Porphyrin-ferrocene conjugates for photodynamic and chemodynamic therapy

Article abstract of DOI:10.1039/C8OB02391C

Chemodynamic therapy can convert endogenous hydrogen peroxide (H₂O₂) at tumor localization into the toxic hydroxyl radical (OH) destroying tumor cells. Photodynamic therapy as a noninvasive method utilizes photosensitizers (PSs) to c

Full text of DOI:10.1039/C8OB02391C

Organic &
Biomolecular Chemistry
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Porphyrin–ferrocene conjugates for
photodynamic and chemodynamic therapy†
Cite this: Org. Biomol. Chem., 2018,
6, 8613
1
a,b
a
b,c
b
b
Zhitao Lei, Xiaoyu Zhang,* Xiaohua Zheng, Shi Liu and Zhigang Xie
*
2 2
Chemodynamic therapy can convert endogenous hydrogen peroxide (H O ) at tumor localization into
•
the toxic hydroxyl radical ( OH) destroying tumor cells. Photodynamic therapy as a noninvasive method
1
utilizes photosensitizers (PSs) to convert O
2
into cytotoxic reactive oxygen species (e.g., O
2
) upon laser
irradiation, which is dependent on the content of oxygen. The combination of the two therapeutic strat-
egies on a single platform can enhance the anticancer effect. Herein, we report a porphyrin–ferrocene
theranostic agent for combined photodynamic and chemodynamic therapy. Compared to monotherapy,
the as-prepared porphyrin–ferrocene conjugates exhibit superior efficiency and potency in killing cancer
cells at low drug doses. This study suggests the rational design of molecular structures as multifunctional
therapeutics for potential clinic application.
Received 26th September 2018,
Accepted 25th October 2018
DOI: 10.1039/c8ob02391c
rsc.li/obc
developed a manganese dioxide (MnO )-based nanoagent as a
2
Introduction
CDT agent, which possesses both glutathione (GSH) diminution
2
+
10
Despite the rapid advances in medical technology, cancer is properties and Fenton-like Mn delivery. However, the treat-
still a difficult problem to be overcome. The high mortality ment effect of CDT is greatly weakened because of the reaction
•
rate of cancer has led to the rapid development of various of between OH and GSH in cancer cells.
treatments, including surgery, chemotherapy, radiotherapy
As a noninvasive cancer treatment, phototherapy mainly
1
–5
22–31
and phototherapy. Reactive oxygen species (ROS), including includes photothermal and photodynamic therapy (PDT).
the superoxide anion, hydrogen peroxide (H O ), singlet Photosensitizers can transfer energy from light to the
2
2
oxygen and hydroxyl radicals, possess the ability to efficiently surrounding molecular oxygen and produce poisonous ROS,
6
,7
1
kill cancer cells. In recent years, a lot of effort has been especially singlet oxygen ( O ), which can lead to increased
2
invested on the development strategy of cancer treatment permeability of the cell membranes and further interfering
through ROS, such as chemodynamic therapy and photo- with the normal function of cells. Porphyrin and its derivatives
3
2–35
dynamic therapy. Chemodynamic therapy (CDT) produces ROS have been proposed as potential photosensitizers for PTT
using endogenous chemical energy, which could evoke cell and PDT, owing to their high photostability and good
4
,36–41
death, in the absence of additional energy stimulation (e.g., biocompatibility.
However, because of tissue hypoxia and
8
–16
laser irradiation).
only generate the most toxic ROS ( OH) by disproportionation porphyrin alone exhibit insufficiency of treatment to some
reactions of H but also produce O in excess of H extent. Therefore, it is important and imperative to combine
Fenton-like reactions are commonly used in CDT, for example, PDT with other treatment methods, such as chemotherapy and
Fenton or Fenton-like reactions can not limited light penetration, the photodynamic effects of
•
2
O
2
2
2 2
O .
1
1,42–46
ferrocene (FC) and its derivatives can generate hydroxyl CDT.
Chemodynamic therapy (CDT) can convert
radicals ( OH, the most poisonous ROS) in the presence of endogenous hydrogen peroxide (H ) at tumor localization
•
2 2
O
1
7–21
•
hydrogen peroxide (H O ).
