An aminophosphonate ester ligand-containing platinum(ii) complex induces potent immunogenic cell death: In vitro and elicits effective anti-tumour immune responses in vivo

Article abstract of DOI:10.1039/c9cc06563f

A platinum(ii) complex containing an aminophosphonate ligand preferentially accumulates in the endoplamic reticulum (ER) in association with potent ER stress and reactive oxygen species generation, followed by the activation of damage-associated molecular pattern signals and immune responses. Importantly, the Pt complex exhibits potent anti-tumour activities in two independent mouse models via an immunogenic cell death pathway.

Full text of DOI:10.1039/c9cc06563f

Volume 55 Number 87 11 November 2019 Pages 13019–13186
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Taotao Zou, Zhen-Feng Chen, Hong Liang et al.
An aminophosphonate ester ligand-containing platinum(II)
complex induces potent immunogenic cell death in vitro
and elicits effective anti-tumour immune responses in vivo

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An aminophosphonate ester ligand-containing
platinum(II) complex induces potent immunogenic
cell death in vitro and elicits effective anti-tumour
immune responses in vivo†
Cite this: Chem. Commun., 2019,
55, 13066
Received 23rd August 2019,
Accepted 23rd September 2019
Ke-Bin Huang, ‡a Feng-Yang Wang,‡b Hai-Wen Feng,a Hejiang Luo,c Yan Long,c
DOI: 10.1039/c9cc06563f
cd
Taotao Zou,
*
Albert S. C. Chan,c Rong Liu,a Huahong Zou,a
a
Zhen-Feng Chen,*a Yan-Cheng Liu,a You-Nian Liub and Hong Liang
*
rsc.li/chemcomm
A platinum(II) complex containing an aminophosphonate ligand pre- complexes. Only a handful of metal-based ICD compounds
ferentially accumulates in the endoplamic reticulum (ER) in association have been reported, including a luminescent cyclometallated
with potent ER stress and reactive oxygen species generation, followed Pt complex,19 KP1019,20 and a Pt(IV) prodrug containing an
by the activation of damage-associated molecular pattern signals and oxaliplatin framework.21
immune responses. Importantly, the Pt complex exhibits potent anti-
Many calcium storage proteins, including calreticulin (CRT), are
tumour activities in two independent mouse models via an immuno- localized in the ER which thus carries a high concentration of Ca2+;
genic cell death pathway.
disruption of calcium homeostasis has been reported to cause ER
stress and to promote CRT exposure to the cell membrane, which
Cisplatin and its derivatives have received worldwide attention serves as an ‘‘eat me’’ signal to be recognized by phagocytic dendritic
in clinical cancer treatment.1–4 Their mechanisms of action are cells, subsequently eliciting other immune cells to respond.22–24
considered to involve DNA binding via forming Pt-guanine Phosphate/phosphonate-containing compounds are known to pos-
adducts in association with downstream DNA damage and strand sess mineral calcium-targeting properties25–27 and are able to alter
break-mediated apoptosis.5,6 Besides directly killing cancer cells, calcium trafficking in cells.28 As many labile Pt(II) complexes are able
oxaliplatin, the third-generation cisplatin analogue, has been to induce ROS,29,30 we assume that the Pt(II) complexes bearing an
reported to induce immunogenic cell death (ICD) by activating aminophosphonate ligand could potentially trigger ICD through
innate and adaptive immune responses, which is likely caused by ER targeting and ROS generation.31,32 Herein we report a novel
targets other than DNA.7,8 The tumour-specific immune responses platinum(II) complex containing an aminophosphonate ester ligand
evoked by ICD inducers endow a ‘‘second hit’’ to the residual cancer displaying a lipophilicity amenable to bioactivity and inducing
cells which were not killed by the original drug cytotoxicity.9–11 potent ER stress accompanied by ROS generation, subsequently
As a result, a long-term therapeutic benefit from ICD may be triggering immunogenic responses that kill cancer cells. Importantly,
possible.12–15 This has inspired a growing interest to develop more the Pt complex displays a low acute toxicity while effectively suppres-
promising ICD-inducing complexes.16–18 Unfortunately, the last sing tumour growth in a vaccination mouse model and a tumour-
10 years witnessed very slow advances in developing novel ICD bearing mouse model.
We synthesized 12 novel aminophosphonate–platinum(II)
complexes (Fig. 1) with full characterization by 1H NMR,
a State Key Laboratory for Chemistry and Molecular Engineering of Medicinal
ESI-MS and elemental analysis (see details in the synthesis
section and Fig. S1 and S2, ESI†). We also performed X-ray
crystallography on 9 complexes (Fig. S3 and Table S1 in ESI†).
