Development and use of iron oxide nanoparticles (Part 1): Synthesis of iron oxide nanoparticles for MRI
1 Division of Medical Radiations, School of Medical Sciences, RMIT University, Victoria, Australia
2 Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia
Contrast agents, such as iron oxide, enhance MR images by
altering the relaxation times of tissues in which the agent is present. They
can also be used to label targeted molecular imaging probes. Unfortunately, no
molecular imaging probe is currently available on the clinical MRI market. A
promising platform for MRI contrast agent development is nanotechnology, where
superparamagnetic iron oxide nanoparticles (SPIONS) are tailored for MR
contrast enhancement, and/or for molecular imaging. SPIONs can be produced
using a range of methods and the choice of method will be influenced by the
characteristics most important for a particular application. In addition, the
ability to attach molecular markers to SPIONS heralds their application in
There are many reviews on SPION synthesis for MRI;
however, these tend to be targeted to a chemistry audience. The development of
MRI contrast agents attracts experienced researchers from many fields including
some researchers with little knowledge of medical imaging or MRI. This
situation presents medical radiation practitioners with opportunities for
involvement, collaboration or leadership in research depending on their level
of commitment and their ability to learn. Medical radiation practitioners
already possess a large portion of the understanding, knowledge and skills
necessary for involvement in MRI development and molecular imaging. Their
expertise in imaging technology, patient care and radiation safety provides
them with skills that are directly applicable to research on the development
and application of SPIONs and MRI.
������ �In this paper we argue that MRI SPIONs, currently
limited to major research centres, will have widespread clinical use in the future.
We believe that knowledge about this growing area of research provides an
opportunity for medical radiation practitioners to enhance their specialised
expertise to ensure best practice in a truly multi-disciplinary environment.
This review outlines how and why SPIONs can be synthesised and examines their
characteristics and limitations in the context of MR imaging. � 2010
Biomedical Imaging and Intervention Journal. All rights reserved.
Keywords: Magnetic resonance imaging (MRI), iron oxide,
Nanotechnology has evolved into a multidisciplinary field,
revolutionising industries such as applied physics, mechanical, chemical,
electrical and biological engineering, machine design, robotics, and medicine
. In medical imaging, the development of nanoparticles has attracted a
phenomenal amount of research, particularly for applications in molecular
The nano size (<100nm) of these particles enables
conjugation with many molecular markers, which can interact at molecular and
cellular levels, thereby offering an ever increasing range of disease targets
for molecular imaging.
Nanoparticles also have the potential to revolutionise
conventional imaging techniques . Conventional imaging modalities lack the
combination of high sensitivity and high spatial resolution required for
molecular imaging. MRI has high resolution, but lacks sensitivity to molecular
signals, while high sensitivity nuclear medicine modalities such as single
photon emission computed tomography (SPECT) and positron emission tomography
(PET) provide superb sensitivity, at the cost of reduced spatial resolution
The use of nanoparticles in modalities like MRI can
greatly increase sensitivity, presenting the potential for high-resolution molecular
imaging. MRI has high spatial resolution [2, 5], is non-invasive in nature,
uses non-ionising radiation, and offers multi-planar tomographic capabilities
. Nanoparticles can be engineered to have magnetic characteristics that can
be detected by MRI at low concentrations, and at the same time contain ligands
which target specific molecules .
Iron oxide nanoparticles have been widely researched for
MRI, as they are mainly superparamagnetic. There are several types of iron
oxide nanoparticles, namely maghemite, γ-Fe2O3,
magnetite, Fe3O4, and haematite, α-Fe2O3,
among which magnetite, Fe3O4, is very promising, because
of its proven biocompatibility .
For molecular imaging purposes, superparamagnetic iron
oxide nanoparticles (SPIONS) need to be biocompatible, non-toxic and magnetic.
They also need to bind to a range of drugs, proteins, enzymes, antibodies, or
other molecular targets.
There have been a number of approaches to the production
of SPIONS for use as MRI contrast agents, and each method produces particles
with different sizes and magnetisation parameters. The iron oxide nanoparticles
can also be coated with a surface layer, usually of organic material, that
provides an interface between the core and the surrounding environment .
This surface layer can be used to direct the particles to a target site.
In this review, we summarise some of the chemical routes
for the synthesis of SPIONS, such as classical synthesis, reactions in
constrained environments, and high temperature reactions. It will also discuss
some of the major methods for structural and physicochemical characterisation
of the SPIONS, such as x-ray powdered diffraction (XRD), transmission electron
microscopy (TEM), dynamic light scattering (DLS), nuclear magnetic resonance spectroscopy
(NMR), and atomic absorption spectroscopy (AAS).
