Chemistry Reference
In-Depth Information
important is the fact that biodistribution studies showed that there was a statistical difference between the uptake of the con-
trast agent by the tumour and the uptake by the liver. Furthermore, these targeted nanoparticles were able to recognise and
tag spontaneous micrometastases in the lungs, livers, and bone marrow of these mice indicating the potential for MRI detec-
tion of micrometastases. Control NPs showed no labelling of metastatic cells, highlighting the importance of targeting for
delivery to metastatic disease.
New examples of the application of nanoparticles as MRI contrast agents are published every week - though many now fea-
ture as multimodal or theranostic nanoparticles and not solely as contrast agents. Here are a few key contrast agent examples that
have appeared recently. Bianchi et al. published the preparation of ultrasmall silica nanoparticles functionalised with gadolinium
chelates for the detection of non-small-cell lung cancer [169]. The main novelties of this work are the top-down approach used
for the preparation of the nanoparticles (final hydrodynamic size <5nm), and the combination of orotracheal administration of the
particles with ultrashort echo time (uTe) free-breathing MRI acquisitions to identify and segment the tumours. Also in the field
of T
1
contrast agents, Xing and co-workers published the preparation and application of ultrasmall NaGdF
4
nanodots for MR
angiography and atherosclerotic plaque imaging [170]. In this work the authors show that the performance of Gd containing inor-
ganic fluoride nanoparticles can be superior to commercially available T
1
contrast agents (Magnevist), while their safety can be
preserved by a rapid renal excretion (due to the small size) and by the inclusion of chelating molecules (DTPA) on the surface of
the nanoparticles. Moving now to T
2
contrast agents, Liu et al. prepared iron oxide nanoparticles following thermal decomposi-
tion protocols, and after bringing them to water by their encapsulation into phospholipidic shells, applied them to quantitatively
test reticuloendothelial system function by MRI [171]. In this piece of work the authors took advantage of one of the most
common drawbacks of the application of nanoparticles
in vivo
, their rapid clearance from circulation by the immune system. In
another T
2
example, Gallo et al. prepared magnetite nanoparticles functionalised with a complex ligand system designed to give
an MRI signal enhancement only in the tumour environment [172]. using the CXCR4 receptor as a target and matrix metallo-
proteinase (MMP) enzymes as triggers, the nanoparticles self-assemble only in the tumour to give an enhanced signal.
9.8
conclusIons and outlook
The examples summarised in the previous section show how the application of nanotechnology to human health, although still
in its initial stages, is most promising. One of the main advantages of nanoparticle formulations is the possibility of using the
motif as a functional platform onto which a number of different ligands can be assembled. This allows the simultaneous
delivery of different drugs, or the combination of different imaging probes (treated in Chapter 16), together with targeting
molecules to gain specificity. It also allows the multivalent presentation of ligands (giving even more versatility to the system
as weaker targeting molecules can be used). All these properties can give rise to the appearance of synergistic effects between
drugs, and their targeted delivery to the diseased site has the potential to reduce side effects from the aggressive treatment of
diseases like cancer. The targeted delivery of contrast agents will also help in the early diagnosis of diseases because the
specific delivery of the imaging probes will allow the imaging of smaller features by a reduction in the background signal.
Despite the good results obtained so far in
in vivo
tests mainly in mice, there are still a number of problems to be solved
before the widespread application of targeted MRI contrast agents in humans. The accumulation of nanoparticles in general
in the liver/spleen represents a problem for their application in this field, and issues such as optimised blood half-lives of these
systems are still not completely solved. The toxicity of nanoparticles is an area onto which great efforts are being concentrated
upon, and long-term toxicity issues with nanomaterials are only really starting to be fully investigated. More studies are also
needed to fully understand the relationship between the size, shape, and charge and the behaviour of the probes
in vivo
.
Finally, the intrinsic low sensitivity of MRI is still an important, and sometimes limiting, factor in any healthcare appli-
cation. A good deal of work is being carried out in this respect; the development of new materials with higher relaxivity
properties, the design of more complex ligands to enhance the performance of magnetic materials, and also developmental
work on MRI technology, are all expected to help increase the sensitivity of MRI and thus help translate the magnetic
nanoparticles from the laboratory to the clinic.
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[3] T. D. schladt, K. schneider, H. schild and W. Tremel,
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