MRI with Gadolinium-Based Nanoparticles - Nanotechnology for Biomedical Imaging and Diagnostics - page 232

ammonia core by an ethylenediamine leads to longer blood retention and slower
renal uptake [95]. ultimately, circulation and excretion properties can be modulated
by modification in the surface of dendrimers. examples are peGylation of the surface
of pAMAM-dTpA dendrimers, which leads to longer blood clearance and faster
excretion with lower liver and kidney accumulation [96, 97]. Also, faster excretion
was obtained by coinjection of lysine [98], by the use of a lysine-based dendrimer
[99], or by administration of an avidin chase after injection of the dendrimer previ-
ously modified with biotin on its surface [100]. Interestingly, it was demonstrated
that the nature of the ligand could be chosen to optimize elimination rate of the
dendrimers as shown by nwe et al . who compared dTpA with dOTA on two identical
G4 pAMAM dendrimers and concluded that dOTA was more suitable ( T 1/2 = 16 min
for dOTA vs. 29 min for dTpA) [101]. Alternatively, cleavable cystamine linkers
were proposed to conjugate the Gd 3+ complex to the dendrimer in order to accelerate
the elimination of the metallic complex [102, 103]. These studies are particularly
important to lower the potential toxicity of these long-lasting particles in the body in
the perspective of clinical uses.
Selective and Targeted Dendrimers The first attempts to improve selectivity of
dendrimers were proposed with the use of an antibody with tumor targeting prop-
erties. The first study reported a G2 pAMAM dendrimer coupled to monoclonal
antibody (mAb) 2e4 that was efficiently loaded without loss of immunoreactivity
[104]. similarly, OsT7, a murine monoclonal IgG1, conjugated to a G4 pAMAM-
dTpA dendrimer exhibited no loss of immunoreactivity. Biodistribution studies
indicated accumulation in the tumor site and better blood clearance than the anti-
body labeled directly with dTpA without the dendrimer. Recently, nwe et al .
reported the preparation of G4 and G5 dendrimers with a cystamine core that, after
cleavage of the disulfide bond, were coupled as half dendrimers to F(ab') 2 frag-
ments of panitumumab premodified with a maleimide linker [105]. The relaxivity
was higher than the monocomplex alone but lower than the dendrimer without anti-
body. even though the studies cited previously reported promising results on the
relaxivity and on the in vitro and in vivo behavior of these dendrimer-antibody sys-
tems, no data are available yet on their ability to effectively enhance the visualiza-
tion of the targeted tumors. Alternatively, the (strept)avidin-biotin system has been
employed in pretargeting strategies similarly to that used for the site-specific
delivery of radionuclide developed by paganelli [106]. A three-step strategy was
proposed by Zhu et al . consisting in injecting a biotinylated antibody (trastuzumab),
followed by avidin that targets biotin on the antibody. In the last step, the dendrimer
with chelated Gd 3+ and also conjugated to biotin is injected and accumulates on the
antibody-avidin adduct [107]. Although accumulation was observed in tumors, no
significant improvement of the MR contrast was observed, probably because of a
saturation of the binding sites on the avidin (four binding sites available per avidin)
by the biotinylated antibody. This system was also used in a two-step approach by
sano et al . who injected the antibody conjugated to streptavidin first , followed
by the biotinylated Gd 3+ dendrimer 3 days later. Good relaxivity was measured,
and signal enhancement of FM3A tumors in mice was clearly observed [108].