An iridium(III)-palladium(II) metal-organic cage for efficient mitochondria-targeted photodynamic therapy

Article abstract of DOI:10.1016/j.cclet.2019.09.034

An Ir₈Pd₄-heteronuclear metal-organic cage (MOC-51) was assembled from bipodal metalloligand [Ir(ppy)₂(qpy)(BF₄)] (qpy = 4,4′:2′,2″:4″,4?-quaterpyridine; ppy = 2-phenylpridine) with Pd(II) salt. The cubic barrel shaped MOC shows one-photon and two-photon excited deep-red emission, as well as large singlet oxygen quantum yields under visible light irradiation, therefore exhibiting great potentials in organelles-targeted cell imaging and photodynamic therapy (PDT). Compared with the Ir(III) metalloligand, the Ir₈Pd₄-MOC showed less dark toxicity and higher mitochondria-targeting efficiency. The localization in mitochondria overcomes the limitation of short lifetime and diffusion distance of ROS in cell, thus improved PDT effect can be obtained in low light dose usage of the MOC. This study presents the first case of Ir-based metal-organic cages for bio-applications in successful integration of imaging diagnosis and photodynamic therapy

Full text of DOI:10.1016/j.cclet.2019.09.034

Journal Pre-proof
An iridium(III)-palladium(II) metal−organic cage for efficient
mitochondria-targeted photodynamic therapy
Chaojie Li, Yaping Wang, Yulin Lu, Jing Guo, Chengyi Zhu, Haozhe
He, Xiaohui Duan, Mei Pan, Chengyong Su
PII:
S1001-8417(19)30570-4
https://doi.org/10.1016/j.cclet.2019.09.034
CCLET 5240
DOI:
Reference:
To appear in:
Chinese Chemical Letters
Received Date:
Revised Date:
Accepted Date:
2 August 2019
11 September 2019
18 September 2019
Please cite this article as: Li C, Wang Y, Lu Y, Guo J, Zhu C, He H, Duan X, Pan M, Su C, An
iridium(III)-palladium(II) metal−organic cage for efficient mitochondria-targeted photodynamic
therapy, Chinese Chemical Letters (2019), doi: https://doi.org/10.1016/j.cclet.2019.09.034
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Communication
An iridium(III)-palladium(II) metal−organic cage for efficient mitochondria-targeted
photodynamic therapy
‡, a
‡, a
a
a
a
b
c
a,

Chaojie Li , Yaping Wang , Yulin Lu , Jing Guo , Chengyi Zhu , Haozhe He , Xiaohui Duan , Mei Pan ,
Chengyong Sua
aMOE Laboratory of Bioinorganic and Synthetic Chemistry, Lehn Institute of Functional materials, School of Chemistry, Sun Yat-Sen University, Guangzhou
510275, China.
bSchool of Materials Science and Engineering and School of Chemistry, Sun Yat-Sen University, Guangzhou 510275, China.
cSun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
 Corresponding author. E-mail address: panm@mail.sysu.edu.cn
‡These authors contribute equally to this work.
Graphical Abstract
An Ir8Pd4-heteronuclear metal−organic cage (MOC-51) was assembled from bipodal metalloligand [Ir(ppy)2(qpy)(BF4)] with Pd(II)
salt, which presents the first case of Ir-based metal-organic cages for bio-applications in successful integration of imaging diagnosis
and photodynamic therapy.
ABSTRACT
An Ir8Pd4-heteronuclear metal−organic cage (MOC-51) was assembled from bipodal metalloligand [Ir(ppy)2(qpy)(BF4)] (qpy = 4,4':2',2'':4'',4'''-
quaterpyridine; ppy = 2-phenylpridine) with Pd(II) salt. The cubic barrel shaped MOC shows one-photon and two-photon excited deep-red emission, as
well as large singlet oxygen quantum yields under visible light irradiation, therefore exhibiting great potentials in organelles-targeted cell imaging and
photodynamic therapy (PDT). Compared with the Ir(III) metalloligand, the Ir8Pd4-MOC showed less dark toxicity and higher mitochondria-targeting
efficiency. The localization in mitochondria overcomes the limitation of short lifetime and diffusion distance of ROS in cell, thus improved PDT effect can
be obtained in low light dose usage of the MOC. This study presents the first case of Ir-based metal-organic cages for bio-applications in successful
integration of imaging diagnosis and photodynamic therapy
Article history:Received 2 August 2019 Received in revised form 11 September 2019 Accepted 12 September 2019 Available online
Keywords:Metal−organic cage Photodynamic therapy Mitochondria-targeted Ir(III) metalloligand Two-photon
———

