Niacin-ligated platinum(iv)-ruthenium(ii) chimeric complexes synergistically suppress tumor metastasis and growth with potentially reduced toxicity: In vivo

Article abstract of DOI:10.1039/c9cc09016a

Niacin-ligated platinum(iv)-ruthenium(ii) chimeric complexes (PtRu 1-4) have been synthesized and evaluated for their antitumor performance. Using the optimal complex, PtRu-1, we show that this water-soluble chimeric prodrug not only potently inhibits the metastasis and proliferation of tumor cells but also has an unexpectedly higher safety margin in animals compared with the traditionally-used, clinically approved drug cisplatin.

Full text of DOI:10.1039/c9cc09016a

View Article Online
View Journal
ChemComm
Chemical Communications
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: L. Shu, L. Ren, Y.
Wang, T. Fang, Z. Ye, W. Han, C. Chen and H. Wang, Chem. Commun., 2020, DOI:
1
0.1039/C9CC09016A.
Volume 54
Number
January 2018
Pages 1-112
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
1
4
ChemComm
Chemical Communications
rsc.li/chemcomm
Accepted Manuscripts are published online shortly after acceptance,
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
shall the Royal Society of Chemistry be held responsible for any errors
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
S. J. Connon, M. O. Senge et al.
Conformational control of nonplanar free base porphyrins:
towards bifunctional catalysts of tunable basicity
rsc.li/chemcomm

Page 1 of 5
Please d oC hn eo mt Ca do mj u ms t margins
View Article Online
DOI: 10.1039/C9CC09016A
ChemComm
COMMUNICATION
Niacin-Ligated Platinum(IV)-Ruthenium(II) Chimeric Complexes
Synergistically Suppress Tumor Metastasis and Growth with
Potentially Reduced Toxicity in Vivo
Received 00th January 20xx,
Accepted 00th January 20xx
a,b
b
a,c
d
d
b
Liwei Shu, Lulu Ren, Yuchen Wang, Tao Fang, Zhijian Ye, Weidong Han, Chao
DOI: 10.1039/x0xx00000x
e,
a,
Chen, * and Hangxiang Wang *
www.rsc.org/
Niacin-ligated platinum(IV)-ruthenium(II) chimeric complexes therapies into a single platinum platform that would be likely to
PtRu 1-4) have been synthesized and evaluated for their antitumor provide long-term survival benefit to patients.
(
performance. Using the optimal complex, PtRu-1, we show that this
water-soluble chimeric prodrug not only potently inhibits the
metastasis and proliferation of tumor cells but also has an
unexpectedly higher safety margin in animals compared with the
traditionally-used, clinically approved drug cisplatin.
Octahedral Pt(IV) complexes generally perform as prodrugs to
improve the therapeutic index relative to that of their parent Pt(II)
7
drugs. Through oxidizing planar Pt(II) drugs and subsequent
chemical derivatization of axial hydroxide ligands, toxic Pt(II)
compounds can be rationally engineered into clinically relevant
Chemotherapy is still used for the treatment of patients with cancer agents with enhanced efficacy and safety profiles. The presence of a
1
and has improved the life expectancy of countless patients.
hydroxyl group on the axial ligand makes this oxidized Pt(IV) species
8
Unfortunately, a large proportion of patients do not respond to this accessible for modification. To date, numerous bioactive agents,
treatment yet still experience substantial side effects as well as such as clinically approved drugs, enzyme inhibitors, and activators
tumor recurrence and metastasis. Chemotherapy generally is not or suppressors for signaling pathways, have been installed at the
capable of suppressing metastasis. More disappointingly, emerging axial positions of a Pt(IV) prodrug, yielding a synergistic effect with
evidence suggests that chemotherapeutics achieve local tumor cytotoxic platinum drugs. Pt(IV) prodrugs are inert outside tumor
2
9
control but occasionally promote the dissemination of cancer cells to cells but can be activated following intracellular reduction, thus
3
distant organs. Clinically, metastatic cancer accounts for the regenerating the Pt(II) complexes and the two axially ligated
majority (~90%) of human death.4 Platinum(II) (Pt(II)) complexes, bioactive agents.
