Metallostar Assemblies Based on Dithiocarbamates for Use as MRI Contrast Agents

Article abstract of DOI:10.1021/acs.inorgchem.0c01318

Two different octadentate gadolinium chelates based on DO3A and DOTAGA chelates (hydration number q = 1) have been used to prepare a series of bi-, tri-, and tetrametallic d-f mixed-metal complexes. The piperazine-based dithiocarbamate linker ensures that

Full text of DOI:10.1021/acs.inorgchem.0c01318

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Article
Metallostar Assemblies Based on Dithiocarbamates for Use as MRI
Contrast Agents
Hannah L. Perry,† Il-Chul Yoon,† Nicolas G. Chabloz, Susannah Molisso, Graeme J. Stasiuk,
́
Rene M. Botnar, and James D. E. T. Wilton-Ely*
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ABSTRACT: Two different octadentate gadolinium chelates
based on DO3A and DOTAGA chelates (hydration number q =
1) have been used to prepare a series of bi-, tri-, and tetrametallic
d−f mixed-metal complexes. The piperazine-based dithiocarba-
mate linker ensures that rotation of the gadolinium chelates is
restricted, leading to enhanced relaxivity (r1) values, which increase
with the overall mass and number of gadolinium units. The r1 value
(at 10 MHz, 25 °C) per gadolinium unit rises from 5.0 mM−1 s−1
for the Gd-DO3A-NH2 monogadolinium chelate to 9.2 mM−1 s−1
in a trigadolinium complex with a ruthenium(III) core. Using a 1.5
T clinical scanner operating at 63.87 MHz (25 °C), an 86%
increase in the relaxivity per gadolinium unit is observed for this
multimetallic compound compared to clinically approved Dot-
arem. The gadolinium complexes based on the DOTAGA chelate also performed well at 63.87 MHz, with a relaxivity value of 9.5
mM−1 s−1 per gadolinium unit being observed for the trigadolinium d−f mixed-metal complex with a ruthenium(III) core. The
versatility of dithiocarbamate coordination chemistry thus provides access to a wide range of d−f hybrids with potential for use as
high-performance MRI contrast agents.
INTRODUCTION
■
Magnetic resonance imaging (MRI) is a noninvasive medical
imaging technique that provides detailed anatomical images
with the highest spatial resolution of all of the nonionizing and
noninvasive imaging modalities.1 Different tissues are charac-
terized by MRI-specific relaxation parameters (longitudinal
relaxation time, T1; transverse relaxation time, T2) and
differing proton densities. The intrinsic soft tissue contrast
observed enables detailed anatomical images to be acquired
using MRI. However, because of the poor contrast often
Figure 1. Two commonly used, clinically approved gadolinium
contrast agents, which both have a hydration number (q) of 1.
observed between different tissue types (such as healthy and
diseased), contrast agents2 are often employed in order to alter
allowing a single coordination site for a water molecule (q = 1).
and accelerate the relaxation of water protons in healthy and
The release of gadolinium cations into the body leads to the
diseased tissue, thereby improving the image detail and
formation of salts with endogenous anions, such as phosphate
or carbonate. Upon entering tissues, these species stimulate an
contrast. This is achieved by the presence of an exogenous
paramagnetic species (e.g., trivalent gadolinium), which affects
inflammatory response, which results in scarring of the tissue.
both T1 recovery and T2 decay due to its strong local magnetic
This nephrogenic systemic fibrosis (NSF) can lead to severe
moment. Higher relaxivity values (in mM−1 s−1) correlate with
better contrast enhancement.2 The contrast agents currently
Received: May 4, 2020
used in a clinical setting are almost all based on paramagnetic
(4f7) trivalent gadolinium ions. Examples of these monogado-
linium compounds are Dotarem and Primovist (Figure 1),
which are both extracellular probes with a nonspecific
biodistribution. Their design features an octadentate chelate,
which prevents loss of the toxic gadolinium ion, while still
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Scheme 1. Synthesis of Gd-DO3A-DTC and Gd-DOTAGA-DTC
renal impairment in patients and has led to restrictions in the
use of contrast agents with acyclic chelates.2
oxidation states (both high and low) indicates the vast
potential that dithiocarbamates with additional functionality
could promise.9,10
Interactions between the paramagnet and coordinated water
as well as the surrounding water molecules lead to an
improvement in the relaxation rates of these water protons,
enhancing the image contrast and signal-to-noise perform-
ance.2 Due to the inherent low sensitivity of MRI, very high
concentrations (typically 0.1 mmol/kg patient weight) of
contrast agent are required, and so efforts have been made to
increase the relaxivity performance of each Gd3+ ion. This
could also reduce the amount of contrast agent that needs to
be administered.