Metal−organic cages (MOCs) have well-defined shapes and cavities, and possess potential applications in confined space catalysis
[1], separation [2], photocatalytic hydrogen production [3], fluorescence [4], and so on [5,6]. Among which, MOCs assembled from
metalloligand strategy can be afforded with structural controllability and predictability, due to the composition and configuration of
metalloligands are generally stable during secondary Keywords:
Metal−organic cage
Photodynamic therapy
Mitochondria-targeted
Ir(III) metalloligand
Two-photon assembly. Meanwhile, ensembles of the obtained MOCs will bring unique chemical, physical and biological properties
superior than the precursors, owing to the synergistic effects among different components and “concentration effect” of the uniquely
confined cage configuration [7-10]. However, up to now, the above advantages have been barely studied in the bio-applications of MOCs
[11].
Iridium(III) complexes have excellent photoelectric and remarkable chemo-physical properties, such as great chemical stability, high
quantum yield and good cell permeability, so they have attracted extensive attention in the field of biological imaging and sensing probes
[12]. In addition, in recent years, Ir(III) complexes were also reported to be good photosensitizers for the photodynamic therapy (PDT)
[13-16]. It is expected that metal−organic cages assembled from Ir(III) metalloligands can not only possess controllable shapes and inner
cavities, but also hold and optimize the pristine property of Ir(III) complexes. As far as we know, the successful assembly of Ir(III)-based
MOCs remains quite rare, even less for their bio-applications in cell imaging and cancer therapy [17-20]. To achieve this purpose, apart
from good photophysical properties, the following concerns should also be considered for the MOCs, including chemical stability, water-
/lipo-solubility, bio-compatibility, long-term toxicity, and so on. Bearing the above considerations in mind, we report herein the stepwise
assembly of an Ir(III)−Pd(II) MOC from a predesigned bipodal Ir(III) metalloligand. Inspired by its good one-photon and two-photon
luminescence, as well as large singlet oxygen quantum yield, the MOC was applied in mitochondria-targeted cell imaging and
photodynamic therapy successfully, presenting the first example of Ir(III)-based MOC in PDT field.
a
b
g
b
Irqpy
a
c d
h
l
MeOH/CH2Cl2
(v:v=1:1)
j
m
i
k
k
60⁰C; NaBF4
g
h
Pd:Irqpy=5:8
d
c
f
e
b
l
m
j
a a′
c′
d′
i
i′
i
a
j
e
Pd:Irqpy=4:8
m
c
b
h
d
f
g
l
k
Pd:Irqpy=3:8
Pd:Irqpy=2:8
DMSO
Pd2+
80 ℃
Pd:Irqpy=1:8
MOC-51
Fig. 1 (a) Synthetic route of Ir8Pd4-cage (MOC-51) from Irqpy metalloligand (for the simulated MOC structure, Ir, orange, Pd, turquoise, C, gray, N, blue, and the
1
yellow ball represents inside cavity, hydrogen atoms, anions and solvents are omitted for clarity). (b) H NMR titration of Irqpy metalloligand (top) with the
addition of Pd(CH3CN)4(BF4)2 in DMSO-d6 at 298 K.
The bipodal metalloligand [Ir(ppy)2(qpy)](BF4) solvents (Irqpy), possessing two coordinated 2-phenylpyridine moieties, one
coordinated bipyridine linker, and two uncoordinated pyridine (Py) pendants, was prepared by reaction of qpy (4,4':2',2'':4'',4'''-
quaterpyridine, Scheme S1 in Supporting information) with [Ir(ppy)2(μ-Cl)]2, and the structure was unambiguously confirmed by single-
crystal diffraction analyses, (Fig. S1 and Tables S1-S3 in Supporting information). Irqpy was further assembled with Pd(CH3CN)4(BF4)2
at 80 °C to result in formation of an Ir(III)-Pd(II) heteronuclear cage ([Pd4(Irqpy)8]·(BF4)16 solvents, MOC-51, in which Ir(III) centers
are 6-coordinated, and Pd(II) ions are 4-coordinated (Fig. 1a and Fig. S1). The composition of the cage structure can be further proved
by detailed solution NMR and MS study (Figs. S2-S6 in Supporting information).
1
First, the solution assembly process for MOC-51 was monitored by H NMR titration in DMSO-d6 (Fig. 1b). It can be seen that the
proton signals of pure Irqpy metalloligand can be divided into eleven sets. When Pd(CH3CN)4(BF4)2 is added to a solution of Irqpy, new
proton signals appeared besides those of “free” Irqpy ligand. Along with the titration process, broadness of the NMR signals is observed,
clearly indicating the complexation between Irqpy and Pd(II) ions, and formation of dynamics for large molecules with slow rotational
1
diffusion. When the concentration of Pd(II) was low (Pd:Irqpy ratio below 3:8), the H NMR spectra exhibit signals for the mixture of
Pd-coordinated and free Irqpy metalloligand. When the ratio increases above 4:8, the proton peaks no longer change, which indicates
that a thermodynamically [Pd4(Irqpy)8]16+ cage is preferentially formed. Compared with the free Irqpy metalloligand, the proton peaks of
1
the [Pd4(Irqpy)8]16+ cage show different shifts (Fig. S2), which are coincident with the NMR titration results. From the H−1H COSY
spectra, proton correlation can be established for the pendant pyridine peaks (Fig. S3). As we can see, upon formation of the cage, the
signals of pendant pyridine H-atmos (b, c) are moved downfield, due to the coordination-induced effect between Py-donor and Pd(II).
While other proton signals (a, i, m) manifest upfield shift, showing increase of shielding effect after MOC formation.