9
including cisplatin, oxaliplatin, and carboplatin, have been
extensively used as a mainstay anticancer chemotherapy. These
agents induce DNA damage and arrest cell division, eventually
Recently, ruthenium (Ru)-based compounds have attracted a
surge of interest and been regarded as promising anticancer
5
1
0
candidates due to the diversity of their structures and functions.
leading to apoptotic cell death. However, the efficacy of these
platinum drugs in patients has been greatly compromised by dose-
limiting toxicity, inherent or acquired resistance, and tumor
1
1
Several groups, including ours, have reported that Ru complexes
possess unique activities, such as anti-metastasis and anti-
angiogenesis activities, that platinum agents do not possess. More
intriguingly, Ru complexes generally exhibit a lower systemic toxicity
1
1
6
recurrence and metastasis. Systemic administration of platinum
agents results in prolonged local tumor control but is unable to
1
2
than other metallodrugs.
imiH]trans-[Ru(N-imi)(S-dmso)Cl
have efficient anti-metastatic activity, although this agent had
As
a well-documented example,
7
inhibit treatment escape pathways. To address these unmet medical
[
4
] (NAMI-A) was demonstrated to
needs, we attempted to combine anti-metastatic and cytotoxic
1
3
negligible cytotoxicity in preclinical studies. Specifically, Ru(II)-
arene complexes have shown remarkable efficacy against
a
The First Affiliated Hospital; Key Laboratory of Combined Multi-Organ
1
4
metastases.
Transplantation, Ministry of Public Health, School of Medicine, Zhejiang
University, Hangzhou, 310003, P. R. China.
Inspired by these findings, we employed the Pt(IV) prodrug
approach to facilitate the incorporation of Ru(II) species with anti-
metastatic capacity to address the limitations of platinum agent-
based therapies. In addition to combined cytotoxic and anti-
metastatic mechanisms, this class of hetero-nuclear hybrid
complexes showed substantially reduced toxicity in animals, thus
deserving further exploration in terms of dose intensification and
clinical translation.
E-mail: wanghx@zju.edu.cn
Department of Medical Oncology; Sir Run Run Shaw Hospital; School of
b
Medicine, Zhejiang University, Hangzhou, 310016, P. R. China.
c
Department of Chemical Engineering, Zhejiang, University, Hangzhou, P. R.
China.
d
Jinhua People’s Hospital, Jinhua, Zhejiang Province, 321000, P. R. China
College of Life Sciences, Huzhou University, Huzhou, 313000, P. R. China.
e
E-mail: chenc@zjhu.edu.cn
†Electronic Supplementary Information (ESI) available: Experimental details
and supplementary figures. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
Chem. Commun., 2019, 00, 1-4 | 1
Please do not adjust margins

Please d oC hn eo mt Ca do mj u ms t margins
Page 2 of 5
COMMUNICATION
ChemComm
N
1
for at least 24 days as evidenced by H NMR measurements (Figure
O
O
View Article Online
O
Cl
Cl
S15). We further incubated PtRu-1 with eDxOcIe:s1s0.1e0q3u9i/vC9oCfCs0o9d0i1u6mA
ascorbate to mimic the intracellular reduction. As a result, the
formation of Ru-3 was observed in H NMR spectroscopy, supporting
the reduction-triggered release of active drugs (Figure S16).
N
O
N
Cl
Ru
Ru
OH
Pt
O
Pt
O
Ru
Cl
N
Cl
Cl
NH3
NH3
2.1 eq
Cl
Cl
NH3
NH3
Cl
Cl
Ru-1
1.5 eq
DMF, dark, RT
O
1
OH
12 h, N2
O
DMF,
O
Pt
O
dark,
h, N2
Cl
Cl
NH3
NH3
12
RT
O
N
Pt-1
O
O
We next evaluated the cytotoxicity of these compounds against
human cancer cell lines, including the ovarian carcinoma A2780, lung
carcinoma A549, gastric cancer SGC7901, and colon cancer LoVo cell
lines. After exposing cells to the compounds for 72 h, the cell viability
was determined by a standard MTT assay, and the half-maximal
inhibitory concentrations (IC50) were extrapolated from the dose-
response curves (Table 1 and Figure S17-20, ESI†). Ru-based
compounds (i.e., Ru-1, Ru-2, and Ru-3) alone did not produce
inhibition of cancer cells after treatment at 128 μM, suggesting low
cytotoxicity. Moreover, Pl(IV) species such as Pt-1 and Pt-2 showed
moderate activity in cells, probably due to reduced cellular uptake
and the reduction required to convert inert Pt(IV) into active Pt(II).
