Chemistry Reference
In-Depth Information
9.2
t
2
contrast agents
Magnetic nanoparticles, especially those featuring iron oxide, are the leading type of nanoparticle structures in biomedicine,
especially for diagnosis. since the first
in vivo
MRI images were obtained back in 1974 [10], the technique has evolved rap-
idly with many companies and research groups becoming involved in the field. Magnetic nanoparticles were developed at
the end of the 1970s—in 1978 Ohgushi and co-workers [11] used dextran-coated iron oxide nanoparticles in
in vitro
studies
for the first time, whilst in 1986 the first
in vivo
studies with magnetic nanoparticles were carried out by Lauterbur in dog
models [12].
Generally, there are two different approaches for the preparation of a nanoparticle: the top-down physical protocols and
the bottom-up chemical methods. The main advantage of the physical methodologies is that they can produce large batches
of the product, but they have been hardly used in this field because it is difficult to control the size and size distribution of
the final products. On the other hand, a number of different chemical protocols have been developed that achieve, with
varying degrees of success, the goals desired for preparation of nanoparticles for this application—high crystallinity, con-
trollable size and chemical nature, and narrow size distribution [6].
9.2.1 t
2
nanoparticle preparation
A variety of different chemical approaches for the preparation of magnetic nanoparticles have been explored to date, but with
regard to MRI applications, only two of them account for more than 90% of the published works. These two methodologies,
co-precipitation of iron(II) and iron(III) salts and thermal decomposition of organometallic compounds, are the 'gold stan-
dard' for the preparation of magnetic nanoparticles.
9.2.1.1 Co-precipitation of Fe
2+
and Fe
3+
Salts
Co-precipitation protocols are widely used for the preparation of magne-
tite (Fe
3
O
4
) and maghemite (γ-Fe
2
O
3
) nanoparticles due to their simplicity, good-enough quality of the resulting nanoparti-
cles, and the large amounts of product that can be obtained in a single batch. However, particle size distribution and
crystallinity are the weak points of these protocols because only kinetic factors control the growth of the crystals [13].
2
+
3
+
−
Fe
+
2
Fe
+ →+
8
OH
Fe OHO
4
(9.1)
34
2
In this methodology, a basic solution is added to an aqueous 2:1 mixture of ferric and ferrous salts (equation 9.1) to obtain
magnetite nanoparticles [14]. Magnetite (Fe
3
O
4
) is the preferred chemical nature of iron oxide for MRI applications due to
its superior performance when compared to other iron oxides such as maghemite (γ-Fe
2
O
3
) or hematite (α-Fe
2
O
3
) [15].
According to the thermodynamics of this reaction, if a stoichiometry of Fe
3+
:Fe
2+
(2:1) is maintained and the reaction is car-
ried out under non-oxidising and oxygen-free conditions, a complete precipitation is expected at a pH between 8 and 14 [16].
The size and, to some extent, the shape of the resulting nanoparticles can be tuned by exerting a close control of the pH, the
reaction temperature, the ionic strength of the reaction media, the chemical nature of the iron salts (usually chlorides, but
perchlorates, nitrates and sulphates have also been used), and the ratio of Fe
3+
and Fe
2+
. To prevent magnetite from further
oxidation and to avoid particle aggregation, whilst at the same time controlling the size of the final product, organic coating
molecules (e.g., polymers) are usually introduced into the reaction media during the precipitation process. The most widely
used of these polymeric materials is dextran, a branched glucose polymer (for a review on dextran-coated iron oxide nanopar-
ticles see [17]) that due to its biocompatibility, biodegradability, and good performance has become the most popular option
even for commercial T
2
contrast agents. Other popular polymeric choices include chitosan; synthetic polymers such as PeG,
poly(vinyl alcohol) (PVA), poly(acrylic acid) (PAA), poly(methylacrylic acid) (PMAA), poly(lactic acid), polyvinylpyrrol-
idone (PVP), polyethyleneimine (PeI); and AB- and ABC-type block copolymers containing the above polymers as seg-
ments [5]. The main drawback of using polymeric materials is that while the size of the magnetic core remains in the low
nanometre range, the overall hydrodynamic radii is far larger (i.e., Feridex: magnetic core diameter = 4.96 nm; hydrodynamic
diameter = 160 nm). This feature makes it easier for the immune system to detect and clear away these contrast agents and
reduces their half-life in the body. small molecules, usually containing carboxylic acid moieties, have also been used
in situ
as coating ligands, the most common example being citric acid [18]. These molecules act as chelating agents, absorbing onto
the magnetic surface and helping to control the size of the final particles.
9.2.1.2 Thermal Decomposition and/or Reduction Routes
Thermal decomposition protocols appeared in the late 1990s
to early 2000s. They were designed to overcome the two main disadvantages of co-precipitation routes: poor crystallinity
and wide size distribution. As the name suggests, they are based on the decomposition of organometallic compounds at high
temperatures, usually in high boiling point non-polar solvents. In 1999, Alivisatos et al. developed the thermal
