Platinum(II)-gadolinium(III) complexes as potential single-molecular theranostic agents for cancer treatment

Article abstract of DOI:10.1002/anie.201407406

Theranostic agents are emerging multifunctional molecules capable of simultaneous therapy and diagnosis of diseases. We found that platinum(II)-gadolinium(III) complexes with the formula [{Pt(NH₃)₂Cl}₂GdL](NO₃)₂ possess such properties. The Gd center is stable in solution and the cytoplasm, whereas the Pt centers undergo ligand substitution in cancer cells. The Pt units interact with DNA and significantly promote the cellular uptake of Gd complexes. The cytotoxicity of the Pt-Gd complexes is comparable to that of cisplatin at high concentrations (≥0.1 mm), and their proton relaxivity is higher than that of the commercial magnetic resonance imaging (MRI) contrast agent Gd-DTPA. T₁-weighted MRI on B6 mice demonstrated that these complexes can reveal the accumulation of platinum drugs in vivo. Their cytotoxicity and imaging capabilities make the Pt-Gd complexes promising theranostic agents for cancer treatment.

Full text of DOI:10.1002/anie.201407406

Angewandte
Chemie
DOI: 10.1002/anie.201407406
Antitumor Complexes
Platinum(II)–Gadolinium(III) Complexes as Potential Single-
Molecular Theranostic Agents for Cancer Treatment**
Zhenzhu Zhu, Xiaoyong Wang,* Tuanjie Li, Silvio Aime, Peter J. Sadler, and Zijian Guo*
Abstract: Theranostic agents are emerging multifunctional
molecules capable of simultaneous therapy and diagnosis of
diseases. We found that platinum(II)–gadolinium(III) com-
plexes with the formula [{Pt(NH ) Cl} GdL](NO ) possess
poorly understood. Thus, a reliable strategy for real-time
monitoring of the drug location and therapeutic responses
during treatment is highly desired. Direct information on drug
action would provide the basis for minimizing the duration of
ineffective courses of treatment and for adopting a personal-
3
2
2
3 2
such properties. The Gd center is stable in solution and the
cytoplasm, whereas the Pt centers undergo ligand substitution
in cancer cells. The Pt units interact with DNA and signifi-
cantly promote the cellular uptake of Gd complexes. The
cytotoxicity of the Pt–Gd complexes is comparable to that of
cisplatin at high concentrations (ꢀ 0.1 mm), and their proton
relaxivity is higher than that of the commercial magnetic
resonance imaging (MRI) contrast agent Gd–DTPA. T1-
weighted MRI on B6 mice demonstrated that these complexes
can reveal the accumulation of platinum drugs in vivo. Their
cytotoxicity and imaging capabilities make the Pt–Gd com-
plexes promising theranostic agents for cancer treatment.
[
4]
ized therapeutic regimen in cancer therapy.
Multifunctional Pt complexes are likely to exhibit synergic
[
5]
actions against tumor cells. Commonly, they can enhance
selectivity for cancer cells or modulate the drug distribution in
[
1,6]
the body to increase drug accumulation at tumor sites.
Furthermore, by the conjugation of Pt pharmacophores to
fluorescent groups, these complexes could be developed as
theranostic agents with both therapeutic and diagnostic
[
7]
capabilities. Nevertheless, since these functions rely on
drug release and fluorescence changes induced by tumor-
associated stimuli, the fluorescence intensity may not corre-
late well with the actual drug concentration if the release is
incomplete or blocked; besides, no direct information can be
obtained on the therapeutic efficacy.
P
latinum anticancer drugs, such as cisplatin, have been
widely used to treat various cancers for nearly 40 years.
