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A Review on Synthesis, Characterization and Potential Biological Applications of

Superparamagnetic Iron Oxide Nanoparticles

Antony V. Samrot, Chamarthy Sai Sahithya, Jenifer Selvarani A, Sajna Keeyari

Purayil, Paulraj Ponnaiah

PII: S2666-0865(20)30045-X
DOI: https://doi.org/10.1016/j.crgsc.2020.100042
Reference: CRGSC 100042

To appear in: Current Research in Green and Sustainable Chemistry

Received Date: 19 September 2020

Revised Date: 17 November 2020
Accepted Date: 18 November 2020

Please cite this article as: A.V Samrot, C.S. Sahithya, J. Selvarani A, S.K. Purayil, P. Ponnaiah, A
Review on Synthesis, Characterization and Potential Biological Applications of Superparamagnetic Iron
Oxide Nanoparticles, Current Research in Green and Sustainable Chemistry, https://doi.org/10.1016/
j.crgsc.2020.100042.

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A Review on Synthesis, Characterization and Potential Biological Applications of
Superparamagnetic Iron Oxide Nanoparticles.

Antony V Samrot1#, Chamarthy Sai Sahithya2, Jenifer Selvarani A2, Sajna Keeyari Purayil1,
and Paulraj Ponnaiah1
1
School of Bioscience, Faculty of Medicine, Bioscience and Nursing, MAHSA University,
Jalan SP2, Bandar Saujana Putra, 42610, Jenjarom, Selangor, Malaysia
2
Department of Biotechnology, School of Bio and Chemical Engineering, Sathyabama
Institute of Science and Technology, Chennai 600119, Tamil Nadu, India

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# - corresponding author

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Dr Antony V Samrot
Senior Lecturer
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School of Bioscience, Faculty of Medicine, Bioscience and Nursing, MAHSA University,
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42610 Jenjarom, Selangor, Malaysia.
Email: antonysamrot@gmail.com
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ABSTRACT
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Superparamagnetic iron oxide nanoparticles (SPIONs) have been recognized in numerous

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fields including nanobiotechnology, biomedical engineering, and many other fields for its
inestimable applications. Superparamagnetic property and the smaller size of SPIONs are the
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major reasons for its utilization in various fields. In this review, the overall view on work
done so far on SPIONS is detailed. Where, it started with different methods of synthesis of
SPIONs including various types physical (such as gas-phase deposition, pulsed laser ablation,
power ball milling,), chemical (chemical co-precipitation, micro-emulsions, hydrothermal
synthesis) and biological methods (using bacteria and plant) and are also elaborated. Its
properties and characteristics are detailed. The formulation of SPIONs into drug-laden
nanocarrier for exhibiting targeted drug delivery and its use in cancer treatment as
hyperthermia is emphasised. Its various other applications consist of radiation therapy,
environmental remediation, tissue engineering etc., and are also elaborated.
Keywords: Superparamagnetic iron oxide nanoparticles; Synthesis; Characteristics; toxicity;
hyperthermia; Nanocarrier
1 INTRODUCTION
Nanotechnology is an emerging scientific discipline which deals with particles or materials at
a size range of 1 - 100 nm. A particle at this nanoscale range can facilitate easy adsorption,
absorption and penetration due to increased molecular interaction. The upcoming inventions
and innovativeness in all fields are expected to have the role of nanoparticles to make it reach
the next level of achievement and thereby revolutionizing the future with nanotechnology.
The unique characteristics of these particles compared to its bulk material, make them be
extensively studied in research and development of various fields such as medical,
environmental, biomedical, electrical and communication etc. [1-5]. Metal oxides
nanoparticles have found to be in an engine to make a better performance [6-10]. These metal

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nanoparticles could be produced by either biological method or chemical method [11-22].

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Among the various range of nanoparticles, metal nanoparticles, especially iron oxide
nanoparticles possess an important place due to its superparamagnetic nature, its small size
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and its wide range of uses [23]. Iron oxide is biocompatible to some extent with the human
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system as the chelator of haemoglobin consists of Fe(II) atoms. However, the high
concentration exposure can disturb the normal physiological function of cells [24]. These iron
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oxides can be conjugated with a variety of components and increase wide usage. Trials have
been attempted to fabricate these metal oxide nanoparticles into biodegradable after serving
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the purpose by coating with different materials like polyethylene glycol (PEG), citric acid,
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oleic acid, lactic acid, nonanoic acid and decanoic acid [25-30] and this process of coating
prevent aggregation and promote stable colloidal dispersion [31,32].
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Superparamagnetic Iron Oxide Nanoparticles (SPIONs) mostly magnetite (Fe3O4),

maghemite (γ-Fe2O3) and ferrites are usually crystalline in nature [33]. In nature, the
microorganism namely magnetotactic bacteria have evolved to produce nanosized magnetic
particle inside a membrane-bound organelle called magnetosomes. This chain of
magnetosomes containing the magnetic nanoparticles imparts magnetic dipole against the
earth’s magnetic field which acts as nano-compass and helps in positioning and directing
itself [34]. Purifying magnetite out of bacteria and using it most applications is hard, thus
chemical co-precipitation is a better choice as it is easy and fast to produce as magnetite is
most considered for research purposes [35], maghemite slowly emerged to prove its
importance in the research field [36], ferrites are also being used as hyperthermia agents[37].
Extremely small size SPIONs ranging between 3 nm and 15 nm has found its place in various
medical science applications [38]. Individual nanoparticle exhibits magnetism and has
magnetization present in a single domain. The temperature at which the ferric and
ferromagnetic particles exhibit the aforementioned magnetic property is known as the Curie
temperature [39,40]. Under the external magnetic field, these individual nanoparticles will
express magnetic moment as a single domain and behave as a gigantic paramagnetic atom to
show magnetism. When the external magnetic field is removed, the magnetism of the
individual particles becomes zero [41]. This peculiar behaviour of SPIONs has gained the
focus of many types of research to reach a targeted action and for easy elimination of used
SPIONs from the working zone. In this review article, the various techniques used for the
synthesis of SPIONs using physical, chemical and biological agents are emphasized and the
morphological and magnetic characteristics of SPIONs are detailed. Determination of
crystallinity, physical and chemical characteristics, techniques used for characterization is

