CoII Complexes as Liposomal CEST Agents

Article abstract of DOI:10.1002/anie.202003479

Three paramagnetic Co^II macrocyclic complexes containing 2-hydroxypropyl pendant groups, 1,1′,1′′,1′′′-(1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetrayl)tetrakis- (propan-2-ol) ([Co(L1)]²⁺, 1,1′-(4,11-dibenzyl-1,4,8,11-tetraazacyclotetradecane-1,8-diyl)bis(propan-2-ol) ([Co(L2)]²⁺), and 1,1′-(4,11-dibenzyl-1,4,8,11-tetraazacyclotetradecane-1,8-diyl)bis(octadecan-2-ol) ([Co(L3)]²⁺) were synthesized to prepare transition metal liposomal chemical exchange saturation transfer (lipoCEST) agents. In solution, ([Co(L1)]²⁺) forms two isomers as shown by ¹H NMR spectroscopy. X-ray crystallographic studies show one isomer with 1,8-pendants in cis-configuration and a second isomer with 1,4-pendants in trans-configuration. The [Co(L2)]²⁺ complex has 1,8-pendants in a cis-configuration. Remarkably, the paramagnetic-induced shift of water ¹H NMR resonances in the presence of the [Co(L1)]²⁺ complex is as large as that observed for one of the most effective Ln^III water proton shift agents. Incorporation of [Co(L1)]²⁺ into the liposome aqueous core, followed by dialysis against a solution of 300 mOsm L^?1 produces a CEST peak at 3.5 ppm. Incorporation of the amphiphilic [Co(L3)]²⁺ complex into the liposome bilayer produces a more highly shifted CEST peak at ?13 ppm. Taken together, these data demonstrate the feasibility of preparing Co^II lipoCEST agents.

Full text of DOI:10.1002/anie.202003479

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Accepted Article
Title: Co(II) Complexes as Liposomal CEST Agents
Authors: Samira M Abozeid, Didar Asic, Gregory E Sokolow, Jonathan
Lovell, Alexander Nazarenko, and Janet Ruth Morrow
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Angewandte Chemie International Edition
10.1002/anie.202003479
RESEARCH ARTICLE
Co(II) Complexes as Liposomal CEST Agents
Samira M. Abozeid,[a] Didar Asik,[a] Gregory E. Sokolow,[a] Jonathan F. Lovell,[b] Alexander Y.
[c]
[a]
Nazarenko, and Janet R. Morrow *
Abstract: Three paramagnetic Co(II) macrocyclic complexes
containing 2-hydroxypropyl pendant groups, 1,1',1'',1'''-(1,4,8,11-
tetraazacyclotetradecane-1,4,8,11-tetrayl)tetrakis(propan-2-ol)
full potential of paraCEST agents in MRI. Strategies to increase
paraCEST agent signal have long been pursued.[4]
The incorporation of paramagnetic MRI probes into
supramolecular complexes or nanoparticles can improve their
sensitivity by several orders of magnitude.[4b, 5] Liposomal CEST
2+
(
[Co(L1)]
,
1,1'-(4,11-dibenzyl-1,4,8,11-tetraazacyclotetradecane-
2+
1
,8-diyl)bis(propan-2-ol) ([Co(L2)] ), and 1,1'-(4,11-dibenzyl-
,4,8,11-tetraazacyclotetradecane-1,8-diyl)bis(octadecan-2-ol)
1
approaches, or “lipoCEST” agents, have shown CEST signal at
2
+
[4a]
([Co(L3)] ) were synthesized to prepare transition metal liposomal
nanomolar concentrations of probe.
LipoCEST agents have a
chemical exchange saturation transfer (lipoCEST) agents. In
pool of intraliposomal water molecules with proton resonances
that are shifted by the paramagnetic complex. An increase in
sensitivity is produced by loading high concentrations of the shift
2+
1
solution, ([Co(L1)] ) forms two isomers as shown by H NMR
spectroscopy. X-ray crystallographic studies show one isomer with
1
,8-pendants in cis-configuration and a second isomer with 1,4-
2+
pendants in trans-configuration. The [Co(L2)] complex has 1,8-
pendants in a cis-configuration. Remarkably, the paramagnetic
1
induced shift of water H NMR resonances in the presence of the
2+
[
Co(L1)] complex is as large as that observed for one of the most
2+
effective Ln(III) water proton shift agents. Incorporation of [Co(L1)]
into the liposome aqueous core, followed by dialysis against a solution
of 300 mOsm/L produces a CEST peak at 3.5 ppm. Incorporation of
2+
the amphiphilic [Co(L3)] complex into the liposome bilayer produces
a more highly shifted CEST peak at -13 ppm. Taken together, these
data demonstrate the feasibility of preparing Co(II) lipoCEST agents.
