MRI with Gadolinium-Based Nanoparticles - Nanotechnology for Biomedical Imaging and Diagnostics - page 221

[Gd(H 2 O) 8 ] 3+ ( τ m = 1.2 ns). τ m can be measured by 17 O nMR and short values of
approximately 2 ns have been obtained with HOpO-like Gd 3+ complexes [23],
suggesting possible applications in high magnetic fields. Higher relaxivities can also
be obtained by optimizing the hydration number and the residence time in the second
sphere ( q ss and τ mss ). For instance, the presence of phosphonates or phenolates
which promotes hydrogen bond formation can increase relaxivity in dOTA and
dTpA derivatives [25-28]. studies have shown the high contribution that can be
achieved by the second sphere as molecules with q = 0 with optimized second sphere
characteristics could even exhibit relaxivities close to q = 1 complexes [29, 30].
Finally, it has been observed that increasing the rotation correlation time, τ r , enhances
relaxivity. This can be achieved by increasing the molecular volume/size (and con-
sequently molecular weight) of the molecule, as demonstrated by the enhancement
of the relaxivity from 4 mM −1 s −1 for [Gd(dota)(H 2 O)] − to 23.5 mM −1 s −1 for [Gd(dota-
glu 12 )(H 2 O)] − (25°C, 20 MHz) [31]. Increasing the rigidity of the complex is also a
method that can be used to increase τ r [32, 33]. specific examples of τ r enhancement
in the case of nanoparticles are discussed in the second part of this chapter.
8.2.3 approved Gadolinium-Based contrast agents: clinical
applications and limitations
Magnevist TM was the first CA approved for clinical use in 1988. There are currently
nine approved Gd 3+ -based CAs (Table 8.1). They are all derivatives of dTpA or
dOTA with a relatively low molecular weight (~600-800 da). Their relaxivities
range from 4.1 to 6.9 mM −1 s −1 except for the most recently introduced Ms-325
whose relaxivity is 27.7 mM −1 s −1 (1.5 T, 37°C), because it binds serum albumin
in vivo leading to a macromolecular species with a low tumbling rate of the complex.
They differ in charge, shape, and chemical functions, conferring specific clearance
rates and routes of excretion and thus different applications. They can be classified
according to three main classes: extracellular fluid (eCF) agents or extracellular
space (eCs) agents, liver agents, and intravascular or blood pool agents. eCF
agents are hydrophilic, distribute nonspecifically in the whole eCF space, and are
excreted exclusively by glomerular filtration through the kidneys with a half-life of
approximately 1.5 h. They allow visualization of abnormalities in blood vessels
and inflamed or diseased tissues. Because these molecules do not normally cross
the blood-brain barrier, they can be used to visualize abnormalities causing perme-
ability to these molecules in this area (Fig. 8.2a). MultiHance TM and eovist TM are
dTpA-based CAs with a benzyl group in their structure conferring higher lipophi-
licity. They are cleared by the hepatobiliary system and by the kidneys, allowing
for their use as eCF and liver CAs (Fig. 8.2b). Ablavar is a dTpA-based CA with
a biphenylcyclohexyl group that binds reversibly to serum albumin resulting in a
macromolecule in vivo with a long rotational correlation time and, consequently,
a high relaxivity [34]. A phosphodiester in its structure limits hepatic uptake that
would be induced by the presence of the phenyl groups. This affinity for albumin
makes this CA a blood pool agent with long blood half-life and applications in MR
angiography [35] (Fig. 8.2c).