Enhanced Photodynamic Therapy by Reduced Levels of Intracellular Glutathione Obtained By Employing a Nano-MOF with CuII as the Active Center

Article abstract of DOI:10.1002/anie.201710800

In photodynamic therapy (PDT), the level of reactive oxygen species (ROS) produced in the cell directly determines the therapeutic effect. Improvement in ROS concentration can be realized by reducing the glutathione (GSH) level or increasing the amount of photosensitizer. However, excessive amounts photosensitizer may cause side effects. Therefore, the development of photosensitizers that reduce GSH levels through synergistically improving ROS concentration in order to strengthen the efficacy of PDT for tumor is important. We report a nano-metal–organic framework (Cu^II-metalated nano-MOF {CuL-[AlOH]₂}_n (MOF-2, H₆L=mesotetrakis(4-carboxylphenyl)porphyrin)) based on Cu^II as the active center for PDT. This MOF-2 is readily taken up by breast cancer cells, and high levels of ROS are generated under light irradiation. Meanwhile, intracellular GSH is considerably decreased owing to absorption on MOF-2; this synergistically increases ROS concentration and accelerates apoptosis, thereby enhancing the effect of PDT. Notably, based on the direct adsorption of GSH, MOF-2 showed a comparable effect with the commercial antitumor drug camptothecin in a mouse breast cancer model. This work provides strong evidence for MOF-2 as a promising new PDT candidate and anticancer drug.

Full text of DOI:10.1002/anie.201710800

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Enhanced Photodynamic Therapy by Reduced Intracellular
Glutathione Levels Employing Nano-MOF with Cu (II) as Active
Center
Authors: Wei Zhang, Jun Lu, Xiaonan Gao, Ping Li, Wen Zhang, Yu
Ma, Hui Wang, and Bo Tang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201710800
Angew. Chem. 10.1002/ange.201710800
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Enhanced Photodynamic Therapy by Reduced Intracellular Glutathione
Levels Employing Nano-MOF with Cu (II) as Active Center
Wei Zhang, Jun Lu, Xiaonan Gao, Ping Li*, Wen Zhang, Yu Ma, Hui Wang, and Bo Tang*
[
9]
Abstract: In photodynamic therapy (PDT), the level of reactive
oxygen species (ROS) produced in the cell directly determines
therapeutic effect. Improvement in ROS concentration can be
realized by reducing the glutathione (GSH) level or increasing the
photosensitizer amount. However, excessive photosensitizer may
cause side effects. Therefore, the development of photosensitizers
combining the ability of reducing GSH levels through synergistically
improving ROS concentration to strengthen the efficacy of PDT for
tumor is important. We report a nano-metal-organic framework (Cu
ROS and improved the PDT effect. Ju’s group combined the
photosensitizer Ce6 and MOF, with the photosensitizer Ce6
[10]
used to produce ROS applied for PDT of cancer. The above-
mentioned works merely employed the MOF or MOF combined
other photosensitizer to generate ROS for tumor treatment.
Considering active center and large specific surface area of the
MOF, we supposed that a rationally designed nano-MOF with
dual function is should be qualified to directly reduce GSH levels
and synchronously serve as PDT photosensitizer, which should
intensify treatment efficacy. Moreover, the above-mentioned
MOF may reduce photosensitizer dose, avoiding side effects of
(II)-metalated
nano-MOF {CuL-[AlOH]
2
}
n
(MOF-2,
H
6
L
=
mesotetrakis(4-carboxylphenyl)porphyrin)) based on Cu (II) as active
center for PDT. This MOF-2 is readily uptaken by breast cancer cells, PDT treatment.
and high-level ROS is generated under light irradiation. Meanwhile,
intracellular GSH is considerably decreased owing to absorption on
MOF-2, synergistically increasing ROS concentration and
accelerating apoptosis, thereby enhancing the effect of PDT. Notably,
based on direct adsorption of GSH, MOF-2 showed comparable
effect with commercial antitumor drug camptothecin in mouse breast
cancer treatment. This work provides strong evidence for MOF-2 as
a promising new PDT candidate and anti-cancer drug.