Introduction
Paramagnetic chemical exchange saturation transfer (CEST)
agents or paraCEST agents are a class of compounds that are
[1]
under development as MRI contrast agents.
CEST and
paraCEST agents contain protons, generally as OH or NH groups,
that exchange with bulk water protons. Saturation of these
exchangeable protons with a selective radiofrequency pulse
[1a]
reduces the water proton signal to produce contrast.
While
reagent into a small intraliposomal volume.[6] Typically, the
paramagnetic complex contains a trivalent lanthanide ion (Ln(III))
with a rapidly exchanging bound water that produces a large shift
of the proximal water proton resonances.[7] The shift of the
intraliposomal water protons may be further increased by
osmotically shrinking the liposome into an oblong shape and by
incorporating additional Ln(III) complex into the lipid bilayer by
attachment of a long alkyl chain.[13, 17]
most examples of paraCEST agents are paramagnetic lanthanide
complexes, paramagnetic transition metal complexes have also
Transition metal
paraCEST agents are uniquely suited for development as
responsive MRI probes that switch oxidation state or spin state
according to biological environment.[3] However, the low
sensitivity of the agents must be addressed in order to realize the
shown promise as paraCEST agents.[2]
High spin Co(II) and Fe(II) macrocyclic complexes are
alternatives to Ln(III) complexes for the production of highly
[2b-g]
paramagnetically shifted water protons.
Interestingly, while
[
a]
S. M. Abozeid, D. Asik, G. E. Sokolow, Prof. J. R. Morrow
Department of Chemistry
paramagnetic complexes with inner-sphere water ligands
University at Buffalo, the State University of New York
Amherst, NY 14260, United States
produce strongly shifted water protons, so do complexes that
[2a-c]
interact with water through second-sphere interactions.
Here
*E-mail: jmorrow@buffalo.edu
we report three new Co(II) complexes that produce highly shifted
water proton resonances. The large shift is attributed to an
unusual geometry at Co(II) and to the hydroxyalkyl groups. Two
Co(II) complexes presented here shift water protons to nearly the
same extent as the best lanthanide shift agents, and when
incorporated into an osmotically-shrunken liposome, produce a
lipoCEST effect.
[
[
b]
c]
Prof. J. F. Lovell
Department of Biomedical Engineering
University at Buffalo, the State University of New York
Amherst, NY 14260, United States
Prof. A. Y. Nazarenko
Chemistry Department
SUNY College at Buffalo
1
300 Elmwood Avenue
Buffalo, NY 14222, United States
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
Results and Discussion
configuration (Figure 1 and Figure S26). The complex cation of
the bis-benzyl substituted complex [Co(L2)]2+ has the
hydroxypropyl pendants coordinated in a cis-configuration. The
cis-complex of [Co(L1)]2+ and [Co(L2)]2+ have the Co(II) ion
displaced by 0.705(6) Å and 0.751(18) Å, respectively, from the
centroid of the plane formed by the cyclam nitrogens, whereas the
trans-isomer has the Co(II) nearly in the plane of the cyclam
macrocycle. The 1,4-[Co(L1)]2+ isomer has the macrocycle in the
common trans-III form (S,S,R,R at nitrogen). This form is the
most stable for divalent transition metal ion complexes.[8]
Previous examples of Co(II) cyclam complexes with four pendant
amides show the 1,8-isomer of [Co(L4)]2+ in the trans-III form but
the 1,4-isomer in the trans-II form.[9] Both the [Co(L2)]2+ complex
cation and the 1,8-[Co(L1)]2+ complex cation have the rare folded
cis-I configuration with all nitrogen pendant groups oriented up.[10]
This configuration has been observed for a Cd(II) complex of
cyclam which has a bidentate carbonate,[8] but has not been
Co(II) complexes with 2-hydroxypropyl pendants were
prepared from cyclam (1,4,7,11-tetrazacyclododecane) and also
from 1,8-bis(benzyl) cyclam and S-propylene oxide (Scheme 1).