Interestingly, among the four complexes, PtRu-1 was the most
effective based on extrapolation from the in vitro dose-response
curves. Compared with that of the other complexes, the increased
cytotoxicity of PtRu-1 could be attributable to the lipophilicity
imparted by niacin derivatives. We therefore used PtRu-1 for further
investigation.
O
N
O
O
Cl
N
3
.3 eq
Cl Cl
Ru-1
.5 eq
Cl Ru
1
N
O
Pt
O
N
Ru
OH
NH
3
HO
Ru
N
3
Cl
Cl
Cl
O
H
O
Cl
PtRu-1
PtRu-2
N
Cl
Cl
Ru-2
1.5 eq
O
Ru
O
O
Ru
Cl
OH
Cl
Cl Cl
O
O
O
Pt
O
Cl
Cl
NH3
NH3
OH
N
O
Pt
O
NH HO
N
Ru
OH
Ru
N
3
DMF, dark, RT
12 h, N2
Cl
3
Cl
Cl
O
H
O
Cl
PtRu-3
O
N
Pt-2
Cl
Ru
O
O
Ru-1
.5 eq
Cl Cl
Cl
0
N
O
Pt
O
N
O
N
Ru
Cl
OH
NH
HO
N
3
Cl
3
H
HO
O
O
Ru-3
PtRu-4
Scheme 1. Synthetic route and chemical structures of Pt(IV)-Ru(II)
complexes.
To elucidate the mechanism of action causing cell death, the
acridine orange (AO)/ethidium bromide (EB) assay was used to
examine cell apoptosis. AO penetrates the membrane of both live
and dead cells and emits green fluorescence, while EB only enters
necrotic cells with damaged membranes, emitting red fluorescence.
Thus, in this assay, necrotic and late apoptotic cells fluoresced
orange, and early apoptotic and healthy cells appeared green. We
found that late apoptosis, characterized by orange nuclear
fragmentation, appeared in A2780 cells treated with cisplatin and
the PtRu-1 complex (Figure 1a). Further quantification validated the
superiority of PtRu-1 in terms of apoptosis-inducing capacity;
however, the difference was not statistically significant (Figure 1b).
An Alexa Fluor 488 annexin V/propidium iodide (PI) staining assay in
A2780 cells confirmed that cell death induced by PtRu-1 was indeed
due to apoptosis (Figure S21a and S21b, ESI†). Furthermore, cell
cycle analysis indicated that PtRu-1 treatment arrested the cells in
G2 phase, whereas cisplatin blocked the cells at S phase (Figure S21c
and S21d), probably due to the cytotoxic effect induced by Ru
complexes.
To proceed toward this goal, we chose nicotinic acid (niacin, also
known as vitamin B or vitamin PP) and its derivatives as ligands to
3
ligate two metal centers. This class of compounds has a nitrogen in
the pyridine ring that can be coordinated through an electron-
1
5
donating pair and does not cause side effects in humans. Moreover,
Ru-1 (i.e., p-cymene Ru(II) dichloride dimer) or Ru-2 (i.e.,
Hexamethylbenzene Ru(II) dichloride dimer) was selected as the
antimetastatic precursor to coordinate with niacin. Accordingly, we
constructed four niacin-ligated Pt(IV)-Ru(II) chimeric complexes, as
shown in Scheme 1. First, the oxidation of cisplatin with 30%
hydrogen peroxide yielded the Pt(IV) pedestal (c,c,t-
[
Pt(NH
high yield (99%).