Photodynamic therapy (PDT) plays an important role in cancer
therapy as treatment for skin cancer and subcutaneous tumor
Scheme 1. Schematic of the mechanism of the nano-MOF for enhanced PDT.
[1]
tissue. The main principle of PDT is to produce a large number
of ROS by using photosensitizers under light irradiation and thus
utilize the toxicity of reactive oxygen species (ROS) to kill cancer
The nano-MOF can adsorb GSH efficiently and decrease the level of GSH for
highly efficient PDT. Schematic of nano-MOF enhanced PDT by decreased
intracellular glutathione levels.
[2]
cells, achieving the treatment of tumor.
For improving
therapeutic effect, numerous studies focused on producing more
[3]
To achieve the above goal, we designed and constructed a
nano-metal-organic framework (Cu (II)-metalated nano-MOF
ROS by using different kinds of photosensitizer. However, the
ROS generated from the photosensitizer could be reduced by a
high concentration of glutathione (GSH) in cells, which
{
CuL-[AlOH]
2
}
n
(MOF-2,
H
6
L
=
meso-tetrakis(4-
[4]
carboxylphenyl)porphyrin)) for PDT. Thereinto, Cu(II) as active
center of MOF-2 can specifically bind and absorb GSH, thus
directly decreasing intracellular GSH concentration, increasing
the ROS level. In the meantime, porphyrin ligand can be used as
photosensitizer to generate abundant ROS under light irradiation.
The two actions of MOF-2 will combine to substantially heighten
the levels of ROS. We utilized MOF-2 in the treatment of mouse
breast cancer tumors, and found it exhibited comparable
therapeutic effect with commercially available anticancer drug
camptothecin (CPT). Importantly, MOF-2 used in mouse breast
cancer tumors synergistically increase ROS concentration,
resulting in apoptosis and enhanced PDT. Altogether, the study
is of universal value and practical significance for the accurate
treatment of cancer.
decreases the effect of PDT. Moreover, excessive amounts of
the photosensitizer may cause side effects. Thus, to develop the
solution with moderate photosensitizers combining concurrently
reduced GSH levels, which can synergistically raise ROS levels
to strengthen the efficacy of PDT is highly significant. However,
to date, few works have been reported on the direct reduction of
intracellular GSH in PDT. At present, Stone group used the
cysteine enzyme to eliminate the levels of cysteine as raw
material for GSH, thereby decreased the GSH level, increasing
[5]
ROS levels, and inhibited tumor growth. Zhang and Tan group
developed a photosensitizer chlorine6/MnO nanosystem, which
Qu’s group used g-C
nanosheets, enhancing light-triggered ROS generation and the
2
[6]
decreasing the level of GSH by MnO
2
.
3 4
N
[7]
depletion of intracellular GSH levels. Therefore, the design of a
new bifunctional material that integrates the production of ROS
and simultaneous elimination of intracellular GSH is of great
importance.
We synthesized two kinds of nano-MOF, including the
aluminum–copper mixed metal MOF (MOF-2) with Cu (II) as the
active center, and aluminum–metal nano-MOF (MOF-1) without
Cu (II) active center as a control, in order to confirm the GSH-
binding role of Cu (II) in MOF. The crystal structure and
morphology of nano-MOF were characterized by XRD, IR, EDS,
As a new type of porous complex, metal–organic frameworks
(
MOF) have been widely used in biosensing, catalysis, and PDT
owing to the advantages of structural diversity and high specific
[11]
[8]
SEM, and TEM, respectively. To test if MOF-2 can effectively
absorb GSH, considering GSH could scavenger ROS, we
compared ROS amount induced by MOF-2 and MOF-1 in the
surface area. In particular, MOF can improve the ROS level as
photosensitizers. For example, the Liu group synthesized a new
4
+
MOF based on Hf and a porphyrin derivative, which produced
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absence or presence of GSH. ROS levels were measured using
a commercial fluorescent probe DCFH (2,7-dichlorofluorescein)
were 603 and 650 nm. Figure S6 showed that the fluorescence
response of HS with MOF-2 was significantly weaker than that
-
[7]
(
Figure 1b). When 1.0 mM GSH was added, the fluorescence
of GSH. The Cys/GSH ratio was selected at the physiological
concentration range, and we found that the fluorescence
response of MOF-2 with Cys was remarkably less than that of
GSH. As for other sulfur compounds of high concentrations,
intensity decreased in the solutions of MOF-1 and MOF-2,
meaning the decrease of ROS concentration resulted from the
interaction between ROS and GSH. Apparently, fluorescence in
MOF-2 solution was about 2-time stronger than MOF-1, which
indicated higher concentration of ROS generated by MOF-2.