1H DOSY NMR spectroscopy (Fig. S4) clearly indicates that a single substance is formed in the DMSO-d6 solution of MOC-51, which
has a diffusion coefficient of 7.1 × 10-11 m2/s. From the value of diffusion coefficient, it can be seen that the structure is much larger than
that of the Irqpy metalloligand (1.7 × 10-10 m2/s). The calculated hydrodynamic radius (rs) of the MOC-51 is 15 Å. In order to further
prove the structure of [Pd4(Irqpy)8]16+ cage in solution, high-resolution electrospray ionization time-of-flight mass spectrometry (HR-
ESI-TOF-MS) was measured. Figs. S5 and S6 show a series of isotopically resolved peaks related with different [Pd4(Irqpy)8]16+ plus
anions species, which can be matched well with the simulated spectra. For example, the peak at 1099.006 can be attributed to heptavalent
[(C42H30IrN6)8Pd4(BF4)9]7+, which can be confirmed by comparing experimental data with simulated data. Based on the above results,
molecular structure of MOC-51 was simulated as shown in Fig. 1a. As we can see, eight Irqpy metalloligands form a cubic barrel, and
each Irqpy extends two pendant pyridines to link with Pd(II) ions. In general, an Ir8Pd4 cage is formed, which possesses suitable molecular
size (~1.5 nm) and high valence states (+16). This may contribute to the cell uptaking and photodynamic therapy applications, as will be
further explored below.
1.2
(d)
(c)
MOC-51 Ex 470 nm
Ir-qpy Ex 430 nm
MOC-51 Em 665 nm
Ir-qpy Em 665 nm
Irqpy
MOC-51
60000 (a)
50000
40000
30000
20000
10000
0
0.0
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0.6
0.8
1.0
(b)
80
60
40
20
0
MOC-51
Irqpy
1.0
0.8
0.6
0.4
0.2
0.0