with nicotinic
Cl (nicotinate)
was generated under mild conditions through complexing Pt-1 with
3 2 2 2
) Cl (OH) ]) intermediate with two axial hydroxyl groups at a
7
b, 16
Second, modification of the hydroxyl moiety
anhydride generated Pt-1 (c,c,t-
]) at a yield of 45%. Finally, the adduct PtRu-
[
1
Pt(NH )
3 2
2
2
Ru-1 and was purified by silica gel chromatography. Using a similar
protocol, the hybrid Pt(IV)-Ru(II) complexes PtRu-2, 3, and 4 were
also synthesized. All reactions involving metallic elements and the
storage of compounds were carefully conducted in the dark. The
detailed synthetic procedures and characterization using NMR
spectroscopy, infrared absorption spectra, and mass spectra are
provided in the supporting information (Figure S1-S13, ESI†). In
addition, we attempted to crystalize these Pt(IV)-Ru(II) complexes
but unfortunately failed to obtain single crystals. Thus, only the
structure of intermediate Pt-1 was confirmed by the single-crystal X-
ray structure analysis (Figure S14, Table S1, and S2, ESI†). The
complexes PtRu-1-4 were stable over several months when stored at
room temperature and showed no degradation, as determined by
HPLC analysis. Furthermore, choosing PtRu-1 as a model compound,
we found that this compound remained stable in the DMSO solvent
Metastasis remains the major cause of death and is associated
17
with poor prognosis of cancer patients. Unfortunately, there is no
effective therapy despite significant advances in new anticancer
strategies. Migration and invasion are crucial steps in metastatic
colonization, known as the invasion-metastasis cascade. Previous
studies indicated that Ru-based metallodrugs have the ability to
18
inhibit tumor cell metastasis. Using PtRu-1 as a target complex, we
investigated its potential to inhibit the migration and invasion of
cancer cells. A Transwell assay (invasion assay) verified that the PtRu-
1
and Ru-3 complexes reduced the number of human umbilical vein
endothelial cells (HUVECs) that penetrated through Matrigel (Figure
c and 1d). In a wound-healing assay (migration assay), the cell
1
Cell line
Cisplatin
Pt-1
Pt-2
Ru-1
Ru-2 Ru-3
PtRu-1
PtRu-2
PtRu-3
PtRu-4
SGC7901 8.19±1.99 14.01±0.65 76.27±22.73 90.00±13.36 >128 >128 1.81±0.14 1.95±0.53
30.75±7.43
68.29±7.77
6.79±0.68
6.00±0.68
5.40±0.54
LoVo
A2780
A549
6.32±0.24 35.73±1.64
2.86±0.10 6.57±0.62
4.90±0.30 14.72±1.28
23.66±2.75
8.98±1.31
20.95±1.37
>128
>128
>128
>128 >128 1.35±0.15 28.69±1.47
>128 >128 6.52±0.64 14.92±1.20 28.49±2.207
>128 >128 6.57±0.58 14.89±0.76 43.27±11.25 14.86±1.51
Table 1. In vitro cytotoxicity of Pt(IV)-Ru(II) complexes. Cell viability was determined by an MTT assay after a 72-h treatment (expressed as
IC50 ± SD in μmol/L).
2
| Chem. Commun., 2019, 00, 1-4
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 5
Please d oC hn eo mt Ca do mj u ms t margins
ChemComm
COMMUNICATION
migration of A2780 cancer cells (Figure 1e) and HUVECs (Figure S22, weight in ICR mice (Figure 2a). Higher doses, such as 5Vieowr A1r0ticmle Og/nklinge,
ESI†) was clearly reduced after drug treatment. Moreover, PtRu-1 of cisplatin caused mouse death. Very encouDrOagI:i1n0g.1ly0,3t9h/eC9mCiCc0e9w01e6rAe
exhibited a higher suppression rate than Ru-3 in A2780 cells (Figure able to tolerate PtRu-1 at a dose of 77 mg/kg, which is equivalent to
1
f).
20 mg/kg of cisplatin, representing at least an 8-fold increase in the
maximum tolerated dose (MTD) compared to that of clinically used
cisplatin. Histological analysis was performed to examine the
potential organ damage produced by different treatments. As shown
in Figure 2b, in kidneys, cisplatin treatment (2.5 mg/kg) caused
extensive atrophy of the renal capsule, accompanied by the
disappearance of Bowman's space and the loss of cell polarity.
Moreover, cytoplasmic relaxation and vacuolization (accumulation
of white vesicles) indicated hydropic degeneration in liver
parenchyma as well as the high toxicity of cisplatin. Noticeably,
organs excised from the mice receiving PtRu-1 at an 8-fold cisplatin-
equivalent dose (20 mg/kg) still presented normal histopathological
features that were similar to those in saline-treated mice (Figure 2b
and Figure S25, ESI†).
