Traceable cancer cell photoablation with a new mitochondria-responsive and -activatable red-emissive photosensitizer

Article abstract of DOI:10.1039/c9cc00764d

A mitochondria-responsive and -activatable photosensitizer (PS), MPS, composed of a pyridinium cation as a mitochondria targeting group and a dibenzylideneacetone derivative with environment-sensitive emission properties as the ROS generator and self-efficacy tracer, is reported. This multifunctional PS offers a new strategy for traceable photodynamic ablation of cancer cells.

Full text of DOI:10.1039/c9cc00764d

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Traceable Cancer Cell Photoablation with A New Mitochondria -
Responsive and -Activatable Red-Emissive photosensitizer
Chenlin Yang,a,c Rui Hu,*a Fengxian Lu,a,c Xudong Guo,a Shuangqing Wang,a Yi Zeng,*b,c Yi Li b,c and
Received 00th January 20xx,
Accepted 00th January 20xx
Guoqiang Yang*a,c
DOI: 10.1039/x0xx00000x
www.rsc.org/
A mitochondria-responsive and -activatable photosensitizer (PS), cells and organelles. Introducing activation step to PSs is
MPS, composed of pyridinium cation as mitochondria targeting another strategy to manipulate PSs and PDT, by which PSs
group and dibenzylideneacetone derivative with environment- become phototoxic only when they are activated or released by
sensitive emission property as the ROS generator and self-efficacy disease-related enzymes18-21 or microenvironment in targets.22-
24
tracer is reported. This multifunctional PS offers a new strategy for
traceable photodynamic ablation of cancer cells.
Furthermore, to minimalize side effects on normal cells,
strategies by integrating indicators of PDT response into PSs
have also attracted increasing attentions.25 For example, the
The increasing emergence of drug resistance and side effects PSs with a built-in singlet oxygen sensor26 have been developed
during cancer therapy urges developments of novel drugs or to kill cancer cells and indicate O2 generation simultaneously.
1
therapeutics for future treatments. Photodynamic therapy Another smart design via combination of apoptosis-associated
(PDT) is
a
minimally invasive treatment involving
a
enzyme substrate20,27into PS was also achieved the direct
photosensitizer (PS) as the drug in combination with light and reporting of therapeutic response. However, the challenging
oxygen. The therapy is initiated upon photoirradiation which molecular design and synthetic routes are frustrating.
gives rise to reactive oxygen species (ROS) after serial Therefore, it is still appealing to develop simple and efficient
photochemical processes. ROS attack various biological species strategies for traceable cancer therapy.
Mitochondria are indispensable cellular organelles
responsible for the major energy supply for cells, and involved
in cells resulting in apoptosis or necrosis of cells and consequent
treatment of diseases.1 The highly reactive ROS with relatively
short lifetime and light dependence provide multiple-targets
destruction within the irradiation-confined killing zone, which
make PDT a promising treatment with little drug resistance and
highly spatial selectivity.
PSs such as porphyrin derivatives have been approved for
clinical applications for many diseases, including cancer
treatments.2-6 Currently, the development of PSs is entering the
stage of smart drugs that are capable of cell or organelle
targeting and imaging, aiming to increase therapeutic effects
and lower down side effects at the same time.7-10 Various
targeting ligands, such as antibodies,11 RGD peptide,12-14
aptamers,15, 16 2-deoxyglucose,17 and triphenylphosphonium,10
have been attached to PSs to enhance drug delivery to diseased
in many other cellular networks, including cell growth,
29
differentiation and apoptosis.28,
On account of the high
susceptibility to reactive oxygen species (ROS) damage,
mitochondria are idea targets for virous drugs and
chemotherapies especially PDT treatment.30-36 Herein, a red
emissive dibenzylideneacetone derivative P1 with obviously
a. Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of
Photochemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing
100190, China
b. Key Laboratory of Photochemical Conversion and Optoelectronic Materials,
Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing
100190, China
Scheme 1. Structure of MPS and schematic illustration of MPS
used for cell photoablation and the resulting cytotoxicity report.
c. University of Chinese Academy of Sciences, Beijing 100049, China
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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environment-sensitive emission property37 was first built off.