Solution studies were consistent with high spin Co(II) complexes
as shown by magnetic moments of 4.98 ±0.07 and 4.84±0.12, for
Co(L1)]2+ and [Co(L2)]2+, respectively at 25 C, characteristic of
o
[
1
S = 3/2 Co(II) complexes. The H NMR resonances of the Co(II)
complexes range from -100 to +340 ppm (Figure S1). [Co(L2)]2+
has 14 strongly paramagnetically shifted proton resonances
assigned to macrocycle backbone and methylenes of benzyl and
hydroxypropyl pendants, consistent with apparent C
the complex with both hydroxy pendants bound. In contrast, there
are approximately 34 proton resonances for [Co(L1)]2+
The
2
symmetry of
.
unequal intensity of the resonances suggests that there is more
than one isomer in solution. Comparison with the 1H NMR
spectrum of [Co(L2)]2+ suggests that one set of resonances is
produced by a 1,8-isomer, as the major species, and the other set
of resonances is produced by a smaller amount of a different
isomer of lower symmetry. Heating of the [Co(L1)]2+ complex to
observed for
a divalent metal ion cyclam complex with
coordinating pendant groups, to the best of our knowledge.
Crystallographic data is given in Table S6. Bond lengths, bond
angles and additional description of structures for all three
complexes are given in Tables S7-S12 and Figures S26-S36.
37 °C or 60 °C, followed by cooling does not change the
1
The solution H NMR data for [Co(L1)] and [Co(L2)]2+, as
described above, in conjunction with the structural data support
the predominance of the cis-I form in solution. The minor form of
[Co(L1)]2+ is most likely the 1,4-isomer in trans-III form based on
comparison of proton shifts to that of the [Co(L4)]2+ isomers.[9b]
The z-spectra of the two complexes also support this analysis by
showing weak CEST peaks characteristic of OH exchangeable
protons bound to Co(II).[2a, 2b] [Co(L2)]2+ shows a single CEST
peak at 33 ppm versus bulk water, consistent with a single isomer.
[Co(L1)]2+ produces two CEST peaks consistent with the two
isomers, one at 33 and one at 58 ppm. The pH dependence of
the CEST effect increases with pH up to pH 7.2 with exchange
1
2+
percentage of the isomers as gauged by H NMR spectroscopy,
suggesting equilibrium is attained. [Co(L1)]2+ is inert towards loss
of Co(II) at pH 7.12, 37 °C for 18 hours in the presence of
carbonate and phosphate, but dissociates appreciably in acid at
pD 3.4 (Figures S8-S10, Table S3). The greater degree of
dissociation between 1 hour and 18 hours is consistent with a
1
kinetic effect. However H NMR studies and pH potentiometric
studies show that Co(L1) reforms as the pH is returned to neutral,
consistent with thermodynamic stability under these conditions
S10). A third Co(II) complex [Co(L3)]2+ which is amphiphilic was
(
1
prepared and characterized by NMR spectroscopy. The H NMR
spectrum of [Co(L3)]2+ resembled that of [Co(L2)]2+ , consistent
with the formation of a complex with similar geometry (Figure S2).
This hydrophobic complex was prepared for the purpose of
making liposome type B which has [Co(L3)]2+ incorporated into
-1
rate constants ranging from 800 to 3900 s , characteristic of
ligand donor groups that have exchanging OH protons.[2a, 2b] The
low intensity of CEST peaks suggest that these complexes would
not be useful as paraCEST agents. However Co(II) complexes
with hydroxypropyl pendants are excellent water proton shift
reagents (SR).[2b] Encapsulation of such SRs in the interior of a
liposome magnifies the number of exchangeable protons and
produces a more effective CEST agent.
the liposome bilayer with core loaded [Co(L1)]2+
.