The results indicated that the binding between GSH and Cu (II)
of MOF-2 maybe reduce GSH level. Then, we analyzed the
amount of GSH remaining in the supernatant after centrifugation
to remove MOF, using a GSH fluorescence kit. As can be seen
from the illustration in Figure 2b, in the presence of GSH, the
2
−
2−
2−
such as SO
4
(1.0 mM), SO
3
(1.0 mM), S
2
O
3
(1.0 mM), and
−
(8) SCN (1.0 mM), although the concentration of the above-
mentioned sulfur compounds was markedly higher than that of
GSH, whereas the fluorescence change was small. These
results indicated that MOF-2 exhibited highly selective
adsorption capacity for GSH. To study the interaction between
MOF-2 and GSH in depth, we optimized the experimental
amount of ROS in MOF-2 material was more than that of MOF-1, conditions including effects of pH and concentration (Figure S7).
which indicated that MOF-2 was adsorbed more GSH. Figure 1c
showed strikingly less GSH in MOF-2 solution than MOF-1.
Further experiment displayed that the concentration ratio of GSH
before and after treatment with MOF-2 of 15 µM reached 8.0
Under optimal conditions, we investigated the ability of MOF-2 to
selectively adsorb GSH by fluorescence response. We found
that low concentrations of GSH could enhance the fluorescence
intensity of MOF-2 in the concentration range of 0−200 µM
(Figures S8 and S9), with linear relationship in the range of
0−5.0 µM and 5.0 µM−100 µM, and the correlation coefficients
were 0.9915 and 0.9706, respectively. We speculated the GSH
competed with nitrogen atoms in porphyrin and coordinated with
Cu (II); therefore, the fluorescence of porphyrin quenched by Cu
(
Figure 1d). These results demonstrate that Cu (II) and porous
property of MOF-2 endow it excellent adsorption capacity for
GSH.
(
II) was linearly restored. Conversely, at concentrations
exceeding 200 µM, GSH can quench the fluorescence of MOF-2.
In this case, we supposed that MOF-2 existed as a fluorescence
quenching aggregation state. Based on these principles, the
fluorescence response of the MOF was employed to
characterize the adsorption interaction between MOF and GSH
in live cell.
Figure 1. (a) PXRD patterns for the as-synthesized sample MOF-1 and MOF-
[12]
2, and PXRD patterns for the reported crystal sample;
(b) Influences of
MOF-2 (Cu-MOF) and MOF-1 (copper-free MOF) on GSH adsorption using
the ROS probe under 650 nm light irradiation, inset is the illustration of
quantitative description for influences on MOF-2 and MOF-1 during GSH
adsorption, F
MOF-2 respectively; (c) The concentration of GSH in the supernatant solution
treated with MOF-1 and MOF-2 via commercial kit measurement; (d)
1 2
& F are the fluorescence intensities of DCFH in MOF-1 &
a
Supernatant solutions’ GSH concentration via a commercial kit measurement
after the treatment of different amount of MOF-2.
Figure 2. Dynamic light scattering image of (a) MOF-2 (5.0 µM); (b) MOF-2
(
5.0 µM) and GSH (30.0 µM); (c) MOF-2 (5.0 µM) and GSH (3.0 mM); (d)
MOF-2 (5.0 µM) and GSH (3.0 mM), followed by an addition of Cu (II) (100
µM).
To verify the specificity adsorption of MOF-2 to GSH, we
studied the fluorescence response between MOF-2 with GSH,
mercapto compounds, and sulfur-containing small molecular
species. The coordination of Cu (II) with nitrogen atoms in the
porphyrin structure quenched fluorescence of MOF-2. While
fluorescence of porphyrin in MOF-2 restored when the GSH
bound Cu (II), of which excitation was 420 nm, emission peaks
Next, mechanism of fluorescence change caused by ad-
sorption was further explored. We used dynamic scattering to
examine the hydration radius of MOF-2 in the presence of
different concentration GSH. Figure 2b showed that there was
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no significant change in the hydration radius of MOF-2 with 30.0
µM GSH, indicating no gathering of MOF-2 occurred. After
addition of 3.0 mM GSH, the hydrated particle size of the
material evidently increased (Figure 2c), indicating that a large
amount of GSH resulted in the aggregation of MOF-2.
