedical applications. The iron oxide nanoparticles used in biomedical fields such as antibacterial,
antifungal and anticancer were reviewed. The uses of hematite (α-Fe2 O3 ), maghemite (γ -Fe2 O3 ) and magnetite (Fe3 O4 )
nanoparticles, for an inhibition time in biological activities, are listed in this work. Also, this review explains the use of iron
oxide nanoparticles in the biomedical fields with particular attention to the application of hematite and superparamagnetic
iron oxide nanoparticles. In this review, analysis reveals that the role of iron oxide in biological activity is good due to its
biocompatibility, biodegradability, ease of synthesis and different magnetic behaviours. The change of properties of iron
oxide nanoparticles such as particle size, morphology, surface, agglomeration and electronic properties has specific impact
in biomedical application. The review mainly focused in and discussed about antibacterial, anticancer, bone marrow and cell
labelling activities. From this review work, the iron oxide nanoparticle may be specialised in particular bacterial and cancer
treatments. Also discussed are the iron oxide nanoparticle-specific biomedical applications like human placenta, insulin and
retinal locus treatments.

Keywords Hematite · Maghemite · Magnetite · Antimicrobial · Anticancer · Cell labelling

1 Introduction biogeochemical cycles of iron in the environment. There

The iron oxide nanoparticles play a role in the biomedi-
cal system and have a vibrant position in the day-to-day
needs. There are plenty of nanoparticles fulfill the advanced
development in the field of biological application. The iron
oxide nanoparticles play a major role in different applica-
tions, such as magnetic, electrochemical, gas sensor, energy
storage, cancer therapy and magnetic storage, and biomedi-
cal treatments. Among the different types of nanoparticles,
hematite (iron oxide) is one of the most common, natu-
ral and environmental-friendly. It has a significant part in
 P. Sangaiya
sangaiahbose@gmail.com
R. Jayaprakash
Jayaprakash.rajan.2015@gmail.com
1 Nano Technology Laboratory, Department of Physics, Sri
Ramakrishna Mission Vidyalaya College of Arts and Science,
Coimbatore, Tamil Nadu, 641020 India
are different phases of iron oxide crystallites exhibited as
hematite (α-Fe2 O3 ), maghemite (γ -Fe2 O3 ), goethite FeOH
(OH) and magnetite (Fe3 O4 ) [1]. The hematite phase is con-
sidered as the more stable n-type semiconductor behaviour.
Nowadays, researchers have given more attention towards
the stable hematite iron oxide for biomedical application.
The reason for choosing this α-Fe2 O3 (hematite) iron oxide
as a specific nanoparticle is only due to its low cost
and being non-toxic. This hematite iron oxide nanoparti-
cle possesses a band gap of 2.1–2.2 eV [2]. The influence
of environmental-friendly iron oxide nanoparticles can be
investigated in the biological system. In this aspect, many
researchers have made different attempts in biological appli-
cations [3]. The uses of magnetic and antiferromagnetic
iron oxide nanoparticles in biomedical areas date back four
decades ago. The role of nanoparticles on antibacterial
agents is to kill some bacterial species causing no dam-
age to the human host cells. Iron oxide nanoparticles are
recently used as sensors for metabolites, hyperthermia and
biomolecules, toxicity and magnetic nanotoxicology. Thus,
this review has discussed the importance and enhancement

of iron oxide nanoparticles on antimicrobials, therapeutic
activities on cancer cell and other specific treatments. The
iron oxide nanoparticles synthesised in different ways may
enhance physical and chemical properties, such as chemi-
cal precipitation, sol-gel and forced hydrolysis techniques,
hydrothermal technique, surfactant-mediated/template syn-
thesis, biomimetic mineralisation, precipitation by anhy-
drous solution, microemulsion technique, flow injection
syntheses, electrochemical methods, aerosol/vapour meth-
ods and sonochemical technique [4]. Also, many researchers
focused on green synthesis like fruit extracts used for bio-
logical studies [5]. This review is mainly focused on the
role of iron oxide in nanoparticles to the great extent of
antimicrobial, antitumour and cancer treatments. The spe-
cific applications of bone marrow cells, cell labelling and
human placenta, as well as insulin are also discussed.
2 Role of Iron Oxide Nanoparticle in
Antimicrobial Activity
There are plenty of nanomaterials emerging at the present
scenario to act as specific components in bio-analytical
devices. Bacterial infections are among the most impor-
tant infectious diseases. The extensive research studies have
been made by S. Z. Moghadamtousi et al. [6], achieving
new antimicrobial medicines, which is isolated from differ-
ent sources, and the differences of physical and structural
variations of antibacterial, antifungal and antiviral isolations
play an important role in antimicrobial studies. Figure 1
shows the specific three classifications from biomedical
applications. According to the progress in the development
of antibacterial agents, there are still special attentions to
find new antibacterial agents due to the development of
multidrug-resistant bacteria. In many cases, the change in
the property of material in the nanorange certainly occu-
pies a definite position in this field. It is clearly understood
due to the enhancement of performances of sensitivity
and detection limit down to single molecule detection. At
the same time, the different combinations of nanomateri-
als, according to its characteristic feature, are capable to
increase the performances of microbial application. The 17
bacterial species are named as follows: Vibrio harveyi, Vib-
rio alginolyticus, Vibrio vulnificus, Vibrio parahaemolyti-
cus, Vibrio cholerae, Bacillus subtilis, Bacillus cereus,
Aeromonas hydrophila, Streptococcus agalactiae, Staphy-
lococcus aureus, Staphylococcus intermedius, Staphylococ-
cus epidermidis, Edwardsiella tarda, Pseudomonas aerug-
inosa, Enterococcus faecalis, Klebsiella pneumoniae and
Escherichia coli [7]. Among these bacterial species, the
five bacteria respond for iron oxide nanoparticles, such as
Bacillus subtilis, Bacillus cereus, Aeromonas hydrophila,
Escherichia coli and Staphylococcus aureus.
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Fig. 1 Differences between antiviral, antibacterial and antifungal
activity [14]
M. Mohamed Rafi et al. [8] have synthesised α-Fe2 O3
nanoparticles with the thermal decomposition route. They
have chosen Fe2 SO4 ·7H2 O as the source of iron. They used
agarose dextran and gelatin as template components of the
polysaccharide. The average crystalline size of α-Fe2 O3 as
10 nm was achieved by them. The antibacterial activity
of α-Fe2 O3 nanoparticles on six bacteria, including these
Gram-positive S. aureus, A. hydrophila and Streptococcus
pyogenes and three Gram-negative P. aeruginosa, E.
faecalis and E. coli, was determined. The inhibition of α-
Fe2 O3 nanoparticles over the above-mentioned bacteria was
tested by them. They found that α-Fe2 O3 nanoparticles did
not create any change in the dosage of 12.5 mL, but the
possible inhibition effect occurred due to an increase in
dosage. The novel biopolymer templates were synthesised
by using a simple thermal decomposition method. As
evidenced from FTIR, good interaction between hematite
and polysaccharide functional groups controls the hematite
crystal growth. The XRD measurements revealed a pure-
phase α-Fe2 O3 . HRSEM and HRTEM confirmed the
dumbbell nature of the iron oxide nanoparticles obtained
at 800 ◦ C, and the lowest particle size was found to be
77 nm for gelatin-Fe2 O3 . The magnetisation measurements
of the iron oxide nanoparticles prepared at 800 ◦ C exhibit
a ferromagnetic behaviour at room temperature for all the
samples. The hematite nanoparticles have an outstanding
antimicrobial efficiency against some bacterial pathogens. It
is concluded that further exploration of this field is needed
to develop eco-friendly bionanomaterials for biomedicines.
M. Arakha et al. [9] have studied the growth kinetic
analysis. They studied the effect of interaction pattern at
the iron oxide nanoparticle-bacterium interface initially by
following the growth kinetics of B. subtilis and E. coli in the
absence and presence of different negative surface potential
iron oxide nanoparticles and p-iron oxide nanoparticle
concentrations. They also performed the study by preparing
the mother cultures of test organisms in nutrient broth
on taking a loop full of bacteria from the specified slant
J Supercond Nov Magn
culture, which were cultured overnight at 37 ◦ C and 150 rpm
agitation. They have studied it for different concentrations
of both negative surface potential iron oxide nanoparticles
and positive surface potential iron oxide nanoparticles as
2.5 μM, 5 μM, 10 μM, 25 μM and 50 μM (micrometres).
The stock solution of iron oxide nanoparticles was prepared
by them on dispersing iron oxide nanoparticles in sterilised
nutrient broth and sonicated for 10 min, followed by
UV radiation sterilisation. The reaction mixtures without
nanoparticles were taken as controls. The bacterial mother
cultures of 20 μL (microlitres) were added by them to
the different reaction mixtures, and the reaction volumes
were also adjusted by adding nutrient broth to a final
volume of 300 μL with nanoparticles. They performed
the growth kinetic studies by measuring an optical density
at 600 nm using a plate reader at regular time interval.
At the approximately mid log phase of bacterial growth,
respective concentrations of nanoparticles were added by
them in the respective reaction mixtures and its different
doted colours which show growth reaction are shown in
Fig. 2. The influence of nanoparticle on bacterial growth
has been estimated by them from the data collection in the
growth curve.
W. Zhang et al. [10] have mentioned that E. coli cells had
noticeable deformation with hematite treatment for 45 min
with a statistical significance. Their study said that the
hematite-treated cells became significantly harder or stiffer
than the untreated ones, which was evidenced by indentation
and spring constant measurements. The average indentation
of the hematite-treated E. coli cells was 120 nm, which
was significantly lower than that of the untreated cells. The
spring constant of hematite-treated E. coli cells (0.28 nN/nm
and 0.11 nN/nm) was about 20 times higher than that of
untreated ones (0.01 nN/nm and 0.01 nN/nm). The zeta
Fig. 2 Fluorescence
microscopic images of B.
subtilis and E. coli in the
absence and presence of n-IONP
and p-IONP [9]
potential of E. coli cells was measured by dynamic light
scattering. The repercussions of iron oxide nanoparticle due
to progressive surface adsorption were further identified by
the researchers from the potential shift 42 to 278 mV.
The antibacterial activity of glycol chitosan with iron
oxide nanoparticles was studied by B. S. Inbaraj et al. [11],
particularly for E. coli O157:H7, Salmonella enteritidis
and S. aureus. The magnetic property of iron oxide
nanoparticles widely used for this activity was reduced
after coating with iron oxide nanoparticles for future
biomedical applications. The reason for utility of iron oxide
nanoparticle is due to the rapid and efficient action as well
as the biomedical application due to the magnetic field
which remains unabsorbed in the body. They mentioned
that this property facilitated access to deep regions in the
living tissues. The size effect was studied by W. Zhang
et al. [12], and the adsorption of hematite nanoparticles
on E. coli cells was due to nanoparticles as the adsorbent
in adsorption experiments onto E. coli cells. They used
the equation as Kb = Kc s/(1 − s) to calculate the
total interaction energies between hematite nanoparticles
and E. coli cells. They found that the total interaction
energy for each size describes the variation of the interfacial
energy as a function of the interacting distance when a
single hematite nanoparticle approaches an E. coli cell.
Also, S. Arokiyaraj et al. [13] tested leaf extract with
iron oxide into E. coli cells by co-precipitation method. E.
Fazio et al. [14] have prepared polymeric-based iron oxide
nanoparticles by varying the ablation parameters of pulsed
laser ablation. They found that polymeric phase increased
the iron oxide nanoparticle’s stability. The antimicrobial
activity of iron oxide nanoparticles on Staphylococcus
aureus was also studied by C. Narendhar et al. [15] and
N. Tran et al. [16] on MTT assay. Their results indicated