[1]
However, novel Pt complexes still attract much attention
MRI provides a powerful noninvasive diagnostic modality
for cancers with high spatial resolution (10–100 mm) and
precise 3D positioning. We recently showed that Pt drugs
because resistance and severe side effects are frequently
[
2]
II
[8]
observed with existing Pt drugs. The cationic Pt complex
+
cis-[Pt(NH ) (py)Cl] (py is a pyridyl ligand), for example,
could be attached to Fe O nanoparticles to form anticancer
3
2
2
3
displayed significant anticancer activity in murine tumor
models and showed promise for overcoming drug resistance.
theranostic agents, in which nanoparticles act as both drug
[3]
[9]
carriers and T -weighted MRI contrast agents (CAs). How-
2
Regrettably, the behavior of these complexes, such as
distribution, accumulation, and metabolism, in tumors is
ever, release procedures are indispensable for these nano-
medicines. As alternatives, Gd complexes are widely used as
III
T -weighted CAs in MRI through the interaction of inner-
1
III
[*] Z. Zhu, Dr. T. Li, Prof. Dr. Z. Guo
sphere water with paramagnetic Gd and rapid exchange of
the coordinated water with the bulk solvent. For example,
[
10]
State Key Laboratory of Coordination Chemistry
School of Chemistry and Chemical Engineering
Nanjing University, Nanjing 210093 (P. R. China)
E-mail: zguo@nju.edu.cn
gadolinium diethylenetriaminepentaacetate ([Gd(DTPA)-
2À
(
H O)] , Gd–DTPA, or Magnevist) is one of the most
2
common MRI CAs in the clinic because of its low toxicity,
Prof. Dr. X. Wang
[11]
rapid renal clearance, and high stability. Some polymeric
State Key Laboratory of Pharmaceutical Biotechnology, School of
Life Sciences; State Key Laboratory of Analytical Chemistry for Life
Science, Nanjing University, Nanjing 210093 (P.R. China)
E-mail: boxwxy@nju.edu.cn
micelles derived from the self-assembly of Gd–DTPA, Pt
pharmacophores, and block copolymers, such as PEG-b-
P(Glu) and PEG-b-PAsp(DET), have been developed as
[
12]
theranostic agents. Interestingly, a Pt–Gd complex contain-
Prof. Dr. S. Aime
Center of Molecular Biotechnology, University of Torino
Via Nizza, 52, 10126 Torino (Italy)
II
ing Gd–DTPA and {Pt (2,2’:6’,2’’-terpyridine)} units was
[13]
shown to selectively accumulate in the nuclei of tumor cells.
Prof. Dr. P. J. Sadler
Department of Chemistry, University of Warwick
Gibbet Hill, Coventry, CV4 7AL (UK)
We herein report two Pt–Gd complexes, 1 and 2, as cancer
theranostic agents (Scheme 1). Multidentate ligands L1 and
L2 were obtained by modifying DTPA with pyridin-2-
ylmethanamine and pyridin-2-ylethanamine, respectively;
[
**] We appreciate the financial support from the National Natural
Science Foundation of China (No. 21271101, 21131003, 21021062,
1
and 2 were formed by conjugating GdL1 and GdL2 to the
91213305), the National Basic Research Program of China
+
cytotoxic cis-[Pt(NH ) Cl] complex, respectively. Thus, the
3
2
(
2011CB935800), and the ERC (No. 247450). We also thank Dr.
Gd–DTPA and Pt complexes were integrated into a single
molecule with both anticancer and imaging functionalities.
These complexes can enter cancer cells and interact with
DNA; more importantly, they show higher proton relaxivity
Rebecca Steele and Dr. Gianni Ferrante of Stellar for the NMRD
measurement.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407406.
Angew. Chem. Int. Ed. 2014, 53, 13225 –13228
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
13225

.
Angewandte
Communications
DNA (Figure 1B), whereas GdL1 induced no significant
changes in the migration of DNA (see Figure S3), thus
indicating that only 1 can unwind the DNA superhelix.
Similar results were also observed for 2 and GdL2 under the
same conditions (see Figure S4). The results confirm that
1
and 2 can significantly interfere with the helicity of DNA,
and that the interference is primarily induced by the Pt
moieties. If these complexes can enter cancer cells, such
interference may lead to distortions in nuclear DNA and
[
1]
result in cell death.
The cellular uptake of GdL1, GdL2, 1, and 2 in HeLa
cells was determined by ICPMS after the cells were
exposed to each complex for 24 h. The content of Gd and
Pt in the cytoplasm and nucleoplasm is listed in Table 1. The
results indicate that all the complexes can enter the cells
and accumulate in the cytoplasm, but only 1 and 2 can
travel further into the nuclei. The molar ratios of Pt to Gd
for 1 and 2 did not match with their stoichiometric ratio, as
it was less than 2:1 in the cytoplasm (0.35 and 0.34,
respectively) but larger than 2:1 in the nucleoplasm (13.89
and 2.40, respectively). This observation suggests that 1 and
Scheme 1. Synthetic route to Pt–Gd complexes 1 and 2.
than that of Gd–DTPA and similar cytotoxicity to that of
cisplatin at imaging concentrations. Therefore, they are
capable of simultaneous drug tracing and cancer restraint.