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also highlighted. Wider range applications of SPIONs in special reference to biological

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applications in vitro & in vivo are explained.
2 SYNTHESIS OF SPIONs
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SPIONs can be synthesized by different methods including physical, chemical and biological
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methods. The choice of method of synthesis helps in producing SPIONs of a desired shape,
size, structure, colloidal stability and magnetic properties. These properties of SPIONs play
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an important role and determine its field of application. Among the aforementioned methods,
the most used approach is chemical co-precipitation [41]. Various methods of synthesis and
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their significance are as follows -

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2.1 Physical Methods

2.1.1 Gas-Phase Deposition
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Gas-phase deposition/ vapour phase deposition method includes physical vapour deposition
(PVD) and chemical vapour deposition (CVD). When using metals as raw materials,
especially iron, both methods will produce different outcomes and products. In the case of
PVD, both thin films and composite [42,43] nanoparticles can be formed. In this process, the
formation of particles happens due to supersaturation of the precursor molecules present in
the gaseous phase or by the consolidation by thermal treatment of composites onto a surface
with the whole set up in an inert atmosphere [44]. The process would lead to producing fine
particulate powder and nanocomposite/thin films and in this case, fine iron oxide
nanoparticles [45]. Hence, the thus formed particulate matter is incorporated into the deposit
making it rough, non-uniform and a poor adhesive [46]. Whereas, CVD is used to produce
high-quality iron oxide thin films or nanotubes. Overall, the particles produced by Gas-Phase
Deposition are mostly purer compared to liquid-based synthesis as water adds few unwanted
microbes and other impurities where these contaminants are not present in vapour or gas
phases [47]. Thus, the risk of contamination can be ruled out when synthesized using gas-
phase deposition technique.
In case of iron oxides, it has been recorded that the decomposition of acetylacetone or iron
trifluoro acetylacetonate at 400-500ºC or 300ºC respectively can produce particulate iron
oxides or iron oxide nanoparticles by including steps for the reduction in the later stages [46].
One major advantage of using gas deposition method is that the synthesis of particles can be
done in bulk quantities along with easy execution whereas the disadvantages include the
inability to maintain the size of the nanosize of particles throughout the experiment. The
properties of SPIONs such as particle size, crystallinity, porosity, degree of agglomeration,
stoichiometry, chemical homogeneity etc., produced by this method are seemed to be

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controlled by adding an extra processing step [41]. Differently, structured maghemite was

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produced with a size between 5 nm and 60 nm following gas-phase methods [48,49]. Fe7C3,
an iron – carbon-based hybrid xerogel nanocrystals of sized between 10 and 40 nm were
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produced by a gas-phase deposition method, but the formed nanoparticles were amorphic
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[50]. Producing crystalline SPIONs are hard and require a controlled and expert approach.
2.1.2 Electron Beam Lithography
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Electron beam lithography is a method where a beam of electrons is emitted in a patterned

manner upon a film/resin-coated substrate and selectively lifting off exposed or non-exposed
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regions of the resin [51]. Hence, this method of nanoparticles synthesis involves focusing an
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electron beam to create small-sized nanoparticles that are better than conventional techniques
like photolithography [52]. This technique has been used extensively to produce magnetic
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nanorods and nanorings from thin metallic films onto which an organic resin is spin-coated
[53]. A narrow electron beam is allowed to make patterns onto the metallic film and is
submerged into a solvent bath. This makes the extra metal to be lifted and evaporated to
produce nanoparticles of size below 50 nm. There are studies where the Fe3O4 nanoparticles
are synthesized by implementing a double anion-assisted hydrothermal route [54]. Jia et al.
[53] synthesized single-crystal α-Fe2O3 nano rings which were later converted into Fe3O4 and
γ -Fe2O3 through reduction-oxidation processes. Even though electron beam lithography
technique can provide us with small-sized particles, it also has drawbacks such as high
production cost, time-consuming process, pośtential problems with electron scanning,
resolution limitations etc [55].
2.1.3 Pulsed Laser Ablation
This method of synthesis is simple as well as a promising technique to produce nanoparticles
within a controlled temperature, pressure, density etc., these conditions cannot be maintained
much effectively in other methods. When the ablation produces a plasma plume at high
temperature and pressure having ionized species of the target and solvent, they react with the
ablated material to form metastable particles through nucleation and growth [56]. Due to its
fastness, simplicity, cost-effective process made them a successful practice than other
methods [57]. There is no involvement of chemical exposure or the formation of by-products
that harm the environment as seen in the conventional chemical process [58,59]. Laser
ablation technique involves the ablation of an iron precursor bulk material for iron oxide
nanoparticles, which is present in a container having any particular solvent medium of choice
and focusing a laser beam with known parameters such as intensity, wavelength, diameter
etc., onto the bulk material. There are more reports for the synthesis of iron oxide

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nanoparticles using laser ablation method including the report where six different HPLC

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grade solvents like tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide,
toluene and ethanol with iron precursor were used to produce iron oxide nanoparticles of size
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about 15 nm. Similar results were obtained when water [60-62], SDS [63], ethanol [64],
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acetone [61], poly-(vinylpyrrolidone) [56], oleic acid and oleylamine [65] were used.
Although extensively propagated, this method also has its drawbacks, intrinsic to the ablation
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process or technical problems. The high kinetic energy of some species may cause re-
sputtering and inhomogeneous energy distribution of the laser beam might lead to
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inhomogeneous energy profile in the plume [66].