Aggregation leads to fluorescence quenching of MOF-2. To
further confirm this hypothesis, 100 µM Cu (II) was added. The
result in Figure 2d showed that hydration radius of MOF-2
reduced obviously, which suggested MOF-2 dispersed again. All
together, these results demonstrated that the MOF-2 adsorbed
on GSH was present in a dispersed luminescent form under low
concentration GSH. On the contrary, in the case of high GSH
concentration, MOF-2 was existed as aggregated state of
fluorescence quenching with increasing amount of adsorbed
GSH.
experiment. Figure 3 showed the activity of cancer cells HepG2
and normal cells LX-2 gradually decreased with increasing
concentration of MOF-2. The relative cell viability of normal cells
LX-2 / HepG2 cells was 2.0 when the concentration of MOF-2
was 120 µM (Figure 3b), which demonstrated that the MOF-2
showed potential as a new type of anticancer drug through
regulating the level of GSH in cancer cells. Notably, at the same
MOF-2 concentration, the cell viability of HepG2 cells was
significantly lower than that of normal cells possibly because the
amount of GSH required for cancer cells was significantly higher
than that of the normal cell. Thus, the influence of the same
amount of MOF-2 on cell viability was that the cancer cells were
larger than normal cells.
The adsorption of MOF-2 to the intracellular GSH was studied,
which was reflected via changes on fluorescence properties of
MOF-2. Due to low concentration the GSH enhances its
fluorescence, and high concentration quenches fluorescence.
We found that HepG2 cells incubated with MOF-2 showed weak
fluorescence (Figure S10a). This should be ascribed to high
concentration of GSH in cancer cells that was directly adsorbed
by MOF, which quenches fluorescence of MOF-2. To verify if the
fluorescence change was induced by GSH, GSH scavenging
reagent N-Ethylmaleimide (NEM) was used to treat cells (Figure
S10b). Brighter fluorescence was observed in these cells,
meaning dispersed form of MOF-2 due to significant decrease of
GSH level. These results confirmed that MOF can specifically
absorb GSH in live cells.
Figure 4. (a) Cell viability of 100 µM MOF-2 stained with PBS, MOF-2,
camptothecin (CPT), MOF-2 and CPT in combination for 24 h; (b) Cell viability
of MOF-2 stained with PBS, MOF-2, BSO, MOF-2 and BSO in combination for
24 h. Experimental details: MOF-2, 100 µM; BSO 0.5 mM; CPT, 15 µM.
We further evaluated the effectiveness of MOF-2 to kill tumor
cells by comparing with other anticancer drugs. The influence of
MOF-2, CPT, BSO, MOF-2 and CPT in combination (MOF-
2/CPT), MOF-2 and BSO in combination (MOF-2/BSO) on
viability of HepG2 cells was studied by MTT assay (Figure 4).
The results showed that MOF-2, CPT, and BSO could decrease
the survival rate of cancer cells. While the effect of MOF-2 on
cell viability was significantly higher than those of CPT and BSO,
indicating that MOF directly adsorbed GSH, reducing GSH
levels and exhibiting good killing ability toward cells. When
MOF-2/CPT and MOF-2/BSO were used in combination (Figures
Figure 3. (a) Cell viability of LX-2 cells (green) and HepG2 cells (yellow). (b)
Ratio of cell viability at different concentrations of MOF-2, the ratio = LX-2
cells/ HepG2 cells.
4
a and 4b), lower survival rate of cancer cells was observed,
indicating that MOF-2 enhanced the killing ability of CPT and
BSO to cells by GSH adsorption.