Synthesis of iron oxide nanoparticles
Nanoparticles, being the smallest building block, can
essentially be synthesised to have any structure, and can comprise a core
and/or monolayer(s). For example, some drug delivery applications use multiple
polymer layers surrounding an organic core , while some imaging applications
use a basic structure that incorporates an inorganic core surrounded by an
organic monolayer. The main materials used for the cores include metals such as
gold (Au), platinum (Pt), silver (Ag), cobalt (Co), semiconductors cadmium
selenide (CdSe), lead selenide (PbSe), or hybrids CdSe/zinc selenide(ZnS) .
Materials suitable for composing the organic monolayer can
include; silica shells [12, 13], lipids [14-17], polymers [18, 19] and
amphiphilic ligands [3, 9-11]. This layer can also be augmented with
non-specific ligands or DNA fragments, antibodies, proteins, and drugs.
The choice of core and monolayer material is critical to
the design of specialised contrast agents as each layer dictates a specific
function. The composition of the core material dictates the primary physical
and chemical properties of the nanoparticle, which in turn determine how it can
be imaged. Iron particles, for example, are potentially very useful as MRI
contrast agents because they are magnetic and behave as single magnetic domains
when exposed to an external magnetic field. On the other hand, CdSe
nanoparticles or �quantum dots� can be used as optical probes for fluorescent
The monolayer provides the interface between the core and
the surrounding environment  and can serve two purposes. Firstly, to act as
a barrier between the nanoparticle core and the environment, to protect and
stabilise the core . Some materials used for the core such as iron oxides,
on their own, are not stable, and are readily oxidised, changing valuable
properties of the nanoparticle. Secondly, the chemical nature of monolayers
dictate the reactivity, solubility and interfacial interactions , and may
also determine the biological handling, of the nanoparticle. Most of the
inorganic cores are not soluble in aqueous environments, and monolayer designs
serve to overcome this problem, particularly for in-vivo applications. The
inorganic core, when used alone, does not have a specific target, however if
the monolayer is a particular molecular precursor or is conjugated to a
specific molecule, it can direct the particle to an area of interest.
Nanoparticle design for MRI
As well as having a suitable iron core and monolayer,
SPIONS, need to possess a range of other properties to ensure they are useful
as MRI contrast agents. These are:
- uniform particle size [20, 21]
- a uniform and high superparamagnetic moment [2, 20, 21]
- high colloidal stability 
- low toxicity and high biocompatibility 
The way SPIONs are produced has an influence on all of the
above properties . For MRI, these properties are important as they determine
the overall effectiveness of the contrast agent. For example, an essential
characteristic of an effective MRI contrast agent is a high saturation
magnetisation value, (expressed in electromagnetic unit/gram, [emu/g]).
Saturation magnetisation values are a measure of the magnetic moment, so higher
values produce more magnetic susceptibility, and therefore stronger MRI signals
Relaxation rates are a measure of the ability of a
contrast agent to enhance the relaxation rate of water protons, i.e. increase
the efficiency with which image contrast is produced . SPIONS with high T2
values have faster relaxation with surrounding water protons, and therefore
faster relaxation rates (1/T1 and 1/T2).
Typically, magnetisation values for SPIONS range from
30-50emu/g, while higher values such as 90emu/g have been observed for bulk
material [24, 25]. Factors contributing to the magnetisation value of SPIONS
include; the size of the particles (with the highest emu/g to volume
ratio occurring in the 6-20nm particle size range ), spacing between the
nanoparticles (where coatings such as silica separate the magnetic domains,
allowing each individual magnetite particle to act independently and thus
enhancing the net magnetism per gram) and the crystalline structure of
the iron oxide. It is therefore essential to use a method of SPION production
that generates particles with one or more of the above characteristics.
The overall size and size distribution of the SPIONS is an
important consideration as it can affect the biocompatibility and biodistribution
in-vivo. It is well known that particles above 50nm in diameter are eliminated
by the reticulo-endothelial system (RES) so SPIONs greater than 50nm in
diameter are limited to liver/spleen imaging. A range of synthesis methods have
been developed to produce SPIONs with varying sizes and this relationship
between size and biocompatibility will be discussed in the following section.
Other properties, such as high colloidal stability and low
toxicity, are important, because they increase the chances of translating
developmental contrast agents into the clinical setting.
The following sections will briefly discuss the basic
method of SPION growth, and then discuss the different methods of SPION
production and their respective properties for MRI.