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2.1.4 Laser-Induced Pyrolysis

Laser pyrolysis is used for large scale production where fuel-to-air ratio during combustion
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and vapour pressure of the gaseous precursor was varied. Particles of size 2-7 nm are
commonly obtained by pyrolysis method. In this process, a laser is used to heat iron precursor
gaseous mixture to produce dispersed iron oxide nanoparticles [67,68]. There are reports on
using this method, producing less than 10 nm-sized nanoparticles is possible as it involved
different gaseous precursors and heating them in the air up to high temperatures using laser
beam such as Fe(CO)5 (Iron pentacarbonyl) [69,70], Fe(CO)5 + NO2 [71], Fe(CO)5 + C2H4
[72,73] and have also studied the properties of the synthesized particles. Although this
method does produce small-sized particles, there is a difficulty in obtaining a uniformly sized
nanoparticle for the initial droplets or gaseous mixture and the final nanoparticles made by
this process does have a very broad size distribution [68].
2.1.5 Power Ball Milling
In this process, the powdered mixture is subjected to high-energy collision using balls present
in the mill which produces fine, uniform oxide nanoparticles with good dispersion. This
mechanical alloying or ball milling process requires the proper balance between the
powdered mixtures to form alloys as they are cold-welded and fractured [74]. The particle
size and properties of the iron oxide nanoparticles are highly dependent on the rotational time
and rotational speed of the ball mill. There are different types of mills available when
working with ball milling technique namely planetary mill, oscillating mill, vibrating mill etc.
Amongst all, the planetary mill is said to be efficient in the production of iron oxide
nanoparticles as the name suggests, the milling container rotates in two separate parallel axes
in a manner analogous to the revolution of a planet around the sun [75]. Nanoparticles
produced using planetary ball-mills on an industrial scale has been developed [76]. Ball-
milling technique has been used by researchers to produce uniform & small-sized iron oxide

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nanoparticles and their different properties/activities have been tested already [77,78]. Apart

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from dry milling, wet milling can also be used to produce iron oxide nanoparticles. Can et al
[79] reported the formation of iron oxide nanoparticles from precursor iron solution in
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distilled water using the planetary ball-mill technique. It has also been reported that the water
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helps in the oxidation of the iron molecule into different types of iron oxides depending on
the milling time. Janot and Guérard [80] have reported the partial formation of Fe3O4 after 12
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h of milling and formation of ɣ-Fe2O3 after 24 h milling process in the presence of water.
This might be due to the extended time for the oxidation of particles in water. The drawback
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of this technique is agglomeration due to fine particle interaction which can be ruled out
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using additives such as surfactants [81] and ultrasonication of the particles [82].
2.1.6 Combustion
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Among all other bottoms up methods of preparation, combustion method, also called as
solution combustion method is said to be one of the most undemanding processes since the
other process requires long-reaction time and has a single step involved in the nanoparticles
preparation process [83]. It is a popular choice for the synthesis of many oxides such as
ferrites, cobalt, platinum etc. The precursor reactants are prepared as a homogenous mixture
and heated using fuels up to 1500 °C and as a result, crystalline powders are formed that
posses nano-sizes. Since this process involves dealing with high temperatures, the iron
precursors used here are usually rare and sophisticated precursors such as Fe(N2H3COO)2
(N2H4)2 and N2H5Fe (N2H3- COO)3 H2O due to their thermal decomposition rates and which
would yield maghemite with size 30nm approximately [84,85]. Simpler precursors could be
used to produce magnetite through combustion methods [86]. Many studies used combustion
techniques at lower processing temperature to produce cobalt doped iron oxide nanoparticles
[87]. Another type of this combustion process is microwave combustion (MC) which is an
eco-friendly, economic and environmentally friendly synthetic strategy and works by
converting and transferring microwave energy into heat by rapid kinetics to form final
product within few minutes [88]. α-Fe2O3 nanoparticles were synthesized using the
aforementioned microwave combustion method (MCM) whilst using urea as the fuel [89].
2.2 Chemical Methods
2.1.3 Chemical Co-Precipitation
Chemical co-precipitation synthesis is one of the most popular techniques which is widely
and extensively used to synthesize iron oxide nanoparticles. In this method, iron precursors
are reduced to iron oxides by a weak reducing agent such as sodium hydroxide, ammonia,
TMAOH etc. The reaction is generally given by the equation [90],

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Fe 2+ + 2 Fe 3+ + 8 OH → Fe3O4 + 4H2O

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Different mechanisms of formation of iron oxide nanoparticles using different iron (III)
precursors have been studied [91]. The reaction pathway of the formation of iron oxide
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nanoparticles from precursor molecules through spontaneous nucleation and growth highly
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differs depending on the pH strength of the reducing agents used concentration of the
precursors as well as reducing agents and addition rate of the reducing agents. These
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differences might lead to the production of different iron oxide nanoparticles and the reaction
scheme of these different pathways [92]. The particle size can also be controlled and altered
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by temperature, pH, ionic strength [93]. Similarly, many works have been done in developing
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different strategies of synthesis using chemical co-precipitation method to obtain stable,

uniform, smaller sized, crystalline particles [5,41, 94-97].
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2.2.2 Thermal Decomposition