Tumor growth and metastasis require angiogenesis and formation
1
9
of microvessels to provide oxygen and nutrients. Thus, we
examined the inhibitory effect of PtRu-1 on in vitro angiogenesis
using the Matrigel tube formation assay. The tube-forming ability of
HUVECs was significantly impeded by treatment with the PtRu-1 and
Ru-3 complexes, whereas cisplatin did not have an inhibitory effect
(
Figure S23 and S24, ESI†). Collectively, these in vitro results provide
compelling evidence that ruthenium-based agents retained anti-
metastasis and anti-angiogenesis capacities irrespective of the
complex coordination.
Figure 2. Evaluation of drug toxicity in healthy ICR mice. a) Body
weight changes in different treatment groups. b) Histological
examination of organs excised from the ICR mice. Green and red
arrows indicate normal and damaged glomeruli, respectively. Scale
bars: 100 μm.
Figure 1. a) In vitro cytotoxicity examined by AO/EB double staining
assay after the treatment with different concentrations of cisplatin
and PtRu-1. b) Quantification of the percentage of apoptotic cells. c)
Ru complexes Ru-3 and PtRu-1 inhibit the invasion of HUVECs. The
cells that passed through the Matrigel appear violet when observed
under the microscope. d) Quantification of penetrated cells. e)
Migration of A2780 cells after the treatment with PtRu-1 and Ru-3
for 80 h as determined by a wound-healing assay. Culture medium
with 1% FBS. f) Migration capability expressed as the percentage of
the distance that cells moved compared with that of untreated cells.
ns, not significant, **p<0.01, ***p<0.001. Scale bars: 200 μm.
Ovarian cancer is the second most common cause of malignancy-
caused death among women because of its high capacity for
20
metastasis and invasion in cancer patients. We thus evaluated the
therapeutic efficacy of PtRu-1 using a transcoelomic metastatic
A2780 ovarian cancer model in Balb/c nude mouse (Figure S26, ESI†).
In this model, A2780 cells are intraperitoneally injected into mice,
which enables to form primary tumors throughout the abdomen.
Subsequently, these aggressive cancer cells potentially metastasize
21
to the organs including the ovary, liver, and spleens. Considering
the difference in drug tolerance between Balb/c and ICR mice, we
administered cisplatin at a dose equivalent to the 30% MTD observed
in ICR mice. At the end of the study, mice were sacrificed, and tumors
in abdominal cavities (primarily in mesenteries) were excised for
analysis. The ovaries, livers, and spleens were also collected for
quantification. Compared with cisplatin treatment, PtRu-1 at a low
dose of 0.75 mg/kg was more effective in terms of reducing the
number of abdominal tumors and the total tumor number, but the
difference was not statistically significant. Because PtRu-1 had a
higher safety margin than cisplatin, we thus increased the dosages to
Due to the inertness of Pt(IV) complexes, we expected that these
chimeric complexes would be able to alleviate the systemic toxicity
induced by conventional platinum drugs. By choosing PtRu-1 as a
target complex, we assessed drug tolerability in animals in a dose
escalation manner. Healthy ICR mice were given five doses of PtRu-
1
via intraperitoneal injection. As controls, saline and cisplatin were
also injected. The change in body weight and mouse death were
monitored following injections over period of 15 days.
a
Unfortunately, only a dose of 2.5 mg/kg of cisplatin could be
tolerated, which also caused a significant drop (~12.4%) in body
1
.5 and 3 mg/kg in this model to assess the efficacy. Impressively,
This journal is © The Royal Society of Chemistry 20xx
Chem. Commun., 2019, 00, 1-4 | 3
Please do not adjust margins

Please d oC hn eo mt Ca do mj u ms t margins
Page 4 of 5
COMMUNICATION
ChemComm
administration of PtRu-1 at both tolerable doses significantly 1. R. L. Siegel, K. D. Miller and A. Jemal, CA Cancer J. Clin., 2019, 69,
View Article Online
7
-34.
reduced primary tumor growth (Figure 3a, 3b and 3c) as well as
metastasis to other organs (Figure 3a, 3d and 3e). Moreover, at all
treatment doses of PtRu-1, the low drug toxicity and the tolerability
in nude mice was supported by stable body weights (Figure 3f).