In 2014, we reported for the first time how dithiocarbamates
could be used to incorporate gadolinium units into multi-
metallic assemblies or onto the surface of gold nanoparticles.11
These materials showed promising relaxivity behavior;
however, the hexacoordinate coordination of the Gd3+ ion (q
= 3) raised concerns over the potential loss of this toxic ion
under physiological conditions. This led to new designs based
on an octadentate coordination environment, such as that
found in Dotarem (Figure 1).12 The present work describes
how these improved and highly stable gadolinium chelates can
be employed in the generation of multimetallic compounds
based on both d- and f-block metals, along with an assessment
of their performance in MRI contrast enhancement.
The attachment of Gd3+ chelates to larger assemblies such as
polymers and nanoparticles has been successfully used to
dramatically increase the relaxivity per Gd3+ ion. This can be
explained in terms of the rotational correlation time, which
increases when the assembly rotates slowly, leading to
enhanced relaxation rates. In addition, the degree to which
the relaxation of water protons changes is due to the
multimeric effect, which stems from the increased, localized
RESULTS AND DISCUSSION
■
Two polydentate chelates designed for the immobilization of
gadolinium on the surface of gold nanoparticles,13,14 Gd-
DO3A-DTC and Gd-DOTAGA-DTC, were used to provide
gadolinium chelates with either an overall neutral or anionic
environment for the gadolinium ion. It was expected that
charge on this part of the molecule would have a significant
impact on the interaction of water with the paramagnetic ion
and hence modify the relaxivity observed.
contrast agent concentration.2
3
Pioneering work by Toth, Helm,4 Parac-Vogt,5 and
́
Desreux6 has focused on the synthesis of molecular multi-
metallic gadolinium compounds, with either an organic or
metal-based core. These assemblies have demonstrated
impressive relaxivity in many cases. However, one pitfall
common to all polygadolinium approaches is the difficulty in
eliminating internal rotation of the individual gadolinium
chelates, which undermines the potential for extremely high
relaxivity enhancement.
The Gd-DO3A-NH2 and Gd-DOTAGA-NH2 precursors
were prepared by a straightforward multistep route starting
from commercially available cyclen, as reported previously
(Scheme 1).13,14 The corresponding dithiocarbamates, Gd-
DO3A-DTC and Gd-DOTAGA-DTC, were prepared and
isolated shortly before use as the ammonium precursors are
more suitable for long-term storage than these reactive species.
Synthesis of Multimetallic d−f Hybrids. The benefit of
using reliable linkers, such as pyridyl donors, to form
multimetallic d−f hybrids for use in imaging applications has
been demonstrated by Faulkner and co-workers.15 While less
frequently employed than nitrogen-based donors, the depend-
For over a decade, we have focused on the development of a
wide range of routes to multimetallic compounds,7 with the
8
−
use of dithiocarbamates (R2NCS2 ) being a recurring feature.
This has been driven partly by the ease of formation of
dithiocarbamates from (usually secondary) amines in the
presence of base and carbon disulfide.9 The fact that
dithiocarbamate compounds are known for their ability to
coordinate to all of the transition metals in all common
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Scheme 2. Synthesis of Mono-, Bi-, and Trigadolinium Compounds Based on Ln-DO3A-DTC (Ln = La, Gd)
able reactivity and versatility of dithiocarbamate ligands9 make
them ideally suited to the construction of multimetallic
assemblies.8 Accordingly, the dithiocarbamate Gd-DO3A-
DTC was used to prepare a series of multimeric molecular
gadolinium compounds through the addition of suitable
transition-metal precursors (Scheme 2). In order to enable
characterization by NMR spectroscopy, the lanthanum
analogues of the compounds were also prepared. The synthesis
of La-DO3A-NH2 and La-DO3A-DTC is described in the
Supporting Information.