Both [Co(L1)]2 and [Co(L2)]2+ complexes are effective
+
1
1
water H resonance SRs. Plots of the water H shift as a function
of concentration of the complexes in solution show that the slopes
-
are close to that of [Tm(DOTA)] (Figure 2). In comparison,
Co(L4)] , which contains amide pendants, does not have such a
2
+
[
large effect on the water proton shift. To elucidate the basis for
these paramagnetic induced chemical shift changes, variable
temperature 17O NMR spectroscopy was used to study the nature
of the water interactions with the Co(II) complexes. As shown in
Figure S11, a broad 17O resonance is observed in the presence
of 50 mM [Co(L1)]2+ complex which shifts downfield on raising the
temperature to 60 °C and then sharpens. In comparison, the
Figure1. Molecular structures of cis-1,8-[Co(L1)]2+ (A, only one of two nearly
identical cations shown) and [Co(L2)]2+ (B) cations with thermal ellipsoids drawn
at 50% probability level.
X-ray crystallographic analysis indicated two isomers of the
2+
17
[
Co(L4)] complex shows only a slight upfield shift of the
O
[
Co(L1)]2+ cation including
a
complex with 1,4-pendants
separated by an ethylene group bound in trans-configuration and
complex containing coordinating 1,8-pendants in cis-
NMR resonance upon heating over the same temperature range.
The behaviour of [Co(L1)]2+ and [Co(L2)]2+ is characteristic of
complexes with an exchangeable inner-sphere water molecule,
a
a
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Angewandte Chemie International Edition
10.1002/anie.202003479
RESEARCH ARTICLE
2
+
to produce an enhanced CEST effect.[14] Sizes less than 200 nm
are also preferable for in vivo applications to increase the
circulation time.[14-15] Dynamic light scattering measurements
were consistent with a diameter of 125 nm for [Co(L1)] -based
lipoA (Figure S16)[16] with a low polydispersity index, 0.064,
whereas that of [Co(L4)] is characteristic of a complex with no
innersphere waters. A Swift-Connick plot of the reduced shift (q
2
+
=
4
1) and linewidth for [Co(L1)] and [Co(L2)]2+ gives kex of
6
-1
6
-1
2+
.47 x 10 s and 3.54 x 10 s , respectively, for an inner-sphere
water, similar to rate constants reported previously for Co(II)
macrocyclic complexes (Figure S12 and Table S3).[2a-2c]
indicating a narrow size distribution. LipoA contained 4 mM
+
[
Co(L1)]2 as determined by ICP-MS and NMR spectroscopy
(Evans method). In LipoA, the intraliposomal chemical shift is a
sum of two contributions: the hyperfine interaction between the
intraliposomal water protons and the paramagnetic center, and
bulk magnetic susceptibility effects which are an important for
[13b]
aspherical liposomes (Eq.1).
∆푰풏풕풓풂풍풊풑풐= ∆푯풀푷 + ∆푩푴푺
푬풒. ퟏ
Figure 3. Z-spectra obtained from the liposome type A encapsulating [Co(L1)]2+
Figure 2. Plot of the 1H NMR water shift for Co(II) complexes (non-liposomal
system) at 25 0C. Slopes of lines are 0.0128, 0.0179, 0.0131 and 0.003 for
Tm(DOTA)] , [Co(L1)]2+, [Co(L2)]2+ and [Co(L4)]2+, respectively. The shift was
-
[
corrected for bulk magnetic susceptibility effects.
Plots of the shift of the 17O resonance as a function of
complex are shown in Figure S13 for [Co(L1)]2 , [Co(L2)]
+
2+
,
[
Co(L4)]2+ and Co(NO
3 2
) , as a classic method to determine the
number of bound water molecules. Two pH values, 7.0 and 7.5
were studied in order to probe the effect of deprotonation of the
hydroxypropyl pendants at near neutral pH (7.6 for [Co(L1)]2 and
+
7
.4 for [Co(L2)]2+; Table S5, Figures S14, S15). The slope
decreases for both complexes at pH 7.5 compared to 7.0,
consistent with a decrease in q number at the higher pH. If we
assume that Co(II)aq has six inner-sphere waters, then q is one for
with an osmotic pressure of 300 mOsm/L to 2000 mOsm/L. Experiments were
run at 25 oC, pH 6.50, 11 µT and 2 second irradiation time.