The MOF killing of tumor cells was further performed by flow
cytometry. The effects of MOF-2, CPT, BSO, and MOF-2/CPT
and MOF-2/BSO on the HepG2 were studied and morphological
changes of HepG2 cells were shown in Figure S13. The green
fluorescence imaging was fluorescence imaging of cell
membrane stained by FITC. Notably, imaging brightness was
closely related to the early stages of apoptosis. Improved cell
morphological imaging was observed compared with that of the
control group, indicating that MOF-2, CPT, and BSO induce cells
to the prophase of apoptosis. Green fluorescence brightness
increased significantly after the use of MOF-2/CPT and MOF-
To further confirm the binding of MOF-2 to different
concentrations of GSH in cells, MOF-2 was used to observe
fluorescence changes in buthionine sulf oximine (BSO) induced
HepG2 cells (Figure S11). In the first 30 min of apoptosis, the
high concentration of GSH quenches the fluorescence of MOF-2;
after 30 min, the concentration of GSH decreased during
apoptosis, and the cell fluorescence brightness gradually
increased with time. Generally speaking, with increasing degree
of apoptosis, intracellular GSH concentration decreased, cell
fluorescence imaging brightness gradually increased (Figure
S11). These results confirmed that MOF-2 can adsorb different
concentrations of GSH in cells. Moreover, the concentration of
GSH can be indicated by fluorescence imaging.
2/BSO, respectively, indicating that the degree of apoptosis
increased and the number of cells in the early stage of apoptosis
increased significantly. The orange fluorescent imaging was
stained by propidium iodide. The imaging brightness was closely
Next, we examined the influences of MOF-2 on the survival
rate of normal cells and cancer cells through the MTT
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related to the late stage of apoptosis and necrosis. Compared
with the control group, cell imaging showed evident brightness,
indicating that MOF, CPT, and BSO on the cell killing ability
increased during late apoptosis. After treatment with MOF-
that cell death rate caused by MOF-2 was obviously higher than
that of MOF-1 (Figure S17), further revealing that excellent
therapeutic effect of MOF-2 was achieved by generating
intracellular ROS while reducing GSH. In general, the above-
mentioned results provided strong evidence that MOF-2
exhibited outstanding photosensitive properties, which can be
selected as a powerful PDT photosensitizer.
2/CPT and MOF-2/BSO, we found that the orange fluorescent
brightness was significantly enhanced, indicating that late
apoptotic cells increased significantly, and the process of cell
death was exacerbated. Figure 5 showed the flow cytometry
analysis of apoptosis cells following treatment with different
reagents. After incubation with HepG2 cancer cells, the survival
rates of MOF, CPT, and BSO were 60.44%, 75.22%, and
To validate the efficacy of MOF enhanced PDT on tumors, we
established a mouse breast tumor model (when mouse tumors
3
grow to about 150 mm , we randomly divided the tumors into
eight groups, which were subjected to different treatments, and
measured the weight and tumor size every 2 days). The therapy
efficacy of MOF, CPT, MOF/CPT were investigated by
measuring breast tumor size (a) and body weight (b). As shown
in Figure 6b, the weight of the mice was less affected after 14
days of treatment. Figure 6a showed the influence of MOF, CPT,
MOF/CPT, and 650 nm laser irradiation conditions on the tumor
size. As time went on, the size of the tumor gradually increased.
Compared with control, the production of tumor was inhibited
obviously after using MOF-2. The MOF-2 and the anti-cancer
drug CPT all can inhibit tumor growth. When MOF-2 was
combined with CPT, the treatment effect was markedly improved.
Notably, after fourteen days of treatment, MOF-2 exhibited best
performance in inhibiting tumor growth under 650 nm light
irradiation (Figure 6a). This finding demonstrated the ability of
MOF-2 to direct adsorption of GSH, which remarkably improved
the ROS levels and significantly enhanced PDT effect. The
efficacy of MOF-2 on PDT was basically identical to that of MOF-
8
3.13%, respectively (Figure 5); when MOF-2 and
chemotherapeutic drugs were used in combination, we found
survival rates of MOF-2/CPT and MOF-2/BSO of 40.57% and
17.53%, respectively, which showed that the ability to kill cells
was significantly improved after MOF-2 combined with drugs. By
comparison, we found that the MOF-2 exhibits potential as novel
anticancer drug by directly reducing GSH levels.
