MRI with Gadolinium-Based Nanoparticles - Nanotechnology for Biomedical Imaging and Diagnostics - page 241

relaxation, but instead reduces the magnetization of the water signal with limited effect
on the longitudinal relaxation rate. This new technique is expected to address some of
the drawbacks and limitations of the classical MRI technique, namely, (i) the necessity
of a precontrast image before administration of the CA; (ii) the impossibility to turn off
the contrast after administration of the CA and the fact that its elimination from the body
must be complete before acquisition of a new image or administration of another CA;
(iii) large CA doses are still required; (iv) environment-responsive CAs (such as enzymes,
pH, or temperature) have been developed, but because the concentration of the CA
in vivo is usually unknown, it makes difficult to quantify the environmental parameter
of interest; and (v) only one target per exam can be detected with targeted CA.
The CesT effect was first applied in 2000 by Ward et al . [191]. In a typical CesT
contrasted MRI experiment, the exchangeable protons of the CA are saturated by
a continuous frequency-selective RF saturation pulse. The exchange of protons
between the CA and water from the bulk results in a decrease in the intensity of the
bulk signal along with the rise of a signal that differs in frequency from the bulk (this
difference, named chemical shift, is denoted Δ ω and expressed in Hz or in ppm). The
physical principles and use of the CesT effect in MRI are described in detail in a
recent review by Hancu et al . [192].
Interestingly, this technique is sensitive enough to make use of endogenous mole-
cules bearing exchangeable protons (such as in -OH or -nH 2 functions in glucose
derivatives or proteins) to image their own presence or environmental factors related
to them. For instance, the CesT effect with endogenous CA has been used to detect
pH changes during ischemia in rat brain through the exchangeable amide proton of
cellular proteins and peptides [193] or to measure the concentration of glycosamino-
glycans (a polysaccharide bearing a high number of -OH) in cartilages and other
tissues [194]. The advantage of this technique is that it can be completely noninva-
sive. However, CA of particular interest such as sugars, amino acids, or nucleotides
can also be administered for specific applications. Thus, macromolecular agents such
as polymers bearing a high number of exchangeable protons are of great interest
[192]. The CAs cited previously are diamagnetic and are denoted dIACesT agents.
They offer many advantages such as being noninvasive for the endogenous ones or
biocompatible for the exogenous ones. However, the small chemical shift they induce
can sometimes render difficult detect ion of the CesT signal. That is why pARACesT
agents incorporating paramagnetic ions and able to induce higher Δ ω are also under
investigation.
While Gd 3+ exhibits the best characteristics as a T 1 -shortening agent, other lantha-
nides are preferred as pARACesT agents because of their better hyperfine shifting
constant ( C j ). C j is one of the parameters that influence the Δ ω obtained, and higher
C j are required for a higher Δ ω . Thus, complexes of eu 3+ , Yb 3+ , or Tm 3+ have been
preferred. Another parameter that differs from T 1 -shortening agents is that slow water
exchange rates are beneficial in the case of pARACesT agents. several pARACesT
agents have been investigated, and they could be used to monitor physiological
phenomenon. For instance, eu-d2BAM-2BipyAm is a eu 3+ complex that exhibits
slow water exchange. But in vitro , in the presence of Zn 2+ , water exchange is accelerated,
which makes this CA “on” in the absence of Zn 2+ and “off” in the presence of Zn 2+ [195].