Co(L1)]2+ at pH 7.5, a pH close to the first pK
[
a
, but is higher (q =
o
2+
2) at pH 7, at 37 C. Similarly, studies with [Co(L2)] gave a q
Z-spectra, plotted as the percent decrease in water proton
magnetization as a function of presaturation pulse frequency,
were taken to study the CEST effect (Fig. 3). Several different
conditions with varying osmotic pressure were studied to produce
shrunken liposomes. Shrinking the liposome increases the
concentration of the SR inside the liposome and also increases
the bulk magnetic susceptibility.[13b, 17] Moreover, the CEST peak
position increases upon shrinking the liposome from 3.5 ppm at
value of 1.8 at pH 7. However, estimation of inner-sphere waters
by O NMR spectroscopy is complicated by second-sphere
17
contributions and by the position of the water ligand with respect
to the effective magnetic axes.[11] Nonetheless, both the variable
1
7
1
7
t
e
m
p
e
r
a
t
u
r
e
O
N
M
R
s
t
u
d
i
e
s
a
n
d
t
h
e
p
l
o
t
s
o
f
t
h
e
s
h
i
f
t
o
f
t
h
e
O
resonance as a function of Co(II) complex concentration are most
consistent with an inner-sphere water for [Co(L1)]2+ and [Co(L2)]2+
which may result from formation of a seven-coordinate Co(II)
300 mOsm/L to 10 ppm at 1200 mOsm/L and 18 ppm at 2000
complex, or by displacement of a hydroxypropyl pendant. Thus,
we attribute the large proton water shift produced by [Co(L1)]2+
mOsm/L. This CEST peak disappears upon disrupting the
liposomes with addition of 1% TX100 detergent (Figure S21),
confirming that the Co(II) complex is in the interior of the liposome.
LipoA containing [Co(L2)]2+ (6 mM) as an alternative to [Co(L1)]2+
showed a similar asymmetry in its Z-spectrum (Figure S23).
In order to increase the intraliposomal chemical shift without
using an osmolality larger than that found in blood (300 mOsm/L),
liposome type B (lipoB) with an amphphilic SR [Co(L3)]2+ and core
loaded with [Co(L1)]2+ was prepared. Notably in lipoB, two factors
contribute to the intraliposomal chemical shift; the hyperfine
interaction of intraliposomal water protons with the paramagnetic
and [Co(L2)]2+ to the unusual cis-I geometry and to the large
[
2a,
second sphere effects associated with hydroxylalkyl pendants.
2b, 2m]
LipoA was formed with [Co(L1)]2+ loaded into the liposomal
cavity using an ethanol injection method, followed by extrusion
through polycarbonate membranes.[12] Osmotically-shrunken
liposomes were then prepared by dialysing the liposome
suspension against different concentrations of NaCl and HEPES
buffer. Intraliposomal water chemical shift increases upon
changing the shape of the liposome from spherical to oblong by
increasing osmotic stress.[13] We chose small-sized liposomes to
ꢃꢄꢅ
encapsulated SR, ∆ꢀꢁꢂ , and the hyperfine interaction of
intraliposomal water protons with the incorporated SR pointing
increase surface area to volume ratio which increases the
exchange rate between the intraliposomal water and bulk water
ꢃꢄꢅ
into the liposome cavity, ∆ꢆꢁꢂ (Eq.2). These two hyperfine
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Angewandte Chemie International Edition
10.1002/anie.202003479
RESEARCH ARTICLE
contributions may produce proton shifts in different directions as
shown for Ln(III) reagents.[17] The bulk magnetic suceptibility is
directly proportional to the total concentration of Co(II) complex
loaded inside the cavity or incorporated into the internal layer of
the liposome and pointing inward. As a result, the incorporation of
to 6 ppm at 300 mOsm/L and a CEST peak at 15 ppm at 1200
mOsm/L.[19]
Conclusion
[
Co(L3)]2+ complex in the liposome bilayer increases both the bulk
magnetic suceptibility contribution (BMS) and the hyperfine shift
contribution.
The Co(II) containing liposomes presented here are the
first examples of transition metal-based lipoCEST agents, to the
best of our knowledge. Shrunken liposomes with bilayer
incorporated amphiphilic and core loaded complexes are
especially promising as they demonstrate that Co(II) complexes,
despite having a lower effective magnetic moment than Dy(III) or
Tm(III) complexes, show a pronounced lipoCEST signal. Our
studies suggest ways to improve Co(II)-based lipoCEST agents
including development of Co(II) complexes of increased kinetic
∆푰풏풕풓풂풍풊풑풐= ∆ 푯풆 풏풀 풄푷 + ∆
푯풀푷
+ ∆
푩푴푺
푬풒. ퟐ
풊풏풄
(풆풏풄ꢇ풊풏풄)
[
2b, 2c, 9]
inertness by modifying the macrocycle framework.