The formation of 1 and 2 was confirmed by ESIMS (see
Figure S1 and Table S1 in the Supporting Information). The
complex cations and related species indicate that the skeleton
of 1 and 2 is stable and the chlorides are dissociable in
aqueous solution. Moreover, the inner-sphere water is
exchangeable, which is essential for CAs to increase the
6
Table 1: Cellular uptake of Gd and Pt after the incubation of 10 HeLa
cells with GdL1, GdL2 (100 mm), 1, and 2 (40 mm) for 24 h. Data are
expressed as the mean (mm) Æstandard deviation of at least three
independent experiments, with untreated cells as the control.
[a]
[a]
Complex
Cytoplasm
Pt
Nucleoplasm
Pt
Gd
Gd
[10]
GdL1
GdL2
1
540.3Æ10.0
541.5Æ4.9
668.7Æ38.9
862.4Æ10.3
–
–
–
–
–
–
relaxation rate of the bulk solvent.
It is known that
intracellular glutathione (GSH) tends to react with Pt
complexes and promote leaving of the opposite ligand as
233.8Æ15.2
15.6Æ3.2
216.7Æ10.2
2
290.8Æ16.0
44.5Æ5.6
107.0Æ2.4
[14]
a result of the trans-labilization effect. The stability of 2 in
the presence of GSH was thus examined by ESIMS (see
Figure S2 and Table S2). The results showed that the Pt
moieties could leave the complex in this situation. However,
the complex ion at m/z 642.42 remained the major species
even at 48 h, thus showing that the release of Pt moieties is
a slow and incomplete process. The limited dissociation may
lower the cytotoxicity of the Pt unit(s) towards cancer cells
and enable the Pt–Gd complex to act as an MRI CA at
a relatively high concentration.
[a] The control value has been subtracted.
The interactions of complexes 1 and GdL1 with DNAwere
first studied by circular dichroism (CD). Figure 1A displays
CD spectra of calf-thymus DNA (CT-DNA) in the presence of
1. The dramatic decrease in ellipticity for both positive and
negative bands suggests that 1 can unwind the DNA helix and
[15]
lead to the loss of helicity through rotation of the bases.
However, GdL1 only induced a slight change in ellipticity (see
Figure S3), thus suggesting that it affects DNA mainly through
[16]
electrostatic interactions. Since the CD change induced by
[
17]
cisplatin is a slight increase in ellipticity of the positive band,
the DNA-binding mode of 1 appears to be different from that
of cisplatin. The interactions were further studied by using
supercoiled pUC19 plasmid DNA electrophoresis in a native
agarose gel. It is known that the binding of unwinding agents
to closed circular DNA can reduce its superhelical density and
À4
Figure 1. A) CD spectra of CT-DNA (1.0ꢀ10 m) in the presence of
at different [1]/[CT-DNA] molar ratios, and B) agarose-gel electro-
1
phoresis patterns of supercoiled pUC19 plasmid DNA (200 ng) after
incubation with 1 in a buffer (50 mm Tris–HCl, 50 mm NaCl, pH 7.4;
Tris=2-amino-2-hydroxymethylpropane-1,3-diol) at 378C for 12 h.
Lane 1: DNA control, lanes 2–6: DNA + 1 (20, 40, 60, 80, 100 mm,
respectively).
[18]
hence decrease the DNA migration rate in agarose gel.
Complex 1 caused a conspicuous decrease in the mobility of
1
3226 www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 13225 –13228

Angewandte
Chemie
2
partially dissociated in the cells, and that the released Pt
moieties effused from the cells or entered the nuclei more
readily than the Gd complexes. Interestingly, the Gd content
for 1 and 2 was apparently higher than that for GdL1 and
GdL2 in the cytoplasm, although the incubation concentra-
tion of 1 and 2 (40 mm) was much lower than that of GdL1 and
GdL2 (100 mm). This result suggests that the Pt units facilitate
the cellular uptake of the Gd complexes. Most gadolinium-
based CAs, including Gd–DTPA, are restricted to extracel-
[19]
lular spaces and lack the ability to accumulate within cells.