Specifically, the reduction in metastatic burden could benefit the
long-term survival of patients when considering future use in the
clinic. Together, these data demonstrate that the hybrid Pt(IV)-Ru(II)
DOI: 10.1039/C9CC09016A
2
3
.
.
N. Muhammad and Z. Guo, Curr. Opin. Chem. Biol., 2014, 19, 144-
1
53.
G. S. Karagiannis, J. S. Condeelis and M. H. Oktay, Cancer Res.,
2019, 79, 4567-4576.
4
5
6
.
.
.
N. McGranahan and C. Swanton, Cell, 2017, 168, 613-628.
L. Kelland, Nat. Rev. Cancer, 2007, 7, 573-584.
R. Oun, Y. E. Moussa and N. J. Wheate, Dalton Trans., 2018, 47,
6
645-6653.
complex not only inhibited the growth of bulky primary tumors but 7. X. Wang, X. Wang, S. Jin, N. Muhammad and Z. Guo, Chem. Rev.,
also reduced the potential of metastasis to distant organs, thereby
validating this design rationale for generating multifunctional
anticancer agents with excellent in vivo tolerability.
2019, 119, 1138-1192.
8
.
(a) T. C. Johnstone, K. Suntharalingam and S. J. Lippard, Chem.
Rev., 2016, 116, 3436-3486; (b) S. Dilruba and G. V. Kalayda,
Cancer Chemoth. Pharm., 2016, 77, 1103-1124.
9
1
.
Z. Xu, J. Zhao, S. Gou and G. Xu, Chem. Commun., 2017, 53, 3749-
3
752.
0. (a) L. Zeng, P. Gupta, Y. Chen, E. Wang, L. Ji, H. Chao and Z. S.
Chen, Chem. Soc. Rev., 2017, 46, 5771-5804; (b) A. Notaro and G.
Gasser, Chem. Soc. Rev., 2017, 46, 7317-7337; (c) C. Chen, S. L.
Ni, Q. Zheng, M. F. Yu and H. X. Wang, Eur. J. Inorg. Chem., 2017,
3
, 616-622.
1
1. (a) S. Thota, D. A. Rodrigues, D. C. Crans and E. J. Barreiro, J. Med.
Chem., 2018, 61, 5805-5821; (b) H. Lai, Z. Zhao, L. Li, W. Zheng
and T. Chen, Metallomics, 2015, 7, 439-447; (c) R. H. Berndsen,
A. Weiss, U. K. Abdul, T. J. Wong, P. Meraldi, A. W. Griffioen, P. J.
Dyson and P. Nowak-Sliwinska, Sci. Rep., 2017, 7, 43005.
1
1
2. M. K. Mohamed Subarkhan, L. Ren, B. Xie, C. Chen, Y. Wang and
H. Wang, Eur. J. Med. Chem., 2019, 179, 246-256.
3. (a) A. Bergamo and G. Sava, Chem. Soc. Rev., 2015, 44, 8818-
8
835; (b) S. Leijen, S. A. Burgers, P. Baas, D. Pluim, M. Tibben, E.
van Werkhoven, E. Alessio, G. Sava, J. H. Beijnen and J. H.
Schellens, Invest. New Drugs, 2015, 33, 201-214.
Figure 3. Therapeutic efficacy of PtRu-1 in a Balb/c nude mouse
model bearing human ovarian A2780 cancer cells. a) Representative
ovaries and tumors excised from the mice in each group at the
endpoint of the study. Treatment regimens: Saline (①); Ru-3, 6
mg/kg (②); cisplatin, 0.75 mg/kg (③); PtRu-1, 0.75 (④), 1.5 (⑤)
and 3 (⑥) mg/kg (cisplatin equivalent). Abdominal tumor weights
1
4. (a) C. Scolaro, A. Bergamo, L. Brescacin, R. Delfino, M. Cocchietto,
G. Laurenczy, T. J. Geldbach, G. Sava and P. J. Dyson, J. Med.
Chem., 2005, 48, 4161-4171. (b) Y. K. Yan, M. Melchart, A.