that the iron oxide nanoparticle prepared by pulsed laser
ablation technique in water shows a potential bacterial
effect on Staphylococcus aureus. They also mentioned that
a minimum effect was observed for the bacterial growth in
the PVA-Fe2 O3 nanocolloids. They suggested about PVA-
Fe2 O3 nanoparticle to be non-toxic, and so, this could
be integrated in the drug carrier, multiblock polymeric
nanocomposites. The antibacterial activities of iron oxide
nanoparticles made interesting materials for the potential
applications as efficient vectors for drug delivery-specific
platforms for drug targeting studies. M. P. Kumar et al. [17]
modified the surface of iron oxide nanoparticles promised
to offer useful biomedical applications after biocide coating,
and the particles are found to be 100% effective to deactivate
methicillin-resistant Staphylococcus aureus bacteria within
2 h. A. S. Ahmed et al. [18] presented their investigation
of iron oxide nanoparticles for their antibacterial potential
against Bacillus cereus and Klebsiella pneumoniae. They
found that 5 μg/mL and 40 μg/mL concentrations of
iron oxide nanoparticles exhibit a 40–50% loss in viable
bacterial cells, and that 80 μg/mL concentrations acted
as bactericidal for causing a 90–99% loss in the viability
of antimicrobial applications. G. Silvia et al. [19] have
reported the leaf extracts of Cynometra ramiflora were used
to synthesise iron oxide nanoparticles. The leaf extracts with
iron oxide nanoparticles were very effective in inhibiting
E. coli and S. epidermidis which may lead to interest of
iron oxide property changes with the addition of other
doping materials like Ag, Ti and Co. The researchers S. S.
Tawab et al. [20] reported natural antioxidant gallic acid-
assisted magnetite prepared by in situ and post-synthesis
method. The particle size of 5 nm and 8 nm for in situ
synthesis of gallic acid-functionalised magnetite was found,
and experimental antioxidant activity and antimicrobial
studies proved the outstanding antimicrobial activity on
bacterial and fungal strains. K. H. Prakash et al. [21] tested
the silver-loaded hematite nanocomposites by hydrothermal
process for biomedical application. Y. A. M. Abdulhady et
al. [22] prepared titanium-coated iron oxide nanoparticles
by co-precipitation method and evaluated them against
four pathogenic bacterial. species. Their report showed
promising antibacterial activities against Gram-positive and
Gram-negative strains which offers a high reduction percent
after 30 min by 150 μg/mL of nanoparticles. B. Mayank et
al. [23] first reported that they tried multiple mechanisms
of bactericidal activity, and that iron oxide nanoparticles
exhibited minimal/no cytotoxicity to human cells and were
effective on bacteria. In this work, antibacterial properties
of iron oxide and cobalt oxide nanoparticles enhanced the
bactericidal activity against pathogenic bacterial strains B.
subtilis, S. aureus, E. coli and Salmonella typhi and, also,
were highly biocompatible and found to be non-toxic to
the human cell line MCF-7. The iron oxide nanoparticles
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were very effective and less toxic than the other metal oxide
nanoparticles, and the concentration/size of nanoparticles
have played an important role on antimicrobial studies. In
the future, a rapid and efficient action can be expected
as the iron oxide magnetic field remains unabsorbed in
the body, which facilitates access to deep regions in the
living tissues. Also, the semiconducting and magnetic
iron oxide nanoparticles are advantageous over commercial
antibiotics owing to their smaller dosage requirement
and elimination of possible harmful side effects within
short time duration. The recent studies of iron oxide
nanoparticles show enhanced antimicrobial action against
various microorganisms than the commercial drug. Also,
the diagnosis method of iron oxide nanoparticles was
found to be an easier way in detecting microorganisms at
low level concentration from drinking water samples. The
present review study demonstrates the potential application
of magnetic iron oxide nanoparticles to control the
treatment of fungal infections and antimicrobial indications,
and iron oxide nanomaterial has promising potential for
battling widespread bacterial infection either by themselves
or used in combination with the commercially existing
antibiotics. The biocompatibility of pure and different
doped superparamagnetic iron oxide nanoparticles could
be suitable for antimicrobial applications and medical
devices. In summary, iron oxide nanoparticles have high
antimicrobial activity and excellent safety to mammalian
cells. The greater antimicrobial activity was observed for
hematite compared to conventional magnetite nanoparticles.
3 Iron Oxide’s Role on Anticancer Activity
Studies
In the nanotechnology broad field of the growing mod-
ern world, the growing technology also brings unidentified
social issues, such as atmospheric contaminations, and plays
a vital role on human health issues. The social needs lead
to new invention and more attention on specific iron oxide
nanoparticles. The iron oxide nanoparticle and its applica-
tions were used in a wide range of biomedical applications.
These include anticancer, antitumour, bone marrow cell and
cell binding applications. This review focused on iron oxide
nanoparticles which exhibit omnipresent and unique phys-
ical and chemical properties when their dimensions are
reduced to between several and hundreds of nanometres. M.
Malekigorji et al. [24] clarified that superparamagnetic iron
oxide nanoparticles (SPIONs) are small, synthetic α-Fe2 O3
(hematite), γ -Fe2 O3 (maghemite) or Fe3 O4 (magnetite) par-
ticles with a core diameter ranging from 10 to 20 nm.
Also, X. P. Nguyen et al. [25] discussed the fabrication and
structure characterisation of Fe3 O4 and Fe2 O3 nanoparti-
cles encapsulated by several organic and inorganic materials
J Supercond Nov Magn
such as oleic acid (OL), starch (ST), dextran (D), chitosan
(CS), O-carboxymethyl chitosan (OCMCS) and the co-
polymer of poly(styrene-co-acrylic acid) (St-co-AA). The
stability and toxicity were also considered. J. S.-H. Huang
and R.-S. Juang [26] have reviewed the recent design strate-
gies for biochemical and biomedical applications of mul-
tifunctional magnetic nanoparticles. These nanoparticles
were combined with other materials which enhanced the
potential and broadened the applications of such compos-
ite bi-functional nanomaterials. The magnetic nanoparticles
were conjugated with proper ligands or smart polymers. The
bi-functional nanomaterials exhibit highly selective binding
and high sensitivity. They are using the nanoparticles for
magnetic resonance imaging (MRI) diagnosis and therapy
(hyperthermic and chemotherapeutic drug release). Also,
they mentioned the remarkable use of iron oxide nanopar-
ticles, which is one of the achievements of their diagnostic
and therapeutic purposes. The use of nanoparticles should
be eliminated by biological systems without any other detri-
mental effects. The researchers pointed out that magnetic
nanoparticles could also provide a strong contrast effect in
T2-weighted images due to high magnetisation, conjugated
cancer-targeting agent and core-satellite hybrid nanostruc-
tures. H. Chen et al. [27] made review investigation based
on specific needs to improve cancer management that pro-
vide good detection sensor devices to detect tumours in their
early stage, precise and dynamic monitoring of patients’
response to treatment, simultaneous tracking to the levels
of multiple biomarkers in vivo and high sensitivity that can
be translated into capability in practice to identify cancer
at early or pre-syndrome stage which requires further clini-
cal development and corroboration. This review focused on
iron oxide nanoparticles used in cancer imaging and diagno-
sis. Also, the unique properties of iron oxide nanoparticles
have impact with controlled size, composition, morphol-
ogy and physical properties. Also, Z. Bakhtiary et al. [28]
have pointed out about four different stages to help how
Fig. 3 Four different stages in
identifying cancer using iron
oxide nanoparticles [28]
iron oxide detect cancer. They are as follows: (1) detec-
tion of receipts over-expressed on the cancer cell surface in
the tumour mass, (2) detection of unusual angiogenesis in
the tumour micro-environment, (3) detection of circulating
tumour cells and (4) detection of soluble tumour biomark-
ers, and these stages are shown in Fig. 3. The behaviour
of iron oxide nanoparticles depends on many parameters
such as coating, targeting molecules, overall particle size,
delivery route, doping, coating, surfactant, delivery root and
biomarkers.
The cytotoxicity of hematite nanoparticles on Hek293
cells was identified by H. Yan and B. Zhang [29].
The nanoparticles were prepared by them using the raw
materials Fe(NO3 )3 and BaCl2 which were dissolved in
30 mL deionised water containing PVP. They use NaOH
as the reducing agent. The autoclave method was adopted
for their hematite nanoparticles, and the particle size around
180 nm was achieved by them. They tested the viability
of Hek293 cells by exposing hematite nanoparticles at the
dosage levels 100 μg/mL to 500 μg/mL. The exposure
time given by them is 1 day, and they found that the
hematite nanoparticles did not show the toxicity at the low
dosage level, i.e. < 300 μg/mL; they reported significant
cytotoxicity was beginning to start at higher dosage levels
> 350 μg/mL. Finally, they found that the considerable
decreases were observed for the 500 μg/mL dosage level
with increasing hematite nanoparticles. In conclusion, those
researchers reported that hematite nanoparticles can induce
the oxidative stress in Hek293 cell and decrease both
the antioxidative capacity and activity of antioxidative
enzymes in Hek293 cells. The monodispersed hematite
nanoparticles were successfully prepared via a simple
hydrothermal method. The α-Fe2 O3 nanoparticles have a
homogeneous dispersion in water or ethanol solution with
a diameter distribution of 180 nm. They reported that
hematite nanoparticles showed a dose- and time-dependent
cytotoxicity to Hek293 cells, which was attributed to the

