Cyclometalated Ir(iii) complexes as targeted theranostic anticancer therapeutics: Combining HDAC inhibition with photodynamic therapy

Article abstract of DOI:10.1039/c4cc05215c

The successful design and anticancer mechanistic studies of a series of cyclometalated Ir(iii) complexes with histone deacetylase inhibitory and photodynamic therapy (PDT) activities are reported. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc05215c

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Cyclometalated Ir(III) complexes as targeted
theranostic anticancer therapeutics: combining
HDAC inhibition with photodynamic therapy†
Cite this: Chem. Commun., 2014,
50, 10945
Received 7th July 2014,
Accepted 29th July 2014
Rui-Rong Ye, Cai-Ping Tan,* Liang He, Mu-He Chen, Liang-Nian Ji and
Zong-Wan Mao*
DOI: 10.1039/c4cc05215c
www.rsc.org/chemcomm
The successful design and anticancer mechanistic studies of a series of HDACis are now undergoing clinical trials.9 Recently, some
cyclometalated Ir(III) complexes with histone deacetylase inhibitory and metal-based HDACis have been reported.10
photodynamic therapy (PDT) activities are reported.
Photodynamic therapy (PDT) is an attractive alternative for
cancer treatment due to its high therapeutic efficacy and less side
Although cisplatin and its derivatives have gained great success, the effects in comparison with radiotherapy and chemotherapy.11
development of platinum-based anticancer agents is hindered by Upon irradiation, photosensitizers can cause the oxidative damage
many drawbacks, e.g., serious side-effects and easily acquired drug of tumor tissues by generating highly reactive singlet oxygen (1O2)
resistance.1 Recently, non-platinum-based compounds, such as and other reactive oxygen species (ROS).12 PDT circumvents the
iridium complexes, have attracted increasing attention in the search lack of specificity of conventional therapies to some extent due to
for alternatives to platinum-based metallo-anticancer drugs.2 Multi- its inherent selectivity by localization of the photosensitizer to the
functional theranostic agents are expected to have significant clinical tumor and confined toxicity due to spatial control of illuminated
applications by integrating diagnosis and therapy simultaneously.3 areas.13 Metal complexes have become an attractive class of
Due to their octahedral geometry, iridium complexes can be utilized compounds for PDT with a diverse mechanism of action.14
to construct highly effective kinase inhibitors with high selectivity,4 Recently, several groups reported that cyclometalated Ir(III)
and the catalytic characteristics of iridium complexes endow complexes can function as efficient sensitizers for PDT.15
them with interesting anticancer properties.5 On the other hand,
In this study, we aim to achieve theranostic Ir(III)–HDACi
cyclometalated Ir(III) complexes are widely explored as bioimaging hybrid complexes with synergistic inhibition effects on cancer
and biosensing agents due to their high quantum yields, large cells due to their HDAC inhibitory potency and PDT activity.
Stokes shifts, long-lived luminescence, good photostability and cell Four phosphorescent Ir(III) complexes, [Ir(N–C)2L](PF6) (L =
permeability.6 These unique properties of cyclometalated Ir(III) N1-hydroxy-N8-(1,10-phenanthrolin-5-yl)octanediamide), which
complexes make them ideal candidates for constructing novel is a phenanthroline derivative modelled after SAHA; N–C =
theranostic platforms.
2-phenylpyridine (ppy, 1), 3-(2-pyridinyl)-coumarin (coumarin, 2),
Histone deacetylases (HDACs) regulate the expression and 2-(2-thienyl)pyridine (thpy, 3), and 2-(2,4-difluorophenyl)pyridine
activity of many proteins in both cancer initiation and cancer (dfppy, 4) (Scheme 1), have been synthesized and characterized.
progression by catalyzing the removal of acetyl groups from Complexes 1–4 show potent inhibitory effects on HDACs. As a
histones.7 HDAC inhibitors (HDACis) show potent anticancer consequence, treatment of human cervical cancer (HeLa) cells
activities by promoting the acetylation of histones and non- with 1 leads to an elevation in histone-acetylation levels. Further
histone proteins and inducing transcriptional events involved mechanistic studies show that complex 1 can efficiently induce
in growth arrest, differentiation, and apoptotic cell death.8 apoptosis in HeLa cells through HDAC inhibition and ROS
Suberoylanilide hydroxamic acid (SAHA, vorinostat) is the first elevation. Upon illumination with UV/visible light, the anti-
FDA-approved pan-HDACi that enters the clinic for treatment of cancer activities of 1–4 are greatly enhanced.
cutaneous T-cell lymphoma. Several other organic molecule
Ligand L was synthesized according to our previous work.16
Complexes 1–4 were synthesized by reacting two equivalents
of L with the Ir(III) chloro-bridged dimer. These complexes
were characterized by ESI-MS, H NMR and elemental analysis
(Fig. S1–S4, ESI†).
