Target-Selective Fluorescence Imaging and Photocytotoxicity against H2O2 High-Expressing Cancer Cells Using a Photoactivatable Theranostic Agent

Article abstract of DOI:10.1002/asia.201701004

A purpose-designed and synthesized H₂O₂-reactive and photoactivatable theranostic agent 1 consisting of 1) an arylboronic acid moiety, 2) pro-fluorophore moiety, and 3) photoactivatable moiety (photosensitizer), selectively and effectively reacted with H₂O₂ while simultaneously releasing resorufin for fluorescence detection under neutral aqueous conditions. In addition, 1 was cell-permeable, and exhibited effective photocytotoxicity against fluorescently visualized cells only upon photoirradiation. The results also showed that 1 produced a selective fluorescence response to H₂O₂, even in living cultured cells.

Full text of DOI:10.1002/asia.201701004

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Target-Selective Fluorescence Imaging and Photo-Cytotoxicity
against H₂O₂ High-Expressing Cancer Cells Using a
Photoactivatable Theranostic Agent
Authors: Ryoma Takagi, Ayano Takeda, Daisuke Takahashi, and
Kazunobu Toshima
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Asian J. 10.1002/asia.201701004
Link to VoR: http://dx.doi.org/10.1002/asia.201701004
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10.1002/asia.201701004
Chemistry - An Asian Journal
COMMUNICATION
Target-Selective Fluorescence Imaging and Photo-Cytotoxicity
against H2O2 High-Expressing Cancer Cells Using a
Photoactivatable Theranostic Agent
Ryoma Takagi, Ayano Takeda, Daisuke Takahashi,* and Kazunobu Toshima*
Abstract: A purpose-designed and synthesized H2O2-reactive and
photoactivatable theranostic agent 1 consisting of 1) an arylboronic
acid moiety, 2) pro-fluorophore moiety, and 3) photoactivatable
moiety (photosensitizer), selectively and effectively reacted with
H2O2 while simultaneously releasing resorufin for fluorescence
detection under neutral aqueous conditions. In addition, 1 was cell
permeable, and exhibited effective photo-cytotoxicity against
fluorescently visualized cells only upon photo-irradiation. The results
also showed that 1 produced a selective fluorescence response to
H2O2, even in living cultured cells.
envisioned that consisted of an ROS-reactive pro-fluorophore
and a photoactivatable small molecule (photosensitizer) that
could selectively react with overexpressed H2O2 in cells, while
simultaneously releasing
a
fluorophore for fluorescence
detection. Furthermore, the photosensitizer in the hybrid
molecule would possess effective photo-cytotoxicity against the
fluorescently visualized target cells only under photo-irradiation.
The present report describes the molecular design, chemical
synthesis, and functional evaluation of a ROS-reactive and
photoactivatable theranostic agent targeting live cancer cells
that overexpress H2O2.
Investigation began with theranostic agents 1 and 2,
consisting of three molecular functionalities, as shown in Figure
1a. Photosensitizer moieties were incorporated using AC and
AQ derivatives for 1 and 2, respectively. A pro-fluorophore
moiety, consisting of a protected resorufin possessing good
solubility and low cytotoxicity, was used.[7c, 13] The third was the
H2O2-reactive p-tolylboronic acid pinacol ester moiety that
conjugates with the resorufin (3) moiety through a benzyl ether
link. As illustrated in Figure 1b, exposure of these agents to the
high H2O2-expressing cancer cells, caused H2O2-mediated
The production of reactive oxygen species (ROS), including
hydrogen peroxide (H2O2), hydroxyl radical (OH), and
superoxide anion (O2−), is a process that occurs in living aerobic
organisms.[1] Excess production of ROS, such as H2O2, can
induce oxidative stress, leading to aging and various diseases
such as cancer and neurodegenerative disorders.[2] In addition,
intrinsic enhancement of H2O2 levels inside cancer cells induces
the expression of metastasis-related growth factors, resulting in
invasion and migration.[3] Therefore, cells have
a H2O2-
scavenging pathway to maintain health.[4] However, this balance
can shift toward the production of H2O2, causing cell damage.[5]
Several types of fluorescent imaging probes, which can
selectively react with and detect H2O2, have been developed.[6, 7]
Boronic acid-based probes are one of the most promising for
detecting endogenous H2O2 in live cells.[7] Recently, H2O2-
responsive theranostic agents, which serve the dual purpose of
therapy and diagnosis, have been reported.[8] These agents can
be activated selectively by H2O2-mediated boronate oxidation to
enable fluorescence detection and the simultaneous release of a
therapeutic anti-cancer drug. However, these agents can cause
serious side effects because of their cytotoxicity against cells
other than the target cancer cells expressing high levels of H2O2.