lipid peroxidation of the cells due to the interaction with
nanoparticles.
K. Rajendran et al. [30] have synthesised the hematite
nanoparticles from ferric chloride by eco-friendly biologi-
cal method using the culture supernatant of B. cereus SVK1
at physiological temperature and pH. They formed the
hematite nanoparticles of 15–30 nm diameter, and they stud-
ied anticancer activity against HepG2 cell. Their study sug-
gested that this process was efficient and cost-effective com-
pared to the conventional chemical method for preparing
hematite nanoparticle. Their report showed the possibility of
the use of less-toxic hematite nanoparticles for cancer treat-
ment. The researchers have analysed the cytotoxicity effect
of iron oxide nanoparticles on human HepG2 liver cancer
cell and tried various concentrations of hematite nanoparti-
cles like 50 ng/mL, 100 ng/mL, 250 ng/mL, 500 ng/mL and
1000 ng/mL (nanograms). Their main intention was identifi-
cation of cytotoxicity manifestation towards HekG2 cancer
cells at low concentration. M. Calero et al. [31] have made
another study on incubating the cells with dimercaptosuc-
cinic acid-coated superparamagnetic iron oxide nanoparti-
cles for different time intervals, from 0.5 to 72 h. They found
that their nanoparticles showed efficient internalisation and
relatively slow clearance [31]. Time-dependent uptake stud-
ies revealed that the maximum accumulation was observed
for dimercaptosuccinic acid-coated superparamagnetic iron
oxide nanoparticles after 24 h of incubation, and then
they were slowly removed from cells. The superparamag-
netic iron oxide nanoparticles were verified by them using
energy-dependent endocytosis and localised in endosomes.
The macropinocytosis uptake and clathrin-mediated inter-
nalisation depending on the particle size were observed by
them using transmission electron microscopy. They reported
that the MCF-7 cells accumulated these nanoparticles with-
out any significant effect on cell morphology, cytoskele-
ton organisation, cell cycle distribution, reactive oxygen
species generation and cell viability. They made a confir-
mation with similar behaviour to untreated control cells.
Thus, their findings indicated that dimercaptosuccinic acid
(DMSA)-coated superparamagnetic iron oxide nanoparti-
cles possessed excellent properties in terms of efficiency
and biocompatibility to target breast cancer cells. Also, A.
Marcu et al. [32] tested their antitumour effect on MCF-7
cells and reported that iron oxide nanoparticles may provide
better and more targeted drug accumulation in the tumour
cells. The lower concentrations are more efficient in dis-
turbing tumour cells than commercial ones. They confirmed
lowering the therapeutic dose can consequently reduce the
side effects of chemotherapy.
The next aspects of the role of iron oxide nanoparti-
cles in tumour cells have been studied by S. Kossatz et
al. [33]. They mentioned the tumour cells were effectively
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being killed by heat with the help of magnetic hyperther-
mia. The main challenges in this field is the generation
of therapeutic temperature that is selective in the whole
tumour region. So, they brought this idea to improve mag-
netic hyperthermia of breast cancer by using innovative
nanoparticles. The researchers also reported that a high
heating potential was functionalised with cell internalisa-
tion and a chemotherapeutic agent to increase cell death.
Their report also highlighted that the therapeutic effects
of breast cancer magnetic hyperthermia could be strongly
enhanced by the combination of MF66 functionalised with
N6L and doxorubicin (DOX) and magnetic hyperthermia.
They approached the study on combining two ways of
tumour cell killing such as magnetic hyperthermia and
chemotherapy on injecting nanoparticles intratumourally as
clinical practice. A convenient carrier system for suspending
superparamagnetic iron oxide nanoparticles in an aqueous
medium of PEG-PE-based polymeric micelles was reported
by R. M. Sawant et al. [34]. The stability of superpara-
magnetic iron oxide nanoparticles was also made between
polymeric micelles with respect to superparamagnetic iron
oxide nanoparticles with and without polymeric micelles.
They found that superparamagnetic iron oxide nanoparticle-
loaded PEG-PE micelles provided dramatically improved
T2 relaxation rates. These superparamagnetic iron oxide
nanoparticle measles could be easily modified with anti-
cancer, nuclear some-specific map 2C5 with the preserva-
tion of the antibody-specific activity to make them can-
cer cell-specific. Mob 2C5-superparamagnetic iron oxide
nanoparticle immunomicelles specifically recognise and
bind cancer cells in vitro, bring a higher quantity of super-
paramagnetic iron oxide nanoparticles to these cells and
have a potential to serve as an MRI contrast agent with
improved T2 for better tumour imaging. In addition to this,
the specific accumulation of mAb 2C5-superparamagnetic
iron oxide nanoparticle immunomicelles into the cancer
cells made these micelles good candidates to be used in
conjunction with AC field-assisted hyperthermic cancer
therapy.
P. C. Nagajyothi et al. [35] have tested the hematite
nanoparticles on the cell viability and the percentage of cell
growth inhibition, which were calculated. The concentration
is dependent on cell growth inhibition with the hematite
nanoparticle and exposure on P soraleacorylifolia seeds.
They found that these nanoparticles showed efficient
anticancer activities. Finally, they revealed that an aqueous
extract of Psoralea corylifolia seeds plays a reducing agent
role and became to have a significant anticancer activity
against renal tumour cells at lower concentrations. Also,
DNA fragmentation on A549 cell line with L-arginine-
coated iron oxide nanoparticles and control cells was
examined by D. Rehana et al. [36], and they speculated
J Supercond Nov Magn
the drug paclitaxel-loaded L-arginine-coated iron oxide
nanoparticles could be used as an effective drug carrier
for the destruction of cancer cells. B. Sangeetha and A.K.
Kumaraguru [37] have studied Sargassum myriocystum leaf
extract to be used for synthesis of iron oxide nanoparticles.
The 2.8 nm size of biosynthesised iron oxide was achieved
which was used for cancer treatment, and they were done
for in vitro and in vivo analysis. The flutamide with iron
oxide nanoparticles increased the life span of the tumour-
bearing mice. They reported flutamide nanoparticles at the
dose of 10 mg/kg body weight by decreasing the nutritional
fluid volume controlled the growth of tumour and increased
the life span of Dalton’s lymphoma ascite-bearing mice.
Thus, flutamide nanoparticles at the dose of 10 mg/kg body
weight had antitumour activity against Dalton’s lymphoma
ascite-bearing mice.
S. C. Hong et al. [38] have widely utilised the super-
paramagnetic iron oxide nanoparticles for the diagnosis
and therapy of specific diseases, as magnetic resonance
imaging contrast agents and drug delivery carriers, due
to their easy transportation to targeted areas by an exter-
nal magnetic field for such biomedical applications, and
superparamagnetic iron oxide nanoparticles must have mul-
tifunctional characteristics, including optimised size and
modified surface. However, the biofunctionality and bio-
compatibility of superparamagnetic iron oxide nanoparti-
cles with various surface functional groups of different
sizes have yet to be elucidated clearly. Therefore, it is
important to carefully monitor the cytotoxicity and geno-
toxicity of superparamagnetic iron oxide nanoparticles that
are surfaced-modified with various functional groups of
different sizes. In their study, they evaluated superparam-
agnetic iron oxide nanoparticles with diameters of approxi-
mately 10 nm and 100–150 nm, containing different surface
functional groups. Superparamagnetic iron oxide nanopar-
ticles were covered with O groups, the so-called “bare
superparamagnetic iron oxide nanoparticles”. Following
this, they were modified with three different functional
groups: hydroxyl, carboxylic and amine groups by coat-
ing their surfaces with tetraethyl orthosilicate (TEOS), (3-
aminopropyl)trimethoxysilane (APTMS), TEOS-APTMS
or citrate, which imparted different surface charges and
sizes to the particles. The effects of superparamagnetic iron
oxide nanoparticles coated with these functional groups on
mitochondrial activity, intracellular accumulation of reac-
tive oxygen species, membrane integrity and DNA stability
in fibroblasts (L-929) were determined by water-soluble
tetrazolium, 2,7-dichlorodihydrofluorescein, lactate dehy-
drogenase and comet assays, respectively. The toxicological
observations of their study suggested that the functional
groups and sizes of superparamagnetic iron oxide nanoparti-
cles were critical determinants of cellular responses, degrees
of cytotoxicity and genotoxicity and potential mechanisms
of toxicity. Nanoparticles with various surface modifica-
tions and different sizes induced slight, but possibly mean-
ingful, changes in cell cytotoxicity and genotoxicity, which
would be significantly valuable in further studies of biocon-
jugation and cell interaction for drug delivery, cell culture
and cancer-targeting applications. Furthermore, in geno-
toxicity analysis, the negatively charged (citrate-modified)
superparamagnetic iron oxide nanoparticles presented the
highest toxicity at low concentrations (100 ppm). Above
100 ppm, the tendency towards genotoxicity was similar
regardless of the size and surface charge but the change
was not significant. They observed a detailed dependence
of cell cytotoxicity and genotoxicity on the surface modi-
fication and size of nanoparticles. It is obvious that small
modifications in these nanoparticles induced slight, but
possibly meaningful, changes in cell cytotoxicity and geno-
toxicity; this information would be significantly valuable
in studies of bioconjugation and cell interaction for drug
delivery, cell culture and cancer-targeting applications or
further advanced precise control-required bioengineering.
They observed that superparamagnetic iron oxide nanopar-
ticles affected the cell viability and DNA stability of L-929
fibroblastic cells in a dose-dependent manner.
M. Kumar et al. [39] have reported a novel nanoparticle-
based delivery system that can transport therapeutic car-
gos to the intracellular sites without the need for a cell
transduction or penetration domain. They have used iron
oxide nanoparticles to deliver an oncopeptide, NuBCP-9,
targeting the BCL-2 BH3 domain. Citric acid/2-bromo-2-
methylpropanoic acid-capped superparamagnetic iron oxide
nanoparticles were used to immobilise and deliver the
NuBCP-9 peptide to the cancer cells without any notice-
able off-target effects. Their results have demonstrated that
NuBCP-9-superparamagnetic iron oxide nanoparticles effi-
ciently penetrate into cancer cells and bind to their intracel-
lular target protein BCL-2. Moreover, significant inhibition
of proliferation and substantial induction of cell death were
observed when cancer cells were treated with NuBCP-
9-superparamagnetic iron oxide nanoparticles at different
time intervals. Importantly, the IC50 values for killing of
breast cancer cells with NuBCP-9-superparamagnetic iron
oxide nanoparticles were much lower compared to those of
cells treated with the NuBCP-9 peptide linked with a CPP
(Arg-8; NuBCP-9-R8). Molecular and biochemical anal-
yses further supported that NuBCP-9-superparamagnetic
iron oxide nanoparticles killed breast cancer cells by
apoptosis-mediated mechanisms. Their data also demon-
strated that administration of NuBCP-9 superparamagnetic
iron oxide nanoparticles in mice bearing Ehrlich ascites
tumours (EATs) was associated with loss of tumourigenic-
ity and extensive apoptosis in tumour tissues. These find-
ings showed that a non-CPP-tagged peptide could be suc-
cessfully delivered to undruggable intracellular oncotargets