Herein we demonstrate that Gd–DTPA can be transformed
into a membrane-permeable intracellular CA by linking aryl
amine groups to the ligand, possibly by the minimization of
osmolality owing to their nonionic nature. To our surprise,
+
conjugation with cis-[Pt(NH ) Cl] further improved the
3
2
membrane permeability of the Gd complexes. In view of
their remarkable cellular uptake and appropriate dissociation
tendency (see above), these Pt–Gd complexes have the
potential to produce detectable MRI signals and cytotoxic
activity in cancer cells.
The cytotoxicity of 1 and 2 against the human breast
cancer MCF-7, the human non-small-cell lung cancer A549,
and the human cervical cancer HeLa cell lines are summar-
ized in Table 2 (see also Figure S5). Cisplatin was used as the
control. The inhibition efficacy of 1 and 2 is lower than that of
cisplatin towards these cell lines, particularly at low concen-
Figure 2. A) NMRD profiles of GdL1, GdL2, 1, 2, and Gd–DTPA
1
1 mm) at different magnetic-field-strength values at 378C, and B) T -
weighted MR images of 1 and 2 versus the concentration of Gd at
0.52 T and 378C.
(
III
solutions of 1 and 2 varied markedly, and the signal intensity
was positively correlated with the Gd concentration (Fig-
ure 2B). The minimum detection limit for 1 and 2 was 110 and
Table 2: IC50 (mm) values of complexes 1, 2, and cisplatin for MCF-7, A-
6
2 mm, respectively (see Table S3). Assays of a suspension of
5
49, and HeLa cancer cell lines at 48 h.
HeLa cells treated with 1 or 2 gave similar images; that is, the
signal intensity increased significantly as compared with that
of the untreated cellular suspension (see Figure S7). Under the
same conditions, 1 was somewhat less effective than 2. This
difference seems to be associated with their cellular-uptake
profiles (Table 1). The contrast effect decreased with time,
thus suggesting that some of the Gd complex was excreted
from the cells after releasing the Pt units. The results again
confirm that 1 and 2 can enter cancer cells.
Complex
Cell line
A549
MCF-7
HeLa
cisplatin
1
2
4.18Æ0.32
27.22Æ1.90
27.75Æ2.53
3.89Æ0.62
21.15Æ1.68
25.04Æ3.47
6.39Æ1.05
35.24Æ1.72
29.67Æ1.59
trations (1–50 mm). However, they exhibit similar efficacy to
that of cisplatin at a higher concentration of 0.1 mm (see
Figure S6). Such a concentration is sufficient for gadolinium-
based CAs to produce an effective contrast effect. Excessive
cytotoxicity would destroy the cells before the imaging
concentration was reached. Thus, 1 and 2 can fulfil the
cytostatic and imaging functions simultaneously within the
same dose. As expected, GdL1 and GdL2, or the residual
parts of 1 and 2 after loss of the Pt moieties, are almost
nontoxic towards these cell lines.
In vivo MR images were acquired at various time points
after the solutions of 1, 2, and Gd–DTPA were injected into
B6 mice, respectively. Complexes 1 and 2 induced more
evident MR-signal enhancement in the kidneys than Gd–
DTPA did under the same conditions (Figure 3). The signal
intensity attenuated gradually after 8 min for all complexes;
however, in comparison with Gd–DTPA, 1 and 2 can maintain
the intensity at relatively high levels for more than 1 h,
thereby providing the possibility of renal imaging over an
extended period of time. Since cisplatin can cause renal
Proton nuclear magnetic relaxation dispersion (NMRD) is
commonly used to evaluate the efficacy of potential MRI
[20]
[22]
CAs. Proton NMRD profiles of the relaxivity (r ), which is
tubular damage or dysfunction, many MRI methods have
1
defined as the longitudinal-relaxation-rate enhancement pro-
been developed to detect cisplatin-induced acute renal failure
in animal models. However, the imaging of small animals,
[21]
[23]
duced by a Gd complex at a concentration of 1 mm, are
shown in Figure 2A for GdL1, GdL2, 1, 2, and Gd–DTPA. All
new complexes demonstrated an increased relaxivity relative
such as mice, is quite difficult because the need for rapid
scanning severely limits the image resolution. The fast
accumulation and slow excretion of 1 and 2 in the kidneys
may offer an opportunity for the in situ detection of acute
renal injury caused by Pt drugs during treatment.