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry
and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, P. R. China.
E-mail: cesmzw@mail.sysu.edu.cn, tancaip@mail.sysu.edu.cn;
Fax: +86-20-8411-2245
1
The UV-vis absorption spectra of 1–4 in phosphate-buffered saline
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4cc05215c (PBS), CH3CN and CH2Cl2 at 298 K are shown in Fig. S5 (ESI†).
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Table 1 (Photo)cytotoxicity of the compounds towards HeLa cells
PIc
365 nm 425 nm
IC50 (mM)
Compounds Darka
365 nmb
425 nmb
1
2
3
4
58.9 ꢀ 3.3
50.1 ꢀ 2.6
38.9 ꢀ 3.0
3.4 ꢀ 0.3
3.1 ꢀ 0.3
8.9 ꢀ 0.5
6.8 ꢀ 0.9 17.3
4.5 ꢀ 0.4 16.2
8.7
11.1
15.6
18.9
1.1
1.0
1.0
2.5 ꢀ 0.2
1.6 ꢀ 0.1
4.4
2.7
1.1
1.0
1.2
30.2 ꢀ 1.4 11.2 ꢀ 1.0
L
69.2 ꢀ 5.4 65.3 ꢀ 5.3 63.5 ꢀ 4.3
24.7 ꢀ 2.3 23.6 ꢀ 1.9 24.4 ꢀ 1.1
26.3 ꢀ 1.5 22.4 ꢀ 1.6 25.4 ꢀ 1.6
SAHA
Cisplatin
a
Cells were incubated with the indicated compounds in the dark for
b
48 h. Cells were incubated with the indicated compounds for 12 h in
the dark and then irradiated with light at 365 nm/425 nm. PI =
c
phototoxicity index; PI is the ratio of the IC50 values in the dark to
those obtained upon light irradiation.
Scheme 1 The structures of complexes 1–4.
Complexes 1–4 also show phototoxicity when irradiated at 425 nm.
The photo-induced cytotoxicity of these complexes is not well
correlated with the quantum yields of O2 production, which may
The complexes display intense absorption bands at approximately
250–330 nm attributed to intraligand (p - p*) transitions and
relatively weak bands at approximately 330–470 nm assigned to
metal-to-ligand charge-transfer absorption.17 The photophysical
properties of complexes 1–4 are summarized in Table S1 (ESI†).
Complexes 1–4 exhibit green to red emission in PBS, CH3CN and
CH2Cl2 under ambient conditions upon excitation at 405 nm
(Fig. S6, ESI†).
1
imply that the overall result of photodynamic efficacy is influenced
by many factors including cellular uptake levels, target binding
affinity and 1O2 production capability of photosensitizers in differ-
ent intracellular environments. As expected, these complexes show
much lower cytotoxicity against LO2 cells. Upon irradiation, the
enhancement in the cytotoxicity of cisplatin, SAHA and ligand L is
negligible, which indicates that the intracellular photo-induced
toxicity mainly originates from the reaction between Ir(III) com-
plexes and oxygen.
The HDAC inhibitory activities of complexes 1–4 were measured
using a commercial HDAC activity assay kit by detecting the
deacetylation of a synthetic fluorescent peptide.19 As shown in
Table 2 and Fig. S9 (ESI†), the inhibitory effects of compounds on
HDAC activity are in the following order: 2 4 SAHA 4 3 4 L 4
1 4 4. The result indicates that the conjugation of the HDAC-
targeting ligand with cyclometalated Ir(III) moieties can retain or
even improve the HDAC inhibitory activities.