Habtemariam and P. J. Sadler, Chem. Commun., 2005, 38, 4764-
4776.
1
1
5. (a) V. Gasperi, M. Sibilano, I. Savini and M. V. Catani, Int. J. Mol.
Sci., 2019, 20; (b) E. T. Bodor and S. Offermanns, Br. J.
Pharmacol., 2008, 153 Suppl 1, S68-75.
(
b), abdominal tumor numbers (c), ovarian weights (d), and total
numbers of tumors excised from the abdominal cavity, liver, and
spleen (e) in each mouse group. f) Body weight changes in the mice
after receiving the treatments. *p<0.01, **p<0.01, ***p<0.001.
6. Q. Chen, Y. Yang, X. Lin, W. Ma, G. Chen, W. Li, X. Wang and H.
Wang, Chem. Commun., 2018, 54, 5369-5372.
17. A. W. Lambert, D. R. Pattabiraman and R. A. Weinberg, Cell, 2017,
1
68, 670-691.
1
1
8. X. Zhao, L. Li, G. Yu, S. Zhang, Y. Li, Q. Wu, X. Huang and W. Mei,
Comput. Struct. Biotechnol. J., 2019, 17, 21-30.
Combinations of multiple therapies with distinct mode-of-action
in single platforms hold great promise for synergistically addressing
9. D. Hanahan and R. A. Weinberg, Cell, 2011, 144, 646-674.
the issues of tumor recurrence and metastasis. In this study, we 20. (a) L. A. Torre, B. Trabert, C. E. DeSantis, K. D. Miller, G. Samimi,
C. D. Runowicz, M. M. Gaudet, A. Jemal and R. L. Siegel, CA Cancer
J. Clin., 2018, 68, 284-296; (b) S. Lheureux, M. Braunstein and A.
M. Oza, CA Cancer J. Clin., 2019, 69, 280-304.
successfully constructed Pt(IV)-Ru(II) hybrid chimeric complexes that
combine a Pt(IV) prodrug approach and a hetero-nuclear active
center to address multiple challenges posed by Pt(II)-based
chemotherapy. Among the four synthesized complexes, we
identified PtRu-1 as a potent agent that spanned cytotoxic and anti-
invasive mechanisms according to numerous in vitro and in vivo
results. Further investigation revealed the substantially alleviated
systemic toxicity of PtRu-1 in animals, showing at least an 8-fold
increase in the MTD relative to cisplatin. The unexpectedly high MTD
could be associated with the low toxicity of the Pt(IV) species and the
2
2
1. (a) T. J. Shaw, M. K. Senterman, K. Dawson, C. A. Crane and B. C.
Vanderhyden, Mol. Ther., 2004, 10, 1032-1042; (b) M. Zhu, R. E.
Saxton, L. Ramos, D. D. Chang, B. Y. Karlan, J. C. Gasson and D. J.
Slamon, Mol. Cancer Ther., 2011, 10, 1500-1508.
2. (a) S. Betanzos-Lara, A. Habtemariam, G. J. Clarkson and P. J.
Sadler, Eur. J. Inorg. Chem., 2011, 46, 3257-3264; (b) R. Zhang, X.
Q. Song, R. P. Liu, Z. Y. Ma and J. Y. Xu, J. Med. Chem., 2019, 62,
4543-4554.
2
2
Ru(II) ligands. We foresee that this molecular design approach
holds the potential to yield additional clinically translatable
multimetallic agents that can combat metastatic cancer.
This work was supported by the Zhejiang Province Preeminence
Youth Fund (No. LR19H160002), the National Natural Science
Foundation of China (Nos. 81773193 and 81571799), the Science and
Technology Research Program of Jinhua City (2017-3-020), and the
Social Development Project of Public Welfare Technology Research
in Zhejiang Province (2017c37139).
Conflicts of interest
There are no conflicts to declare.
Notes and references
4
| Chem. Commun., 2019, 00, 1-4
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
ChemComm
View Article Online
DOI: 10.1039/C9CC09016A
Table of Contents:
The chimeric Pt(IV)-Ru(II) complex was designed to simultaneously release
cytotoxic cisplatin and antimetastatic Ru(II)-arene compound, thereby
producing potent anticancer activity with high drug tolerability in animals.