using superparamagnetic iron oxide nanoparticles. Finally,
they suggested that this induced effective anticancer activity
in vitro and in vivo. The effects of the cellular interaction
of MCF-7 cells treated with lower concentrations to higher
concentrations of rhodamine B-conjugated and NuBCP-9
are shown in Fig. 4. The dosage required less frequent dos-
ing (twice/week) as compared to the daily injections that
were necessary for the antitumour activity of the D-amino
acid NuBCP-9-r8 peptide in vivo. Also, T. K. Jain et al.
[40] reported that the folic acid-Pluronic-coated iron oxide
nanoparticles they used have a dose-dependent antiprolifer-
ative effect on breast cancer at the earlier stage of cancer
cell line.
K. Kanazaki et al. [41] have suggested that photo-acoustic
imaging may promise imaging modality for biomedical
information with high sensitivity and resolution. Iron oxide
nanoparticles have low toxicity and biodegradable prop-
erties. Also, they mentioned that iron oxide nanoparticle
delivery was restricted by its modest leakage and retention
in tumours. This study was designed in the basis of iron
oxide nanoparticles sizes 20 nm, 50 nm and 100 nm con-
jugated with anti-HER2 moieties for HER2-targeted photo-
acoustic tumour imaging. The binding affinity, cellular
uptake and in vivo biodistribution were examined by them.
They proposed this 20-nm anti-HER2 scFv-conjugated iron
oxide nanoparticle (SNP20) as a novel photo-acoustic con-
trast agent. SNP20 demonstrated high affinity and specific
binding to HER2-expressing cells. It selectively visualised
Fig. 4 Cellular interaction studies. a Cellular uptake studies of MCF-7. b Co-localisation studies of NuBCP-9 in SPIONs [39]
J Supercond Nov Magn
HER2-positive tumours in photo-acoustic imaging studies.
This data indicated that SNP20 was a potential photo-
acoustic contrast agent for imaging of HER2-expressing
tumours. L. Guo et al. [42] have developed superparam-
agnetic iron oxide nanoparticles by drug delivery system.
In their system, the amino group and carboxyl-modified
dual-function superparamagnetic iron oxide nanoparticles
have been synthesised as carriers. The cyclic arginine-
glycine-aspartic acid (RGD) peptide (c(RGDyK)) was cou-
pled to the carrier for special av B3 integrin targeting. They
used DOX as an anticancer agent and the novel triplex
“hand” reagent Tris-surinch amino triacetate which could
be coupled to one to two amino groups. They synthesised
c(RGDyK)-coupled magnetic nanoparticles by this method
for a specific delivery of large amounts of DOX to integrin
av B3 -expressing tumour cells. They have analysed tumour
cell structure drug-released target cell uptake and cytotoxic-
ity effect. Their results implied that the cell cytotoxicity due
to the c(RGDyK) and DSP carrier was minimal. The inhi-
bition ratio of RDSP of U87MG cells was higher than that
of DDSP under a mole-per-mole basis. They reported that
the inhibition ratio for RDSP reached 66.8% for U87MG
cells while that of DDSP was 37.3% with the DOX concen-
tration of 6.25 μg/mL. The IC50 value of RDSP was also
lower than that of DDSP correspondingly. This behaviour
demonstrated that the special c(RGDyK)-integrin avb3 tar-
geting enhanced the uptake of RDSP to integrin avb3.
They suggested that this behaviour raised the drug delivery
J Supercond Nov Magn
effectively and concluded that RDSP not only showed the
superparamagnetic property high trapping efficient for mag-
netic targeting and the high drug load ratio of RDSP which
could also carried a large amount of DOX to target tumour
cells. Their study reported that the specific method can also
be applicable for targeted delivery of therapeutic agents
in tumours with high efficiency and low carrier toxicity.
H. Mackova et al. [43] reported P(DMAAm-AA) γ -Fe2 O3
nanoparticles have higher antitumour and antimetastatic
activities than cisplatin probably due to an enhanced oxida-
tive stress in tumour cells. A. H. Atta et al. [44] have made
precursor complexes with resulted cytotoxic and antitumour
activity of iron oxide against breast carcinoma cell line with
priority for Fe2 O3 .
M. Singh et al. [45] have focused on optimisation
method to synthesise iron oxide nanoparticles grafted with
PEG silane. The coating of nanoparticle surface with 3-
amino propyl triethoxy silane and carboxylated PEG ligand
has provided stability in solution and size control. They
mentioned these opened nanoparticles surface to conjugate
with various biomolecules containing amine or carboxylic
group at its terminal end. Their report said that the
increased stability of these functionalised nanosystems was
due to the formation of the hydrogen bonding between
PEG molecules on the surface of nanoparticles. Therefore,
their study showed that the surface-modified maghemite
metal nanoparticles have been used in biomedical field
due to their properties and biocompatibility. Thus, they
suggested that the clinical use of maghemite nanoparticles
could come to an end by integration of maghemite
nanoparticles into a hybrid multifunctional structure with
its improved ability to engage specific molecular binding.
The researchers A. Masotti et al. [46] have made an attempt
on polyethylenimine (PEI)-based iron oxide. They found
that the compound PEI-25 is a good contrast agent for
MRI bolus tracking experiments. Actually, they reported
small differences about PEI-coated iron oxide compounds
were less efficient than the commercially available contrast
agent Endorem, and the versatility of these polymers and
derivatives resided in their ability to complex and deliver
DNA in vitro and in vivo; also, they were monitored by
non-invasive optical imaging techniques and conjugated
with dye. B. Bajaj et al. [47] have reported amino
acid-based diethylene trimming pentaacetic acid (DTPA)-
functioned Fe3 O4 nanoparticles synthesised by thermal
decomposition could be useful to radiolabelling and cancer
therapy. The recent development of superparamagnetic iron
oxide nanoparticles targeting drug delivery systems is more
effective on cancer therapy treatments, and it is reviewed
by G. Kandasamy and D. Maity [48]. In the biomedical
applications, natural products and green sythesised iron
oxide nanoparticles have been used for the treatment of
anticancer effects. A research on iron oxide nanoparticles
has developed a method to detect and diagnose cancers,
for diagnosis of cancer relies on medical imaging but,
ultimately, ought to take tissue out for testing by optical
imaging approach which technique is recently used on
cancer diagnosis. The nanoparticle research has been
successful in detecting multiple forms of breast cancer in
mice. Also, the current research has made cancer diagnosis
without the need to take tissue samples via biopsy. The
magnetic iron oxide nanoparticle is important for cancer
diagnosis and treatments compared to semiconducting iron
oxide nanoparticles.
4 Iron Oxide Nanoparticle Treatments
on Human Bone Marrow Cells and Molecular
Cell Binding
4.1 Bone Marrow Cells
The iron oxide nanoparticles have different cell populations
obtained from bone marrow cells (MSCs, BMCs and
the indigenous mobilisation of bone marrow cells) and
have specific effects on MSCs or BMCs or G-CSF. The
iron oxide nanoparticle treatment induces functional and
morphological improvement which may have more effect
on bone marrow cell treatments studied by L. Urdzikova
et al. [49] in which the bone marrow cell treatment
and nanoparticle impacts lead to focus specific area of
research. K. Turnovcova et al. [50] have reported human
mesenchymal stromal cells (hMSCs) are a promising tool
for future clinical application, but their use requires rapid
cell expansion in media suitable for clinical use. Therefore,
they tested the influence of several culture media on
colony formation, population doubling (PD) time, cell
cycle and surface marker expression. The choice of serum
influences hMSC expansion and cell properties; α-MEM
supplemented with hABS seems to be a promising candidate
for clinical use.
S.-Y.-R. Paik et al. [51] analysed the physicochemi-
cal properties and cytotoxicity of iron oxide nanoparticles
in bone marrow cells. They were compared with iron
oxide samples and surface-modified iron oxide nanoparti-
cles. Their results showed that the iron samples were not
cytotoxic to the bone marrow cells and did not affect the
expression of cell surface, and that the effects of phago-
cytosis were stronger in iron oxide nanoparticles than in
surface-modified iron oxide nanoparticles. B. Novotna et al.
[52] tested human bone marrow mesenchymal stromal cells
(hBMSCs) from two donors: hBMSC-1 and hBMSC-2. The
measurements were performed at two intervals: after 3 days
for cell growth without nanoparticles. The dose 15.4 g
Fe/mg/mL of superparamagnetic iron oxide nanoparticles
was selected as being sufficient for in vivo cell tracking