Owing to the enhanced spin-orbit coupling and intersystem
crossing channel supported by the central electron-withdraw
ketone in the molecular scaffold,38 P1 presents conspicuous
ROS generation and photosensitization functions. In order to
endow this new scaffold with traceability, pyridinium cation, a
reversible mitochondria-guiding ligand, was selected to be
tethered then a new hydrophilic PS, MPS, with special affinity
to mitochondrial components and sensitive response to
mitochondrial membrane potential (MMP) changing, was
obtained. The differences of MPS and P1 are illustrated in
Scheme 1. MPS exhibits comparable environment -dependent
emission and 1O2 generation but much improved aqueous
compatibility with P1. Different from the low staining efficiency
of P1 nanoaggregates in cells, MPS guided with the pyridinium
unit highly accumulates on active mitochondrial components
where its red fluorescence is turned on because of the relatively
lower polarity of inner mitochondrial membrane. Upon light
found that the emission spectra from cell suspension and
ethanol were quite similar, implying that the micro-
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DOI: 10.1039/C9CC00764D
environmental polarity of the organelle where MPS
accumulated was very close to that of ethanol (Figure 1A inset).
The fluorescence responses of MPS towards various common
biologically relevant species were examined (Figure S2) and no
noticeable change was observed.
The ROS generation efficacy of MPS and P1 at different
environments was next examined using 1, 3-
diphenylisobenzofuran (DPBF) as a singlet oxygen trap. As
shown in Figure 1B and S3, the absorbances around 410nm
significantly decreased upon exciting either of the two mixtures
of DPBF with MPS and P1 in ethanol. The 1O2 quantum yield was
estimated to be 0.15 and 0.16, respectively. When the polarity
of the solvents increased from pure ethanol to 1:1 (v/v) water
1
and ethanol mixture, both of the O2 producibility of MPS and
P1 were highly suppressed and the 1O2 quantum yield was
dropped to be 0.02 and 0.03 respectively which indicated that
the photosensitizing functions of the dibenzylideneacetone
derivatives were environment-dependent even -activatable.
The photostability of MPS and P1 were also examined by
monitoring their fluorescence changes under the light
irradiation (40 mW cm-2) for different times. As shown in Figure
S4, neglectable emission change of either MPS or P1 was
observed after 150 s irradiation. These in vitro photophysical
assays together exhibit MPS a potential as a photostable
environment-dependent and -activatable photosensitizer for
controllable cancer cell photoablation and self-bioimaging.
Before evaluating the photoablation efficacy towards cancer
cells, the intracellular staining and localization of MPS and P1
were both determined in HeLa cells and A431 cells using
confocal fluorescence microscopy in combination with a
commercially available mitochondrial tracking dye, MitoTracker
Green FM (Figure S5). Different from the low uptake efficiency
as well as the aimless distribution of P1 nanoaggregates in cells,
the bright red emission and high staining overlap between MPS
and MitoTracker with a Pearson’s correlation coefficients of
over 0.95 demonstrated the selected accumulation of MPS on
1
irradiation, the bound MPS can be activated to generate O2
efficiently which initiates MMP disruption and the following cell
apoptosis. After that MPS is released from mitochondria to
cytoplasm, where the environment polarity is increased and the
fluorescence is switched off, showing self-reporting capability
of apoptosis induced by ROS damage to mitochondria.
Meanwhile, the generation of 1O2 is also reduced, deterring the
overproduction of oxidative species.