Studies have shown that H2O2 plays an important role as a
second messenger in normal cellular signal transduction.[9] The
possibility of developing a new type of theranostic agent that
selectively visualizes high levels of endogenous H2O2 production
in live cells but is also cytotoxic toward selected target cells,
even among visualized cells, has attracted much attention for
minimizing side effects. Certain organic small molecules,[10] such
as anthracene (AC)[11] and anthraquinone (AQ) derivatives,[12]
can degrade biomacromolecules (DNA, proteins, and
oligosaccharides) by producing reactive oxygen species (ROS)
upon photo-irradiation. Based on this, a hybrid molecule was
boronate oxidation followed by 1,6-elimination of
a
p-
hydroxybenzylether derivative to release resorufin (3), which can
be visualized via emission of red fluorescence. Furthermore,
these agents possess significant photo-cytotoxicity against
visualized target cells using long-wavelength UV light irradiation.
The synthesis of theranostic agents 1 and 2 is shown in
Scheme 1. Alkylation of the phenolic hydroxyl group of 4 with 1-
bromo-3-chloropropane, followed by substitution with NaN3
provided 5. Palladium-catalyzed transmetalation of bromide 5
H2O2
[*]
R. Takagi, A. Takeda, Prof. Dr. D. Takahashi, Prof. Dr. K. Toshima
Department of Applied Chemistry
Faculty of Science and Technology, Keio University
3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522 (Japan)
E-mail: dtak@applc.keio.ac.jp; toshima@applc.keio.ac.jp
Figure 1. (a) Molecular design and structure of theranostic agents 1 and 2. (b)
Representation of target-selective fluorescence imaging and photo-cytotoxicity
against high H2O2-expressing cells.
Supporting information for this article is given via a link at the end of
the document.
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Scheme 1. Synthetic scheme for 1 and 2. DMF = dimethylformamide, pin =
pinacolate, dppf = 1,1'-bis(diphenylphosphino)ferrocene.
Figure 2. (a) Fluorescence responses of 1 (5 M) and 2 (5 M) to 250 M
H2O2 after 1 h. Dashed and solid lines represent spectra recorded before and
after H2O2 addition (λex = 530 nm). (b) Fluorescence changes in 1 (5 M) after
treatment with 0-500 eq. H2O2 (λex = 530 nm). (c) Fluorescence responses of 1
(5 μM) to 100 μM of several reactive oxygen species (ROS). Bars represent
relative responses at 30, 60, 90, and 120 min after addition of the ROS. All
spectra were acquired in 10% DMSO-PBS (pH 7.4, 10 mM) (λex = 560 nm, λem
= 590 nm).
using bis(pinacolato)diboron under Miyaura conditions[14]
provided 6. Bromination of the benzyl position of 6 using PBr3,
followed by substitution with resorufin (3) provided 8. Copper-
catalyzed Huisgen cycloaddition reaction of 8 with 9 and 10
furnished 1 and 2, respectively, as designed.
After synthesis of 1 and 2, their reactivities against H2O2
were evaluated under neutral aqueous conditions. Progress of
the reaction of 1 or 2 (5 M) with H2O2 (250 M) in 10% DMSO-
PBS (pH 7.4, 10 mM) was monitored by fluorescence
spectroscopy. Results showed that both compounds 1 and 2
exhibited only weak fluorescence max at 590 nm (ex = 530 nm)
in the absence of H2O2 (Figure 2a). In contrast, the fluorescence
intensities of 1 and 2 increased approximately 13- and 9-fold,
respectively, after treatment with H2O2 for 1 h. In addition, after
addition of H2O2, the fluorescence spectra of 1 and 2 were
identical to the emission spectrum of resorufin (3), as shown in
Figure S1 (Supporting Information). The fluorescence responses
over the concentration range of 0–500 eq. H2O2 with 1 (5 M)
were obtained. Figure 2b shows that the fluorescence intensity
of 1 increased in a H2O2 dose-dependent manner. In addition,
time-course kinetics of the fluorescence responses of 1 and 2 to
H2O2 were pseudo-first-order. Figure S2 (Supporting
Information) shows that the observed rate constants for the H2O2
response of 1 and 2 were 1.51×10-3 s-1 and 1.39×10-3 s-1,
respectively. These values are comparable to those of
previously reported boron-based probes.[7c] Furthermore, the
selectivity of 1 for H2O2 over other biologically relevant ROS
species, such as hydroxyl radical (OH), hypochlorite (−OCl),
superoxide (O2−), tert-butyl hydroperoxide (TBHP), and tert-
butoxy radical (OtBu), was evaluated. Figure 2c shows that,
although a small increase in fluorescence was observed with
O2−, compound 1 responded to H2O2 with good to high
selectivity. Similar results were obtained using probe 2, as
shown in Figure S3 (Supporting Information). These results
indicate that 1 and 2 selectively and effectively reacted with
H2O2, while simultaneously releasing resorufin (3) for
fluorescence detection under neutral aqueous conditions.