Nucleation and particle growth
In making iron oxide nanoparticles for MRI, the particles
need to be of uniform size. Uniform particles are usually prepared via
homogeneous precipitation reactions , which involve two processes,
nucleation and growth. This is because iron oxide nanoparticles are crystalline
structures that are governed by the principles of crystal formation and growth.
Generally, for precipitation to occur, there must be a saturated solution, in
which addition of any excess solute will cause precipitation, and the formation
of nanocrystals .
For nucleation to occur, the solution must be
supersaturated , leading to a short single burst of nucleation .
Supersaturation can be achieved by dissolving the solute at a high temperature,
or by adding reactants to produce supersaturation . After the short burst
in nucleation, the concentration drops and nucleation stops. The nuclei then
grow, by diffusion of solutes from the solution onto the nuclear surfaces,
until an equilibrium concentration is achieved.
In order to achieve monodisperse particles, the two phases
of nucleation and growth need to be separated [8, 20, 27, 29]. There are many
different mechanisms which can explain this process, however we refer the
reader to LaMer and Dinegar , who proposed the classical theory method of
the formation of sulphur colloids, Den Ouden and Thompson who explained
�Ostwald ripening growth� [31, 32] and other mechanisms proposed by Morales et
al. , and Ocana et al. .
Size control is ultimately achieved by artificially
separating nucleation and growth. This would occur before the solution reaches
critical supersaturation, or by the end of nucleation . A wide variety of
factors have been adjusted in many ways to promote separation of the two
processes to control size, magnetic characteristics, or surface properties.
Some of the factors have contributed to the development of new synthesis
methods, and some have just improved classical methods. A few of these factors
will be discussed below.
Methods of superparamagnetic iron oxide nanoparticle synthesis
There are numerous methods of iron oxide nanoparticle
synthesis for applications to MRI , for example; chemical precipitation,
constrained environments and high temperature reactions. In keeping with the
scope of this paper, only these selected methods will be discussed.
The precipitation method is the simplest chemical pathway
to obtain SPIONS [8, 20].
The SPIONS, either magnetite (Fe3O4),
or maghemite (γFe2O3), are prepared by
co-precipitating a stoichiometric mixture of ferrous and ferric salts in an
aqueous medium. The thermodynamics of the reaction require a ratio of 2:1 for
Fe2+/ Fe3+, and a pH between 8 and 14. The precipitated
magnetite is black in colour. The overall reaction can be written as [1, 20]:
Fe2+ + 2Fe3+ + 8OH- →
Fe3O4 + 4H2O������������������������ (1)
The ions can become oxidised before precipitation,
critically affecting the physical and chemical properties of the SPIONS. For
iron oxide, or magnetite, oxidation usually means the formation of maghemite.
The reaction must therefore be carried out under a nitrogen environment to
The transformation from magnetite to maghemite can pose a
serious problem for the production of contrast agents. The two differ from each
other in the spinel structure; one occupies positions in the octahedral and
tetrahedral sites, and the other, maghemite, has cationic vacancies in the
octahedral position. This crystal structure results in a different net
spontaneous magnetisation (or emu/g) of the iron particles : at 300oK,
92 emu/g-1 for magnetite, and 78 emu/g-1 for maghemite
Most of the time it is difficult to separate magnetite
from maghemite , given that their diffraction spectra are very similar
. Some synthesis methods suggest the presence of both magnetite and
maghemite in the resulting preparations .
In the co-precipitation process there are two main
processes involved. The first is a short single burst of nucleation, followed
by growth of the nuclei, as discussed in the previous section. The
precipitation method provides an advantage because large quantities can be
synthesised; however, problems arise from the wide particle size distribution.
As mentioned above, size affects the magnetisation values
as well as the biodistribution in-vivo. Factors that influence the
biodistribution of a particle are important, as they also determine the
possible MRI applications. To control the size, and size distribution, it is
essential to adjust factors that determine the precipitation process. Numerous
studies have been conducted adjusting factors such as pH, ionic strength,
temperature, nature of salts, Fe3+/Fe2+ ratio, and
addition of chelating agents, which improve the size and size distribution of
the SPIONS produced.
The Massart process describes the co-precipitation of ferrous
and ferric chlorides, and hydroxides in an alkaline solution . Parameters
such as strength of the base (eg ammonia or NaOH), the pH value, added cations,
and the Fe3+/Fe2+ ratio were evaluated, noting the effect
on yield of the co-precipitation reaction and particle sizes. It was concluded
that the size decreases as the pH, and/or Fe3+/Fe2+
ratio, increase, and as ionic strength in the medium increases.