Thermal decomposing or thermolysis is a method where the substance is treated with heat.
The temperature at which the chemical gets decomposed is known as the thermal
decomposition temperature. This process is an endothermic reaction as it takes in heat to
break the bonds between chemicals. Using this method, iron oxide nanoparticles of high-
quality and size around 15 nm can be produced [98]. Iron oxide nanoparticles can be
produced from precursor molecules such as organometallic precursors by heating them till
they decompose to iron oxide molecules [99]. Hyeon et al [100] have reported succeeding in
synthesizing monodispersed ɣ-Fe2O3 using iron pentacarbonyl along with oleic acid by
thermally decomposing them at 100⁰C and oxidizing the resultant iron−oleic acid metal
complex formed to obtain maghemite (ɣ-Fe2O3) particles. Similar results were obtained when
other precursors were used such as iron chloride in the presence of sodium oleate surfactant
at 317 0C to obtain iron oxide nanocrystals [101], iron (III) acetylacetonate Fe(acac)3 is
phenyl ether in the presence of alcohol, oleic acid, and oleylamine at 265 ⁰C [102], iron
carboxylate salts [103], Fe(CO)5 [104], iron pentacarbonyl salts [105]. The following
chemical equation is the formation of iron oxides in presence of sodium oleate by thermal
decomposition at 320 0C [106].

2.1.4 Microemulsions

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Microemulsions are thermodynamically stable isotropic mixture made of oil, water and
surfactants. Microemulsions form by mixing the components and do not require high shear

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conditions. There are three main categories of microemulsions they are direct emulsions (oil
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in water), reversed (water in oil) and bi-continuous. Metal nanoparticles have been
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successfully synthesized using a reverse microemulsion method using surfactants to produce
uniform and small-sized nanoparticles. Many studies have been done and experiments have
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been performed to produce microemulsions of iron oxide nanoparticles. Silica coated iron
oxide nanoparticles were synthesized using non-ionic surfactants [107]. Reversed
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microemulsion method was performed by Lopez et al [108] to produce iron oxide

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nanoparticles where water droplets were formed in an organic solvent to control particles
size. Similar results were obtained by Chin & Yaacob [109] who have reported to produce
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iron oxide nanoparticles of approximate size range 5-10 nm using micro-emulsion method by
dissolving HTAB in n-octane, followed by addition of 1-butanol (Fig.1). One of the major
drawbacks of this method is that mass production of the particles is difficult to produce when
using micro-emulsion method. Monodispersed and coated small iron oxide nanoparticles
(maghemite) were synthesized in co-precipitation reaction of ferrous and ferric salts with two
organic bases, cyclohexylamine and oleylamine, into a water-in-oil one-pot micro emulsion
[110]. Kekalo et al [111] has synthesized iron oxide nanoparticles by microemulsion method
using three different surfactants namely CTAB, octane and n-butanol and after this method
nanoparticles of size, 8 – 16 nm core and 2 – 3 nm shell were formed [112].
2.1.5 Hydrothermal Synthesis
In this method of synthesis, iron oxide nanoparticles are formed through crystal growth under
high temperature and pressure condition (generally below 300 0C). Usually, reactors which
can maintain high pressure and temperatures are used for this type of synthesis. The reaction
rate is enhanced along with the production of high crystallinity [113]. Highly crystalline iron

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oxide nanoparticles with a size range between 14 and 25 nm have been synthesized using iron

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precursor solution and organic solvent in a pressure-resistant reactor at a temperature of 473

2.2 Biological Methods

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K [113, 114]. The major disadvantage of this process as it needs expensive reactors [115].
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Iron oxide nanoparticles can also be produced using biological entities such as bacteria,
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fungi, plant extracts and protein-mediated. The method of producing the SPIONs using plant
extract and microorganisms is depicted in Fig. 2 and Fig.3. Although these are more
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environment friendly, the particles produced might be less stable, non-uniform with less
homogeneity and more agglomeration, because of the above-stated reasons, there have been
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relatively fewer reports on biological agent mediated synthesis of iron oxide nanoparticles.
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Iron oxide nanoparticles were synthesized through bacteria Acinetobacter sp, which are
known to extracellularly synthesize iron-based magnetic nanoparticles such as maghemite (γ-
Fe2O3) and greigite (Fe3S4) when added with an iron source [116,117]. This synthesis
happens naturally as the formation of iron oxide nanoparticles require the environmental
parameter, like pH, pO2, pCO2, redox potential, temperature. This extracellular synthesis of
the iron oxide nanoparticles/crystals in the culture solution is called Biologically induced
biomineralization. If the synthesis happens within the intracellular space of a magnetotactic
bacteria or sulphur reducing bacteria, then the process is called Biologically controlled
biomineralization (BCM) and the synthesis happens at a specific site within the cytoplasm or
the cell wall. This site is completely warded off the external environment thereby creating the
perfect geochemical conditions. The various steps involving in this process include
supersaturation of iron ions at the specific matrix formed side through transportation followed
by nucleation in a very controlled manner that results in a grown that is highly ordered having
their orientation, morphology and size governed. Thus BCM produces well-ordered
crystalline particles [118]. Not only microbes, but plant extracts can also be used to
synthesize iron oxide nanoparticles or metal nanoparticles in general, through a bottom-up
approach [119]. Madubuonu et al [120] have synthesized iron oxide nanoparticles of size
below 50 nm using extracts of Psidium guavaja and Moringa oleifera. From their
observation, they stated that these iron oxide nanoparticles possessed antibacterial activity
and photocatalytic degradation of methylene blue. Iron oxide nanoparticles with rod-like
morphology were produced using Moringa oleifera leaf extract. These nanorods sized with
the average particle size of 15 nm and showed superparamagnetism. Just like spherical iron
oxide nanoparticles, rod-shaped iron oxide nanoparticles were found to show good

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antibacterial activity [27]. Azadirachta Indica (Neem) extracts have also been used to

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mediate the process of the formation of Iron oxide nanoparticles [121]. Apart from plants and
bacteria, proteins such as ferritin from viruses have shown to provide a platform for the
synthesis of iron oxide nanoparticles [122].
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Fig.2 SPIONs synthesis using plant extracts