using MRI. Concerning cell viability and cell death, only the
hBMSC-2 seemed to be sensitive to the action of superpara-
magnetic iron oxide nanoparticles. The TEM micrograph
results of the cell viability of unlabelled and labelled hBM-
SCs are shown in Fig. 5. On the same way, G. M. van
Buul et al. [53] studied cell-based therapy using a tempt-
ing approach for cartilage repair and articular cartilage
which have very limited intrinsic regenerative capacity. The
cell tracking driven a major step towards unraveling and
improving the repair process of these therapies. They report
superparamagnetic iron oxides for labelling human bone
marrow-derived mesenchymal stem cells regarding effectiv-
ity, cell viability, long-term metabolic cell activity, chondro-
genic differentiation and hBMSC secretion. They studied
limited intrinsic regenerative capacity of articular cartilage,
making cell-based therapy a tempting approach for cartilage
repair. Cell tracking can be a major step towards unrav-
eling and improving the repair process of these therapies.
They studied superparamagnetic iron oxides for labelling
hBMSCs concerning effectivity, cell viability, long-term
metabolic cell activity, chondrogenic differentiation and
hBMSC secretion profile.
Fig. 5 The TEM micrographs of
the labelled and unlabelled
hBMSC-2 with
superparamagnetic iron oxide
nanoparticles. N nucleus, M
mitochondrion [52]
J Supercond Nov Magn
P. Jendelova et al. [54, 55] studied animals with a corti-
cal photochemical lesion or with a balloon-induced spinal
cord compression lesion and the fate of implanted rat bone
marrow stromal cells and mouse embryonic stem cells
labelled with superparamagnetic iron oxide nanoparticles.
They reported that MSCs labelled with iron oxide nanoparti-
cles are more viable and migrate into injured cells. This pro-
cedure is used to track implanted cells in experimental ani-
mals. They found positive results in animals and suggested
that human trials were successful. The effectiveness of
Resovist-labelled bone marrow stem cells was evaluated by
J. Guo et al. [56] in vivo, including their cerebral transplan-
tation in a model of Parkinson’s disease (PD) in rats using
MRI, the effect and fate of transplanted cells in various dis-
ease models and the possibility of longer observation time.
The iron oxide nanoparticles are more beneficial in devel-
oping new strategies of cell-based gene therapy. M. Radu et
al. [57] investigated the effects of numerous anthropogenic
and natural sources and reported the crystalline size of α-
Fe2 O3 nanoparticles is very effective and has a potential to
damage lung cells. The concentration of hematite (α-Fe2 O3 )
nanoparticles during lipid peroxidation was 12.5 μg/mL. An
J Supercond Nov Magn
antioxidative system in MRC-5 lung fibroblast cell’s expo-
sure was tested for 1–3 days. Exposure to α-Fe2 O3 nanopar-
ticles increased lipid peroxidation by different percentages,
such as 81%, 189% and 110% after 1 day, 2 days and
3 days, respectively, and they reported MRC-5 antioxidant
defense mechanisms not efficiently counteract the oxidative
stress induced by exposure to hematite nanoparticles and
possible damaging effects could occur in human lung cells.
D. Horak et al. [58, 59] developed surface-modified iron
oxide nanoparticles by precipitation of Fe(II) and Fe(III)
salts with ammonium hydroxide, and they compared their
results with those using two methods: in the first method, D-
mannose solution (in situ coating) was used, and the second
method involved oxidation of sodium hypochlorite followed
by the addition of D-mannose solution (post-synthesis coat-
ing). Also, rat bone marrow stromal cells (rBMSCs) were
labelled with uncoated and D-mannose-modified iron oxide
nanoparticles and with Endorem. The labelling efficiency
and the viability of both rat and human mesenchymal
stem cells labelled with Endorem, poly(L-lysine) (PLL)-
modified Endorem, uncoated γ -Fe2 O3 , D-mannose and
poly(N, N-dimethylacrylamide) (PDMAAm)-coated iron
oxide nanoparticles were compared. The coated magnetic
iron oxide nanoparticles labelled cells better than did
Endorem. High relaxation rates and in vitro magnetic res-
onance imaging of cells labelled with coated nanoparticles
showed visible contrast compared with unlabelled cells or
cells labelled with Endorem. They reported surface modifi-
cation of iron oxide nanoparticles with D-mannose, PLL and
PDMAAm has a strong impact on cell viability. A. Tomi-
taka et al. [60] tested the composite of gelatin iron oxide
nanoparticles and co-cultured it with human bone marrow-
derived mesenchymal stem cells. They reported gelatin-
based iron oxide composites internalised and degraded
intracellularly on bone marrow-derived mesenchymal stem
cells. The potential cytotoxic effects of superparamagnetic
iron oxide nanoparticles on bone marrow cells become more
predictable in comparison of iron oxide nanoparticles with
the other examined cells. Superparamagnetic iron oxide
nanoparticles are not toxic to the bone marrow used at low
concentrations. The superparamagnetic iron oxide exposure
has an impact in vivo on the viability and key functions of
local bone marrow stromal cells (BMSCs) as investigated,
and they appear suitable for contrast enhancement in bone
marrow, suggesting that this necessitates future research.
4.2 Cell Labelling
The present review work was based on cell labelling and
cell binding with iron oxide nanoparticles. The physical
properties and different magnetic behaviours of iron oxide
like semiconductors (hematite) and superparamagnetic iron
oxide (maghemite and magnetite) nanoparticle generate
more biological research interests. L. Mohammed et al. [61]
have reviewed that the maghemite nanoparticles possessed
all potential applications in both the environmental and
medical fields. Also, they mentioned that magnetic nanopar-
ticles had not yet fully reached their optimal safety than
hematite and efficiency owing to the challenges faced when
used in vivo. They were convinced by overcoming the short-
comings through their article of improvement of magnetic
targeted carriers for preclinical trials.
S. S. Eamegdool et al. [62] studied the comparison
between iron oxide nanoparticle labelling conditions and
neural stem cell function, and they found that human
fetal neural precursor cells can be efficiently loaded with
iron oxide nanoparticles at the optimum conditions. H.
L. Karlsson et al. [63] have made comparisons with the
toxicity of nano- and micrometre particles of different
metal oxides. They tested the particles to cause cell death,
mitochondrial damage and DNA damage, and oxidative
DNA lesions were evaluated after exposure of the human
cell line A549. This study showed that nanoparticles of
metal oxide were much more toxic compared to micrometre
particles of metal oxide. One key mechanism may be the
ability of metal oxide to damage the mitochondria. In
contrast, the micrometre particles of TiO2 caused more
DNA damage compared to the nanoparticles, which is likely
explained by the crystal structures. The iron oxides showed
low toxicity and no clear difference between the different
particle sizes. In conclusion, nanoparticles are not always
more toxic than micrometre particles, but the high toxicity
of metal oxide nanoparticles shows that the nanolevel gives
rise to the specific concern. M. Darroudi et al. [64] have
reported a dose-dependent toxicity with the non-toxic effect
of concentration below 62.5 μg/mL on studied in vitro
cytotoxicity on neuro2A cells.
S. J. H. Soenen et al. [65] have found out that high
intracellular iron oxide nanoparticle concentrations are
more effective to affect cell physiology in a concentration-
dependent manner. High levels of iron oxide cores affect
the actin cytoskeleton, formation and maturation of focal
adhesion complexes and can affect protein expression
levels. J. A. Frank et al. [66] made the validation of
intracytoplasmic iron oxide in labelled cells by using simple
Prussian blue staining. In this study, the lower uptake is
below the threshold of detection with Prussian blue stain.
The HeLa cells were incubated with ferumoxide-PLL and
MION-46L-PLL under the different iron concentrations,
and they observed incubation time with cells caused the
large numbers of intracytoplasmic Prussian blue-positive
particles in cells labelled with ferumoxides versus those
labelled with MION-46L-PLL; then, the cells were co-
incubated at minimum 6 h to12 h, washed and evaluated
by cell labelling using Prussian blue stain. They tested
the combination of FDA-approved dextran-coated iron