displayed a resonance at 213.3 ppm for the CS2 carbon
nucleus,9 while the H NMR spectrum showed broadened
1
peaks attributed to the DO3A-piperazine chelate in addition to
aromatic resonances for the phosphine ligand. The IR
spectrum revealed an absorption at 1599 cm−1 (CO stretch)
as well as a feature at 1430 cm−1 attributed to the C−N stretch
and a band at 999 cm−1 assigned as the ν(C−S) absorption of
the dithiocarbamate ligand.9 Along with a molecular ion for [M
− H2O]+ at m/z 1142 in the mass spectrum (matrix-assisted
laser desorption/ionization, positive mode), these data
confirmed the formulation of the product as La-DO3A-
DTC-AuPPh3. The gadolinium analogue was then synthesized
from Gd-DO3A-DTC using the same protocol to yield an off-
white powder, Gd-DO3A-DTC-AuPPh3. IR analysis sup-
ported the preparation of this analogous product with typical
bands for the PPh3 ligand along with absorptions at 1679 cm−1
[νCN)], 1603 cm−1 [ν(CO)], 1396 cm−1 [ν(C−N)], and
994 cm−1 [ν(C−S)]. These features are consistent with the
anisobidentate binding mode for the dithiocarbamate ligand,
which is typical for gold(I) complexes.9
Dithiocarbamate complexes of gold are well-known,9
particularly of gold(I), in which this 1,1′-dithio ligand typically
bonds in an anisobidentate manner. The versatile starting
material, [AuCl(PPh3)], was chosen for reaction with the
lanthanum complex La-DO3A-DTC (Scheme 2). After stirring
at room temperature in the dark for 1 h, the precipitated KCl
salt was removed by filtration and the product was isolated and
analyzed by 31P{1H} NMR spectroscopy. This revealed a shift
of the PPh3 resonance from 33.2 ppm in the starting material
to 37.3 ppm in the product. The 13C{1H} NMR spectrum
C
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a
Scheme 3. Synthesis of Mono-, Di-, and Trigadolinium Compounds Based on Gd-DOTAGA-DTC
a
All countercations are potassium ions.
Compound La-DO3A-DTC was added to nickel nitrate
hydrate, causing a rapid change in color of the solution from
pale-blue to bright yellow. This solution was then stirred for 1
h at room temperature (Scheme 2) to give Ni(La-DO3A-
DTC)2 as a pale-green powder. The solid-state IR spectrum of
Ni(La-DO3A-DTC)2 indicated the presence of the DO3A-
dithiocarbamate ligand with characteristic features at 1671
cm−1 [ν(CN)], 1599 cm−1 [ν(CO)], 1403 cm−1 [ν(C−
N)], and 1003 cm−1 [ν(C−S)]. The corresponding reaction
between Gd-DO3A-DTC and Ni(NO3)2·6H2O followed the
same pathway to afford a pale-green powder, Ni(Gd-DO3A-
DTC)2. The IR spectrum of this compound confirmed the
presence of the dithiocarbamate ligand with absorptions at
values similar to those found for Ni(La-DO3A-DTC)2. Mass
spectrometry was used to further characterize Ni(La-DO3A-
DTC)2 and Ni(Gd-DO3A-DTC)2.
Following the successful preparation of bimetallic monog-
adolinium and trimetallic digadolinium complexes, attention
then turned to the synthesis of tetrametallic trilanthanide
complexes (Scheme 2). Compound La-DO3A-DTC was
added to CoCl2·6H2O, leading to a rapid change in the
solution color from pale pink to dark green. After stirring for 1
h at room temperature and filtration through Celite, all solvent
was removed to afford a dark-green solid, formulated as
Co(La-DO3A-DTC)3. The IR spectrum of this compound
confirmed the presence of the DO3A-dithiocarbamate ligand
with absorptions similar to those found for the other
complexes. The gadolinium analogue Co(Gd-DO3A-DTC)3
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was prepared in the same manner. In common with many
literature examples,9 the reaction of a divalent cobalt precursor
leads to the isolation of a trivalent diamagnetic tris-
(dithiocarbamate) product. Ru(La-DO3A-DTC)3 and Ru-
(Gd-DO3A-DTC)3 were synthesized following a procedure
similar to that used for their cobalt analogues using RuCl3·
3H2O. Formation of these RuLn3 complexes was accompanied
by a color change from black to dark green. IR spectroscopy
and mass spectrometry confirmed the successful synthesis of
the desired tetrametallic trigadolinium complexes. An inves-
tigation of the magnetic properties through both the Evans
NMR method and measurement using a magnetic suscepti-
bility balance led to μeff values between 1.92 and 2.10 μB,
strongly suggesting only one unpaired electron and a low-spin
(t2g)5(eg)0 configuration for the trivalent ruthenium center.
In a similar manner, the dianionic Gd-DOTAGA-DTC
complex was added to various transition-metal salts to form
anionic multimeric gadolinium compounds (Scheme 3). As
expected, the spectroscopic data for these compounds were
found to be similar to those described above. Characterization
details for these compounds can be found in the Supporting
Information.
Macrocyclic chelates with carboxylate arms, such as Gd-
DOTAGA-DTC, often have faster water exchange rates
(contributing to higher relaxivity) than macrocyclic chelates
with amide arms (like Gd-DO3A-DTC).12 The coordination
environment of Gd-DOTAGA-DTC mimics that found in the
leading, clinically used contrast agent, Dotarem, which is
known for its high stability (log KGdL of 25.3).1 This fact
provides reassurance (particularly in the context of NSF) that
the toxic gadolinium(III) ion will not be released under
biological conditions.