MOC-51
[Ru(bpy)3]Cl2
ABDA
200 300 400 500 600 700 800
Wavelength (nm)
700
750
800
850
900
0
50
100
150
200
300
400
500
600
700
800
Wavelength (nm)
Time (s)
Wavelength (nm)
Fig. 2 (a-c) Photophysical spectra of Irqpy metalloligand (1 × 10-5 mol/L) and MOC-51 (1.25 × 10-6 mol/L) in DMSO solution at room temperature. (a) UV-vis
absorption spectra; (b) Photoluminescent excitation and emission spectra; (c) TPA cross-section at different excitation wavelengths from 720 nm to 880 nm. (d)
Comparison of the quantum yields for 1O2 production (ΦΔ) of MOC-51 and [Ru(bpy)3]Cl2 stantard in water solution.
The UV-vis absorption spectra of the metalloligand and MOC-51 were measured in DMSO solution as shown in Fig. 2a. As we can
see, the two spectra are basically the same, with only slight difference in molar extinction coefficient. In the UV region, Pd4(Irqpy)8 cage
exhibits intense absorption bands between 250 nm and 350 nm, originated from the π-π* transitions of ppy and qpy. Lower absorption
from 350 nm to 450 nm can be attributed to intramolecular charge transfer (ILCT). Characteristically for Ir(III) compounds, broad and
lower intensity bands are observed for the cage from 450 nm to 550 nm, which can be attributed to MLCT (metal-to-ligand charge
transfer) transitions from IrIII metal centers to ppy and qpy organic ligands.
The photoluminescent peak shape and position of MOC-51 are basically the same as Irqpy metalloligand both in DMSO and solid
3
state at room temperature, which indicates that the emission of cage comes from the transition of MLCT of Irqpy. In the solid state,
Irqpy and MOC-51 exhibit wide band emissions centered at 665 nm (Fig. S7 in Supporting information), which fall into the deep-red
region. Importantly, the excitation can be in the visible blue light region of 470 and 430 nm for MOC-51 and Irqpy in DMSO solution,
respectively, showing great advantage to be applied in bioimaging. The decay lifetimes were found to be 57 and 19 ns at room temperature
(Table S4 and Fig. S8 in Supporting information). The decay lifetime of MOC-51 increased to 537 ns at 77 K low temperature (Fig. S9
in Supporting information), which sufficiently shows the characteristics of the 3MLCT and lowest excitation triplet state phosphorescence
of Ir(III) complexes. Compared with the solid state, the emissions of Irqpy and MOC-51 have a similar peak shape and position in the
DMSO solution, with maxima at 654/658 nm (Fig. 2b, Table S4), slightly blue-shifted compared with the solid state. Longer decay
lifetimes of 158 and 141 ns (Fig. S10 in Supporting information) are observed for Irqpy and MOC-51 in DMSO solution at room
temperature, respectively. Compared with Irqpy metalloligand, the quantum yield (Фem) of MOC-51 is reduced to 3.5% due to the
quenching effect of Pd-coordination, but still suitable for the bioimaging study as shown below.
Irqpy and MOC-51 also show two-photon excited emission spectra (Fig. S11 in Supporting information), with the pisitions and shapes
similar to that of the one-photon emission. The slopes of the logarithm of the two-photon induced fluorescence intensity and the excitation
power are approximately 2, indicating that the emissions are indeed via two-photon process (Fig. S12 in Supporting information). The
two-photon absorption (TPA) cross section were further measured from 720 nm to 860 nm in DMSO by using rhodamine B (4 × 10-4
mol/L) as the reference. The maximum TPA cross-sections (max, ex = 820 nm) were measured to be 28 and 83 GM for Irqpy and MOC-
51, respectively (Fig. 2c), showing great potentials for two-photon imaging in living cells.
To research the singlet oxygen generation efficiency of MOC-51, the quantum yields for 1O2 production under a 425 nm xenon lamp
with filter was measured in water using a steady-state method with 9,10-anthracenediyl-bis-(methylene) dimalonic acid (ABDA) as the
1O2 indicator and [Ru(bpy)3]Cl2 as the standard substance (ФΔ = 0.18 in H2O, Fig. 2d, Figs. S13 and S14 in Supporting information). The
ФΔ values of MOC-51 was calculated to be 0.46. This rather high value compared with reported iridium complexes under similar near-
neutral pH conditions indicates that MOC-51 is promising as an efficient photodynamic therapy photosensitizer [13-16].
Due to the excellent photophysical properties of MOC-51, the cellular imaging in Hela cells was conducted by using laser scanning
confocal microscopy. As shown in Fig. S15 (Supporting information), strong red luminescence was observed in the cytoplasm both under
the one-photon and two-photon excitations after incubated with MOC-51 for 2 h, suggesting the good physiological stability and high
cellular uptake efficiency of the cage compound. Then the subcellular localization of MOC-51 with commercial mitochondrial dye Mito-
Tracker Green (MTG), lysosome dye Lyso-Tracker Red (LTR) or the nucleus dye DAPI was further performed. As shown in Fig. 3a, a
great superimposition pattern was observed for MTG and MOC-51 treated cells with a relative high correlation coefficient of 0.88,
indicating that MOC-51 was localized in the mitochondrial of living Hela cells. In comparison, poor overlap was found between MOC-