2
combined with CPT. Hence, the MOF-2 exhibited ability to
enhance the effect of PDT by directly absorbing intracellular
GSH. To further confirm the in vivo efficacy, the therapeutic
effect of the MOF-2 regarding from tumor weights was
performed (Figure S19 and S20). The tumor weights after MOF-
2 treatment was significantly reduced than that of the control
group, which well demonstrated the in vivo efficacy of the MOF-
2 for PDT. In addition, the data about in vivo toxicity of organs
was provided (Figure S21) through test of tissue slides (heart
liver, spleen, lung and kidney, respectively). MOF-2 was injected
directly into the tumor section. After treatment, the MOF-2 has
less effect on other organs, which indicated the MOF-2 has less
in vivo toxicity.
Figure 5. Flow cytometry analysis of HepG2 cells apoptosis following
treatment with different reagents. (a) control; (b) 100 µM MOF-2; (c) 15 µM
CPT; (d) MOF-2 and CPT in combination; (e) 0.5 mM BSO; (f) MOF-2 and
BSO in combination; Experimental details: MOF-2, 100 µM; BSO, 0.5 mM;
CPT, 15 µM.
To investigate a good therapeutic effect can be achieved by
generating intracellular ROS while reducing GSH. We first
measured the production of ROS in vitro using ROS probe
DCFH-DA (Figure S14). We found that the ROS concentration
after light irradiation was three times higher than that of without
light irradiation. Appreciable increase on the amount of ROS
substantiates good photosensitive properties of MOF-2. Then,
produced ROS in cells was measured using ROS probe DCFH-
DA (Figure S15), and the fluorescence brightness was
significantly stronger than that under non-irradiation (Figure
S15d). The corresponding data output showed an intracellular
ROS concentration ratio before and after illumination of 1:1.4
Figure 6. Effects of MOF (10 mg/kg), CPT (2.5 mg/kg) alone and in
(
Figure S15e), indicating that intracellular ROS level increased
combination and the effect of light conditions on tumor size (a) and body
under light irradiation. To further evaluate ROS-producing
capability of MOF-2, we measured the amount of ROS in HepG2
cells incubated with MOF-1 and MOF-2 using DCFH-DA (Figure
S16). By comparison, the ability to generate ROS of MOF-2 was
significantly stronger than that of MOF-1, suggesting that MOF-2
raises the ROS levels through synergies. MTT assay showed
2
weight (b). light irradiation: under 50 mW/cm 650 nm light irradiation 15 min
every day.
To reduce effect of high GSH concentration on PDT, we
developed nano-MOF with Cu (II) as the active center to
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enhance the effect of PDT by the direct adsorption of GSH.
Utilizing the porous structure of MOF-2 and combining the role
of Cu (II), the level of GSH was reduced dramatically. Through
directly interaction between MOF-2 and GSH, the effects of the
MOF-2 toward cancer cells were twice than that of normal cells.
Thus, the MOF-2 showed comparable therapeutic efficacy with
commercial anticancer drug CPT. More importantly, the MOF-2
as photosensitizer for PDT of breast cancer can synergistically
increases the levels of ROS, which enhanced the effect of PDT.
The results of our study not only provide a new approach for the
improvement of PDT but also provide new ideas for other tumor
therapy methods by directly reducing the intracellular GSH to
improve efficacy.
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[
[
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Angewandte Chemie International Edition
10.1002/anie.201710800
COMMUNICATION
Table of Contents
Layout 2:
COMMUNICATION
Wei Zhang, Jun Lu, Ping Li*, Wen
Zhang, Yu Ma, Hui Wang, and Bo Tang*
Page No. – Page No.
Enhanced Photodynamic Therapy by
Reduced Intracellular Glutathione
Levels Employing Nano-MOF with Cu
Text for Table of Contents
(
II) as Active Center
Herein, we report a nano-MOF based on Cu (II) as active center for PDT. Intracellular GSH was
markedly decreased owing to absorption on nano-MOF, synergistically increasing ROS concentration
and accelerating apoptosis, which enhances PDT effect. Notably, through direct adsorption of GSH, the
nano-MOF showed a comparable effect with commercial antitumor drug CPT in mouse breast cancer
treatment. This work provides strong evidence for nano-MOF as a promising new PDT candidate and
anti-cancer drug.
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