Figure 2. NMRD profiles of Dotarem, Gd-DO3A-NH2, and Gd-
DOTAGA-NH2 at 25 and 37 °C.
the relaxivity17,18 due to slow tumbling and a reduction in the
rotational freedom experienced by each individual gadolinium
unit. However, it was anticipated that a particularly
pronounced enhancement would be observed for the materials
prepared in this study. In addition to the increased mass, the
rigidity of the piperazine rings and the multiple-bond character
of the dithiocarbamate and amide bonds also limit rotational
freedom and thus enhance relaxivity. Previous designs based
on an organic or a metal core often allow rotation about the
axis of the tether, and this can have a detrimental effect on the
relaxivity.3−6
Using the Evans method to determine the gadolinium
concentration,19 the relaxivity of Gd-DO3A-DTC-AuPPh3 at
0.01 MHz was found to be 11.3 and 10.3 mM−1 s−1 at 25 and
37 °C, respectively (Figure 3). As the temperature increases,
The synthesis described above resulted in a series of
analogous multimetallic complexes bearing the Gd-DO3A-
DTC and Gd-DOTAGA-DTC units. This allowed their
relaxivity to be evaluated and their potential as MRI contrast
agents to be determined.
Relaxivity Measurements. Using a 0.01−10 MHz fast
field-cycling NMR relaxometer (0.25 T SMARtracer, Stelar),
the relaxivity performance of the polygadolinium compounds
was established and compared to Gd-DO3A-NH2 and Gd-
DOTAGA-NH2 (chosen in preference to the corresponding
dithiocarbamates because of their greater stability) as well as
the clinically approved standard, Dotarem. The data point at
63.87 MHz was acquired using a 1.5 T clinical MRI scanner,
which operates only at room temperature (25 °C).
Fluorescence lifetime measurements reported in previous
studies13,14 for the europium analogues Eu-DO3A-NH2 and
Eu-DOTAGA-NH2 confirmed the expected hydration value of
q = 1 for the octadentate chelates. Both Gd-DO3A-NH2 and
Gd-DOTAGA-NH2 were found to possess a higher relaxivity
than Dotarem, likely because of the slightly higher molecular
mass, which is known to enhance the relaxivity.2 The nuclear
magnetic relaxation dispersion (NMRD) profiles of these
chelates are shown in Figure 2. The presence of an amide arm,
such as that found in Gd-DO3A-NH2, has been reported to
have a potentially negative impact on the relaxivity;16 however,
this does not seem to be a significant factor in the performance
of the chelate design reported here.
Figure 3. NMRD profiles of Gd-DO3A-DTC-AuPPh3 at 25 and 37
°C.
the rate of internal rotation increases, and this results in a
reduction in the relaxivity of the complex. Although the
relaxivity maintained a constant value at Larmor frequencies
between 0.01 and 1 MHz, at Larmor frequencies beyond 1
MHz, the relaxivity of the complex decreased with increasing
frequency, a typical effect seen in small-molecule contrast
agents.20 The relaxivity of Gd-DO3A-DTC-AuPPh3 at 10
MHz was found to be 6.4 and 5.6 mM−1 s−1 at 25 and 37 °C,
respectively.
This represents a modest improvement in the r1 value of Gd-
DO3A-NH2 at 10 MHz (5.2 mM−1 s−1 at 25 °C and 4.5 mM−1
s−1 at 37 °C), and this enhancement can be attributed to the
additional mass provided by the AuPPh3 unit slowing the
rotational correlation time. The trimetallic (digadolinium)
complex, Ni(Gd-DO3A-DTC)2, was found to display r1 values
(at 10 MHz) per Gd3+ ion of 6.1 and 5.5 mM−1 s−1 at 25 and
The relaxivity of the various multimetallic assemblies was
also measured at 25 and 37 °C in water, and the NMRD
profiles were determined. It is known that an increase in mass
of the gadolinium-containing unit results in an enhancement of
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37 °C, respectively (Figure 4). Again, this represents an
increase over the relaxivity of Gd-DO3A-NH2 and is a value
correlation time is no longer a limiting factor. Figure 5 also
shows an increase in relaxivity as the frequency approaches 10
MHz, which is a trend typical of macromolecular struc-
tures.20,21 With three Gd3+ ions in the same molecular
assembly, the high payload of gadolinium ions per complex
gives an overall relaxivity for Co(Gd-DO3A-DTC)3 of 31.4
mM−1 s−1 (25 °C) and 29.0 mM−1 s−1 (37 °C). This is almost
6 times the r1 value of Gd-DO3A-NH2 and is comparable to
the trigadolinium species synthesized by Desreux and co-
workers.6
A second trigadolinium complex based on Gd-DO3A-DTC
was prepared using a ruthenium core, Ru(Gd-DO3A-DTC)3.