51 and LTG or DAPI treated cells (Figs. 3b and c), which further demonstrated the specific mitochondrial targeting of MOC-51. In
addition, the cellular colocalization of Irqpy was also carried out (Fig. S16 in Supporting information). The results showed that Irqpy
were also specifically localized in the mitochondrial, but with smaller correlation coefficient (0.76) than MOC-51, which may be
attributed to the higher positive charge (+16) of MOC-51 due to the introduction of Pd(II) ions.
Fig. 3 Cellular colocalization images of Hela cells incubated with (a) MOC-51 (6 μmol/L, 3 h) and MTG (150 nmol/L, 30 min), (b) LTR (150 nmol/L, 30 min) or
(c) DAPI (8 μg/mL, 20 min). MOC-51: λex = 405 nm, λem = 670 ± 20 nm; MTG: λe x= 488 nm, λem = 516 ± 20 nm; LTR: λex = 548 nm, λem = 590 ± 20 nm; DAPI:
λex = 405 nm, λem=460 ± 20 nm. The scale bar is 20 μm.
As MOC-51 was targeted in mitochondrial, the mitochondrial membrane potentials (MMP) of Hela cells incubated with MOC-51
were determined before and after the light irradiation (425 nm, 7.2 J/cm2). The JC-1 assay was performed to evaluate the MMP changes
[21]. JC-1 will accumulate in mitochondria at high MMP and form aggregation state which exhibits red fluorescence. However, at low
MMP, JC-1 fails to aggregate in the mitochondrial, and forms monomer state which emits green fluorescence. As shown in Fig. 4a,
compared to the control group, MOC-51 treated Hela cells exhibited obvious green fluorescence after light irradiation, indicating the
decrease of MMP, which was associated with the early sign of cell apoptosis [22]. The obvious fluorescence changes of JC-1 further
confirmed that the reactive oxygen species (ROS) generated in photodynamic therapy could decrease the MMP, thus resulting in the
apoptosis and death of Hela cells. Since ROS possessed short lifetime and restricted range of diffusion [23], the PDT effect could be
improved by the selective accumulation of MOC-51 in mitochondrial.
In order to verify whether MOC-51 had a highly efficient photodynamic effect on cells, the cytotoxicity of Hela cells under dark and
light irradiation conditions were both measured by MTT assay. As shown in Fig. 4b, MOC-51 showed no obvious cytotoxicity in the
dark for 48 h (IC50 ≥ 015 μmol/L), which is an important precondition for the well-suitable photodynamic therapy agent. However, high
phototoxicity to Hela cells was observed (IC50 ≥ 1.82 μmol/L) when exposed to an extremely small light dose of 7.2 J/cm2 at 425 nm.
Comparatively, using the same Ir(III) amount-containing MOC-51 and Irqpy samples, the Irqpy treated Hela cells showed apparent dark
cytotoxicity although Irqpy also possessed a similar PDT performance as the MOC-51 (Fig. 4c). As the dark cytotoxicity between MOC-
51 and Irqpy was found to be obviously different, inductively coupled plasma mass spectrometry (ICP-MS) method was employed to
precisely estimate cellular uptake level between MOC-51 and Irqpy. As shown in Fig. S17 (Supporting information), both MOC-51 and
Irqpy exhibited time-dependent cellular uptake, and the maximum uptake efficiency reached to 9.45% and 3.84% at 24 h, respectively.
The difference on the uptake efficiency between MOC-51 and Irqpy implied that MOC-51 was more favorable for uptaking by
mitochondrial than the Irqpy metalloligand, which may be resulted from the appropriate molecular size and increased valence states after
MOC formation. In addition, cells only treated with 1% DMSO as the blank control group exhibited negligible difference on the
cytotoxicity with or without the light irradiation condition (Fig. S18 in Supporting information). And cisplatin as the positive control
showed little phototoxicity, either (Fig. S19 in Supporting information). It is noted that under the same light irradiation (425 nm, 7.2
J/cm2), the Ru(bqy)3Cl2 also showed negligible phototoxicity upon such small light dose (Fig. S20 in Supporting information). Compared
with Ru(bqy)3Cl2, the singlet oxygen quantum yield of MOC-51 is higher, which indicates that MOC-51 has better photodynamic effect,
as revealed before in Figs. S13 and S14.

