MRI with Gadolinium-Based Nanoparticles - Nanotechnology for Biomedical Imaging and Diagnostics - page 236

equilibrium state susceptible to reverse mechanisms with potential release of the free
ion in the organism, fullerenes entrap the metal and isolate it from physiological
conditions, avoiding virtually any risk of release of the free metal. The idea to use
these structures to entrap highly toxic radiometals for nuclear medicine as well as
Gd 3+ for MRI rapidly grew to give birth to a new field of investigations. The first
report of such structure described the incorporation of Gd 3+ into the endohedral
fullerene C 82 , and the resulting compound was designated as Gd@C 82 [142]. The
synthesis involved an electrochemical reaction, named the arc process, with Gd 2 O 3 -
impregnated graphite rods. However, with the resulting species being highly insol-
uble in water, efforts were made to increase the hydrophilicity by modification of the
surface of the fullerenes with functional groups such as hydroxyl (yielding Gd@
C 82 (OH) n ) [143]. similarly, water solubility was obtained by the introduction of
β-alanine that could also be used for bioconjugation purposes [144]. Also, a fullerene
incorporating three Gd 3+ as the nitride, modified with peG on the surface and denoted
Gd 3 n@C 80 -[dipeG5000(OH) n ], was reported [145].
The first reports on the relaxivity of such water-soluble gadofullerenes described
surprisingly high relaxivities, up to 20-fold higher than the Gd 3+ -dTpA complex
[144]. These results were unexpected because the entrapped Gd 3+ is supposed to be
completely isolated from the bulk water as the fullerene surface does not allow
passage of water or ions under physiological conditions. several investigations
reported r 1 values highly dependent to pH, concentration, temperature, magnetic
field strength, and the nature of the groups attached at the surface [146]. The mech-
anisms involved in the production of such high r 1 are not yet fully understood,
but several explanations have been exposed. electron energy loss spectroscopy
(eeLs) experiments have highlighted the fact that the metallofullerene itself was
a paramagnetic structure, due to the three-electron transfer from the Gd 3+ to the
fullerene cage. Consequently, water relaxation can occur at the large surface of
the gadofullerene [147]. Furthermore, gadofullerenes are highly subjected to
pH-dependent aggregation resulting in a higher rotational correlation time as
demonstrated by studies at various pH [148, 149].
The discovery of the interesting properties of gadofullerenes being still recent,
only limited data on the in vitro and in vivo behavior of these particles are available.
Gd@C 60 [C(COOH) 2 ] 10 exhibited favorable characteristics in vitro for the deve-
lopment of targeted intracellular MRI CAs as suggested by a study by sitharaman
et al . [143]. This gadofullerene was shown to internalize in MsC and nIH3T3 cells
with production of high contrast and could be used for tracking mammalian cells.
In vivo studies were performed with Gd@C 82 (OH) n , which, injected at a 20-fold
lower dose than the Gd 3+ -dTpA complex, produced strong signals in the lung, liver,
spleen, and kidney. This unfavorable high uptake in the reticular-endothelial system
could be reduced with the use of Gd@C 60 [C(COOH) 2 ] 10 , which does not form aggre-
gates and is excreted via the kidney 1 h after injection, similarly to the low-molecular-
weight Gd 3+ chelates [150]. Also, fullerenes incorporating three Gd 3+ ions have been
tested for the visualization of brain tumor in rats after direct infusion into the brain.
The very high relaxivity (in the range of 150-200 mM −1 s −1 at 2.4 T) produced good
contrast with only 1/30 and 1/50 of the necessary dose for Gd 3+ -dTpA with