These promising results led to an examination of cellular
uptake and H2O2-mediated fluorescence enhancement of 1 and
2 in living cultured cells using HeLa human cervical cancer cells.
Normal human lung fibroblast cells (WI-38) were used as a
negative control in the assay. When live WI-38 cells were
treated with 1 or 2 (10 M) for 6 h at 37 °C in the absence of
exogenous H2O2, no significant fluorescence signal was
observed by scanning confocal microscopy (Figures 3a-d). In
contrast, when live HeLa cells were treated with 1 (10 M) for 6
h without addition of exogenous H2O2, weak intracellular
fluorescence signals were detected (Figures 3e and f). In
addition, treatment of HeLa cells with 1 for 6 h, followed by
addition of H2O2 (100 M) and incubation for an additional 6 h,
triggered an increase in red intracellular fluorescence (Figures
3g and h). In contrast, 2 did not promote a response in HeLa
cells, even in the presence of exogenous H2O2, probably due to
low cell permeability caused by the relatively hydrophilic AQ
moiety compared to the AC moiety (Figure S4 in Supporting
Information). These results clearly indicate that compound 1 is
cell permeable, and can provoke a fluorescence response to
H2O2 in living cultured cells. Next, compound 1 was applied to
image endogenous H2O2 using B16F10 cells, a highly metastatic
murine melanoma cell line that expresses high levels of ROS.[15]
Live B16F10 cells were incubated with 10 M 1 for 6 h at 37 °C
without addition of exogenous H2O2. A bright fluorescence signal
was observed (Figures 3i-l), suggesting that compound 1 can
visualize endogenous H2O2 production in targeted live cells. Next,
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10.1002/asia.201701004
Chemistry - An Asian Journal
COMMUNICATION
WI-38
HeLa
1
2
1
1 (+ H2O2)
FL
a
c
e
g
h
Merged
b
d
f
Figure 4. Photo-cytotoxic activity of 1
against fluorescently visualized cancer
cells. (a) HeLa cells were seeded into
96-well plates (5.0×103 cells). After 24 h,
cells were treated with 1 (0, 5 or 10 μM)
and incubated for 6 h at 37 °C, followed
by treatment with H2O2 (100 M) and
incubation for 6 h. Additional incubation
was done for 30 min with or without
photo-irradiation. Samples were then
further incubated for 11.5 h at 37 °C. (b)
B16F10 cells were seeded into 96-well
plates (5.0×103 cells). After 24 h, cells
B16F10
A431
−
1
1
1 (+ EGF)
FL
i
k
m
o
p
Merged
j
l
n
were treated with 1 (0, 5 or 10 μM) and
incubated for 12 h at 37 °C. Then, cells
were incubated for 30 min with or
without photo-irradiation. The samples were the further incubated for 11.5 h at
37 °C. (c) A431 cells were seeded into 96-well plates (5.0×103 cells). After 24
h, cells were treated with 1 (0, 5 or 10 μM) and incubated for 40 min at 37 °C.
Then, cells were treated with EGF (50 ng mL-1) and incubated for 20 min, and
further incubated for 30 min with or without photo-irradiation. Samples were
then further incubated for 11.5 h at 37 °C. In all cases, photo-irradiation was
conducted using a long-wavelength UV lamp placed 20 cm from the sample.
MTT reagent was added to each well and the cells were incubated for up to 3
additional hours. Absorbance at 480 nm was read using a plate reader. ***p <
0.001.