Fig. 4 (a) Confocol images of Hela cells after JC-1 staining treated with MOC-51 with or without light irradiation. Scale bar: 20 μm. The dark cell viabilities and
phototoxicity of Hela cells treated with MOC-51 (b) and Irqpy (c), respectively. (d) Confocal images of MOC-51 (10 μmol/L) and Irqpy (80 μmol/L) in Hela cells
before and after irradiation. The cells were double-stained by calcein AM and PI.
To further confirm the in vitro PDT effect of MOC-51, the Hela cells was stained with calcein-AM and PI to directly visualize the cell
viability. The green fluorescence from calcein-AM and red fluorescence from PI indicated the live and dead cells, respectively. As shown
in Fig. 4d, the cells incubated with Irqpy showed some dark cytotoxicity while the MOC-51 showed little cell death as compared to the
untreated cells group, while significant cell death was both observed against the cells with the incubation of MOC-51 and Irqpy irradiated
by light. These observations are consistent with the result of cell viabilities by MTT method, and further revealed that MOC-51 could
serve as an excellent PDT agent due to the excellent properties such as low dark toxicity and high phototoxicity.
Then the intracellular singlet oxygen was also evaluated by using the 2,7-dichlorofluorescein diacetate (DCFH-DA) as the ROS
indicator. The non-fluorescent DCFH could be oxidized by the intracellular ROS to form the green-emitting DCF, thus the cellular ROS
level could be reflected based on the fluorescence intensity of DCF. As shown in Fig. S21 (Supporting information), cell treated with
light and MOC-51 in the dark showed weak fluorescence, while the cells incubated with MOC-51 upon 425 nm light irradiation exhibited
much strong green fluorescence than that of those control cells, further indicating the ROS played a crucial role in the PDT of MOC-51.
In summary, a cubic barrel shaped Ir-Pd heteronuclear metal-organic cage (MOC-51) was assembled from iridium (III) metalloligand,
which shows one-photon and two-photon excited deep-red emission, and large singlet oxygen quantum yield under visible light
irradiation. The Ir-based MOC was applied for bioimaging and photodynamic therapy for the first time. Effectively, MOC-51 reveals
lower dark toxicity and higher mitochondria-targeted light toxicity compared with the precursor Ir-metalloligand, showing advantages
of the synergistic effects of MOCs. These findings suggested the feasibility of MOCs on the integration of luminescence diagnosis and
cancer therapy, which may lead to the evolution of MOCs and related materials in bio-applications, and so on.
Acknowledgments
This work was supported by the National Natrual Science Foundation of China (NSFC, Nos. 21771197, 21720102007, 21821003),
Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (No. 2017BT01C161), and FRF for the central
universities.

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