Under 365 nm irradiation, 1 exhibits the strongest photodynamic
response in HeLa cells, so it is chosen as the model compound to
elucidate the anticancer mechanism, as well as the origin of the
phototoxicity. Increased histone acetylation is an important marker
of the cellular biological activity of the HDACis.8 Western blot
analysis of acetyl-histone H3 was performed to further determine
whether HDACs were the cellular target of 1. As shown in Fig. 1, the
treatment of HeLa cells with 1 increases the acetylation level of
histone H3 in a dose-dependent manner both in the absence and
presence of light. Irradiated cells display higher histone H3
1O2 is considered to be the main cytotoxic species in PDT. By
using methylene blue (MB) as a standard, the quantum yields for 1O2
production (FD) of complexes 1–4 were evaluated in aerated dimethyl
sulfoxide (DMSO) by monitoring the changes in the UV-vis spectra of
1,3-diphenylisobenzofuran (DPBF) at 418 nm.15a,18 The rate of con-
version of DPBF to 1,2-dibenzoylbenzene by 1O2 is shown in Fig. S7
(ESI†) and the calculated FD values are listed in Table S2 (ESI†).
Under UV light irradiation, the FD values increase in the order of 3
(0.21) o 2 (0.38) o 1 (0.45) o MB (0.52) o 4 (0.75). 1O2 quantum
yields were also determined for 1–4 upon illumination at 425 nm. It
can be seen that 1O2 can also be produced by 1–4 under visible light
irradiation, which is more favourable for the application of PDT.
The rich photophysical properties of cyclometalated Ir(III) com-
plexes can be utilized to study their cellular accumulation, trafficking
and biodistribution, and they are ideal models to construct novel
theranostic platforms integrating diagnostic and therapeutic pur-
poses. It can be seen from confocal microscopy images that 1–4 can
be effectively taken up by HeLa cells and are mainly retained within
the cytoplasm after 5 h of incubation (Fig. S8, ESI†).
The cytotoxicity of 1–4 against several different cell lines
(HeLa; human pulmonary carcinoma cell line A549; cisplatin-
resistant cell line A549R; and human normal liver cell line LO2)
was investigated both in the presence and absence of UV/visible
light (Table 1; Tables S3 and S4, ESI†). The exposure of vehicle-
treated cells to the light doses used does not induce the inhibition
of cell proliferation. It can be seen that all Ir(III) complexes show
moderate and selective cytotoxicity towards HeLa cells in the dark.
However, a markedly increased cytotoxicity towards all cancer cells,
including cisplatin-resistant A549 cells, is observed when cells are
irradiated at 365 nm in the presence of 1–4 (IC50 = 3.1–21.9 mM).
The phototoxicity index (PI) values of the compounds against HeLa
Table 2 In vitro inhibition of HeLa nuclear extract HDAC activitya
Compounds
IC50 (nM)
1
2
3
4
112.7 ꢀ 8.5
39.0 ꢀ 2.6
82.8 ꢀ 6.1
665.2 ꢀ 10.2
107.1 ꢀ 8.2
72.3 ꢀ 5.5
L
SAHA
a
The results are mean ꢀ standard deviation of three independent
cells follow the order: 1 (17.3) 4 2 (16.2) 4 3 (4.4) 4 4 (2.7). experiments.
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substrate of activated caspase-3 involved in apoptotic signaling,
poly(ADP-ribose) polymerase (PARP),23 is cleaved to an 85 kD
signature peptide (PARP-CF) in 1-treated HeLa cells in a dose-
dependent manner, and light can further elevate the percen-
tage of cleaved PARP (Fig. S12B, ESI†).
To further elucidate the mechanisms of 1-induced growth
inhibition, the effect of 1 on cell cycle distribution was studied
by flow cytometry in HeLa cells. No obvious disturbance in cell
cycle distribution is observed both in the dark and under light
irradiation (Table S5, ESI†). In the presence of 1, irradiated cells
show a marked increase in the proportion of apoptotic cells
compared with those in the dark, as indicated by the increase
in sub-G1 peaks.24
Fig. 1 Dose-dependent effect of complex 1 on the expression of acetyl-
histone H3.
acetylation levels than cells in the dark, which indicates that
light can enhance the HDAC inhibition capacity of 1 in cellular
environments.