In conclusion, we have developed two bifunctional Pt–Gd
complexes as theranostic agents for cancer treatment. These
complexes partially dissociate in cancer cells to provide
cytostatic Pt moieties, whereas the residual Gd component
À1 À1
to the parent complex Gd–DTPA (4.3 mm s ). This increase
in relaxivity may be induced by the decreased rotational
mobility of the complexes. The high relaxivities of 1 and 2 at
À1 À1
2
0 MHz (ca. 6.3 mm s ) imply that they are potential T -
1
weighted MRI CAs for monitoring real-time drug distribution
during cancer treatment. This behavior was first verified by in
vitro assays. The T -weighted MR images for the cell-free
1
Angew. Chem. Int. Ed. 2014, 53, 13225 –13228
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 13227

.
Angewandte
Communications
[
1] X. Y. Wang, Z. J. Guo in Bioinorganic Medicinal Chemistry (Ed.:
E. Alessio), Wiley-VCH, Weinheim, 2011, pp. 97 – 149.
[
2] a) N. J. Farrer, J. A. Woods, L. Salassa, Y. Zhao, K. S. Robinson,
G. Clarkson, F. S. Mackay, P. J. Sadler, Angew. Chem. Int. Ed.
2010, 49, 8905 – 8908; Angew. Chem. 2010, 122, 9089 – 9092;
b) ꢀ. U. Miodragovi c´ , J. A. Quentzel, J. W. Kurutz, C. L. Stern,
R. W. Ahn, I. Kandela, A. Mazar, T. V. OꢁHalloran, Angew.
Chem. Int. Ed. 2013, 52, 10749 – 10752; Angew. Chem. 2013, 125,
10949 – 10952.
[
3] a) K. S. Lovejoy, R. C. Todd, S. Zhang, M. S. McCormick, J. A.
DꢁAquino, J. T. Reardon, A. Sancar, K. M. Giacomini, S. J.
Lippard, Proc. Natl. Acad. Sci. USA 2008, 105, 8902 – 8907; b) D.
Wang, G. Zhu, X. Huang, S. J. Lippard, Proc. Natl. Acad. Sci.
USA 2010, 107, 9584 – 9589.
[
4] T. Lammers, S. Aime, W. E. Hennink, G. Storm, F. Kiessling,
Acc. Chem. Res. 2011, 44, 1029 – 1038.
[
5] a) D. Griffith, M. P. Morgan, C. J. Marmion, Chem. Commun.
2009, 6735 – 6737; b) Z. Q. Xue, M. X. Lin, J. H. Zhu, J. F. Zhang,
Y. Z. Li, Z. J. Guo, Chem. Commun. 2010, 46, 1212 – 1214.
[
6] S. Ding, X. Qiao, G. L. Kucera, U. Bierbach, J. Med. Chem. 2012,
5
5, 10198 – 10203.
7] a) Y. Yuan, R. T. K. Kwok, B. Z. Tang, B. Liu, J. Am. Chem. Soc.
014, 136, 2546 – 2554; b) S. D. Wu, X. Y. Wang, C. C. Zhu, Y. J.
Song, J. Wang, Y. Z. Li, Z. J. Guo, Dalton Trans. 2011, 40, 10376 –
0382.
[
2
1
[
[
8] R. Weissleder, M. J. Pittet, Nature 2008, 452, 580 – 589.
9] J. Z. Wang, X. Y. Wang, Y. J. Song, J. Wang, C. L. Zhang, C. J.
Chang, J. Yan, L. Qiu, M. M. Wu, Z. J. Guo, Chem. Sci. 2013, 4,
2605 – 2612.
[
[
10] P. Caravan, Chem. Soc. Rev. 2006, 35, 512 – 523.
11] S. Laurent, C. Henoumont, L. Vander Elst, R. N. Muller, Eur. J.