In addition, Lin and co-workers into the toxic hydroxyl radical ( OH) destroying tumor cells,
2
2
thus making up for the O -dependent limitations of PDT to a
2
degree. Synergistic effects of PDT and CDT could enhance the
treatment efficiency of malignant tumors. The combination of
chemotherapy and PDT has been expanded and proved to be
an efficient approach to gain an optimal treatment outcome
and reduce the side effects of each treatment method.
a
College of Environmental and Chemical Engineering, Yanshan University,
38 Heibei Avenue, Qinhuangdao, Hebei 066004, P. R. China.
4
E-mail: xiaoyuzhang@ysu.edu.cn
b
State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of
Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China.
E-mail: xiez@ciac.ac.cn
Herein, we synthesized an agent porphyrin–ferrocene
(
TNCF) from porphyrin and ferrocene, which combines CDT
c
University of Science and Technology of China, Hefei 230026, P. R. China
with PDT (Scheme 1A). Although there are some reports about
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
4
7,48
c8ob02391c
porphyrin–ferrocene conjugates,
their application in
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on a Shimadzu UV-vis spectrophotometer (UV-1800 model).
Confocal microscopy imaging was performed using a Zeiss
LSM 700 confocal microscope and the images were analyzed
using ImageJ (NIH). The mass spectra (MS) of the samples
were obtained by using a German company Bruker autoflex III
smart beam mass spectrometer (MALDI-TOF/TOF).
Synthesis procedures of TPP-NH . TPP-NH was synthesized
2 2
from tetraphenylporphyrin (TPP) in three steps according to
the reported methods.
Synthesis procedures of TNCF. Dicarboxyferrocene (FC)
reacts with TPP-NH2 after chlorination to form the target
product TNCF. FC (274 mg, 1 mmol) and (COCl)
2
1
2
(317.5 mg,
.51 mmol) were added to a round bottom flask. Then,
00 mL of anhydrous tetrahydrofuran and N,N-dimethyl-
formamide (0.2 mL) were added under argon. The reaction
mixture was stirred at room temperature for 24 h. The (COCl)
was removed by reduced pressure distillation and extracted
with CHCl . TPP-NH (705.1 mg, 1.12 mmol) and dicarboxyfer-
rocene chloride were dissolved in CHCl under argon. The
2
3
2
3
reaction was carried out at room temperature for 24 h. Then,
the solvent was removed by evaporation, and the crude
product was purified by column chromatography on silica.
Scheme 1 Schematic illustration of the (A) preparation and (B) appli-
cation of TNCF for cancer therapy.
Singlet oxygen generation measurements
dynamic therapy has not been explored yet. As shown in In order to study the ability of TNCF to produce singlet
Scheme 1B, according to the Fenton reaction, FC reacted with oxygen, DPBF is used as an indicator for detection by using
•
hydrogen peroxide to produce OH, which kills tumor cells ultraviolet visible spectra. The mixture of DPBF and TNCF is
efficiently. However, the GSH localized in tumor cells can illuminated under a 620 nm lamp at 12 mW cm− . The absorp-
2
•
consume OH resulting in the inhibition of CDT. Furthermore, tion value of the DPBF at 415 nm was recorded once every 10 s.
1
2 2
O produced by the PDT of TPP-NH will decrease the level of The experiment was repeated with a separate DPBF as a
GSH, which shows the synergistic therapy efficacy. The control group.
obtained TNCF can be well internalized by cells and consume
GSH in vivo, thereby improving the effectiveness of CDT.
To detect the ability of TNCF to produce hydroxyl radicals
( OH) due to the occurrence of the Fenton reaction, salicylic
•
acid was introduced as a probe. TNCF and salicylic acid were
mixed, then hydrogen peroxide (H O ) was added and the
2
2
absorption value of the mixture at 510 nm was immediately
recorded.