The three types of complexes differ in the number of CH2 units
between the benzene ring and the imide that coordinates to the
Pt center. These Pt complexes are well dissolved in common
organic solvents such as DMF and DMSO and are soluble in
PBS after dilution from DMSO stock solution (1% DMSO unless
otherwise stated33). The stability test by HPLC demonstrated
that the Pt complexes are stable for 48 h at room temperature
under physiological conditions (Tris–KCl–HCl buffer, pH 7.35,
Fig. S4, ESI†).
Resources, School of Chemistry & Pharmacy, Guangxi Normal University, Guilin,
Guangxi, 541004, P. R. China. E-mail: chenzf@gxnu.edu.cn, hliang@gxnu.edu.cn
b College of Chemistry and Chemical Engineering, Central South University,
Changsha, Hunan 410083, P. R. China
c Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of
Pharmaceutical Science, Sun Yat-sen University, Guangzhou 510006, China.
E-mail: zoutt3@mail.sysu.edu.cn
d School of Science and Engineering, The Chinese University of Hong Kong,
Shenzhen 518172, China
† Electronic supplementary information (ESI) available: Synthesis and character-
ization of complexes, procedures for ICD-related experiments and supporting
figures. CCDC 1542728–1542736. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c9cc06563f
‡ These authors contributed equally.
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Fig. 1 chemical structures of the Pt(II) complexes. The racemic mixtures
were used for biological studies.
Fig. 2 The activation of DAMPs in T-24 cells after Pt-1 treatment. (a) Flow
cytometry analysis of CRT on the surface of T-24 cells treated with solvent
control or 0.5 mM Pt-1 for 2 h. (b) The ATP concentration in culture
medium after treating T-24 cells with 0.5 mM of Pt-1 as measured by
luciferase assay. (c) Levels of HMGB1 in culture medium (S-HMGB1) and in
cells (C-HMGB1) after incubating T-24 cells with 0.5 mM of Pt-1.
The complexes generally display cytotoxicity against different
cancer cells, including urinary bladder transitional cell carcinoma
(T-24), bone osteosarcoma (MG-63), hepatocellular carcinoma
(HepG2), and ovarian cancer (SK-OV-3), with IC50 ranging from
0.25–88.7 mM in a 48 h treatment (Table S2, ESI†). These values are
generally smaller than that in normal human liver cells (HL-7702).
As shown in Table S2 (ESI†), the cytotoxicity is decreased by
lowering the lipophilicity from –Cl, to –H to –OMe substituents
Conditions of stress can stimulate damage-associated mole-
for the same type of complexes. Additionally, the electron-inductive cular patterns (DAMPs) that recruit immune cells.13 We treated
effects play a rather important role: the presence of an electron- T-24 cells with 0.5 mM Pt-1 and labelled non-permeabilized cells
withdrawing –Cl moiety at the para-position of aniline (Pt-1, 1) or with an anti-CRT antibody. Fluorescence microscopy revealed
pyridine (Pt-1, 3) significantly improves the cytotoxicity whereas the an intense immunofluorescence distributed in uneven clusters
electron-donating –OMe moiety adversely decreases the cytotoxicity on the undamaged cell surface after 2 h (Fig. S10, ESI†), while
(2, 3). Complex Pt-1, in which the aminophosphonate-pyridine in the control group without Pt-1 treatment, no immunofluor-
ligand contains two Cl atoms that are most electron-withdrawing escence was detected. This elevated surface immunofluores-
and are most lipophilic, exhibits the highest cytotoxicity against cence intensity is confirmed by flow cytometry experiments, in
cancer cells and the largest fold-difference (450-fold) compared to which 43.1% of treated cells displayed a higher fluorescence
normal cells. For comparison, the aminophosphonate-pyridine intensity than the control group (Fig. 2a). As anticipated, secre-
ligand displays a much lower cytotoxicity (Fig. S5, ESI†). Since tion of HMGB1 and ATP, another two DAMP signals, was clearly
the Pt complexes display strong cytotoxicity against bladder transi- evident (Fig. 2b and c). A firefly luciferase assay reveals a time-
tional cell carcinoma that are also suitable to establish immune dependent ATP secretion of up to 72.1 nM in the culture medium
tumour models, bladder cancer cells were used in the following after 12 h treatment with Pt-1. Also, a gradual increase in secreted
biological activity studies.