A comprehensive study on the ratio of Fe2+/Fe3+
was conducted by Jolivet et al. In 1992  and 1994, illustrating the
effects on size, morphology and magnetic characteristics. Small values of the
Fe2+/Fe3+ ratio (<0.3) were known to form goethite.
For ratios less than 0.5, but greater than 0.3, there were two phases,
consisting of smaller (4nm) and larger nanoparticles. However, a ratio of 0.5
corresponded to magnetite stochiometry, and the particles were homogenous in
size and composition.
In 1999, Babes et al.  investigated different
properties such as iron concentration, temperature and oxygen. It was
highlighted that one of the most important parameters was the Fe2+/Fe3+
molar ratio. A high ratio produced larger particles, which is consistent
with the literature [39, 41], suggesting that only ratios between 0.4 and 0.6
produce monodisperse particles, suitable for use as contrast agents in MRI
It is reported that the higher the pH and the ionic
strength, the smaller the particle size and size distribution [41, 42]. Vayssi�res
et al.  observed that for a higher pH and ionic strength, the
particles were smaller due to the thermodynamics of the solution. At a lower pH
and ionic strength, the particles continued to grow during the ageing phase
associated with Ostwald ripening, thus forming larger particles.
A recent study on the size of the SPIONS, and its effect
on magnetisation and MR signal, was conducted by Young-wook Jun et al.
. The SPIONS were highly crystalline, monodisperse, and stoichiometric for
magnetite, and ranged in size from 4nm to 12nm in diameter. The general trend suggested
that as the nanoparticles increased in size, the T2-weighted MR signal
intensity decreased, the particles therefore appearing hypointense on
Apart from modulating the parameters of the reaction to
achieve monodisperse particles, the addition, either in combination or
individually, of chelating organic anions like citric acid [43, 44], amino
acids, and dimercaptosuccinic acid (DMSA) , can also decrease the particle
size by inhibiting the growth of the crystal nuclei. Polymer surface complexing
agents, which form monolayers on the surface of the iron oxide, such as dextran
, carbodextran, and silica  can also be added, instead of varying the
Some polymer complexing agents such as dextran, carbodextran
and silica are commercially available, and are currently used in iron
oxide-based MRI contrast agents. Examples are: silica-coated magnetite, AMI-121
(Lumirem�- US) dextran-coated magnetite, Ferumoxides (Endorem� � Europe,
Feridex� in the USA and Japan) and carboxydextran coated magnetite,
Ferucarbotran (Resovist� � Europe and Japan).
It should be noted that these agents can be used for any
method of iron oxide production. The coatings often serve multiple purposes;
they allow for water solubility , the attachment of various functional
probes [2, 48], promote the formation of monodisperse particles [20, 45] and
stabilise the magnetite core .
Although the co-precipitation method is the simplest and
most efficient chemical pathway to obtain magnetic particles, it has
disadvantages such as large particle size distribution, aggregation and poor
crystallinity, resulting in low saturation magnetisation values. These
disadvantages have led to the development of advanced methods of magnetite
Reactions in constrained environments
Synthesis reactions in constrained environments have made
use of lipid-based structures with amphiphiles [12, 49-53] and dendrimers .
Lipid-based nanoparticles, or colloidal aggregates such as
liposomes, micelles or microemulsions, are composed of lipids and/or other
amphiphilic molecules. Amphiphiles (sometimes referred to as surfactants) are
molecules with both hydrophilic (polar head) and hydrophobic (non-polar tail)
parts that spontaneously assemble into aggregates in an aqueous solution .
Because of these properties, there are various geometries and sizes that can be
formed due to unfavourable interactions between the hydrophobic tails and water
, such as cylindrical, spherical, and bilayered.
The hydrophobic tails can vary in length, affecting the
ratio between hydrophilic and hydrophobic parts, and the hydrophilic heads can
also vary in charge and size, affecting the overall curvature of the aggregate.
Other factors, such as pH, temperature and concentration, can also affect the
Mulder at al.  illustrate the various
geometries that can be formed.
In micelle-forming lipids, the hydrophobic chains are
oriented toward the inside of the micelle, and the hydrophilic chains outward.
Micelles for MR imaging contain a hydrophobic core, where the iron oxide core
is stabilised by the surfactant, which limits particle nucleation and growth
The first magnetic nanoparticles formed in micelles were
produced by oxidation of Fe2+ salts . The size of the magnetite
particles were controlled by varying the temperature and the surfactant
concentration . Micelles give control to the particle size formed, however
reverse micelles are of importance for applications to MRI.