It performed similarly to Co(Gd-DO3A-DTC)3, with
relaxivity values at 10 MHz of 9.2 mM−1 s−1 and 8.5 mM−1
s−1 at 25 and 37 °C, respectively (Figure 6). These values
Figure 4. Relaxivity values per Gd3+ ion for Ni(Gd-DO3A-DTC)2 at
25 and 37 °C.
similar to that measured for Gd-DO3A-DTC-AuPPh3. This is
not surprising given their similar masses. The overall relaxivity
(at 10 MHz) of Ni(Gd-DO3A-DTC)2 was found to be 12.2
and 10.9 mM−1 s−1 at 25 and 37 °C, demonstrating the
benefits of an increased gadolinium payload.
NMRD studies performed on Co(Gd-DO3A-DTC)3
revealed this trigadolinium compound to display relaxivity
values per gadolinium ion (at 10 MHz) of 10.5 mM−1 s−1 (25
°C) and 9.7 mM−1 s−1 (37 °C) (Figure 5). This is almost
double the value obtained for monometallic Gd-DO3A-NH2
and also a significant improvement with respect to the
digadolinium complex Ni(Gd-DO3A-DTC)2.
Figure 6. Relaxivity values per Gd3+ ion for Ru(Gd-DO3A-DTC)3 at
25 and 37 °C.
increase to 27.6 and 25.6 mM−1 s−1 when considering the
overall relaxivity of the trigadolinium complex. The same trend
in relaxivity, with an "upswing" between 7 and 10 MHz, was
observed with Ru(Gd-DO3A-DTC)3, just as it had been with
Co(Gd-DO3A-DTC)3.
A comparison of the complexes in this study based on Gd-
DO3A-DTC at 25 °C is provided in Figure 7. The DOTAGA-
based complexes displayed trends in relaxivity similar to those
of their DO3A-based analogues, with the gold and nickel
complexes achieving relaxivity values of 6.9 and 7.2 mM−1 s−1,
respectively, and the cobalt and ruthenium complexes
performing better with relaxivity values of 10.8 and 9.9
mM−1 s−1, respectively (10 MHz, 25 °C). The overall
Figure 5. Relaxivity values per Gd3+ ion for Co(Gd-DO3A-DTC)3 at
25 and 37 °C.
The rigidity of the dithiocarbamate−piperazine linker, due
to multiple-bond character in both the amide and dithiocarba-
mate units, decreases the internal rotation in the complexes,
thus increasing the relaxivity. However, in the mono- and
digadolinium complexes, this boost in relaxivity is limited by
the rapid overall rotation of the complexes. It appears that the
mass of Co(Gd-DO3A-DTC)3 causes the overall rotation to
decrease sufficiently to allow the gains in relaxivity from the
reduced internal motion to be observed. This results in a
reduced temperature dependence; the difference between the
r1 values recorded at 25 and 37 °C is significantly smaller than
that found in the complexes of lower mass. As the molecular
mass increases, this reduction will continue until the increase
in temperature leads to a situation in which the rotational
Figure 7. Summary of the relaxivity per Gd3+ ion of Dotarem, Gd-
DO3A-NH2, Gd-DO3A-DTC-AuPPh3, Ni(Gd-DO3A-DTC)3, Co-
(Gd-DO3A-DTC)3, and Ru(Gd-DO3A-DTC)3 at 25 °C.
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Figure 8. Overall relaxivity values of the DO3A-based (left) and DOTAGA-based (right) metallostars at 25 °C. The central metal ion is
distinguished by color: cobalt, light blue; ruthenium, green; nickel, yellow; gold, gray. Also displayed are Gd-DO3A-NH2 (orange circles), Gd-
DOTAGA-NH2 (orange squares), and Dotarem (dark blue). Note that the traces for Gd-DO3A-NH2 and Dotarem are superimposed.
relaxivities of the DOTAGA-based complexes are displayed in
Figure 8 to emphasize the benefit of incorporating multiple
gadolinium chelates into a single assembly. The individual
NMRD profiles of the DOTAGA-based complexes at 25 and
37 °C can be found in the Supporting Information, where the
same characteristic upswing in the relaxivity that was seen with
Co(Gd-DO3A-DTC)3 and Ru(Gd-DO3A-DTC)3 is repli-
cated for Co(Gd-DOTAGA-DTC)3 and Ru(Gd-DOTAGA-
DTC)3.
affected by the temperature change than the relaxivity of
Dotarem.