oxide MR contrast agents with tannic acids (TA) which
resulted in the formation of ferumoxide-TA and MION-
46L-TA complexes that allow a universal non-specific
method of magnetically labelling stem cells. The FDA-
approved reagent dextran is used to mouse or human; in
this method of labelling, cells may facilitate the introduction
of MR monitoring of the biodistribution of magnetically
labelled cells in clinical settings. M. Babic et al. [67]
tested the PDMAAm-coated γ -Fe2 O3 nanoparticles were
obtained by the solution radical polymerisation of DMAAm
in the presence of maghemite nanoparticles obtained by
the chemical co-precipitation of Fe(II) and Fe(III) salts
with ammonium hydroxide and subsequent oxidation with
sodium hypochlorite. The presence of PDMAAm coating
on the maghemite surface was confirmed by both elemental
analysis and FTIR spectroscopy. Cellular monitoring is
particularly important for evaluating cell-based therapies. In
the study of C. Heyn et al. [68], MRI of superparamagnetic
iron oxide-labelled cells has become a valuable tool for
studying the in vivo trafficking of transplanted cells.
Cellular detection with MRI is generally considered to be
orders of magnitude less sensitive compared to positron
emission tomography, single photon emission-computed
tomography or optical fluorescence microscopy techniques.
They reported inconsistency with the observed increase
in the experimentally determined Kfsl value relative to
theoretical prediction diffusion is expected to play some
role in the determination of fractional signal loss, given
the comparable dimensions of free water self-diffusion
distance and FIESTA signal refocusing bands. S. J.
H. Soenen et al. [69] made in vitro labelling cells
with iron oxide nanoparticles for a frequent practice in
biomedical research. The potential cytotoxicity of these
iron oxide nanoparticles remains an issue of debate. In
their present study, four different NP types (dextran-
coated Endorem, carboxydextran-coated Resovist, lipid-
coated magnetoliposomes (MLs) and citrate-coated very
small iron oxide particles) were tested on a variety of
cell types, being C17.2 neural progenitor cells, PC12
rat pheochromocytoma cells and human blood outgrowth
endothelial cells. The MRI up to 500 cells/mL labelled with
very small iron oxide particles is required to efficiently
visualise in an agar phantom in contrast to only 50 cells/mL
for MLs and 200 cells/mL for Endorem and Resovist.
Their results highlighted the importance of in-depth
cytotoxic evaluation of cell labelling studies as at non-toxic
concentrations, few of the particles appear to be less suitable
for the MR visualisation of labelled cells. The effects
of iron oxide nanoparticles on cell homeostasis require a
multidisciplinary approach where many parameters should
be analysed as iron oxide nanoparticles can lead to a
wide variety of toxicological belongings and used as a
model system for the further toxicological analysis of
J Supercond Nov Magn
iron oxide nanoparticles. M. Ma et al. [70] reported
amino-superparamagnetic iron oxide nanoparticles can be
used as an MRI contrast agent and bi-functional labelling
probe for neural stem cells. The table shows a brief
review of iron oxide nanoparticles on different parameters
such as preparation method, particle size, incubation time
and specific testing of biological applications. It can be
concluded from this review that the targeting transfer of iron
oxide nanoparticles with DOX plays a significant role in
enhancing the performance of cell labelling and cytotoxic
activity. It was found that in the future nanodrug delivery
systems, the iron oxide nanoparticles can be optimised for
applications and are effective for cell labelling treatment.
4.3 Special Targeted Drug Delivery
The specific biological treatments (human placenta, insulin
and retinal loci) with iron oxide nanoparticles are discussed
here shortly. An investigation was made by J. J. Faust
et al. [71]; they developed the size-dependent effects of
α-Fe2 O3 nanoparticles through an in vitro model of the
human placenta. They predicted that the diameter of the
nanoparticle affected the viability of the epithelium. They
found that exposure of different diameters would affect
the epithelium in different ways. Their study showed that
the large diameters of 50 nm and 78 nm of α-Fe2 O3
disrupted the junctional integrity of the epithelium and
apoptosis. The α-Fe2 O3 nanoparticles of a smaller diameter
of 15 nm have a little effect on the epithelium. They
reported that gross changes as observed due to exposure
of large diameters were not observed for less-diameter
nanoparticles. The report of their study concluded that
the fetal/maternal interface was responsible for selecting
shuttling nutrients to the placenta, which acted as a barrier
to the mother’s immune components, and permitting waste
and gas exchange, junctional disruption or apoptosis of
these cells in pregnancy complications, or resulted in
fetal malnutrition. S. Correia Carreira et al. [72] studied
and demonstrated the transport and uptake of iron oxide
nanoparticles occurs in vitro in the BeWo b30 placental
barrier model, and they found the effect of size on transport
and toxicity was less pronounced in this study archived by
25 nm and 50 nm. Their report concluded the characteristics
driving toxicity and the placental barrier model were
strongly recommended to allow more accurate extrapolation
to specific biological applications. A. Kebede et al. [73]
studied chitosan and iron oxide nanocomposites loaded with
insulin, which resulted in reduction of blood glucose level
for different diabetic levels and achieved a 51% reduction
in blood glucose level. The next discussion goes to specific
iron oxide nanoparticles targeted to retinal loci by A. Yanai
et al. [74]; their reports produced therapeutic possibilities
achievable with MSCs in diseased neurological tissues.
Table 1 Comparative review on iron oxide phases and its applications