Experimental
Materials and characterization
Cell culture
Milli-Q water was obtained from a Milli-Q system (Millipore,
3
USA). Pyrrole, benzaldehyde, chloroform (CDCl ) and ethane- Human breast cancer (MCF-7) and human cervical cancer
dioylchloride ((COCl) ) were purchased from Sigma-Aldrich (HeLa) cells were cultured with Dulbecco’s modified Eagle’s
2
Co., Ltd (St Louis, MO, USA). Triethylamine and trifluoroacetic medium (DMEM) in a Petri dish, observing the state of the
acid (TFA) were purchased from Energy Chemical Co., Ltd. cells and changing the medium in time to facilitate sub-
Dulbecco’s modified Eagle’s medium (DMEM), RPMI-1640 sequent experiments. The temperature of the culture chamber
Medium, and fetal bovine serum (FBS) were purchased from was 37 °C, and the concentration of carbon dioxide (CO
Sigma-Aldrich. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl- 5%.
2
) was
tetrazoliumbromide), Lyso-Tracker Green and 4,6-diamidino-2-
phenylindole (DAPI) were purchased from Beyotime
Cellular uptake
Biotechnology Co., Ltd (China). A Live–Dead Cell Staining Kit Confocal laser scanning microscopy (CLSM) was used to study
was purchased from KeyGen Biotech Co., Ltd. All of the other the cellular uptake of TNCF by MCF-7 cells. First, the MCF-7
chemicals were obtained commercially and used without cells were incubated for 24 h in 6-well plates, making sure that
further purification.
the number of cells in each well was greater than 20 000. Then,
1
−1
H NMR spectra were recorded on an Agilent Mercury the DMEM was sucked up before adding a dose of 15 µg mL
00 MHz spectrometer in chloroform-d. Fluorescence emission of TNCF to each well. The cells were incubated at 37 °C and
4
spectra were obtained using
a
Hitachi fluorometer 4 °C for 0.5, 4 and 6 h, respectively. After that, the DMEM was
(F-7500 model). The UV-vis spectroscopy study was performed removed and the cells were washed three times with PBS. After
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that, the cells were soaked in 1 mL of 4% formaldehyde and dium iodide (PI) for 30 min at room temperature. Finally, the
kept at room temperature for 10 min and then washed twice results of cell staining were detected by fluorescence
with PBS again. The nuclei of the cells were stained with 4′,6- microscopy.
diamidino-2-phenylindole (DAPI) for 5 min and washed three
times with PBS. The samples were examined by CLSM using a
Zeiss LSM 700 system (Zurich, Switzerland).
Results and discussion
Intracellular ROS detection
5
-(4-Aminophenyl)-10,15,20-triphenylporphyrin (TPP-NH ) was
2
Intracellular ROS detection of PDT. CLSM was used to synthesized using the method previously reported. As shown
explore the generation of intracellular ROS. The MCF-7 and in Scheme 1A, 1,1′-ferrocenedicarboxylic acid (FDCA) reacts
HeLa cells were grown in a six-well plate with a cover glass. with TPP-NH after acyl chlorination. After being purified by
2
The cells were incubated for 24 h under 37 °C conditions; then using a silica gel column, the structures of the obtained pro-
the original medium was replaced with a medium with or ducts were validated by proton nuclear magnetic resonance
1
without the added medicine. Four hours later, the light group ( H NMR) (Fig. S1–S3, ESI†) and matrix-assisted laser desorp-
received 20 min of exposure. The cells were washed twice with tion/ionization time-of-flight mass spectrometry (MALDI-TOF
a medium without FBS; then a medium containing DCFH-DA MS), which demonstrated that TNCF was successfully
was added as a probe. The cells were continued to be cultured synthesized.
for 30 min at 37 °C and then observed by CLSM as soon as
possible (excitation wavelength, 488 nm; emission band-pass, using the absorption and photoluminescence (PL) spectra. As
00–550 nm).
shown in Fig. 1A, the absorption spectra of TNCF in N,N-di-
Intracellular ROS detection of CDT. The MCF-7 and HeLa methylformamide (DMF) did not change before and after the
Then, the optical properties of TNCF were investigated
5
cells were grown in a six-well plate with a cover glass and incu- laser irradiation with the maximum absorption at 415 nm,
bated for 24 hours under 37 °C conditions. After incubation indicating good photostability. According to the PL spectrum
with 1 mL of DCFH-DA (10 μM in FBS-free DMEM) at 37 °C (Fig. 1B), TNCF has two distinct peaks at about 650 and
under 5% CO
replaced with media (acidulated DMEM of pH = 6.5) contain- rescence under 365 nm light irradiation.