Figure 3. Confocal fluorescence images of live cells. (a) WI-38 cells incubated
with 1 (10 M) for 6 h at 37 °C (b) with a brightfield overlay. (c) WI-38 cells
incubated with 2 (10 M) for 6 h at 37 °C (d) with a brightfield overlay. (e)
HeLa cells incubated with 1 (10 M) for 12 h at 37 °C (f) with a brightfield
overlay. (g) HeLa cells incubated with 1 (10 M) for 12 h at 37 °C with 100 M
H2O2 added for the final 6 h (h) with a brightfield overlay. (i) B16F10 cells
incubated without 1 for 6 h at 37 °C (j) with a brightfield overlay. (k) B16F10
cells incubated with 1 (10 M) for 6 h at 37 °C (l) with a brightfield overlay. (m)
A431 cells incubated with 1 (10 M) for 1 h at 37 °C (n) with a brightfield
overlay. (o) A431 cells incubated with 1 (10 M) for 1 h at 37 °C with 50 ng mL-
1
added for the final 20 min (p) with a brightfield overlay. All images were
acquired using excitation and emission wavelength of 557 nm and 572 nm,
respectively. Scale bar = 50 m.
cytotoxicity against all types of cells. In contrast, 1 exhibited
significant cytotoxicity against these cancer cells upon photo-
irradiation in a dose-dependent manner. These results clearly
indicate that 1 can not only visualize cancer cells possessing
high levels of H2O2 but also can induce cytotoxicity against the
visualized cells only under photo-irradiation.
visualization of intracellular H2O2 production induced by growth
factor activation was examined. The human epidermal
carcinoma cell line A431, which expresses high levels of
epidermal growth factor receptor (EGFR) on the cell surface,
was chosen.[16] When live A431 cells were incubated with 10 M
1 for 1 h at 37 °C, only weak fluorescence signals were
observed (Figures 3m and n). In sharp contrast, when 1-treated
A431 cells were activated with epidermal growth factor (EGF)
(50 ng mL-1) for 20 min at 37 °C, bright fluorescence was
detected, as shown in Figures 3o and p. These results clearly
indicate that compound 1 can detect natural signaling levels of
H2O2 generated in live cells and can be used as an imaging
probe for aberrant cells that possess high levels of endogenous
H2O2.
In conclusion,
the
novel
H2O2-responsive
and
photoactivatable theranostic agents 1 and 2 were designed and
synthesized. The results showed that 1 and 2 selectively and
effectively react with H2O2, and release resorufin under neutral
aqueous conditions. In addition, although 2 did not promote a
turn-on response in live cells, probably due to low cell
permeability, 1 possessed cell permeability and low toxicity, and
promoted
a
fluorescence response in exogenous and
endogenous H2O2 in live cancer cells. Furthermore, upon photo-
irradiation, 1 exhibited significant cytotoxicity against visualized
cancer cells possessing high levels of H2O2. These findings will
contribute to the molecular design of novel biomarker-
responsive and photoactivatable theranostic agents. This new
methodology provides the ability to control specific functions of
target aberrant cells, and will help realize imaging-guided photo-
dynamic therapy to minimize cancer treatment side effects.
Finally, the photo-cytotoxic activity of
1
against
fluorescently visualized cancer cells by 1 was determined with
exogenous or endogenous H2O2. Cytotoxicity was tested with or
without photo-irradiation using a long-wavelength UV lamp (368
nm, 30 W) placed 20 cm from the sample using an MTT assay.
Results are summarized in Figure 4. Exposure of HeLa cells to 1
with H2O2 (100 M), B16F10 cells to 1, and A431 cells to 1 with
EGF (50 ng mL-1) and without photo-irradiation resulted in no
Acknowledgements
We wish to thank Prof. Dr. Siro Simizu of the Faculty of
Science and Technology, Keio University for helpful discussions
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10.1002/asia.201701004
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COMMUNICATION
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research was supported in part by the MEXT-supported
Program for the Strategic Research Foundation at Private
Universities, 2012-2016 (No. S1201020), JSPS KAKENHI Grant
Numbers JP16H01161 in Middle Molecular Strategy and
Scientific Research (B) (No. 26282212), and Keio Gijuku
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418-425.
Keywords: theranostics • hydrogen peroxide • boronic acid •
resorufin • anthracene
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Entry for the Table of Contents
COMMUNICATION
H2O2 high-expressing cancer cells
R. Takagi, A. Takeda, D. Takahashi,* K.
Toshima*
Page No. – Page No.
H2O2
Target-Selective
Imaging and
against H2O2 High-Expressing Cancer
Cells Using Photoactivatable
Theranostic Agent
Fluorescence
Photo-Cytotoxicity
A
purpose-designed and synthesized H2O2-responsive and photoactivatable
theranostic agent selectively and effectively reacted with H2O2, and simultaneously
released resorufin for fluorescence detection. In addition, the agent was cell
permeable, and promoted a selective fluorescence response to H2O2, even in living
cultured cells. Furthermore, this agent exhibited effective photo-cytotoxicity against
fluorescently visualized cells only upon photo-irradiation.
a
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