In reverse micelles, the hydrophilic head groups are
towards the core of the micelle and the hydrophobic groups are directed
outwards. Reverse micelles can solubilise relatively large amounts of water,
which can be controlled, to make them suitable for the synthesis of nanoparticles.
A diverse range of nanoparticles can be obtained by varying the nature and
amount of surfactant, co-surfactant, and solvent.
Reverse micelles are essentially formed by aqueous iron
salt solutions, encapsulated by a surfactant that separates them from the
surrounding organic solution. Publications have suggested that iron oxide
nanoparticles synthesised via the reverse micelle process can be used for MRI
applications . For example Lee et al. , investigated an
inexpensive, large-scale, and highly crystalline method of magnetite
production. The synthesis was carried out at high temperatures whilst varying
the relative proportion of iron salts, surfactant and solvents. It was
suggested that the particle size could be controlled to produce monodisperse
particles in one sample.
Poly(ethylene glycol) (PEG) stabilised lipids can also be
used for targeting and stabilising the iron oxide core . The advantages of
using PEG stabilised lipids are long blood circulation times, and water
solubility, while the disadvantages are associated with difficult preparation
methods, and excessive size separation processes .
Bi-layer forming lipids are used to create liposomes; they
usually have a polar head group and two fatty acid chains. Iron oxides can be
placed inside the liposomal lumen to create magnetoliposomes . There are
two types of magnetoliposomes; the first consists of water-soluble iron oxide
particles within an aqueous lumen . The second contains iron oxide
particles of approximately 15nm, covered with a lipid bi-layer .
The second type, developed by De Cuyper and Joniau ,
has been used in-vivo for MRI as a bone marrow contrast agent . The
magnetoliposomes are produced by first synthesising iron oxides in solution.
The particles are then solubilised and stabilised by the addition of laurate,
which acts as a surfactant. A solution with excess phospholipids is then added
to the particles and undergoes dialysis for a number of days. The surfactant
molecules on the iron oxide surface exchange with the phospholipid molecules
which, over time, cause the formation of a lipid bi-layer on the iron oxides
nanoparticles. Furthermore, molecules such as PEG can also be added to the
lipid bi-layer, increasing the half life in blood  and therefore increasing
the number of applications for MRI contrast.
Dendrimers are a class of transfection agents that contain
three components: core, branches and end-groups. When dendrimers are coated to
iron oxides they are termed magnetodendrimers. Carboxylated polyamidoamine
dendrimers have been used to coat and stabilise the iron oxide nanoparticles
[54, 65]. More importantly, magnetodendrimers are well suited for the imaging
of cell trafficking and migration using MRI [66-68]. This is due to the charge on
the polymer, which promotes a high non-specific affinity for cellular
membranes, resulting in cellular internalisation [65, 67].
Generally, the oxidation of Fe(II) at an elevated
temperature and pH, in the presence of dendrimers, results in the formation of
highly stable and soluble SPIONS with dendrimers . They have an approximate
size of 20-30nm, and high T2 relaxivities . Cells from different origins:
mouse, rat or human, can then be easily labelled to the magnetodendrimers, by
introducing the magnetodendrimers to the cell culture for 1-2 days at low
High temperature methods
�Monodisperse particles with significant size control, and
high crystallinity, can be achieved using high temperature methods. In this
method, iron complexes are decomposed in the presence of surfactants and
organic solvents. The high temperatures used in this method, and the nature of
the solvent, result in the SPIONS having suitable size, and size distribution,
with high crystallinity .
There are many studies on the synthesis of SPIONS using
the high temperature method, for example Sun and Zeng  prepared iron oxide
nanoparticles of different sizes, 3nm to 20nm. In this reaction, iron(III)
acetylacetonate was decomposed by heating at 265oC in phenyl ether,
alcohol, oleic acid, and oleylamine, to produce SPIONS 4nm in diameter. To make
larger particles, a seed-mediated growth was used, controlling the quantity of
seeds added to obtain various sizes.
Similarly, Hyeon et al.  formed an iron oleate
complex from the decomposition of iron pentacarbonyl in the presence of octyl
ether and oleic acid at 100oC. After cooling to room temperature,
(CH3)3NO was added, and then the SPIONS were obtained by heating, followed by
refluxing. When the molar ratios of iron pentacarbonyl and oleic acid were
changed from 1:2 to 1:4, the particle size increased from 7nm to 11nm.
