MRI with Gadolinium-Based Nanoparticles - Nanotechnology for Biomedical Imaging and Diagnostics - page 240

intravenous (IV) administration of Mn 2+ , a sequestering agent is required, and dipyridoxal
diphosphate (dpdp) is the ligand used in Teslascan ® , the only Mn 2+ complex approved
for clinical use. The complex exhibits a relatively good relaxivity in water (2.8 mM −1 s −1
at 20 MHz and 40°C), and provides selective uptake by normal hepatocytes, allowing
determination of liver function and identification of cancerous tumors [185]. similarly
to Gd 3+ , Mn 2+ has been incorporated to nanosized carriers. The resulting highly Mn 2+ -
loaded compounds combined with the slow tumbling rate minimize the drawback of
the lower relaxivity of Mn 2+ species. Liposomes and other lipid-based compounds have
been used to entrap MnCl 2 or Mn 2+ complexes to produce very high relaxivities,
comparable to the ones obtained with Gd 3+ -loaded structures. Also, dendritic structures
and manganese oxide nanoparticles are the object of increasing attention. Their prepa-
ration and characteristics have been reviewed recently by pan et al . [186]. These studies
show that Mn 2+ is, in some cases, a plausible alternative to Gd 3+ .
Another paramagnetic species under investigation is Mn 3+ . Complexed in porphy-
rins, it exhibits high relaxivities and can be used to target various cancer cells. In this
case, Mn 3+ is used advantageously over Gd 3+ because of the higher stabilities of the
complexes formed, Gd 3+ being released from porphyrins in solution [187]. As a
nanoparticle component, Mn 3+ porphyrins have been coupled to dextran to obtain
macromolecular structures exhibiting tumor cell membrane affinity with relaxivities
50-75% higher than Gd 3+ -dTpA [188]. Another possibility could be the use of the
high-spin d 5 Fe 3+ . It is too toxic to be injected in the free form (Ld 50i.v. = 0.88 mmol kg −1
in mice), but the lower oral toxicity (Ld 50 = 7.9 mmol kg −1 ) allows its use for gastro-
intestinal organ visualization with Geritol ® , a ferric ammonium citrate-based prepa-
ration. For IV administration of Fe 3+ , various ligands deriving from natural iron
chelators have been studied. The limited relaxivities obtained have also been
improved by the use of polymeric structures such as dextran [189]. Finally, because
of its only one unpaired electron resulting in a low relaxivity ( r 1 = 0.9 mM −1 s −1 for
CuCl 2 in water at 20 MHz and 37°C), Cu 2+ has received much less attention than Gd 3+
and the other species cited previously. However, its relatively low toxicity allows
injection of higher doses to offset this low relaxivity. A few chelates have been
investigated for this application, but the relaxivities obtained seem too low to be able
to replace Gd 3+ chelates ( r 1 values <0.1 mM −1 s −1 ). However, when incorporated in
polymers, Cu 2+ exhibits more reasonable relaxivities (values between 0.5 and
2 mM −1 s −1 ) [189]. nonetheless, success with Cu 2+ would be attainable only with high
loads of the paramagnetic ion. pan et al . prepared a nanoparticle made of a Cu 2+ core
encapsulated in a lipid layer [190]; approximately 14,000 copper atoms were mea-
sured per particle with a total relaxivity of 66,000 ± 2,200 mM −1 s −1 . Furthermore, the
incorporation of biotin at the surface of the nanoparticle provided targeting properties.
The size of the particles (~210 nm) could make them useful as a blood pool agent.

8.4.2 cest/paRacest agents

Recently, a new MRI technique named chemical exchange saturation transfer (CesT)
has emerged. Image contrast with this method is obtained in a fundamentally differ-
ent way than discussed in this chapter. With CesT, the CA does not influence proton