Apoptosis is reported to be the primary pathway for cell death
execution of photodynamic cancer therapy as well as HDAC inhibi-
tion.8,12,20 Induction of apoptosis by 1 was first studied by detecting
changes in the cell morphology of HeLa cells. As shown in Fig. S10
(ESI†), treatment of cells with 1 results in an increase (control: 2.5 ꢀ
0.3%; 10 mM 1: 14.2 ꢀ 1.6%; 20 mM 1: 26.7 ꢀ 1.2%) in the percentage
of cells with abnormal nuclear morphology, e.g., chromatin con-
densation and nuclear fragmentation. In the presence of 365 nm
light, a significant increase in the proportion of cells with abnormal
nucleus is observed (control: 3.2 ꢀ 0.2%; 10 mM 1: 30.4 ꢀ 2.1%;
20 mM 1: 70.6 ꢀ 4.3%). Similar results are obtained by annexin-V
labelling, detecting phosphatidylserine externalization, a hallmark of
the early phase of apoptosis.21 Flow cytometric analysis shows that
treatment of HeLa cells with 1 in the absence of light leads to a
concentration-dependent increase in the percentage of cells that are
annexin-V positive (control: 3.6 ꢀ 0.8%; 10 mM 1: 10.0 ꢀ 0.9%;
20 mM 1: 24.3 ꢀ 2.0%) (Fig. 2). Upon illumination, a marked increase
in the percentage of HeLa cells that are annexin-V positive is
observed (control: 4.5 ꢀ 0.3%; 10 mM 1: 25.1 ꢀ 1.3%; 20 mM 1:
75.4 ꢀ 4.8%). The fluorescence microscopy experiment also shows
that light irradiation can greatly increase the percentage of apoptotic
cells induced by treatment with 1 (Fig. S11, ESI†).
1
ROS, particularly O2, are the most important mediators of
cell death induced by PDT.12 The effect of 1 on intracellular
ROS levels was examined by 20,70-dichlorofluorescein (DCF)
fluorescence assay using confocal microscopy and flow cyto-
metry. A moderate concentration-dependent increase of ROS is
observed in HeLa cells treated with 1 for 6 h in the dark, and
illumination at 365 nm can greatly improve the capability of 1
to produce ROS (Fig. S13A and B, ESI†). Under irradiation,
treatment of 1 at 40 mM resulted in B5-fold higher fluorescence
signals compared with the vehicle-treated cells.
ROS elevation and mitochondrial dysfunction are two closely
related events. During apoptosis, several key events occur in
mitochondria, including the release of caspase activators and
the loss of mitochondrial membrane potential (MMP, DCm).25
Therefore, confocal microscopy and flow cytometry were used
to confirm whether 1-induced apoptosis occurred through
damaging mitochondria using 5,50,6,60-tetrachloro-1,10,3,30-
tetraethylbenzimidazolylcarbocyanine iodide (JC-1) as the MMP-
sensitive probe. As shown in Fig. S14A (ESI†), in the presence of 1,
light-irradiated cells display a more significant red to green color
shift indicating the loss of MMP compared with cells treated in the
dark. Representative JC-1 red/green ratio signals recorded by flow
cytometry are shown in Fig. S14B (ESI†). Under dark conditions, a
concentration-dependent decrease in the red/green fluorescence
intensity ratios can be detected (control: 54.6 ꢀ 2.2; 20 mM 1: 43.6 ꢀ
3.1; 40 mM 1: 32.4 ꢀ 2.2). PDT treatment markedly decreases the
ratios of red to green fluorescence (control: 54.7 ꢀ 1.4; 20 mM 1:
18.1 ꢀ 1.5; 40 mM 1: 5.4 ꢀ 0.4).
Caspases have been identified as key executors of apoptosis
under various stimuli, and the activation of capase-3 is considered
to be a marker of apoptosis.22 As shown in Fig. S12A (ESI†),
treatment of HeLa cells with 1 results in a concentration-
dependent increase in caspase-3/7 activity in the dark. At the
same time, light can greatly increase the activation of caspase-
3/7 caused by treatment with 1. Accordingly, the well-known
In summary, a series of cyclometalated Ir(III) complexes as
HDACis and photodynamic therapeutic agents have been explored.
Upon UV (365 nm) or visible (425 nm) light irradiation, complexes
1–4 show potent cytotoxicity towards the cancer cell lines screened,
and display much lower phototoxicity against human normal cells.
Mechanistic studies show that 1 induces apoptotic cell death mainly
through inhibition of HDACs, ROS production and mitochondrial
damage. Under UV light irradiation, the biological effects of 1
mentioned above are significantly enhanced. Our study demon-
strates that the combination of the molecular targeted drug design
methodology with the PDT potential of phosphorescent Ir(III) com-
plexes may be a very useful strategy to develop novel tumor-oriented
multifunctional metallo-anticancer therapeutics.
This work is supported by National Natural Science Founda-
tion of China (No. 21172274, 21231007, 21121061, 21201183
Fig. 2 Characterization of apoptosis induced by complex 1 using annexin
V-FITC staining.
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