In another study by Park et al. , iron salts
were used instead of toxic organometallic compounds such as iron carbonyl. Iron
salts are more suited for contrast agent research and applications in MRI
because they are less toxic. An iron-oleic complex was formed using iron
chlorides, (FeCl3�6H2O) and sodium oleate, which was slowly heated to 320oC
in 1-octadecene. The solution was aged at this temperature for 30 minutes,
generating monodisperse iron oxide crystals. Various temperatures and solvents
were also tried, which produced particles of different sizes and dispersity. It
was concluded that monodisperse particles could be attributed to the separation
of growth and nucleation phases, which occured at different temperatures;
nucleation at 200-240�C, and growth at 300�C.
Monolayers for superparamagnetic iron oxide nanoparticles
On their own, iron oxides are not very stable, and are not
soluble in water. Stabilisation of SPIONS is essential to prevent against
aggregation and oxidisation. Furthermore, for use as MRI contrast agents
in-vivo, the SPIONS need to be soluble in water and be easily conjugated to
molecular and cellular markers.
As discussed briefly in the previous sections, there are
numerous ways for SPIONS to achieve water solubility and stability. Some of
these methods include coating with carboxylates (such as citric acid),
inorganic materials such as silica, and polymers such as dextran and PEG. These
compounds protect the iron core, and also provide an avenue for conjugation of
molecular precursors, therefore providing a biocompatible functional component
for the SPIONS.
The surface of the magnetite nanoparticles can be
stabilised in an aqueous dispersion by the absorption of citric acid . This
process, as described in Sahoo et al. , occurs by the citric acid
being coordinated via one or two of the carboxylate functionalities, depending
on steric necessity, and the curvature of the surface. As a result, at least
one carboxylic acid group is exposed to the solvent, and this group is
responsible for making the surface charged and hydrophilic. The presence of the
terminal carboxylic group provides an avenue to extended bond formation with
fluorescent dyes, proteins, hormone linkers, and other molecules, so that
specific targeting within biological systems can be facilitated.
Molecules such as DMSA can also be used to stabilise the
SPIONS, achieve water solubility and allow conjugation of molecular precursors
. DMSA has successfully been used as a monolayer , where the DMSA is
introduced to the SPIONS, in excess, through simple mixing. The DMSA binds to
the magnetite surface through its carboxylate bonding, and the intermolecular
disulfide cross-linking between surface-bound DMSA ligands strengthens the
stability. The remaining free carboxylic acid and thiol groups make the SPIONS
hydrophilic, and can be used for further conjugation of target-specific
Iron oxide nanoparticles can also be coated with silica
. Silica is an inert molecule that coats the surface of the iron oxide
nanoparticle, and, as a result, prevents aggregation of the SPIONS, and
provides stability . This is achieved by two processes: (1) sheltering
of the magnetic dipole interaction by the silica shell; and (2) charging
the magnetic nanoparticles, as silica is negatively charged . These two
features are essential, particularly for applications in MRI, as aggregation of
the magnetite particles can reduce or diminish their ability to be
There are two widely used methods to produce silica-coated
iron oxide nanoparticles. The first method is based on the Stober process ,
which comprises the hydrolysis and condensation of a sol-gel precursor such as
tetraethyl orthosilicate (TEOS). There have been numerous studies conducted on
the formation of iron oxides coated with silica using the Stober process [46,
The second most common method of generating iron
oxide-coated silica nanoparticles is via the microemulsion process, where
reverse micelles are used to confine and control the silica coating. In this
method, non-ionic surfactants are used to form inverse microemulsions for
preparation or suspension of magnetic nanoparticles . The silica is formed
around the magnetic nanoparticles by hydrolysis and condensation of TEOS .
Dextran is a polysaccharide polymer that is composed of
α-D-glucopyranosyl units and can vary in length (1000 to 2,000,000 Da) and
branching. Dextran offers a suitable monolayer for SPIONS because of its
biocompatibility . The formation of iron oxide coated by dextran was first
documented by Molday and Mackenzie . In this study, dextran 40 000 was
coated to the iron oxide nanoparticles by reacting a mixture of ferrous
chloride and ferric chloride with the dextran polymers, under alkaline
Other studies have looked at smaller dextran coatings such
as dextran 10 000 [21, 81, 82]. Reducing the size of dextran has an effect on
the formation and stability of the dextran-coated iron oxide nanoparticles [83,
84]. Paul et al.  describe that the smaller dextran has significant
effects on particle size, coating stability, and magnetic properties. It was
concluded that SPIONS coated with a reduced dextran were more stable than those
coated with a larger molecular weight dextran. Higher molecular weight dextran
produced larger particles, and only the 10,000 Da dextran gave a particle with
high magnetic properties.