The T1-weighted MRI images of the compounds (Figure 9)
were measured using a clinical scanner at 63.87 MHz (1.5 T)
In order to provide a convenient numerical comparison, the
r1 values (10 MHz) at 25 and 37 °C for each complex are
shown in Table 1, both per Gd3+ ion and overall. Upon an
Table 1. Summary of the Relaxivity Values (mM−1 s−1) for
the Multimetallic Complexes Measured at 25 and 37 °C (10
MHz)
25 °C
37 °C
r1
r1
r1 per Gd overall r1 per Gd overall
Figure 9. T1-weighted MRI images (shown in “16 colors”, ImageJ) of
the multimetallic complexes (DO3A-based, above, and DOTAGA-
based, below) and Dotarem at 25 °C and 63.87 MHz. [Gd3+] = 0.2
mM in all cases.
Dotarem
Gd-DO3A-NH2
5.4
5.2
6.4
6.1
10.5
9.2
6.4
6.9
7.2
10.8
9.9
5.4
5.2
6.4
12.2
31.4
27.6
6.4
4.0
4.5
5.6
5.5
9.7
8.5
5.0
5.9
5.9
9.8
9.6
4.0
4.5
5.6
10.9
29.0
25.6
5.0
Gd-DO3A-DTC-AuPPh3
Ni(Gd-DO3A-DTC)2
Co(Gd-DO3A-DTC)3
Ru(Gd-DO3A-DTC)3
Gd-DOTAGA-NH2
Gd-DOTAGA-DTC-AuPPh3
Ni(Gd-DOTAGA-DTC)2
Co(Gd-DOTAGA-DTC)3
Ru(Gd-DOTAGA-DTC)3
and compared to Dotarem. This revealed that, for the same
concentration of Gd3+ ions (0.2 mM), significantly greater
contrast can be achieved per Gd3+ unit in Gd-DO3A-DTC-
AuPPh3 (r1 = 5.0 0.1 mM−1 s−1), Ni(Gd-DO3A-DTC)2 (r1
= 5.7 0.1 mM−1 s−1), Co(Gd-DO3A-DTC)3 (r1 = 7.2 0.1
mM−1 s−1), and Ru(Gd-DO3A-DTC)3 (r1 = 8.2 0.1 mM−1
6.9
5.9
14.4
32.4
29.7
11.9
29.5
28.7
s−1) compared to Dotarem (r1 = 4.4
clinical field strength.
0.2 mM−1 s−1) at
The multimetallic complexes based on the DOTAGA
chelate consistently showed greater relaxivity values than
their equivalent DO3A complexes, demonstrating the
importance of the gadolinium chelate design. This is despite
the short alkyl chain that features in the DOTAGA linker,
which could facilitate undesirable internal flexibility. It appears
that, in this case at least, the additional flexibility generated by
this unsaturated linkage is not sufficiently significant to affect
the relaxivity noticeably. It is also likely that other factors
associated with the DOTAGA chelate, such as an increased
water exchange rate at the metal center, provide a greater
contribution to the observed relaxivity. The relaxivity values
measured for the DOTAGA compounds at a clinical magnetic
increase in the temperature of the Dotarem solution, the
relaxivity decreased from 5.4 to 4.0 mM−1 s−1, which
represented a 26% decrease. The relaxivity of Ru(Gd-
DOTAGA-DTC)3, on the other hand, decreased by only
3%, from 9.9 to 9.6 mM−1 s−1. In fact, all of the multimetallic
complexes were far less affected by the temperature change
than Dotarem. This can be traced to their larger size, compared
to Dotarem, and the internal rigidity present in their structures.
As the temperature was increased, the rotational motion of the
smaller Dotarem chelates increased more significantly than was
the case for the multimetallic complexes. This led to the
relaxivity values for the multimetallic complexes being less
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Figure 10. Uptake of Gd-DOTAGA-DTC-AuPPh3 (A), Ni(Gd-DOTAGA-DTC)2 (B), Co(Gd-DOTAGA-DTC)3 (C), Ru(Gd-DOTAGA-
DTC)3 (D), and Dotarem by HeLa cells following 24 h of incubation.
field strength were particularly impressive, with greater contrast
being achieved by Gd-DOTAGA-DTC-AuPPh3 (r1 = 5.9
toxicity) up to 106 4% for Ni(Gd-DO3A-DTC)2 (showing
no toxicity). In the HeLa cell line, the cell viability at 250 μM
ranged from 88 2% for Ru(Gd-DO3A-DTC)3 to 103 2%
for Co(Gd-DO3A-DTC)3.