HMGB1 (S-HMGB1) was found by Western blot analysis in the
To examine whether the phosphonate ester is hydrolysed culture medium after treating T-24 cells with 0.5 mM Pt-1 for 24 h.
in vitro, we incubated T-24 cells with Pt-1 for 24 h. The ESI-MS This was accompanied by a time-dependent reduction in cellular
analysis of the supernatant after ethanol precipitation of cell HMGB1 (C-HMGB1). While under similar conditions, cisplatin
lysates showed the presence of mono- and bi-hydrolyzed phos- did not obviously elicit these DAMP signals (Fig. S11, ESI†).
phonate with one Pt–Cl bond hydrolysis (Fig. S6, ESI†). The ICP-
To study the effects of Pt-1-induced DAMPs on immune
MS of subcellular fractions from Pt-1-treated T-24 cells after activity, we treated T-24 cancer cells with 0.5 mM Pt-1 for 48 h,
24 h (Fig. S7, ESI†) shows a major localization of the complex to and used the cell-conditioned-culture medium (supernatant) to
the ER (2.20 ꢀ 0.18 ng Pt per million cells) over the mitochon- test its effects on immune cells.10 We first examined the activity
dria (0.80 ꢀ 0.26) and nucleus (0.94 ꢀ 0.15). This ER accumula- on the maturation of dendritic cells, since mature dendritic cells
tion may be attributed to the ER’s high concentration of Ca2+
,
(mDCs) are one of the major antigen presenting cells.34 The
which has a high affinity for phosphonate.25 By Western blot imDCs isolated from human peripheral blood mononuclear cells
analysis, we observed a protein profile characteristic of ER (PBMCs) were incubated with Pt-1-treated cell-conditioned culture
stress, including the expression of phosphorylated protein medium. Western blot analysis (Fig. 3a) revealed an increased
kinase RNA-like endoplasmic reticulum kinase (PERK), phos- expression of the DC maturation marker, CD83, on the surface of
phorylated eukaryotic initiation factor 2a (eIF2a), and C/EBP non-permeabilized DCs after 4 h, which gradually increased after
homologous protein (CHOP), in T-24 cells treated at an IC50 12 and 24 h. The surface expression of CD80, another important
concentration (0.5 mM) of Pt-1 for 48 h (Fig. S8, ESI†). This DC maturation marker, exhibited a similar trend.12 We next
treatment is also associated with a time-dependent increase in assessed the extracellular levels of the proinflammatory cytokines
ROS, as indicated by 20,70-dichlorodihydro-fluorescein diacetate IFN-g and TNF-a, both of which are critical for innate and
(DCFH) staining (Fig. S9, ESI†).
adaptive immunity.13 As shown in Fig. 3b and c, the Pt-1-treated
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Fig. 4 Anti-tumour vaccination. MB-49 cells were firstly treated with Pt-1
(0.5 mM), oxaliplatin (1.3 mM) or solvent control for 48 h; then the treated
MB-49 cells were subcutaneously injected into the left flanks of C57BL/6
mice (n = 10), which were then re-challenged in the right flanks with
untreated MB-49 cells 7 days later. Percentage of tumour-free mice after
re-challenging with MB-49 cells was shown.
Fig. 3 The induction of immune responses in PBMCs: (a) Expression of
CD80 and CD83 on the surface of imDCs incubated with Pt-1-treated
T-24 cell-conditioned culture supernatant for the indicated time. (b and c)
Secretion of (b) IFN-g and (c) TNF-a from human primary PBMCs after
incubation with Pt-1-treated T-24 cell-conditioned culture supernatants
for the indicated time. (d) The average cell viability (%) of T-24 cells after
treating with the activated PBMCs for the indicated time.
in the Pt-1 group was identified at day 12. Gradually more tumour-
bearing mice were identified by oxaliplatin treatment and reached
a stable stage of 20% tumour-free mice after 22 days. Complex
Pt-1 displayed a slightly slower rate of tumour formation than
oxaliplatin with a stable stage of 30% tumour-free mice after 23
days. The significantly delayed tumour formation suggests an
activation of immunity to prevent tumour formation at a distant
site.7,16
We further tested the ability of Pt-1 to inhibit tumour growth
in an immunocompetent mouse model. We initially examined
the acute toxicity in C57BL/6 mice. Pt-1 or oxaliplatin was
administered (i.v.) at the doses shown in Table S3 (ESI†). In the
oxaliplatin treatment group, one of the three mice died at 20 mmol
kgꢁ1 (8 mg kgꢁ1), and the rest of the mice were found dead at
doses higher than 30 mmol kgꢁ1 (12 mg kgꢁ1). In contrast, all
mice survived Pt-1 doses of 30 mmol kgꢁ1 (20 mg kgꢁ1), demon-
strating a significantly lower acute toxicity of Pt-1 than oxaliplatin.
