Biomedical Engineering Reference
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(a)
(b)
A
BCDEF
Relaxivity per
particle
(mM
-1
s
-1
)
Ionic relaxivity
(mM
-1
s
-1
)
Magnevist or unlabeled MS2
1
Size
(nm)
MS2(Gd-DTPA )
514
2
Contrast agent
1.5 T
9.4 T
1.5 T
9.4 T
MS2(Gd-DTPA)
360
(FITC)
55
3
Magnevist
ND
26.9
5.2
5.2
None
5.2
None
5.2
None
MS2 soaked in Magnevist
4
MS2 (unlabeled)
None
Concentration
MS2 soaked with Magnevist
MS2(Gd-DTPA-ITC)
514
MS2(Gd-DTPA-ITC)
360
-
(FITC)
55
28.4
28.9
29.1
None
14.0
16.9
None
3.4
4.3
None
7200
6100
None
1782
1525
500
µM
250
µM
125
µM
63
µM
32
µM
383
µM
1
Concentration
of contrast agent
(magnevist or
Viral nanoparticle)
580
nM
290
nM
145
nM
58
nM
29
nM
15
nM
2
610
nM
305
nM
153
nM
61
nM
31
nM
15
nM
3
383
nM
192
nM
96
nM
38
nM
19
nM
10
nM
4
A
BCDEF
figure 14.6
(a)
T
1
-weighted image of MS2-based contrast agents taken with a 1.5 T
clinical scanner. row 1, Magnevist as a positive control (A-e) and unlabeled MS2 as a negative
control (F). row 2, MS2(Gd-DTpA). row 3, MS2(Gd-DTpA)(FiTC). row 4, MS2 soaked in
Magnevist without covalent attachment. (b) Measurement of relaxivities. ND, not determined.
None, no enhancement of relaxivity over buffer. (reprinted with permission from ref. [102].
© American Chemical Society.)
groups on either surface followed by oxime condensation to attach approximately
90 bis(hydroxypyridonate)terephthalamide (bis(hopo)-TAM) ligands. These
ligands were chosen for gadolinium chelation because contrast agents based on
hopo have been shown to have three-fold greater relaxivities compared to com-
mercially available agents. it was found that internally modified MS2 conjugates
had higher relaxivities than externally modified capsids, with relaxivities of
41.6 mM
−1
s
−1
per Gd
3+
ion or 3900 mM
−1
s
−1
per particle compared to 30.7 mM
−1
s
−1
per ion and 2500 mM
−1
s
−1
per particle at 30 Mhz. it was also found that internally
functionalized particles was more soluble and had greater capsid stability [103].
Continuation of this work explored the parameters that affect relaxivity using
nuclear magnetic resonance dispersion (NMrD). it was demonstrated that the
higher relaxivity of the internally modified capsids was the result of easy accessi-
bility of water through diffusion to the interior surface and the rigidity of the aro-
matic tyrosine linkers compared to the flexible lysines [104]. These results are
highly encouraging, as internal attachment would diminish the potential interaction
of gadolinium
in vivo
as well as allow the possibility of tissue-specific imaging
through modification of exterior groups with targeting ligands.
For the intelligent design of more advanced Mri contrast agents, the effect
of linker rigidity on relaxivity was further explored. hopo-based gadolinium
ligands were attached to genetically introduced cysteine residues on the interior of
MS2 particles using flexible linear and rigid cyclohexyl linkers. The MS2 cysteine
mutant was chosen due to a two-fold increase in bioconjugation efficiency over the
previously used tyrosine residues. in addition, two enantiomers of the rigid
trans
-
1,2-cyclohexyldiamine linker (
S
,
S
and
R
,
R
) were tested to investigate whether a
difference in relaxivity would result from interaction with the chiral capsid. The
design concept was confirmed, with some of the highest relaxivities reported for
Gd
3+
complexes observed. MS2-hopo-
S
,
S
had an ionic relaxivity of 41.2 mM
−1
s
−1
at 60 Mhz or 7416 mM
−1
s
−1
per particle, which was greater than that found for
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