Inorg. Chem. 2012, 1889 – 1915.
Figure 3. In vivo T -weighted MR images of B6 mice at 8 and 60 min
after the injection of 1, 2, and Gd–DTPA at a dose of 0.1 mmol Gd /
kg of body weight and the corresponding signal-decay curves. The
circles indicate the area of the kidneys.
[12] a) S. Kaida, H. Cabral, M. Kumagai, A. Kishimura, Y. Terada, M.
Sekino, I. Aoki, N. Nishiyama, T. Tani, K. Kataoka, Cancer Res.
2010, 70, 7031 – 7041; b) P. Mi, H. Cabral, D. Kokuryo, M. Rafi,
Y. Terada, I. Aoki, T. Saga, I. Takehiko, N. Nishiyama, K.
Kataoka, Biomaterials 2013, 34, 492 – 500.
1
III
[
13] E. L. Crossley, J. B. Aitken, S. Vogt, H. H. Harris, L. M. Rendina,
and the untouched complex can be used for imaging. The Pt
units can greatly improve the cellular uptake of Gd com-
plexes, and the proton relaxivities of the Pt–Gd complexes are
higher than that of Gd–DTPA under physiological conditions.
Furthermore, these complexes display the extraordinary trait
of biocompatibility: Their relatively low cytotoxicity enables
them to satisfy the tumor-imaging and inhibition require-
ments at the same dose. In particular, these complexes remain
longer in the kidneys of mice, which offers the possibility of
the noninvasive diagnosis of acute renal injury by nephrotoxic
platinum drugs in mice models, or probably, after further
development, in patients. In a more general sense, these
membrane-permeable complexes may be used to monitor the
temporal distribution of Pt drugs in vivo, to directly assess the
therapeutic response in situ, or to obtain diagnostic images for
preventing irreversible damage to patients.
Angew. Chem. Int. Ed. 2010, 49, 1231 – 1233; Angew. Chem.
2
010, 122, 1253 – 1255.
14] M. E. Oehlsen, Y. Qu, N. Farrell, Inorg. Chem. 2003, 42, 5498 –
506.
[
[
5
15] a) W. C. Johnson in Circular Dichroism: Principles and Appli-
cations (Eds.: K. Nakanishi, N. Berova, R. W. Woody), VCH,
New York, 1994, pp. 523 – 540; b) K. Karidi, A. Garoufis, N.
Hadjiliadis, J. Reedijk, Dalton Trans. 2005, 728 – 734.
[
[
[
16] S. P. Tang, L. Hou, Z. W. Mao, L. N. Ji, Polyhedron 2009, 28,
586 – 592.
17] M. Gay, ꢂ. M. MontaÇa, V. Moreno, M. J. Prieto, R. Llorens, L.
Ferrer, J. Inorg. Biochem. 2005, 99, 2387 – 2394.
18] M. V. Keck, S. J. Lippard, J. Am. Chem. Soc. 1992, 114, 3386 –
3390.
[
23]
[19] P. Caravan in Molecular and Cellular MR Imaging (Eds.:
M. M. J. Modo, J. W. M. Bulte), CRC, Boca Raton, FL, 2007.
pp. 13 – 36.
[
20] P. Caravan, J. J. Ellison, T. J. McMurry, R. B. Lauffer, Chem. Rev.
999, 99, 2293 – 2352.
1
Received: August 1, 2014
Published online: September 26, 2014
[
21] K. Kimpe, T. N. Parac-Vogt, S. Laurent, C. Piꢃrart, L. Vander
Elst, R. N. Muller, K. Binnemans, Eur. J. Inorg. Chem. 2003,
3021 – 3027.
[
22] H. Zhou, T. Miyaji, A. Kato, Y. Fujigaki, K. Sano, A. Hishida, J.
Lab. Clin. Med. 1999, 134, 649 – 658.
[
23] H. Kobayashi, S. Kawamoto, S. K. Jo, N. Sato, T. Saga, A. Hiraga,
J. Konishi, S. Hu, K. Togashi, M. W. Brechbiel, R. A. Star,
Kidney Int. 2002, 61, 1980 – 1985.
Keywords: antitumor agents · gadolinium · imaging agents ·
platinum · theranostic agents
.
1
3228 www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 13225 –13228