S. no. Nanoparticles Preparation methods Particle size Duration Applications References

1 Leaf extract + iron oxide Co-precipitation 10–30 nm 24 h P. mirabilis and E.coli S. Arokiyaraj et al. [13]
2 Iron oxide Wet chemical method 239 nm 12 h S. aureus C. Narendhar et al. [15]
J Supercond Nov Magn

3 PVA + iron oxide Precipitation 4–9 nm 12–24 h S. aureus N. Tran et al. [16]
4 Hematite Direct heating 85–77 am 10–15 min A. hydrophila and E.coli M. Mohamed Rafi et al. [8]
5 Magnetite Co-precipitation 10–20 nm 45 min Antimicrobial activity E.coli M. Arakha et al. [9]
6 Hematite Penners and Koopal method 120 nm 24 h Antibacterial activity W. Zhang et al. [10]
7 GC + superparamagnetic Co-precipitation 8–9 nm 24 h E. coli B. S. Inbaraj et al. [11]
iron oxide
8 Hematite Chemical precipitation 26–98 nm 25–45 min S. aureus W. Zhang et al. [12]
9 Iron oxide Laser ablation technique 5–10 nm 9h S. aureus E. Fazio et al. [14]
10 Hematite Hydrothermal method 180 nm 2 days Hek293 cells H. Yan and B. Zhang [29]
11 Hematite Biosynthesis 15–30 nm 48 h HepG2 cells K. Rajendran et al. [30]
12 DMSA + superpramagnetic Thermal decomposition 15 nm 72 h MCF-7 cells M. Calero et al. [31]
iron oxide
13 Maghemite Laser pyrolysis 8–10 nm 4h Violamycine B1 and MCF-7 A. Marcu et al. [32]
14 Superparamagnetic iron oxide Co-precipitation 3–11 nm 120 h Tumour cell MF66-DOX S. Kossatz et al. [33]
15 Superparamagnetic iron oxide Lipid film rehydration 25–50 nm 2 weeks MCF-7 M. Rishikesh et al. [34]
16 Hematite Green synthesis 39 nm 48 h Anticancer MCF-7 and HBL-100 P. C. Nagajyothi et al. [35]
17 Superparamagnetic iron oxide Chemical co-precipitation 26–31 nm 48 h A549 cancer cell line D. Rehana et al. [36]
18 Iron oxide Precipitation 6–12 nm 12 h Antitumour B. Sangeetha and A.K. Kumaraguru [37]
19 Superparamagnetic iron oxide Co-precipitation 10–150 nm 20 min L-929 fibroblastic cells S. C. Hong et al. [38]
20 Superparamagnetic iron oxide Thermal decomposition 7–10 nm 16–96 h MCF-7 and HepG2 M. Kumar et al. [39]
21 OA + iron oxide Ultracentrifugation 2–11 nm 2–48 h MCF-7 and PC3 cells T. K. Jain et al. [40]
22 Maghemite Ultrasonication 20–100 nm 24 h Anti-HER2-PA tumour K. Kanazaki et al. [41]
23 C(RGDyK)-sperparamagnetic Co-precipitation 60–70 nm 75 h Tumour cells L. Guo et al. [42]
iron oxide
24 Maghemite Co-precipitation 54–86 nm 28 days Antitumour and H. Mackova et al. [43]
antimetastatic
25 Iron oxide Co-precipitation 20–60 nm 24 h MCF-7 cells A. H. Atta et al. [44]
26 Iron oxide Co-precipitation 86 nm 12 h Tumours M. Singh et al. [45]
27 Iron oxide Ultrafiltration process 150–250 nm 2 min MRI A. Masotti et al. [46]
28 Iron oxide Thermal decomposition 22 nm 24 h Radio-labelling and B. Bajaj et al. [47]
cancer therapy
29 Iron oxide Sonication 200–2000 nm 72 h Bone marrow cells S.-Y.-R. Paik et al. [51]
Table 1 (continued)