Characterisation of superparamagnetic iron oxide nanoparticles
There is a wide variety of analysis tools to characterise
SPIONS. It is important to define the exact characteristics of SPIONS, as these
characteristics can influence the application of SPIONS in MRI.
For any biological application, a range of tests such as
biocompatibility, toxicity and efficacy, needs to be considered. However,
within the scope of this paper, and for preliminary development of SPIONS in
MRI, the most general properties that need to be analysed are the physical
(size, shape, chemical phases) and magnetic (MR properties, magnetic saturation
values (emu/g)) properties.
When analysing the size of the SPIONS, we are in fact
measuring a range of dimensions. This includes different parts of the
nanoparticle: size of the iron oxide core, size of the monolayer e.g. silica or
DMSA, size of the iron oxide core and monolayer, e.g. silica or DMSA, combined.
It also includes the size range of the particles present in the sample.
The size of the iron oxide core can be determined by
transmission electron microscopy (TEM) [83-85]. TEM gives the total particle
size, core and monolayer, and also provides details on the size distribution
and the shape of the SPIONS. There are two different types of TEM; low
resolution and high resolution. With the high resolution TEM, the atomic
arrangement of the SPIONS can be deduced. It also allows better
characterisation, or separation, between the core and monolayer. The lattice
arrangement and the surface atomic arrangement of the crystals can also be
studied, by the use of diffraction patterns.
Generally for TEM, a small portion of the sample is placed
on a coated copper grid and then imaged. Although it provides precise direct
information about size, size distribution and shape of the particles, it has
several disadvantages such as operator bias, a risk of change in particle
properties as the sample dries and contrasting of the sample .
Dynamic light scattering (DLS) is also a useful technique
in particle size characterisation, and holds some advantages over TEM. DLS can
obtain information about the size and size distribution in solutions generally
at a lower cost and with less time. In DLS, the distribution of diffusion
coefficients are calculated which are transformed into measurements of the
hydrodynamic or total diameter of the particles [21, 86]. Like all modalities,
DLS also has disadvantages such as contamination by dust or small amounts of
aggregates in the sample; these can create misleading results .
X-ray powdered diffraction (XRD) can also be used to
estimate the size of the particles, and the crystalline structure. XRD gives a
diffraction pattern of the sample, and this is compared to a reference peak or
pattern. Line broadening from the XRD pattern is used to calculate the crystal
sizes , using the Scherrer formula, and these results can indeed be compared
to the TEM results.
Mossbauer spectroscopy is another method that can be used
to approximate the size of the SPIONS  to complement DLS and TEM results. A
resonant absorption of nuclear gamma radiation, e.g. of the non-radioactive 57Fe
isotopes, gives information on the magnetic coupling of the sample, the valence
state of the iron ions, and also on the size of the core.
Measurements of the magnetisation as a function of the
applied magnetic field allow the determination of magnetic properties: magnetic
susceptibility, saturation magnetisation, and r1 and r2
A vibrating sample magnetometer (VSM) or Superconducting
Quantum Interference Device (SQUID) magnetometer can be used to analyse the
magnetic properties. Parameters such as magnetic moment and hysteresis loop
measurements can be measured. The necessary equipment is scarce, and although
these parameters are useful, for the requirements of MRI, other analytical
tools can be used.
Nuclear magnetic resonance spectroscopy (NMR) can be used
to analyse properties such as the T1 and T2 relaxivities.
After analysing the iron concentrations (see below), the r1 and r2
relaxivities can be calculated by plotting the T1 and T2
over the iron concentration . Alternatively, MRI can be used, using the
same process for analysis.
The iron concentration of the sample is generally measured
using atomic absorption spectroscopy (AAS), or inductively coupled plasma mass
AAS compares light absorbance of the unknown sample with
light absorbance from known calibrated standards. It is relatively easy to use
and well understood; however some limitations are that only one sample can be
measured at a time and there can be interference with some elements. On the
other hand, ICPMS is a form of mass spectrometry that is highly sensitive and
can determine a range of metals and non-metals at very low concentrations.