Fig.3 SPIONs synthesis using Microorganisms

3 PROPERTIES AND CHARACTERISTICS OF SPIONs
The iron ore itself is found as magnetite, hematite and other forms of iron oxides. The natural
magnetite is reported to show higher catalytic performance in the degradation of organic
contaminants such as p-nitrophenol (p-NP) [123]. Natural hematite are one of the oldest
pigments used by humankind in ancient days. Recent reports suggested the use of natural
hematite as cathode material and it has found its application in developing microbial fuel
cells [124,125]. Magnetite, maghemite or any other ferrite with size below 100 nm and
superparamagnetic property forms SPIONs. The expression of superparamagnetism has made
SPIONs a novel nanoparticle for use as they can be controlled by an applied external

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magnetic field. This has made SPIONs to find special application in biomedicine to exhibit

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controlled action at the target site [126]. It can be used as scavengers [127] or can be used to
increase the temperature around cancerous cells. This property cannot be fulfilled by a bare
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SPIONs, hence it must be surface coated with a biopolymer or any other biocompatible
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chemical molecule such a way to produce the desired effect [128]. Another important
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property is dispersion, as the naked nanoparticles have a larger surface to volume ratio they
get easily oxidized and form aggregates in the aqueous system [129]. Thus, it is necessary to
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modify the surface of these nanoparticles so that they can be used for a wide range of
applications. The size and shape of the nanoparticle play a very crucial role in the properties
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exhibited by the nanoparticles. Only those particles with a uniform surface and a size less
than 20 nm are said to exhibit the superparamagnetic behaviour and they become
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permanently magnetized in the presence of applied external magnetic field [130]. But again,
agglomeration is a major problem. Hence various strategies or methods must be incorporated
to prevent the nanoparticles from getting agglomerated and maintaining them in a stable
monodispersed form [131]. Functionalization of these nanoparticles favours the mono
dispersion and helps in linking with the other metal or drug or any molecules of interest.
Linking with other nanoparticles improves the property of the nanoparticle and can also be
used as a multifunctional entity. Recent advances have been made to link SPIONs with gold
nanoparticles which can be used in hyperthermia treatment of cancer more efficiently [132].
This above-illustrated behaviour of SPIONs and functionalizing agents enabled us to exploit
more efficiently for vast applications with ease.
3.1 Structure
There are three major commonly found iron oxides they are maghemite (γ-Fe2O3), hematite
(α-Fe2O3), and magnetite (Fe3O4); where they are found in polluted air, soil etc [39,133,
134]. The crystal structure of the iron oxides can be essentially described in terms of oxygen
anions and iron cations in octahedral or tetrahedral interstitial sites. In hematite, oxygen ions
are in a hexagonal close-packed arrangement, with Fe (III) ions occupying octahedral sites. In
magnetite and maghemite, the oxygen ions are arranged as a cubic close-packed structure.
The close similarities between magnetite and maghemite make it difficult to distinguish them
using typical spectroscopy such as XRD and other spectroscopy techniques such as
Mossbauer spectroscopy can be a well-suited technique [135]. Maghemite (α-Fe2O3) has the

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following major diffraction pattern at (012), (104), (110), (024) and (116) [136]. Magnetite

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has an inverse spinel structure made up of Fe (III) ions which are randomly distributed
between octahedral and tetrahedral sites whereas, Fe(II) ions in octahedral sites [137]. Cubic
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crystalline magnetite shows the reflection pattern of as (220), (311), (400), (511) and (440)
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[138]. Where extra peaks for maghemite is commonly observed at (210) and (211) [139]
which form a spinel structure with differences in vacancies of the cation sublattice. Here,
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two-thirds of the sites are filled with Fe(III) ions which are arranged with two filled sites in a
regular manner being followed by one vacant site [39].
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3.2 Magnetic Properties

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In nature, any magnetic substance has a magnetic dipole and a magnetization that represents
the magnetic substance’s ability to retain magnetic power (Retentivity). The substance
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retained a positive/negative dipole or magnetization when exposed to any external magnetic

field due to the alignment of the individual domains inside the magnetic substance. In the
case of SPIONs, they only act as magnets in the presence of any magnetic field and returns to
unmagnetized condition with no net dipole. Hence, the VSM graph of SPIONs does not have
the hysteresis curve which implies no retention. This state is called superparamagnetism and
is a very ideal property to work within a biological system as it can react to strong magnetic
fields anywhere and can be detectable by thermo detectors even with systems as it generates
heat when introduces to a magnetic field. Hematite is paramagnetic at temperatures above
956 K. At room temperature, it is weakly ferromagnetic and undergoes a phase transition at
260 K (the Morin temperature, TM) to an antiferromagnetic state [140]. Magnetite is
ferrimagnetic at room temperature and has a Curie temperature of 850 K. Magnetite particles
smaller than 6 nm are superparamagnetic at room temperature, although their magnetic
properties is depended majorly on the methods used in their synthesis. Maghemite is
ferrimagnetic at room temperature, unstable at high temperatures, and loses its susceptibility
with time [141].
Superconducting quantum interference device (SQUID) a precise magnetometry method
useful for measuring very low magnetic can measure 5 a [142]. where the addition of zero-
field cooled (ZFC) and field cooled (FC) help in finding the stability of SPIONs in terms of
magnetometry at a various temperature [143]. Thus this is useful for the application of
SPIONs in hyperthermia.
3.3 Colloidal Stability
Colloidal stability refers to the ability to resist clumping/ agglomeration and remain
monodispersed in a suspension/solution as a colloid. Generally, SPIONs tend to get

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agglomerated in the in vivo systems and gets degraded. In an aggregated state, all the