S. no. Nanoparticles Preparation methods Particle size Duration Applications References

30 Maghemite Commercially 145–260 nm 72 h Bone marrow cells B. Novotna et al. [52]

available (CA)
31 Superparamagnetic iron oxide CA 73–273 μm 5–44 days hBMSCs G. M. van Buul et al. [53]
32 Iron oxide CA 20–30 nm 2–47 days MSCs Jendelova et al.
33 Superparamagnetic iron oxide CA 60 nm 1–4 weeks MSCs and ESCs P. Jendelova et al. [54, 55]
34 Superparamagnetic iron oxide CA 4–60 nm 1–12 weeks PD-BMSCs J. Guo et al. [56]
35 Hematite Laser ablation technique 40–60 nm 24–72 h MRC-5 cells M. Radu et al. [57]
36 D -Mannose + iron oxide Co-precipitation 6–7 nm 2–3 days rMSCs Horak et al.
37 Maghemite Co-precipitation 10 nm 1–5 weeks rMSCs D. Horak et al. [58, 59]
38 Iron oxide Co-precipitation 1–5 nm 7–44 days rMSCs and MRI A. Tomitaka et al. [60]
39 Superparamagnetic iron oxide Massart method 10–15 nm 1–7 days hNPCs S. S. Eamegdool et al. [62]
40 Iron oxide Sonication 30–60 nm 4–24 h Human alveolar epithelial cell line H. L. Karlsson et al. [63]
41 Superparamagnetic iron oxide Co-precipitation 30–40 nm 24 h Neuro2A cells M. Darroudi et al. [64]
42 Iron oxide CA 8–150 nm 72 h Cell viability S. J. H. Soenen et al. [65]
43 Superparamagnetic iron oxide CA 530–575 nm 2–48 h MSCs + HeLa cells J. A. Frank et al. [66]
44 Superparamagnetic iron oxide Co-precipitation 50–170 nm rMSCs + hMSCs M. Babic et al. [67]
45 Superparamagnetic iron oxide CA 100 μm 5 days THP-1 cell types C. Heyn et al. [68]
46 Iron oxide CA 3–14 nm 1–7 days C17.2 and PC12 cells S. J. H. Soenen et al. [69]
47 Superparamagnetic iron oxide Co-precipitation 10–60 nm 60 min Neural stem cells M. Ma et al. [70]
48 Hematite Penners and Koopal method 15–78 nm 12–72 h Human placenta J. J. Faust et al. [71]

49 Iron oxide – 25–50 nm 4–48 h BeWo b30 placental cell barrier S. Correia Carreira et al. [72]
50 Iron oxide Laser ablation – 24 h Insulin A. Kebede et al. [73]
51 PEG + magnetite Co-precipitation 70–140 nm 30 min Reduction of cytochrome c M. Anindita et al. [79]
52 Superparamagnetic iron oxide 200 nm 4 weeks MSCs and retinal loci A. Yanai et al. [74]
53 Iron oxide 2h Staphylococcus aureus M. P. Kumar et al. [17]
54 Iron oxide 22–26 mm Bacillus cereus and Klebsiella pneumoniae A. S. Ahmed et al. [18]
55 Cynometra ramiflora with iron oxide E. coli and S. epidermidis G. Silvia et al. [19]
56 Gallic acid + magnetite Post-synthesis methods 5–8 nm Bacterial and fungal species S. S. Tawab et al. [20]
J Supercond Nov Magn
J Supercond Nov Magn
They suggested that iron oxide-targeted cell delivery for a
limited area of tissue leads to adverse collateral damage by
direct injection of cells.
The iron oxide nanoparticles doped with different
dopants were used to enhance the chemical and physical
properties. The dopants such as amino covalent binding
[29, 38, 63], agarose [8], arginine [35], citric acid [31],
c(RGDyK) [35], DMSA [24], DMAA [60], dextran [8,
72], D-mannose [51], ethylene glycol [71], glycol chitosan
[11], gelatin [8, 53], L-arginine [28], PVP [22, 75],
polysaccharide [8], PVA [16], PEI [39, 70], PEG [27, 38, 68,
71], PVC [76], peptide [32], polymer [60, 73], silane [69],
saccharide [74], leaf extracts [13, 28, 30] and tannins [77]
for different biological applications are listed in Table 1.
The systematic studies on the relationships between the
nanoparticle size and structures of iron oxide or different
morphologies play an important role in the early diagnosis
and post treatments.
5 Conclusion
The property of iron oxide in nanorange shows the sig-
nificant performance as biological applications, which is
evidently confirmed from this review analysis. It helps to
improve iron oxide property by adding dopants and surfac-
tant, which may be a supporting aid that makes a big impact
on specified target-based biomedical applications. The co-
precipitation method is the more appropriate than the other
preparation processes to prepare iron oxide nanoparticle.
The response of iron oxide in antimicrobial activities was
identified to be more effective on certain types of bacteria:
Bacillus subtilis, Bacillus cereus, Aeromonas hydrophila,
Escherichia coli and Staphylococcus aureus. The antimicro-
bial efficiency against the bacterial pathogens due to iron
oxide nanoparticles is more effective for Staphylococcus
aureus and less for Aeromonas hydrophila. Similarly, the
role of iron oxide in anticancer activity emphasised that the
level of toxicity was due to the dosage level of iron oxide
nanoparticles. The iron oxide nanoparticle, in this review,
was found to play a role in analysis and cytotoxicity level in
cancer treatment, which is due to the iron oxide synthesised
from different methods and analyses. The iron oxide parti-
cle size and incubation time play a main role on targeted
drug delivery systems. The magnetic (maghemite and mag-
netite) properties of iron oxide nanoparticles are appropriate
to anticancer, antitumour and cell labelling. The semicon-
ducting behaviour of iron oxide (hematite) nanoparticle is
apt and effective on antibacterial and antimicrobial stud-
ies from this review analysis. The predominant cancer and
tumour cell controlled by iron oxide nanoparticle are iden-
tified from this review study as Hek293, HepG2, MCF-7
and rMSCS cells. Another typical role in molecular cell
binding is due to the hybrid and multifunctional structure of
iron oxide nanoparticles and its improved ability to employ
specific PEG silane molecular binding. The review study
projected that the iron oxide materials are eco-friendly and
less toxic for biological studies. Recently, cancer diagno-
sis and therapies advanced into the next level of research.
On that, the energy relay approaches are implemented in
lifetime imaging and provide a low toxicity. The risk of ther-
mal accumulation and tissue damage as well as damages
of healthy tissues is also reduced compared to that using
ordinary intensity imaging methods of cancer chemother-
apy, rendering the use of hyperthermia/thermal treatment
less a concern [78]. These technologies have high transfor-
mational diagnoses for a wide range of clinical application
and biomedical research studies.
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