2
for 20 min, the culture media were then 750 nm. As shown in Fig. 1B, TNCF has a strong red fluo-
−1
ing the following samples: 200 μM H
2
O
2
, 20 μg mL TNCF
To explore the ability of TNCF as a CDT reagent to produce
−
1
•
and a mixture of 200 μM H and 20 μg mL TNCF. The cells
2 2
O
OH, salicylic acid was introduced as an indicator, and its
were further incubated at 37 °C under 5% CO . After 2 h, the absorbance was monitored (Fig. 2A). As shown in Fig. 2A, the
2
•
cells were washed with PBS three times. The level of intracellu-
lar ROS was evaluated by detecting the fluorescence of DCF.
OH produced by the Fenton reaction could react with salicylic
acid, and the resulting 3-dihydroxybenzoic acid has absorption
at 510 nm. In Fig. 2A and B, with the prolongation of time, the
Cytotoxicity assay
absorbance of 2,3-dihydroxybenzoic acid increased, which
•
DMEM was used to dilute TNCF and H
2
O
2
to different concen- showed that more OH were produced with the increase of
•
trations. MCF-7 and HeLa cells were cultured and divided into time. The formation of OH at the cell level was further
two groups in 96-well cell-culture plates, and then incubated detected via confocal laser scanning microscopy (CLSM) by
in a culture medium for 24 h. The medium was replaced with using 2′,7′-dichlorofluorescein diacetate (DCFH-DA) as
different concentrations of TNCF, and the cells were continued probe. The intracellular OH generation of TNCF was studied
to be cultured for 6 h. The first group of cells remained in the in human breast cancer (MCF-7) cells. In Fig. S7,† when the
a
•
dark, and the second group was irradiated with a laser concentration of H
2
O
2
was 200 μM, MCF-7 cells still had a
−
2
(
620 nm, 12 mW cm , 30 min). Then 20 µL of MTT (5 mg high survival rate. As shown in Fig. 2C, the cells treated with
−
1
mL ) were added to each hole and the cells were incubated TNCF and
H
2
O
2
emitted obvious green fluorescence.
for another 4 h. Finally, the liquid in the hole was sucked up Meanwhile, almost no green fluorescence was found in the
and 150 µL of DMSO were added to each well to dissolve the
formazan crystals formed. The baseline corrected absorbance
at 590 nm (A(570 nm) − A(630 nm)) was applied to calculate
the relative number of viable cells. Finally, the plates were
shaken for 3 min, while the absorbance of the formazan was
measured at 590 nm (A(570 nm) − A(630 nm)) by using a
microplate reader.
Live–dead cell staining assay
The cells were planted in a 96-well plate and incubated for
Fig. 1 (A) UV-vis absorption spectra of TNCF (in DMF) with or without
laser irradiation; the inset is a picture of TNCF in DMF. (B) PL spectrum
of TNCF in DMF; the inset is a photograph of TNCF in DMF upon
2
4 h. After 4 h of incubation with TNCF, TPP-NH
2
and FC, the
−
2
cells were irradiated using a 620 nm LED lamp (12 mW cm
,
4
0 min). Then, the cells were stained with calcein-AM/propi- irradiation with 365 nm light.
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investigated by UV-vis absorption spectroscopy. In Fig. S4A,† the
absorption peaks of TNCF were basically unchanged under
20 nm laser irradiation (12 mW cm− for 40 min), indicating
2
6
its eminent photostability. DCFH-DA was still used as a probe to
study the ability of TNCF as a PDT reagent to produce ROS in
MCF-7 cells. In Fig. 3C, strong green fluorescence was found in
the TNCF + L group (treated with TNCF and laser irradiation)
and the TNCF + H O + L group (treated with TNCF, H O and
2
2
2 2
laser irradiation) compared to the control groups. The same
results were found in HeLa cells (Fig. S8†). In short, TNCF has
an efficient ability to produce singlet oxygen and can be poten-
tially used as a photosensitive agent for PDT.