When the tumour volumes of C57BL/6 mice inoculated with
MB-49 cells reached B60 mm3 (n = 5 per group), an equimolar
concentration of oxaliplatin (6 mg kgꢁ1) or Pt-1 (9.8 mg kgꢁ1) was
administered (i.v.) once every two days. As shown in Fig. 5a, Pt-1
significantly suppressestumour growth with a 59.6% inhibition
compared to the solvent control (p o 0.001) after 18 days. The
inhibition by Pt-1 is more potent than oxaliplatin which elicited a
49.2% inhibition after 18 days (p o 0.01). No death or body weight
loss was detected during the treatment (Fig. S12, ESI†).
cell-conditioned culture medium boosted the IFN-g secretion
from 2.1 pg at 0 h to 74.5 pg at 24 h per 106 PBMC cells (35-fold)
and the TNF-a from 350 pg at 0 h to 1700 pg at 24 h per 106
PBMC cells (4.8-fold). However, incubating PBMCs with cell-
conditioned culture medium without Pt-1 treatment only led to
the basal cytokine secretion (data not shown). Then the cytotoxi-
city of activated PBMCs was tested by MTT assay according to the
literature procedure.35 PBMCs pre-treated with the conditioned
culture supernatants suppressed the tumour cell viability to
72.5% after 24 h and further decreased to 54.6% and 37.1%
after 48 h and 72 h treatment, respectively (Fig. 3d); while the
control group, which was co-incubated for 72 h with PBMCs
treated with cancer cell-conditioned medium without drug treat-
ment, showed a basal cytotoxicity with a mean cell viability of
85.6%. These results collectively indicate that the Pt-1-treated
conditioned culture medium activates an immune response in
PBMCs to kill cancer cells.
To examine the putative immunogenicity of exposed DAMPs
from Pt-1 in vivo, a syngenetic MB-49 mouse urothelial carcinoma
tumour vaccination model was established.36 The ICD inducer,
oxaliplatin, which has been shown to be effective in urothelial
cancer patients,37 was used as a control. In general, MB-49 cells
were treated with Pt-1 (0.5 mM) or oxaliplatin (1.3 mM), or with
solvent only for 48 h, and then the treated cells were injected (s.c.)
into the left flanks of C57BL/6 mice (n = 10 in each group) as a
tumour vaccine. After 7 days, these mice were re-challenged in the
opposite flanks by inoculation with untreated MB-49 cells (Fig. 4).
The formation of tumours in the right flanks was then monitored
every day for 35 days. In the solvent control group, tumours were
found in 20% of mice 7 days after re-challenging, and 90% of
mice in this group were detected with a tumour in the right flank
after 10 days. While in the oxaliplatin and Pt-1 treatment group,
tumour development was significantly delayed from the second
inoculation (Fig. 4). One mouse was found to carry a tumour at
day 11 in the oxaliplatin group and the first mouse with a tumour
Fig. 5 The induction of anti-tumour immune responses in vivo: (a)
Tumour volumes of C57BL/6 mice bearing MB-49 cells (n = 5) after
treatment with 9.8 mg kgꢁ1 Pt-1 or 6 mg kgꢁ1 oxaliplatin. (b) Percentage
of cytotoxic CD3+CD8+ T lymphocytes in the total cells isolated from
peripheral blood, spleen, and tumours of C57BL/6 mice treated with Pt-1
or oxaliplatin. *p o 0.05, **p o 0.01, ***p o 0.001.
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Then the amounts of CD3+ T cells and CD3+CD8+ T cells in
the peripheral blood, spleen and tumours of C57BL/6 mice after
18 day treatment were determined.10 We observed no change in
the total CD3+ proportions in peripheral blood, while a slight
increase in the spleen and tumours was detected compared to
the solvent control (Fig. S13, ESI†). The number of CD3+CD8+ T
lymphocytes in the peripheral blood and spleen slightly increases
after treatment (Fig. 5b); notably, the proportions of CD3+CD8+
cytotoxic T lymphocytes in tumour tissues were significantly
increased from 6.5% of total cells in the solvent group to
20.7% in the Pt-1 treatment group, which is higher than that
of the oxaliplatin group (16.4%). These results provide further
support that Pt-1 can activate the immune system to alleviate
cancer, with a higher activity than oxaliplatin.