0.1 mM−1 s−1), Ni(Gd-DOTAGA-DTC)2 (r1 = 6.2
0.1
mM−1 s−1), Co(Gd-DOTAGA-DTC)3 (r1 = 9.0 0.2 mM−1
s−1), and Ru(Gd-DOTAGA-DTC)3 (r1 = 9.5 0.1 mM−1 s−1)
The MTT cell viability assay was also performed on an
additional complex, Gd-DO3A-DTC-AuPPh2C6H4COOH
(Supporting Information). This multimetallic compound was
prepared based on work by Bodio et al.,23 who demonstrated
the antiproliferative properties of a number of gold(I)
phosphine dithiocarbamate complexes featuring a central
cyclam motif. The empty cyclam in the previous design was
replaced with the Gd-DO3A chelate with the aim of creating a
theranostic complex for combined MRI and cancer therapy.
Unfortunately, no evidence of a therapeutic effect was
observed following 24 h of incubation of Gd-DO3A-DTC-
AuPPh2C6H4COOH with HeLa (cervical cancer) cells as the
cell viability remained at 89%, even at a concentration of 250
μM. The addition of a carboxylic acid group to one of the
phenyl rings was found to have little effect on the relaxivity of
the complex because it performed very similarly to Gd-DO3A-
DTC-AuPPh3 at magnetic field strengths up to 0.25 T
(Larmor frequency of 10 MHz).
Cell Uptake Studies. The uptake study was designed to
gather further information on the behavior of these multi-
gadolinium systems in a biological environment. Because of the
superior relaxivity performance of the DOTAGA-based
contrast agents, compared to the equivalent DO3A-based
complexes, only the DOTAGA-based agents were taken
forward to the uptake studies. Additionally, the negative
charge on the DOTAGA chelates and lack of amide arm render
them closer in structure to Dotarem, which allows an easier
comparison to be made. By focusing on the DOTAGA-based
agents, the charge density and lipophilicity were maintained
(DOTAGA and Dotarem both have a negative charge, whereas
DO3A is neutral), which ensured that the uptake of
gadolinium depended principally on changes in the structure
of the agent (i.e., number of Gd3+ units per complex).
The uptake of the DOTAGA-based multimetallic complexes
by HeLa cells (Figure 10) was determined after incubation
with the complexes for 24 h. The gadolinium concentration,
not the complex concentration, was kept constant for each of
the contrast agents, and the results showed that the uptake of
gadolinium per cell increased as the number of gadolinium
chelates per complex increased. The mass of gadolinium
compared to Dotarem (r1 = 4.4
0.2 mM−1 s−1). Most
noteworthy were the relaxivity values for the trigadolinium
complexes, Co(Gd-DOTAGA-DTC)3 and Ru(Gd-DOTAGA-
DTC)3, at 1.5 T, which were at least twice that of Dotarem.
Stability and Toxicity Studies. The designs of the
chelates used to complex the gadolinium ion are intentionally
closely based on that of Dotarem, one of the leading clinically
approved contrast agents. The stability of the chelate toward
the loss of gadolinium ions (and, hence, its toxicity) has been
probed in previous studies.13,14 This revealed that the addition
of excess Zn2+ ions to Gd-DO3A-NH2 and Gd-DOTAGA-
NH2 led to no change in the relaxivity values obtained,
indicating that no displacement of Gd3+ ions occurred.22
Stability studies were repeated for the multimetallic
complexes, again in the presence and absence of excess Zn2+
ions. When the multimetallic complexes were dissolved only in
phosphate-buffered saline (pH 7.4), there was no change in
relaxivity for at least 72 h, indicating that the multimetallic
complexes had remained intact and not degraded in this time.
When the multimetallic complexes were in the presence of 10
equiv of Zn2+ ions, the relaxivity once again remained constant,
confirming that no transmetalation had occurred between the
Zn2+ and Gd3+ ions. These results were crucial for their
potential use as clinical contrast agents as unchelated Gd3+ is
known to be highly toxic, whereas chelated Gd3+ is generally
well tolerated by the body.
In earlier studies, cytotoxicity assessment of the Gd-DO3A-
NH2 and Gd-DOTAGA-NH2 gadolinium units revealed no
toxicity to MCF-7 (breast cancer) or HeLa (cervical cancer)
cells, even at concentrations of 250 μM.13,14 In order to
ascertain whether the multimetallic compounds described in
this contribution had any adverse effects on the cell viability,
the same 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide (MTT) assay as previously reported13,14 was carried
out in human embryonic kidney (HEK) and HeLa cell lines
(Supporting Information). The multimetallic complexes all
demonstrated low or no toxicity at concentrations up to 250
μM. In the HEK cell line, the cell viability at 250 μM ranged
from 82
4% for Co(Gd-DOTAGA-DTC)3 (showing low
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delivered to each cell increased from 1.2
0.1 pg [Gd-
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.inorgchem.0c01318.
