MRI with Gadolinium-Based Nanoparticles - Nanotechnology for Biomedical Imaging and Diagnostics - page 239

higher than Gd 3+ -dTpA, with better results when the concentration was decreased
[174]. However, it was shown in aqueous media that these nanoparticles tend to
agglomerate with subsequent decrease in the relaxivity [175]. nonetheless, improved
contrast was obtained in the visualization of brain tumors [176] or in the detection of
glioblastoma cancer cells in vivo [177]. These particles can furthermore be modified
on their surface by incorporation of various functional groups such as organic acids
[178] or peG [179], suggesting potential control over stability and biodistribution.
Alternatively, the Gd 2 O 3 core has been incorporated in polysiloxane shells allowing
also derivatization on the surface for the design of targeted or multimodal probes
[180, 181]. Apoferritin was also described by sanchez et al . as a potential sequestering
agent for Gd 2 O 3 with relaxivities 10 to 25 folds higher than Gd 3+ -dTpA, depending on
the field strength [182].

8.4 alteRnatIves to GadolInIuM FoR MRI

The second most used metal for MRI is iron in superparamagnetic iron oxides to
produce T 2 or T 2 *-weighted pictures. Their preparation and use have already been
described in Chapter 2. The last part of this chapter focuses on alternative metal ions
to Gd 3+ as T 1 CAs and also on the recently discovered chemical exchange saturation
transfer (CesT) effect.

8.4.1 Manganese and other alternative Metals

Gd 3+ is by far the most studied metal ion as T 1 CA because of its ideal characteristics
as described in section 8.2. However, the use of Gd 3+ -based CAs has recently been
linked to the apparition of serious side effects for patients with impaired renal
function named nephrogenic systemic fibrosis (nsF). This pathology is character-
ized by thickening and hardening of the skin of the extremities and affects also
numerous organ systems such as the liver, lungs, muscles, and heart [183]. More than
90% of the nsF cases reported have appeared after administration of a Gd 3+ -based
CA. Also, nsF is much more frequent when acyclic complex is used as compared to
the more stable macrocyclic ligands, suggesting an effect of the free Gd 3+ released
from the complex. Another concern is the increasing amount of gadolinium in waste-
water effluents as a result of the increasing clinical use of Gd 3+ -based CAs [184].
For these reasons, metal ions such as Mn 2+ , Mn 3+ , Fe 3+ , and Cu 2+ have received an
increasing interest in recent years, since they are naturally present in the organism
and their behavior in biological systems is well documented.
Although not as effective as Gd 3+ , Mn 2+ exhibits interesting properties as T 1 CA,
thanks to its five unpaired electrons. Besides, Mn 2+ in the MnCl 2 form was among the
very first species to be studied as a CA for MRI [8]. However, although Mn 2+ is naturally
present in the organism at low concentration, it is toxic at relatively low doses when
injected intravenously (Ld 50 = 0.3 mmol kg −1 in mice). But it is much less toxic when
administered orally (13.6 mmol kg −1 ), and LumenHance ® , an oral preparation of MnCl 2 ,
is used routinely in clinical exams for visualization of the gastrointestinal system. For