MRI with Gadolinium-Based Nanoparticles - Nanotechnology for Biomedical Imaging and Diagnostics - page 223

Although more than 30% of MRI exams use one of the CAs cited earlier, their
characteristics continue to confine their use to limited applications. The main issue
is their rapid clearance time that does not allow visualization of tissues out of the
vasculature. Larger sizes of CAs have been proposed to address this issue. With
molecular weight higher than 20 kda, permeability and retention in leaky vasculature
is enhanced, allowing better visualization of additional pathologies such as cancer
or vascular diseases. Furthermore, as described in section “Complexation chemistry of
gadolinium: a compromise between stability and relaxivity” of this chapter, higher
molecular weights induce generally higher relaxivity. Combined with the high pay-
load of Gd 3+ they can carry, they reduce the necessary dose of CA for image acqui-
sition. With diameter greater than 1 nm, these agents have reduced renal excretion,
allowing prolonged retention time as compared to the small approved chelate, which
then increases the need to address stability and retention of chelated Gd 3+ . polymers,
dendrimers, liposomes, and other nanoparticles have the advantage to be modifiable
to provide them specific targeting properties or distribution. The second part of this
chapter describes their preparation and characteristics as well as their potential appli-
cations in MRI.
8.3 GadolInIuM-Based nanopaRtIcles
8.3.1 linear polymers
8.3.1.1 Enhanced Relaxivity and Circulation Time The use of polymers has
rapidly appeared as a popular strategy to produce new CAs with high relaxivities and
prolonged circulation. Commercially available poly-l-lysine (p-Lys) or polyethylene
glycol (peG) can be obtained in a wide variety of molecular weights and are easily
chemically modified to modulate their biodistribution properties. Furthermore, a
high number of Gd 3+ chelates can be introduced to get high molecular relaxivity.
p-Lys have been the most widely explored linear polymers. They are easily
conjugated to dTpA or dOTA on the ε-amino group of the lateral chain of the lysines,
resulting in the introduction of a high number of Gd 3+ per molecule [39, 40]
(Chart 8.3). It was shown that relaxivity was improved as compared to the mono Gd 3+
chelate; however, relaxivity was not influenced significantly by the size of the
polymer [39]. As shown in animal studies [41, 42], p-Lys-based agents are predomi-
nantly excreted through the kidneys and exhibit prolonged circulation time as the
molecular weight increases, leading to constant enhancement in tissue signal over a
1 h period [43]. These characteristics make them interesting as blood pool agents.
Gd 3+ -dTpA-p-Lys was used in MR angiography in rabbits to monitor blood flow in
the extremities, allowing visualization of vessels smaller than 1 mm [44], or to visualize
lung lesions exhibiting abnormal blood flow [45-47]. Furthermore, Gd 3+ -dTpA-p-Lys
was shown to accumulate in tumors and produced a contrast enhancement of approx-
imately 300% lasting for several days in rat [48].
peGs have been studied for their low immunogenicity and long circulation
time. dresser et al . compared dTpA-peG of various sizes for visualization of