■
DOTAGA-DTC-AuPPh3] to 2.6
0.2 pg [Co(Gd-
sı
DOTAGA-DTC)3], which represents an uptake similar in
mass to that achieved by other polygadolinium systems.13,14
This supported our hypothesis that incorporating multiple
gadolinium chelates into the same assembly results in a more
efficient delivery of gadolinium into cells. Extrapolation of this
procedure from a cellular scale to a larger “tissue scale” would
lead to an uptake of micrograms or even milligrams, which is
adequate for MRI, as has already been observed with small-
molecule gadolinium complexes both in vitro24 and in vivo.25
By keeping the concentration of gadolinium constant, it is
possible to deduce that the increase in delivery of gadolinium is
due to the design of the tetrametallic complexes and not simply
because the cells were incubated with more gadolinium.
Furthermore, the assessment of the ratio of gadolinium ions to
central metal ions before and after uptake (Supporting
Information) revealed no significant change, indicating that
the complexes were entering the cells as a whole unit and
therefore were stable toward degradation, even under bio-
logical conditions.
Additional details on characterization of the compounds
described here along with details of relaxivity, cytotox-
icity, and cell uptake studies (PDF)
AUTHOR INFORMATION
Corresponding Author
■
James D. E. T. Wilton-Ely − Department of Chemistry,
Imperial College London, London W12 0BZ, U.K.;
orcid.org/0000-0002-5192-3038; Email: j.wilton-ely@
imperial.ac.uk
Authors
Hannah L. Perry − Department of Chemistry, Imperial College
London, London W12 0BZ, U.K.; School of Biomedical
Engineering and Imaging Sciences, King’s College London,
London SE1 7EH, U.K.
Il-Chul Yoon − Department of Chemistry, Imperial College
London, London W12 0BZ, U.K.
Nicolas G. Chabloz − Department of Chemistry, Imperial
College London, London W12 0BZ, U.K.
Susannah Molisso − Department of Chemistry, Imperial College
London, London W12 0BZ, U.K.
Graeme J. Stasiuk − School of Biomedical Engineering and
Imaging Sciences, King’s College London, London SE1 7EH,
U.K.; orcid.org/0000-0002-0076-2246
CONCLUSIONS
■
A series of bi-, tri-, and tetrametallic d−f mixed-metal
complexes have been synthesized using either DO3A- or
DOTAGA-based gadolinium chelates to generate potential
MRI contrast agents with consistently greater relaxivity values
than Dotarem, a clinically approved MRI contrast agent. Most
remarkable were Co(Gd-DOTAGA-DTC)3 and Ru(Gd-
DOTAGA-DTC)3, which achieved relaxivity values (per
Gd3+ ion) of more than twice the value of Dotarem at a
clinical magnetic field strength. This can be partly attributed to
the larger mass of the multimetallic complexes compared to
Dotarem, which leads to slower rotational motion and
consequently greater relaxivity. However, a significant factor
is also the rigidity of the piperazine-based dithiocarbamate
linkers, which reduce the internal flexibility of the chelates and
further enhance the relaxivity.
́
Rene M. Botnar − School of Biomedical Engineering and
Imaging Sciences, King’s College London, London SE1 7EH,
U.K.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.inorgchem.0c01318
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
A number of tests were performed to probe the stability,
toxicity, and cellular uptake of the multimetallic complexes.
The stability tests revealed that the complexes were stable
toward degradation and transmetalation, and an assessment of
the gadolinium to central metal ion ratio before and after
uptake by cells revealed that this stability toward degradation
was maintained, even under biological conditions. MTT cell
viability assays showed no evidence of toxicity, even at
concentrations up to 250 μM, and cell uptake studies
demonstrated the improved delivery of gadolinium into cells
when using a multigadolinium system.
ACKNOWLEDGMENTS
■
The authors express their gratitude to the EPSRC Centre for
Doctoral Training in Smart Medical Imaging (King’s College
London and Imperial College London) for the provision of
relaxometer facilities and a studentship (to H.L.P.). I.-C.Y.
thanks Imperial College for the award of a President’s Ph.D.
Scholarship, and N.G.C. thanks the EPSRC for a DTP
studentship. We are grateful to Andrew Coulson for assistance
with tissue culture facilities, Patricia Carry for assistance with
ICP-MS, and Dr. Giovanna Nordio for assistance with the
MRI. G.J.S. thanks the MRC for funding (MR/T002573/1).
The metallostar assemblies described here display significant
potential as multigadolinium MRI contrast agents. Given the
versatility of dithiocarbamate coordination chemistry, there is a
wealth of opportunity to further develop these multimetallic
complexes into targeted, multimodal or theranostic agents by
exchanging a gadolinium chelate for an appropriate dithio-
carbamate-linked ligand. Such a modification would improve
the clinical appeal of these assemblies while avoiding a
significant adjustment to an already straightforward synthetic
route.
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