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individual nanoparticles align and clump together to give out a net polarization/dipole and
even under the absence of a magnetic field. It also depends on the collision that occurs among
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the particles in a suspension. Although many, the three major factors that determine the
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frequency of collisions are Brownian motion, hydrodynamic flow and nanoparticle
concentration. All these factors are broadly classified into attractive and repulsive forces.
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Naturally, when attractive forces surpass repulsive forces, aggregation occurs. Unfortunately,
the superparamagnetic properties of SPIONs degrade when aggregation occurs [143]. To
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maintain the colloidal stability of nanoparticles and to increase its efficiency, the surface of
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the nanoparticle must be modified using biopolymers or by using other ligands or surfactants
[144]. The state at which the However, one must be cautious in using only those polymers
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that are biodegradable and biocompatible [145]. The most commonly used biopolymers to
make the nanoparticle monodispersed are dextran, starch, polyethylene glycol (PEG),
chitosan. Further other organic molecules such as silica, citric acid, ascorbic acid, growth
hormones, antibodies etc. The addition or encapsulation of the biopolymer can be done
during the synthesis process i.e., addition along with the iron precursors, or after the synthesis
by employing certain techniques like ultra-sonication [146, 147]. Value of zeta
potential ≥ +25 mV or ≤ –25 mV shows good stability, as lesser
values tend to show aggregation formed because of Van der Waal
interparticle attractions [148].
3.4 Size and Shape
Size and shape play a very crucial role as stability. The size of the SPIONs should be less
than 20 nm for it to exhibit superparamagnetic behaviour. This extremely small size enables
the efficient exploitation of SPIONs by the researchers for in vivo application [150]. The
small size brings about stability and it can easily cross the several barriers that are present in
vivo [151]. Apoptosis at the reticuloendothelial system is usually skipped due to the small
size. Very small sized SPIONs can easily invade the tumour regions and produce therapeutic
effect [152]. Further, the crystalline nanoparticles are preferred rather than amorphous
particles likewise, nanoparticles with spherical surface morphology are preferred [153]. The
deviations in the surface morphology from the usual spherical to rod-shaped may be due to
increasing in the temperature during the synthesis process for a longer duration [154]. The
size, shape and crystallinity of the synthesized nanoparticle can be found by using various
analytical techniques. To mention a few, Scanning Electron Microscopy (SEM) for

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topographic imaging, Transmission Electron Microscopy (TEM) for high-resolution 2-D

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imaging, Atomic Force Microscopy (AFM) for 3-D imaging and X-ray Diffraction (XRD) for
verifying the size of a crystallite [122].
3.4 Surface Charge
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Surface charge is likely to show direct influence on particle stability and functionalization.
For SPIONs, zeta potential values with high magnitude positive or negative values indicate
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that the nanoparticle is highly stable and can remain dispersed inside the system [155]. Also,
the stability and the zeta potential values are influenced by electrostatic interactions. The
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stability of the particle ensures, in turn, indicates the duration up to which the nanoparticle
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can stay inside the system before getting degraded. Only those nanoparticles that are highly
stable and dispersive are selected for therapeutic purposes [156].
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3.5 Toxicity
Since metal nanoparticles are non-biodegradable particles, they cannot be eliminated by the
body. Samrot et al [157] has reported that the improper disposal of SPIONs can pose a
significant threat to the soil environment. They evaluated the impact of SPIONs on
earthworms under controlled conditions and identified its impact in the gut region.
Accumulation of the SPIONs in the epithelium was also observed. Likewise, the
accumulation of iron oxide nanoparticles in kidneys was observed in an in-vivo trial with rats
[158]. This makes the metal nanoparticles toxic and unfit for in vivo applications. Of the
several metal nanoparticles, SPIONs are found to be less toxic [159], still, it must be tested
on more live systems. The biopolymers that encapsulate these SPIONs should also be
biocompatible and nontoxic. Various in vitro toxicity assays are performed by the researchers
before testing these particles in vivo [160].
4 APPLICATIONS OF SPIONs
4.1 Imaging
Magnetic Resonance Imaging (MRI) has been successfully done with the help of SPIONS
which became a revolution in the field of diagnostics. These SPIONs are less toxic,
superparamagnetic and hence are widely used for a plethora of medical applications. The
therapeutics that are administered can be monitored using the SPIONs as MRI contrasting
agents. MRI uses nanoparticles of size less than 5 nm [161]. Recent advances have enabled
the tracking of stem cells by using SPIONs. The success or failure of the administered
therapy and the clearer image of organ structure can be obtained by using SPIONs [162].
Sruthi et al [163] and Justin et al [164] have shown the use of SPIONs in X-Ray imaging.

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Magnetic particle imaging (MPI) is a recent imaging technique which is used widely for

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imaging cancer cells, neuro imaging, inflammation imaging etc [165, 166]. MPI is much
superior to MRI, here the cell localization is most accurate.
4.2 Magnetic Hyperthermia
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Magnetic Hyperthermia (MHT) is the response of SPIONs to an external alternative magnetic
field in the form of dissipation of heat energy where the temperature of SPIONs is raised
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above 45 ⁰C. [167]. Due to alternative magnetic field (AMF), SPIONs express
magnetization reversal dynamics which is governed by two rotational mechanisms –
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Brownian alignment and Néels rotation [168]. The force imparted on the particle in solution
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to rotate on itself with a fixed magnetic moment is defined as Brownian alignment whereas
Néels rotation occurs when the magnetic moment restructures the electronic spins of the
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particle such that the particle reorients to the applied field [169]. As a struggle from this dual
force, SPIONs in AMF produces heat energy. However the release of heat energy
(hyperthermia) is predominantly pronounced to be the effect of Néel rotation [170]. MHT is
widely encouraged for the treatment of cancer than radiation therapy or chemotherapy. The
stable SPIONs are coated with a biopolymer to increase its biocompatibility. These SPIONs
can be intravenously injected to the target site such as tumour and is exposed to an external
alternating magnetic field (AMF). By doing so the dipole of the SPIONs shift following the
direction of applied alternating magnetic field thereby generating heat energy (Fig.4). This
rapid increase in temperature kills the local cancerous cells [171]. Further, the SPIONs can be
loaded with an anticancer agent to increase the efficacy and induce apoptosis in tumour cells
[172].
Fig. 4 Cancer cell treatment using Hyperthermia technique

