Biomedical Engineering Reference
In-Depth Information
O
O
H
N
H
N
O
O
HN
n
n
O
-
O
N
m
O
HN
H
N
H
N
HN
O
Gd
3+
N
N
O
O
O
-
O
N
HN
O
-
O
N
-
O
m
N
N
O
Gd
3+
O
-
-
O
Gd
3+
O
-
O
O
O
-
O
O
-
O
N
N
n
O
O
O
O
O
-
O
O
-
O
l
O
O
Gd
3+
-DTPA-Poly-
L
-lysine
Gd
3+
-DTPA-PEG
Gd
3+
-DTPA-PEG-poly-
L
-lysine
chaRt 8.3
polymers discussed in the text.
tumors in rabbits. They were synthesized by reacting dTpA dianhydride with α,ω-
diaminopolyethylene glycols to yield polymers ranging from approximately 11 to
83 kda incorporating ranges of 6-7 up to 35-36 Gd
3+
-dTpA chelates (Chart 8.3).
For molecular weights lower than 20 kda, no significant differences were observed
as compared with the monomer Gd
3+
-dTpA; however, longer circulation times with
better and faster tumor contrast enhancements were observed above 20 kda with the
best results being obtained for the 21.3 kda polymer [49]. peGs have especially been
shown to be useful in combination with other polymers to improve their solubility
and immunogenicity. peG covalently bound to p-Lys (Chart 8.3) was proposed as
blood pool agent [50]. This copolymer exhibited a 14 h blood half-life and a constant
vascular enhancement for 2 h in rats. The relaxivity was also improved due to the
higher rigidity of the polymer and possible involvement of the peG units in the com-
plexation of Gd
3+
. With necessary dose to obtain contrasted images being 10 fold
lower than the clinically used Gd-dTpA and with longer-lasting contrast, this agent
was expected to be useful for whole-body, central nervous system, or peripheral MR
angiography. However, the very long residence time of this copolymer in the body
(half-life = 88 h) and a lack of knowledge on the resulting toxicity and total clearance
are limitations of this system.
A wide variety of other linear polymers have been studied such as polyaspartate
with up to 40 Gd
3+
per molecule [51], dTpA dianhydride copolymerized with
various monomers such as tartaric acid leading to macromolecules with high
hydrophilicity [52], or alkyldiamine-based polymers exhibiting a high rigidity result-
ing from hydrophobic interaction [53]. Alternatively to dTpA, a HOpO-based
polymer with remarkable molecular relaxivity (111 mM
−1
s
−1
at 60 MHz and 22°C)
was produced via ring-opening metathesis [54]. In an interesting study by Lad and
coworkers, the influence of several properties in the design of a good blood pool
agent such as the molecular weight, relaxivity, metal content, viscosity, and chelate
stability was evaluated. The best results were obtained with a dOTA dendrimer
that was the result of the incorporation of optimized features, that is, high rigidity,
low viscosity, high number of Gd
3+
chelate, and high stability provided by the
dOTA. These combined characteristics contributed to a long blood half-life and a
high relaxivity [55].
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