V. Jooste, P. van Endert, M. Ducreux, L. Zitvogel, F. Piard and G. Kroemer,
Oncogene, 2010, 29, 482.
´
8 L. Galluzzi, A. Buque, O. Kepp, L. Zitvogel and G. Kroemer, Cancer
Cell, 2015, 28, 690–714.
9 K. Lu, C. He and W. Lin, J. Am. Chem. Soc., 2015, 137, 7600–7603.
10 X. Zhao, K. Yang, R. Zhao, T. Ji, X. Wang, X. Yang, Y. Zhang,
K. Cheng, S. Liu, J. Hao, H. Ren, K. W. Leong and G. Nie, Biomater-
ials, 2016, 102, 187–197.
11 K. Lu, C. He, N. Guo, C. Chan, K. Ni, R. R. Weichselbaum and
W. Lin, J. Am. Chem. Soc., 2016, 138, 12502–12510.
12 L. Zitvogel, O. Kepp and G. Kroemer, Nat. Rev. Clin. Oncol., 2011,
8, 151.
13 D. V. Krysko, A. D. Garg, A. Kaczmarek, O. Krysko, P. Agostinis and
P. Vandenabeele, Nat. Rev. Cancer, 2012, 12, 860.
14 I. Mellman, G. Coukos and G. Dranoff, Nature, 2011, 480, 480.
15 N. Wang, Z. Wang, Z. Xu, X. Chen and G. Zhu, Angew. Chem., Int. Ed.,
2018, 57, 3426–3430.
16 A. Terenzi, C. Pirker, B. K. Keppler and W. Berger, J. Inorg. Biochem.,
2016, 165, 71–79.
In summary, platinum(II) complexes containing phospho-
nate esters were found to preferentially accumulate in the ER
followed by ROS-associated ER stress, which triggers the expo-
sure CRT on the cell membrane and the secretion of ATP and
release of HMGB1. These DAMP signals primed the immune
cells and cause cytotoxicity towards cancer cells. The gold-
standard in vivo vaccination assay verified that Pt-1-treated
cancer cells are immunogenic by showing a significantly
delayed generation of tumours in the treatment group. Further
in vivo study revealed that Pt-1 displayed a lower acute toxicity
and stronger anti-tumour activity than oxaliplatin in the
tumour-bearing immunocompetent mouse model in a manner
associated with the activation of tumour immunity, rendering
the Pt-aminophosphonate class of complexes a new scaffold for
developing chemotherapeutics capable of triggering immune
responses against solid tumours.
The Natural Science Foundation of China (No. 21401031,
21431001, 81473102), IRT_16R15, Natural Science Foundation of
Guangxi Province (No. 2015GXNSFAA139043, 2016GXNSFGA380005),
the Fundamental Research Funds for the Central Universities,
Guangdong Key Lab of Chiral Molecule and Drug Discovery
(2019B030301005), and Shenzhen Fundamental Research Fund
JCYJ20180508163206306 are acknowledged.
¨
17 U. Jungwirth, D. N. Xanthos, J. Gojo, A. K. Bytzek, W. Korner,
P. Heffeter, S. A. Abramkin, M. A. Jakupec, C. G. Hartinger,
U. Windberger, M. Galanski, B. K. Keppler and W. Berger, Mol.
Pharmacol., 2012, 81, 719–728.
18 B. Englinger, C. Pirker, P. Heffeter, A. Terenzi, C. R. Kowol,
B. K. Keppler and W. Berger, Chem. Rev., 2019, 119, 1519–1624.
19 D. Y. Q. Wong, W. W. F. Ong and W. H. Ang, Angew. Chem., Int. Ed.,
2015, 54, 6483–6487.