The cellular uptake of TNCF by MCF-7 cells was verified by
CLSM. The cellular nuclei were stained blue with 4,6-di-
amidino-2-phenylindole (DAPI). Time dependent internaliz-
Fig. 2 (A) Time-dependent UV-vis absorption spectra of salicylic acid
•
with H
generation kinetics of salicylic acid at 510 nm with H
2
O
2
in water (200 μM) from 0 to 20 min. (B) Time-dependent OH ation of TNCF was observed. As the time extended from 0.5 to
2
O
2
(200 μM). (C) 6 h, the intensity of the fluorescence increased (Fig. S5†).
Generation of ROS in vitro (MCF-7) denoted by the fluorescence of DCF.
Scale bars, 20 μm.
When the temperature was reduced from 37 to 4 °C, the fluo-
rescence intensity decreased significantly (Fig. S6†), revealing
an ATP-mediated endocytosis pathway. As shown in Fig. 4,
after incubation with TNCF for 2 h, the cells were stained with
Lyso-Tracker Green and continued to be incubated at 37 °C for
other three control groups. The same results were also
observed in human cervical cancer (HeLa) cells (Fig. S8†).
These results demonstrated that TNCF could be used as an
excellent CDT reagent for tumor therapy.
30 min. It was found that the green fluorescence coincided
well with the red fluorescence, indicating lysosome-mediated
endocytosis of TNCF.
The ability of TNCF as a PDT reagent to produce ROS under
laser irradiation was chemically determined by using 1,3-
diphenylisobenzofuran (DPBF) as a pointer, and the absor-
bance of DPBF was monitored by UV-vis absorption spec-
troscopy. As shown in Fig. 3A and B, the absorbance of DPBF
at 415 nm gradually decreased with increasing illumination
time (630 nm, 12 mW cm ) in the presence of TNCF. In con-
trast, the absorbance of DPBF with laser irradiation alone was
unchanged (Fig. S4B†). The results prove that ROS was pro-
duced because of the addition of TNCF. The photostability was
The in vitro cytotoxicity of TNCF against MCF-7 cells was
evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazo-
lium bromide (MTT) assays. In order to investigate the CDT
effect of TNCF, the cells were treated with or without H O for
2
2
1
h in advance. We first studied the dark toxicity of TNCF,
TPP-NH and FC against MCF-7 cells, and no obvious cyto-
toxicity was observed in the absence of H O , denoting their
2
−
2
2
2
pronounced cytocompatibility without laser irradiation
Fig. 5A). Then the MCF-7 cells were incubated with H for
h and subsequently FC, TPP-NH2 and TNCF were added
respectively. TNCF and FC showed conspicuous cytotoxicity
toward MCF-7 cells compared with TPP-NH because of CDT
Fig. 5B). We then incubated the cells with TNCF, TPP-NH2
(
2 2
O
1
2
(
and FC for 6 h and later irradiated the cells using an LED
lamp at a power density of 12 mW cm− for 40 min. As shown
2
Fig. 3 (A) Time-dependent UV-vis absorption spectra of a mixture of
Fig. 4 (A) CLSM images of MCF-7 cells incubated with TNCF in the
presence of Lyso-Tracker Green. For each panel, the images show cell
nuclei stained with DAPI (blue), the fluorescence of TNCF (red), lyso-
somes stained with Lyso-Tracker Green (green) and overlays of three
images. Scale bars, 20 mm. (B) Fluorescence of TNCF and Lyso-Tracker
Red in cells in 2.5D mode.
DPBF and TNCF in DMF upon irradiation with a 620 nm laser (12 mW
−2
cm ) from 0 to 240 s. (B) Comparison of the decline rate of DPBF alone
and a mixture of DPBF and TNCF under laser irradiation. (C) Generation
−2
of ROS in vitro under laser irradiation (620 nm, 12 mW cm , 40 min)
denoted by the fluorescence of DCF. Scale bars, 20 μm.