MRI with SPIONS: current status and future directions
The previous sections discuss many studies that have
researched and developed SPIONS. Some research has improved magnetic
characteristics, while other studies have developed novel methods for reducing
the size of the SPIONS, as well as producing monodisperse particles. Despite
research over many years, SPIONS as MRI contrast agents, particularly for
molecular imaging, are still not available clinically. The problems in the
translation of SPION research for MRI to the clinic lie primarily in particle
size: larger particles limit applications; dosage: large amounts of SPIONS are
needed to produce adequate contrast; and production: the ability to adapt
synthesis methods to industrial levels of production.
SPIONS that are larger than 50nm are eliminated by the
RES, therefore they are mainly useful for liver/spleen imaging applications.
Smaller SPIONS are also taken up by the RES; however, because of their smaller
size, their blood circulation time is longer, providing greater opportunity for
specific localisation. SPIONS produced commercially generally have had narrow
applications and have been withdrawn from some markets due to low demand. An
example is SHU-55A, Resovist. Resovist has an iron oxide core of 4.3nm and is
coated with carbodextran to a total diameter of 60nm. Resovist also has excellent
T2 relaxivities of 151.0 mmol-1sec -1, and was used only
for liver/spleen imaging. Products like OMP (Abdoscan) and AMI-121 (Lumirem,
Gastromark) have total diameters of approximately 300nm and are coated with
polystyrene and silica. They are administered orally and used for
gastro-intestinal contrast. Unfortunately the prices of these products are
high, and they are only available on the European and US markets.
Smaller-sized SPIONS such as AMI-227 (Sinerem, Combidex)
and SHU-55C (Supravist an optimisation of Resovist, SHU-55a) are ultra-small
iron oxide particles coated with dextran and carboxy-dextran respectively. Both
products yielded a total diameter of approximately 20nm.They have been proposed
for applications in lymph node and bone marrow imaging, as well as the imaging
of inflammatory processes. These products are not yet approved and are still
undergoing development and/or clinical trials. Another product, NC100150
(Clariscan) for perfusion/MR angiography was discontinued. The iron core was 5-7nm,
and it was coated with PEG, having a total diameter of 20nm.
There are other SPION contrast agents that are available
at a pre-clinical imaging level. Monocrystalline iron oxide particles (MION)
are used for angiography, lymphography, tumour detection, and infarction.
Companies such as BioPhysics Assay Laboratory (BioPAL) Inc. provide products
such as Molday ION and FerroTrack that can be used for molecular and cellular
imaging at the pre-clinical level. See Table 1 for a summary of SPION contrast
For SPIONS to be used for more than one application, they
need to be coated with a monolayer that can promote the attachment of molecular
and cellular probes. An example is a study by Hilger et al. , in
which iron oxide nanoparticles were coated with dextran, and then attached to
anti-Her2/neu antibodies via the carboxyl groups on the dextran surface, for
breast cancer imaging. Most of the SPIONS available or undergoing developments
(see Table 1) have suitable surface coatings for molecular/cellular imaging;
however, their clinical and/or proposed uses have been restricted to relatively
narrow generic roles.
Another drawback in the translation of contrast agent
research to the clinic has been the large amount of iron needed to produce
adequate contrast. The challenge is to develop highly magnetic particles that
can produce the strong signal enhancement, allowing low doses of SPION to be
administered without compromising the MR signal.
Other problems are in translating the synthesis of SPIONS,
easily made in the lab, to industrial processes able to produce large
quantities on a consistent basis.
With the wide range of SPIONS that are currently being
developed for single MR applications there are possibilities that in the future
these SPIONS will be available for use as MR contrast agents. As for molecular
and cellular imaging with MRI, the current research sets a platform for the
further development of SPIONS. If SPIONS as MR contrast agents for single
applications can be utilised, then the next step in SPION development would be
towards molecular imaging. Although molecular imaging with MRI will not likely
replace nuclear medicine and PET, it may play a useful complementary role. The
current decade has seen extensive progress in SPION design, utilisation and
characteristics, and we expect that the future will see highly magnetic SPIONS
available for molecular and cellular imaging in MRI.
Table 1 Summary of SPION Contrast Agents
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|Received 5 August 2009; accepted 24 November 2009
Correspondence: Division of Medical Radiations, School of Medical Sciences, RMIT University, Bundoora West campus, PO Box 71, Bundoora 3083, Victoria Australia. Tel.: + 61 3 9925 6660; Fax: +61 3 9925 7466; E-mail: firstname.lastname@example.org (Jyoti Lodhia).
Please cite as: Lodhia J, Mandarano G, Ferris NJ, Eu P, Cowell SF,
Development and use of iron oxide nanoparticles (Part 1): Synthesis of iron oxide nanoparticles for MRI, Biomed Imaging Interv J 2010; 6(2):e12