The
preparation of complexes with an overall neutral charge and with
multiple Co(II) centers will further improve the liposome loading
efficiency in order to produce increased CEST peak shifts.18
Moreover, new applications may be realized with transition metal
ion liposome based agents, such as capitalizing on changes in
oxidation and spin state for the development of biochemically
responsive agents.[3, 20] In the long term, paramagnetic transition
1 2
metal liposomes that generate a combination of T , T or CEST
[21]
MR contrast would be beneficial for in vivo applications.
Figure 4. Z-spectra of liposome type B (lipoB containing surface conjugated
Co(L3)]2+ & core loaded with [Co(L1))]2+ and dialyzed against osmotic pressure
[
Acknowledgements
of 300 mOsm/L, Experiment was run at 17 µT, pH 6.5 with 2 second irradiation.
JRM acknowledges the NSF (CHE-1710224 and CHE-1310374)
for support. This project used ICP-MS and FTMS instruments
purchased with funding from NSF CHE-0959565 and National
Institutes of Health (S10 RR029517). We thank Alejandra P.
Lopez for assistance in fitting potentiometric data
The incorporation of paramagnetic amphiphilic complex in
the lipid bilayer along with core loaded [Co(L1)]2+ (12 mM total Co)
changes the intraliposomal chemical shift from 3.5 ppm observed
for lipoA at 300 mOsm/L to -13 ppm at 300 mOsm/L (Figure 4).
CEST experiments of LipoB were run at two different
o
o
temperatures (25 C and 37 C) and little change in the CEST
peak intensity was observed (Figure S25). The change in the sign
of the CEST peak for lipoB suggests a change in orientation of
the liposome with respect to the static magnetic field.[13] The
alignment of shrunken paramagnetic liposomes in a magnetic
field is influenced by the sign of the magnetic susceptibility
anisotropy of the paramagnetic metal complex, which is
modulated by the electronic configuration and geometry of the
metal complex, and the mode of insertion of the complex into the
lipid bilayer.[4a, 13, 17] For example, the magnetic field alignment of
liposomes filled with Ln(III) complexes changes from parallel to
perpendicular upon incorporation of an amphiphilic Ln(III)
complex, to reverse the direction of the intraliposomal chemical
shift.[13] Thus, the incorporation of [Co(L3)]2+ into the liposomal
membrane not only increased the CEST peak shift, but also
changed the sign which suggests that the major population of
Keywords: ParaCEST • Water Shift Agents • LipoCEST,
amphiphilic shift reagent.
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1]
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shrunken liposomes is oriented with the longer axis perpendicular
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The Co(II) lipoCEST agents described here compare
favorably to those based on lanthanides. For comparison,
shrunken liposomes with 40 mM encapsulated Tm(III) complex
produce shifts of up to 10 ppm, and incorporation of amphiphilic
500-511.
[
2]
a) S. M. Abozeid, E. M. Snyder, A. P. Lopez, C. M.
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2
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and core loaded 20 mM (Dy)-1,4,7,10-tetraazacyclododecane-
Tittiris, C. M. Steuerwald, A. Y. Nazarenko, J. R. Morrow,
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Sokolow, M. R. Crawley, P. J. Burns, J. M. Cox, R.
Mayilmurugan, J. R. Morrow, Inorg. Chem., 2019, 58,
1,4,7,10-tetraacetic acid (DOTA)-Na produced a CEST peak at 4
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Angewandte Chemie International Edition
10.1002/anie.202003479
RESEARCH ARTICLE
8710-8719; d) P. J. Burns, J. M. Cox, J. R. Morrow,
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This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.202003479
RESEARCH ARTICLE
1
Paramagnetic Co(II) complexes produce water H
shifts that rival those of lanthanide(III) complexes.
Incorporation of these complexes into the interior and
bilayer of shrunken liposomes gives highly shifted
intraliposomal water protons for chemical exchange
saturation transfer (CEST) experiments as the first
examples of transition metal ion lipoCEST agents.
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This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.202003479
RESEARCH ARTICLE
This article is protected by copyright. All rights reserved.