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4.3 Targeted Drug Delivery

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Traditionally, the drugs are administered either orally or intravenously. Further, the
administered drugs enter the systemic circulation before reaching the site of injury. But as
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this process continuous most of the drug is lost before it reaches to the targeted site leads to
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lower bioavailability of drug [173]. However, in modern medical researchers have shown that
SPIONs can be used as competent drug carriers upon suitable fabrication which could
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prevent oxidation, to sustain the drug molecules and also to limit the intrusion of the
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reticuloendothelial system (RES), further increasing the in-vivo retention time within the
circulatory system. These nanoparticles are extremely small and hence can cross the
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biological barrier easily [174]. To increase its bioavailability and to remain dispersed these
SPIONs are encapsulated by biopolymers which are both biocompatible and biodegradable
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[175]. These SPIONs can be used to administer a drug directed to a more specific site where
there is a need for therapy rather than the usual methods of direct administration of bare drug
[176].
4.4 In vitro bioseparation
The classical separation techniques followed in molecular biology are soon to be
replaced with magnetic bioseparation. The use of SPIONs can promote ease of performance,
quality, specificity and high-throughput separation of biomolecules like DNA, protein,
antibodies. Paul et al. [177] used SPIONs (size 8nm) prepared by chemical coprecipitation
method and performed DNA isolation from the soil sample. SPIONS dispersed in
polyethylene glycol (PEG) acted as the binding buffer. The separated DNA was found to be
devoid of RNA contamination with an equivalent in quality and quantity to commercial kit
methods. The contact between DNA and SPIONs is usually driven by electrostatic force,
hydrogen bond and hydrophobic interaction. The negative phosphate group in DNA is
expected to form Fe-O-P bonding with SPIONs [178,179]. In this manner, the bound DNA
can be removed out along with SPIONs by a magnetic field. Later they can be recovered by
using suitable elution buffer. A recent study proved that SPIONs with definite fabrication can
also be used for bioseparation of immune components. A nanocore shell of magnetic
nanoparticle and gold was prepared whose size was identified as 10nm [180]. Further, these
nanocore shells were immobilized with human anti-IgG. Bao et al. [180] reported that
binding of IgG on the nanocore shells was assisted by a gold metal deposited upon MNP. The
final fabricated MNP expressed high-efficiency separation of human IgG from test solution.
Thus he emphasised the use of SPIONs as rapid detection tool in immunoassay analysis.

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4.5 Tissue Engineering

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Use of iron oxide nanoparticles for tissue repair was a breakthrough in the field of
nanotechnology. Protein linked nanoparticles placed between the damaged tissue and the
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subsequent increase in temperature above 50 0C join two adjacent tissues. Further, gold-
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coated SPIONs can be used for tissue repair and tend to absorb light. Stem cells are
considered as a boon to tissue engineering due to their pluripotent nature. Coupling of these
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with the SPIONs would aid in site-specific repair. Other proteins can also be linked to
facilitate the repair mechanism. SPIONs are also used to track, target and localize the stem
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cells at the tissue damage site [181] where mesenchymal stem cells were magnetized using
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SPIONs with the optimal intake by the cells and these were used to enhance the retention of
these stem cells at the affected site for tissue engineering as well as the MR-visualization for
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cell tracking. Similarity glycosylated SPIONs, loaded with growth factors were used to direct
the action towards the target site to promote osteogenesis of human mesenchymal stem cells
[182].
4.6 Magnetic nanoparticles in cancer therapy
Magnetic nanoparticles especially superparamagnetic iron oxide nanoparticles, based drug
delivery system in chemotherapy are in the rage nowadays. As mentioned in the application
of hyperthermia, one way of using SPIONs is to inject the particles intravenously and
inducing rice in temperature to kill the local cancer cells. Apart from this, there are many
other ways such as targeted drug delivery using an external magnetic field as a guide to the
site of action [183]. Targeted drug delivery vehicles like iron oxide nanoparticles can
overcome the limitation of a chemotherapy drug, where it cannot directly release at the target
site. This results in an increased concentration of drug intake to see the pharmaceutical
effects and pharmacodynamics of the drug. SPIONs core-shell can also be formed as
illustrated in below Fig.5. Whereas, SPIONs coated with an anti-cancer drug will be able to
carry the drug directly to the tumour site and maintains a sustained drug release at the site of
action that in turn limits the exposure time to healthy tissue and organs (Fig.6). One major
issue that needs to considered carefully is the colloidal stability of SPIONs and BSC class of
the drug as it affects the dissolution, solubility and permeability in the blood. These
complications can be avoided by surface engineering the SPIONs by functionalization, to
maintain stability and encapsulation by a stable biopolymer that dissociated/dissolves on at a
specific pH prevailing in the targeted site.