The fluorescence spectra of MPS and P1 in different solutions
were firstly recorded and shown in Figure S1. Both MPS and P1
presented positive solvatochromism with remarkable emission
shifts of about 100 nm as increasing the polarity of solvents,
which demonstrated the typical intramolecular charge transfer
(ICT) property of the used dibenzylideneacetone scaffold. The
fluorescence quantum yield (ΦF) of P1 kept above 0.1 in all
solvents even though it forms into aggregates in water. While
the ΦF of MPS lowered to nearly one third of P1 in organic
solvents because of the introduction of electrophilic pyridinium
unit, and a more than 40-fold decrease of the emission intensity
at 600 nm was detected in water compared to that in EtOH (in
Figure 1A), indicating MPS can be used as a smart turn-off
indicator for environment polarity. Due to the improved
aqueous compatibility, the emission spectra of MPS in fresh
HeLa cell suspension was following collected and compared
with the fluorescence spectra of MPS in organic solvents. It was
Figure 2. Images of MPS (A) and P1 (B) incubated HeLa cells co-
stained with DCHF-DA in the absence (1 and 3) and presence (2
and 4) of white light LED irradiation (15 s, 40 mW cm-2). Cell lines
were first incubated with MPS (5 μM) or P1 (5 μM) for 30 min
then subjected to irradiation for 15 s. After another 15 min
incubation, all cells were stained with DCHF-DA (10 μM). (1-2)
Green channel for DCF (EX: 488 nm, Em: 500-520 nm). (3-4) Red
channel for MPS or P1 (EX: 488 nm, Em: 580-640 nm). The scale
bar represents 20 μm for all the images.
Figure 1. (A) Emission spectra of MPS (5 μM) in ethanol (red)
and in water (blue) normalized to the absorbance at the
excitation wavelength. Inset shows the normalized
fluorescence spectra of MPS (5 μM) in HeLa cell suspension
(black) and in ethanol (red). (B) Time dependent absorption of
DPBF (20 μM) mixed with MPS (10 μM) in ethanol and 1:1 (v/v)
ethanol-water mixture (inset) upon 532 nm laser diode
irradiation with power density of 80 mW cm-2.
2 | J. Name., 2012, 00, 1-3
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mitochondria. The specific affinity of MPS towards
mitochondria was further examined by an MMP disruption
assay in which carbonyl cyanide m-chlorophenyl hydrazine
(CCCP), a mitochondrial depolarizing reagent, was used. CCCP
can induce MMP loss and mitochondria disruption then lose the
affinity with lipophilic cations. After treated cells with CCCP, the
bright emission of MPS almost faded (in Figure S6), illustrating
that the mitochondria-targeting and -responsive property
possessed by MPS is MMP-dependent. By combining the
environment-sensitive emission property of MPS in Figure 1, it
can be inferred that the MMP loss engenders MPS leak from
mitochondria of low polarity to cytosol of high polarity
accompanied with the fluorescence quenching, which verified
the validity of MPS as a new indicator of mitochondria activity.
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DOI: 10.1039/C9CC00764D
Figure 4. (A) Relative cell viability of cancer cells treated with
various concentrations of MPS upon white light irradiation (40
mW cm-2) for 15 and 45 s, respectively. (B) Comparison between
MTT method and MPS fluorescence method (FL) for monitoring
Hela cell viability during photodynamic treatment with MPS (EX:
488 nm, EM: 600 nm).
The
intracellular
versatilities
of
the
two
dibenzylideneacetone derivatives were next explored
encouraged by their superior performances in vitro. we first
measured the ROS producibilities of MPS and P1 in HeLa cells
and A431 cells using 2’,7’-dichlorodihydrofluorescin diacetate
(DCHF-DA) as an indicator. DCHF-DA is non-fluorescent but can
be oxidized by ROS to 2’,7’-dichlorofluorescin (DCF), which
emits strong green fluorescence. As shown in Figure 2 and S7,
only cells that were treated with MPS followed by white light
irradiation show the green DCF signal, which confirmed that
MPS was able to generate ROS efficiently in cells upon light
irradiation. The extremely low intracellular ROS productivity of
P1 is possibly due to the poor membrane permeability as well
as the intracellular aimless dispersion of P1 nanoaggregates.
Subsequently, the cell apoptosis induced by MPS generated
ROS was examined by staining cells with the Annexin V-FITC
membrane staining, meaning cell apoptosis occurred, while the
red fluorescence of MPS in mitochondria was synchronously
decreased, showing the expectation of MPS to be
a
mitochondria-activatable photosensitizer and a synchronous
tracer of the photoablation effect. The response of MPS to cell
apoptosis was further validated by addition of exogenous ROS.
