MRI with Gadolinium-Based Nanoparticles - Nanotechnology for Biomedical Imaging and Diagnostics - page 227

nodes and liver. When conjugated to Gd 3+ -dTpA, it exhibited enhanced vasculature
visualization and was excreted primarily through the kidneys [71]. Many results have
been published on carbohydrate-based CAs, and the reader is referred to the recent
review by Villaraza [72] for more information about their preparation and applications.

8.3.2 dendrimers

8.3.2.1 Preparation and Characteristics dendrimers are polymers built from a
small polyfunctional core by repeated iterative branching reactions, each reaction
accounting for a generation (denoted G1 for the first generation, G2 for the second
one, and so on through the series—see Villaraza [72] for a detailed description on
nomenclature of dendrimers in this application). The first example of such an itera-
tive synthetic procedure, named cascade synthesis by the authors, was described in
1978 by Buhleier et al . [73]. synthesis strategies permit high modulation in dendrimer
size, shape, and functionalities, and their potential medical applications have increased
exponentially over the last three decades [74]. Their use as a platform for Gd 3+ hosting
for MRI CA development was first suggested in 1994 by Wiener et al . [75], allowing
the introduction of up to 180 gadolinium ions into a single molecule with production
of high relaxivity per particle (5800 mM −1 s −1 as compared to 5.4 mM −1 s −1 for the
monomeric Gd 3+ -dTpA at 20 MHz and 20°C).
The processes used in dendrimer syntheses involve simple reagents, efficient
reactions, and relatively easy purification allowing the production of accurately
size-controlled particles with very narrow polydispersities (polydispersity index (pI)
generally below 1.01) and a high number of functional group sites allowing, for
instance, introduction of a high number of Gd 3+ chelates in the case of MRI applica-
tions. Two main strategies based on two different expansion methods are used for
their preparation. The first strategy to be described was the divergent approach
consisting in expanding the branches from a central core in a cascade-like manner
(Fig. 8.3). starting from a mono- or a diamine core, each generation was produced by
Michael addition of acrylonitrile, subsequent reduction of the nitrile producing reac-
tive amines for a new iteration that in turn gave birth to a new generation [73]. similar
expansion of polyalcohol to produce molecules named arborols was described by
newkome [76]. At the same time, the first three-dimensional dendrimer was described
by Tomalia et al . [77]. exhibiting a radial symmetry, these macromolecules called
starburst dendrimers were produced from an ammonia or an ethylenediamine core,
each generation being produced via Michael addition of an acrylate ester followed by
alkylation with alkylene diamine. Consequently to this three-dimensional growth,
the number of terminal amines increased exponentially with each generation, 256
terminal amines being obtained at the sixth generation with an ethylenediamine core.
These dendrimers are named poly(amidodiamine), or pAMAMs, are commercially
available, and are also the most studied dendrimers as platform for development of
CAs in MRI. Alternatively, poly(propylene imine) (ppI) dendrimers with a diamino-
butane core have been synthesized with a pI of 1.002 for the first five generations
[78-80]. In the second strategy called convergent approach, the synthesis is started
from the periphery to end at the core (Fig. 8.3). In this way, the number of reaction