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Fig.5 Production of core-shell SPIONs 1) Naked SPIONs, 2) functionalization, 3) loaded
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with a drug, 4) encapsulation with polymer

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Fig. 6 Cancer cell treatment using Drug loaded SPIONs

4.7 Radiotherapy
Brachytherapy, a kind of radiotherapy where a localized area can be treated with a sealed
radiation source. Rahman et al [184] studied radio sensitization character of SPIONs by
electron beam radiotherapy and brachytherapy against HeLa cells in-vitro. Irradiations were
done at different doses of electron beams of energy and brachytherapy source and they
determined the survival of cells by clonogenic assay. SPIONs were found to enhance the
radiosensitization activity and it was dependent on concentration. Histone deacetylase
inhibitors (a radiosensitizer) has been used to treat tumour cells [185]. Hoffman et al [186]
used radiolabeled [(59)Fe]-SPIONs to show the emission of gamma and positron to the
SPIONs from the incorporated inorganic radionuclides. He further proposed that
radiolabelled SPIONs can serve as a contrasting agent in MRI. In cancer treatment, these
radionuclides can act as reactive oxygen species in cancer cells and induce apoptosis
[187,188].
4.8 Environmental Remediation

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SPIONs are highly investigated to discover its remarkable role in environmental remediation.

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Heavy metal contamination in potable water resources has become a widespread topical crisis
due to industrialization and improper discharge of effluents [189]. This puts mankind and the
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ecosystem into a potent risk of heavy metal toxicity and biomagnification [190]. The most
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common heavy metals pollutants are arsenic, lead, mercury, cadmium, chromium, aluminium
etc. Chronic exposure of these heavy metals will lead to paralysis, mental retardation, birth
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defects, autism, psychosis, brain damage, kidney damage, muscular weakness, and may even
cause death in humans [191]. With the fact that nanoparticles offer better molecular
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interaction for its small size, SPIONs were checked for the removal of heavy metals from
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water sources. It was found that SPIONs were capable to adsorb these heavy metals onto its
surface through electrostatic interactions and ultimately eliminated the heavy metals from the
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liquid phase. The efficacy of adsorption differed based on surface coating and amalgamation
of SPIONs. Samrot et al. [192] revealed that SPIONs coated with chitosan biopolymer was
able to remove hexavalent chromium (100 ppm) at acidic pH 2. He observed that biopolymer
coating onto SPIONs has enhanced its adsorption efficiency when compared with naked
SPIONs, thus it can be used for removal of heavy metals as prescribed in fig.7. A hybrid
nanoparticle of SPIONs developed by polymerization with poly(methylmethacrylate)
(PMMA) showed adsorption against Pb(II), Hg(II), Cu(II), and Co(II) where adsorption
occurred in accord to radii of metal ions [193]. SPIONs performed as a good adsorbent of
cadmium at neutral pH when incorporated with amberlite resin. This encouraged Goher et al.
[194] to device a nano sorbent from SPIONs for cadmium removal from industrial effluents.
Likewise, SPIONs have been reported to remove synthetic dyes where the adsorption was
dependent on the pH and electric charge of the adsorbent and adsorbate. Cationic synthetic
dyes like basic blue dyes showed better adsorption on SPIONs at alkali pH and vice versa
with an anionic dye such as methyl orange and congo red [195].

Fig. 7 Heavy metal removal using SPIONs

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5. Limitations of SPIONs

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Even though there are more uses of SPIONs in a versatile field there are few limitations there
to its applications which are as follow - The major problem associated with SPIONs are their
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unstableness, maintenance of nanostructure and agglomeration, even though functionalization
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could make it stable but it is not for longer storage [192,196 - 198]. Using SPIONs of size
below 2 nm can cross the cell membrane and may get accumulated inside the cell and cause
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damage to cell organelles [156], a specific measure must be taken while preparing and using
it in biological systems. There are reports that macrophages uptake the SPIONs into the
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system [199]. Nanoparticles can be accumulated inside the cell by at least anyone of the
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following a) simple diffusion and b) receptors facilitated endocytosis [200, 201]. Once
entering the cell, lysosomal enzyme converts the SPIONs into Fe2+ and leads to the
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production of reactive oxygen species which ends with cellular abnormality and activation of
inflammation [150,202, 203]. Stroh et al. [204] showed SPIONs coated with citrate to involve
in oxidative stress and protein degradation where it was done by generating reactive oxygen
species (ROS). Ferritin is found to be a key factor for the generation of ROS and which
sometimes lead to neurodegeneration in vivo [205- 207]. Van den Bos et al. [208] reported
lipid peroxidation by SPIONs coated with dextran which is dose-dependent. Magnetite
nanoparticles coated with poly aspartic acid has shown increased micronucleus in vivo [209].
Even more, there are several reports about its toxicity in earthworm [157, 210] where it
caused degradation of epidermis, guts etc. Samrot et al [210] reported accumulation of these
nanoparticles in Vigna radiata. Even though more are reporting researches to overcome the
toxicity [211], still more work is to be done to reduce the toxicity and also require proper
disposal for SPIONs.
6. Conclusion
This review holds a comprehensive discussion on magnetic metal nanoparticles, SPIONs. We
have addressed the various methods of synthesis of SPIONs involving high-tech devices to
easy one-pot synthesis and formation of SPIONs by biological agents is also described. The
properties and characteristics of SPIONs with a special note to its magnetic behaviour is
mentioned. Amongst all the method, chemical co-precipitation method is easier and have got
many applications. Stability of SPIONs are major concern always, thus the importance of
functionalizing with appropriate agents is also highlighted in this review. SPIONs are less
toxic and biocompatible to other metal nanoparticles, thus it turns out to be an ideal metal
nanoparticle for biomedical application. With this regard, the current and futuristic service of
SPIONs in targeted drug delivery, hyperthermia, SPIONs in radiation therapy are also

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addressed. SPIONs utilized drug delivery or treatment system may be a better substitute to

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treat cancer.

Funding
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This review is written to the RMC funding of MAHSA with reference number RP169 –
05/19.
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• Different methods of synthesis of SPIONs (Superparamagnetic iron oxide
nanoparticles) such as physical, chemical and biological methods are explained.
• The surface and magnetic property of SPIONs are described.
• Application of SPIONs in various sectors like imaging, hyperthermia and cancer
treatment are also addressed.

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Declaration of interests

☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.

☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:

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