MRI with Gadolinium-Based Nanoparticles - Nanotechnology for Biomedical Imaging and Diagnostics - page 225

8.3.1.2 Targeted and Functionalized Polymers Biodistribution properties of
Gd 3+ polymers for visualization of specific area can be modulated by functionaliza-
tion or by conjugation to targeting moieties. Albumin received considerable attention
in applications to improve blood retention and relaxivity of many compounds,
including polymers. Indeed, the first studies involving the monomeric Gd 3+ -dTpA
conjugated to albumin highlighted a longer blood retention time and a higher relaxivity
than the single Gd 3+ -dTpA due to the slow tumbling rate of the resulting macro-
molecule [56]. In the same way, various polymers such as polylysine have been
conjugated to albumin to enhance their blood pool behavior [40]. Although no details
were given on the in vivo behavior, pashkunova-Martic et al . studied the relaxivity of
several copolymers of dTpA bound to albumin and to lectin, a protein that binds
specifically to endothelial and epithelial cells [57]. Antibodies directed against
specific cancer cells have also been studied as polymer carriers but with limited
success: p-Lys has been particularly studied, allowing the introduction of 30-65 Gd 3+
per antibody [58, 59], but high loss of immunoreactivity was observed along with
poor clearance and accumulation in nonspecific tissues limiting their use.
Alternatively, it was shown in several studies that selection of the copolymer and
of the nature of the polymer bond could influence the biodistribution. Yan et al .
studied several polyaspartamides with Gd 3+ -dTpA complexes containing sulfadia-
zine groups and selected the best of the series as a CA specific to hepatoma in mouse
[60]. For long-term cell tracking, Tachibana et al . proposed the use of poly(vinyl
alcohol) copolymerized with Gd 3+ -dOTA [61]. The resulting compound exhibited high
hydrosolubility with long retention inside living cells in contrast to rapid clearance
from blood [61]. N -(2-hydroxypropyl)methacrylamide copolymerized with manno-
samine and conjugated to Gd 3+ -dOTA was used for the targeting and imaging of
activated macrophages [62] or breast cancer cells when conjugated to RGdfK, a
peptide with specificity to α v β 3 receptors [63].
novel strategies currently under investigation are the development of “activatable” Gd
polymers exhibiting high relaxivity but only under specific conditions of biological
interest. For instance, pH-sensitive agents have been studied to map changes in pH that is
generally associated to various pathologies such as tumors, strokes, and infections. For
instance, a Gd 3+ -dO3A-polyornitine was shown to exhibit a linearly increasing relaxivity
from 23 mM −1 s −1 at pH 4 to 32 mM −1 s −1 at pH 8 [64]. Alternatively, a CA sensitive to an
enzyme was proposed by Bogdanov et al . In this strategy called MR signal amplification
(MRamp), a Gd-dTpA chelate linked to a catechol derivative is administered in the
monomeric form. Then, it polymerizes in the presence of exogenous horseradish peroxi-
dase (HRp) to generate the polymer in situ exhibiting enhanced relaxivity. This method
was shown to be sensitive enough to detect nanomolar amounts of peroxidase in cell
culture and allowed visualization of carcinoma in mouse when HRp conjugated to a
tumor-specific antibody was injected prior to administration of the CA [65].
8.3.1.3 Biodegradable Polymers Many encouraging results were obtained with
polymers that exhibit higher relaxivities and visualization of new targets as com-
pared to the currently approved CAs. However, their introduction into the clinic has
been hampered by the slow excretion of these high-molecular-weight compounds