MPS-incubated A431 cells were treated with 400 μM hydrogen
peroxide (H2O2) to induce cell apoptosis and followed by
subjected to Annexin V-FITC conjugate. The staining results
were shown in Figure S9. The weakened red fluorescence
emission on mitochondria accompanied by the bright green
emission at the cell membrane region reconfirmed that MPS
could be as a turn-off indicator for ROS-induced cell apoptosis.
Taken together, these results validate that MPS can not only be
a mitochondria-responsive and -activatable photosensitizer to
controllably release ROS inducing cell apoptosis but also a built-
in tracer for evaluation of the photoablation effect via its
fluorescence signal changes.
conjugate which possesses
a
special affinity with
phosphatidylserine exposed on the plasma membrane surface
of early apoptotic cells. As shown in Figure 3 and S8, both the
two cell lines sheltered from white light showed only strong red
fluorescence from MPS at mitochondria region but no green
emission from cell membrane. After irradiation for 15 s, cell
lines labelled by Annexin V-FITC presented characteristic green
The cytotoxicity of MPS for cancer cells was more evaluated
by
using
3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-
tetrazolium bromide (MTT) assay. As in Figure S10, MPS showed
low toxicity to HeLa cells and A431 cells in dark, revealing their
relatively inert property without photoexcitation. Upon white
light irradiation, significant cytotoxicity was soon caused by only
treated the both cell lines with 2 μM of MPS, and prolonging the
time of irradiation increased the photocytotoxicity (Figure 4A).
In contrast, only moderate phototoxicity of P1 aggregates to the
two cell lines were observed even at high concentrations (Figure
S11) which was consistent with the results of DCHF-DA assay.
The prompt and high photocytotoxicity of MPS is rationalized by
the precise mitochondria-targeting, efficient ROS generation
and consequent induced apoptosis. The half-maximal inhibitory
concentration (IC50) of MPS upon light irradiation at 0.6 J cm-2
(15 s irradiation) to HeLa cells and A431 cells was determined to
be 3.2 and 1.9 μM, respectively, which confirmed that MPS is an
efficient PS for photodynamic ablation of cancer cells.
Furthermore, the fluorescence change (F/F0) of MPS-incubated
HeLa cells before and after irradiation was examined. The value
was well related with the cell viability evaluated by MTT assays
Figure 3. (A) Images of HeLa cells without MPS treatment in the
presence of white light irradiation (15 s, 40 mW cm-2), HeLa cells
with MPS treatment (5 μM) in the absence (B) and presence (C)
of white light irradiation (15 s, 40 mW cm-2). Cell lines were first in Figure 4B which reconfirmed that MPS could traceably report
the cell apoptosis induced by itself generated ROS.
incubated with MPS (5 μM) for 30 min then subjected to
irradiation for 15 s. After another 90 min incubation, all cells
were stained with Annexin V-FITC. (A1-C1) Green channel for
Annexin V-FITC (EX: 488 nm, EM: 500-520 nm); (A2-C2) Red
channel for MPS (EX: 488 nm, EM: 580-640 nm); The scale bar
represents 20 μm for all the images.
In conclusion, we have rationally designed and synthesized a
couple of dibenzylideneacetone derivatives P1 and MPS, in
which MPS presents environment-sensitive on-off fluorescence
and activatable photosensitizing abilities. Under the guidance of
pyridinium unit, MPS mainly accumulates on mitochondrial
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components with bright red emission and silent photoablation.
Upon light irradiation, copious ROS are generated from
mitochondria which causes MMP loss and cell apoptosis. Then
the red emission on mitochondrial components turns off and
the ROS generation is ceased due to the MMP disruption
induced MPS leakage from mitochondria to cytosol. The
integrated functionalities of target-controlled photoablation
and self-efficacy traceability offer MPS a new opportunity for
visualized and hazard-free cancer PDT with synchronous
evaluation of the therapeutic responses.
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This work was supported by the National Natural Science
Foundation of China (21233011 ， 21205122) and Youth
Innovation Promotion Association (2017032) of Chinese
Academy of Sciences.
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Conflicts of interest
There are no conflicts to declare.
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A mitochondria-responsive and -activatable photosensitizer MPS, with a built-in tracer for
cancer cell photoablation was constructed.