20 D. Wernitznig, K. Kiakos, G. Del Favero, N. Harrer, H. Machat,
A. Osswald, M. A. Jakupec, A. Wernitznig, W. Sommergruber and
B. K. Keppler, Metallomics, 2019, 11, 1044–1048.
21 M. Sabbatini, I. Zanellato, M. Ravera, E. Gabano, E. Perin,
B. Rangone and D. Osella, J. Med. Chem., 2019, 62, 3395–3406.
22 M. Obeid, A. Tesniere, F. Ghiringhelli, G. M. Fimia, L. Apetoh,
J.-L. Perfettini, M. Castedo, G. Mignot, T. Panaretakis, N. Casares,
´
D. Metivier, N. Larochette, P. van Endert, F. Ciccosanti, M. Piacentini,
L. Zitvogel and G. Kroemer, Nat. Med., 2006, 13, 54.
23 R. Tufi, T. Panaretakis, K. Bianchi, A. Criollo, B. Fazi, F. Di Sano,
A. Tesniere, O. Kepp, P. Paterlini-Brechot, L. Zitvogel, M. Piacentini,
G. Szabadkai and G. Kroemer, Cell Death Differ., 2007, 15, 274.
24 J. Krebs, L. B. Agellon and M. Michalak, Biochem. Biophys. Res.
Commun., 2015, 460, 114–121.
25 Z. Xue, M. Lin, J. Zhu, J. Zhang, Y. Li and Z. Guo, Chem. Commun.,
2010, 46, 1212–1214.
26 Y. Zhang, R. Cao, F. Yin, F. Y. Lin, H. Wang, K. Krysiak, J. H. No,
D. Mukkamala, K. Houlihan, J. Li, C. T. Morita and E. Oldfield,
Angew. Chem., Int. Ed., 2010, 49, 1136–1138.
27 M. Wilhelm, V. Kunzmann, S. Eckstein, P. Reimer, F. Weissinger,
T. Ruediger and H.-P. Tony, Blood, 2003, 102, 200–206.
28 Y. Xu, J. Aoki, K. Shimizu, M. Umezu-Goto, K. Hama, Y. Takanezawa,
S. Yu, G. B. Mills, H. Arai, L. Qian and G. D. Prestwich, J. Med. Chem.,
2005, 48, 3319–3327.
29 K. Becker, C. Herold-Mende, J. J. Park, G. Lowe and R. H. Schirmer,
J. Med. Chem., 2001, 44, 2784–2792.
Conflicts of interest
´
30 A.-B. Witte, K. Anestål, E. Jerremalm, H. Ehrsson and E. S. J. Arner,
There are no conflicts to declare.
Free Radical Biol. Med., 2005, 39, 696–703.
31 K.-B. Huang, Z.-F. Chen, Y.-C. Liu, Z.-Q. Li, J.-H. Wei, M. Wang,
X.-L. Xie and H. Liang, Eur. J. Med. Chem., 2013, 64, 554–561.
32 K.-B. Huang, Z.-F. Chen, Y.-C. Liu, Z.-Q. Li, J.-H. Wei, M. Wang,
G.-H. Zhang and H. Liang, Eur. J. Med. Chem., 2013, 63, 76–84.
33 The Pt compounds could react with DMSO and therefore the active
species may be the DMSO adducts. Further studies are needed to
verify this hypothesis.
References
1 Y. Jung and S. J. Lippard, Chem. Rev., 2007, 107, 1387–1407.
2 N. P. E. Barry and P. J. Sadler, Pure Appl. Chem., 2014, 86, 1897.
3 M. Fanelli, M. Formica, V. Fusi, L. Giorgi, M. Micheloni and P. Paoli,
Coord. Chem. Rev., 2016, 310, 41–79.
¨
4 N. Muhammad and Z. Guo, Curr. Opin. Chem. Biol., 2014, 19, 34 N. Romani, S. Gruner, D. Brang, E. Kampgen, A. Lenz, B. Trockenbacher,
144–153.
G. Konwalinka, P. O. Fritsch, R. M. Steinman and G. Schuler, J. Exp.
Med., 1994, 180, 83–93.
´
5 M. A. Fuertes, C. Alonso and J. M. Perez, Chem. Rev., 2003, 103,
645–662.
35 A. A. van de Loosdrecht, E. Nennie, G. J. Ossenkoppele, R. H. Beelen
and M. M. Langenhuijsen, J. Immunol. Methods, 1991, 141, 15–22.
36 A. S. I. Loskog, M. E. Fransson and T. T. H. Totterman, Clin. Cancer
Res., 2005, 11, 8816–8821.
6 C.-H. Leung, S. Lin, H.-J. Zhong and D.-L. Ma, Chem. Sci., 2015, 6,
871–884.
7 A. Tesniere, F. Schlemmer, V. Boige, O. Kepp, I. Martins, F. Ghiringhelli,
L. Aymeric, M. Michaud, L. Apetoh, L. Barault, J. Mendiboure, J. P. Pignon, 37 S. Zhang, H. Xue and Q. Chen, Oncotarget, 2016, 7, 58579–58585.
This journal is ©The Royal Society of Chemistry 2019
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