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Fig. 6 Flow cytometry analysis of the MCF-7 cells treated with (A) only
H
2
O
2
, (B) only irradiation, (C) only TNCF, (D) TNCF + H
and (F) TNCF + H
+ L (L = irradiation at 620 nm, 12 mW cm−
0 min). The four areas represent different phases of the cells: necrotic
Q1), late-stage apoptotic (Q2), early apoptotic (Q3), and live (Q4).
2 2
O , (E) TNCF + L,
2
2
O
2
,
4
(
no living cell was seen, validating the efficacy of dual CDT and
PDT. These results were in accordance with that of MTT.
To explore the anti-cancer mechanism, the MCF-7 cells
with various treatments were stained with fluorescein isothio-
cyanate (V-FITC) and PI for the flow cytometry analysis.
Compared with the control groups, the mortality rates (Q2 + Q3)
are 1.45% and 3.66% for the cells treated with laser irradiation
2
Fig. 5 In vitro cytotoxicity of TNCF, TPP-NH and FC against MCF-7
cells: (A) dark and (B) H
2 2
O (0.2 mM). (C) Phototoxicity at different con-
centrations of porphyrin (0–40 μM) with an LED lamp at a power density
−2
of 12 mW cm for 40 min and (D) H
2 2
O and an LED lamp. In vitro cyto-
toxicity of TNCF, TPP-NH and FC against MCF-7 cells which have been and H
2
2 2
O , respectively, as compared to 90.5% of mortality for
pretreated with NEM (0.5 mM): with (E) or without (F) an LED lamp. (G)
Fluorescence images of calcein-AM (green, live cells) and PI (red, dead
cells) co-stained MCF-7 cells after different treatments. Scale bars:
those treated with both laser irradiation and H . These
results were consistent with the MTT assays, which showed that
TNCF possesses the effect of CDT and PDT (Fig. 6).
2 2
O
1
00 μm.
Conclusions
2
in Fig. 5C, TNCF and TPP-NH showed a dramatic photocyto-
toxicity toward MCF-7 cells compared with FC. The IC50 values
of the three kinds of agents were 25 μM, 29.7 μM and >50 μM,
respectively. These results substantiated the superiority of
TNCF as a potential PDT agent. Interestingly, the IC50 value of
In conclusion, we have designed and synthesized an agent by
the reaction of a photosensitizer TPP-NH
2
and a chemical anti-
cancer drug FC, which was applied in CDT and PDT. As an
•
−
effective photosensitizer, TNCF can transform O2 into O
2
2
TNCF is less than TPP-NH , and we boldly assume that there is
under the irradiation of an LED lamp for PDT. What’s more,
the Fenton or Fenton-like reaction can significantly improve
the cytotoxicity under irradiation. TNCF can consume gluta-
•
synergy between PDT and CDT. GSH can consume OH in vivo,
which reduces the cytotoxicity of CDT. We introduced
N-ethylmaleimide (NEM) to reduce the GSH content in the
thione and overcome tumor hypoxia by catalyzing H
2 2
O to
4
9–54
cells in order to enhance the efficacy of FC.
We first incu-
produce O . TNCF can achieve a synergistic effect between
2
bated the cells for 1 h with NEM and then added FC, TPP-NH2
CDT and PDT, and lead to enhanced cytotoxicity, which
possesses great potential in cancer treatment.
and TNCF, respectively. Fig. 5E shows a very similar result to
that of H O treatment.
2 2
To observe the therapeutic effect intuitively, the cells were
differentiated by live/dead cell staining. Live cells displayed
green color after being stained with calcein-AM, and dead cells
Conflicts of interest
displayed red color when dyed with propidium iodide (PI). In There are no conflicts to declare.
Fig. 5G, almost no red fluorescence appeared in the three
control groups. The cells treated with TNCF and H O have
2 2
some red fluorescence because of the result of CDT. A large
amount of red fluorescence appears in the cells after being
Acknowledgements
treated with TNCF and laser irradiation, which result from PDT. Financial support was kindly provided by the National Science
For the cells treated with TNCF, H O and irradiation, almost Foundation of China (Project No. 51522307).
2
2
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2
4 X. Zheng, Z. Li, L. Chen, Z. Xie and X. Jing, Chem. – Asian
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