Three-Pronged Attack by Homologous Far-red/NIR AIEgens to Achieve 1+1+1>3 Synergistic Enhanced Photodynamic Therapy

Article abstract of DOI:10.1002/anie.202000740

Photodynamic therapy (PDT) has long been shown to be a powerful therapeutic modality for cancer. However, PDT is undiversified and has become stereotyped in recent years. Exploration of distinctive PDT methods is thus highly in demand but remains a severe challenge. Herein, an unprecedented 1+1+1>3 synergistic strategy is proposed and validated for the first time. Three homologous luminogens with aggregation-induced emission (AIE) characteristics were rationally designed based on a simple backbone. Through slight structural tuning, these far-red/near-infrared AIE luminogens are capable of specifically anchoring to mitochondria, cell membrane, and lysosome, and effectively generating reactive oxygen species (ROS). Notably, biological studies demonstrated combined usage of three AIE photosensitizers gives multiple ROS sources simultaneously derived from several organelles, which gives superior therapeutic effect than that from a single organelle at the same photosensitizers concentration. This strategy is conceptually and operationally simple, providing an innovative approach and renewed awareness of improving therapeutic effect through three-pronged PDT.

Full text of DOI:10.1002/anie.202000740

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
International Edition Chemie
www.angewandte.org
Accepted Article
Title: Three-Pronged Attack by Homologous Far-Red/NIR AIEgens to
Achieve "1+1+1>3" Synergistic Enhanced Photodynamic Therapy
Authors: Wenhan Xu, Michelle M. S. Lee, Jing-Jun Nie, Zhihan Zhang,
Ryan T. K. Kwok, Jacky W. Y. Lam, Fu-Jian Xu, Dong Wang,
and Ben Zhong Tang
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 be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202000740
Angew. Chem. 10.1002/ange.202000740
Link to VoR: http://dx.doi.org/10.1002/anie.202000740
http://dx.doi.org/10.1002/ange.202000740

Angewandte Chemie International Edition
10.1002/anie.202000740
RESEARCH ARTICLE
Three-Pronged Attack by Homologous Far-red/NIR AIEgens to
Achieve "1+1+1>3" Synergistic Enhanced Photodynamic Therapy
[a,e,+]
[a,+]
[c]
[a]
[a,d]
Wenhan Xu,
Michelle M. S. Lee,
Jing-Jun Nie, Zhihan Zhang, Ryan T. K. Kwok,
Jacky W.
[
a,d]
[c]
,[b]
,[a,d,e]
Y. Lam,
Fu-Jian Xu, Dong Wang,* and Ben Zhong Tang*
[
a]
W. Xu, M. M. S. Lee, Z. Zhang, Dr. R. T. K. Kwok, Dr. J. W. Y. Lam, Professor B. Z. Tang
Department of Chemistry, Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction, State Key
Laboratory of Neuroscience, Department of Chemical and Biological Engineering, and Division of Life Science, The Hong Kong University of Science and
Technology, Clear Water Bay, Kowloon, 999077, Hong Kong, China
E-mail: tangbenz@ust.hk
[
b]
Dr. D. Wang
Center for AIE Research, College of Materials Science and Engineering, Shenzhen University, Shenzhen, 518060, China
Email: wangd@szu.edu.cn
[
[
c]
d]
Dr. J. -J. Nie, Dr. F. -J. Xu
Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing, 100029, China
Professor B. Z. Tang
Center for Aggregation-Induced Emission, SCUT-HKUST Joint Research Institute, State Key Laboratory of Luminescent Materials and Devices, South
China University of Technology, Guangzhou, 510640, China
[
e]
+]
W. Xu, Professor B. Z. Tang
HKUST Shenzhen Research Institute, Shenzhen, China.
These authors contributed equally to this work.
[
Supporting information for this article is given via a link at the end of the document.
Abstract: Photodynamic therapy (PDT) has long been proven to
a promising alternative therapeutic protocol for various types
of cancers.4
be a powerful therapeutic modality for cancer. However, PDT
strategy is undiversified and stereotyped in recent years.
Exploration of distinctive PDT protocol is highly in demand but
Numerous photosensitizers have been developed thereby
for clinical trials. However, conventional photosensitizers
often possess certain drawbacks, such as poor photostability
and chemical stability, low fluorescence quantum yield in
aqueous media, small Stokes shift, and limited ROS
remains
a
severe challenge. Herein, an unprecedented
“1+1+1>3” synergistic strategy is proposed and validated for the
first time. Three homologous luminogens with aggregation-
induced emission (AIE) characteristics are rationally designed
based on a simple backbone. By slight structural tuning, these
far-red/near-infrared AIE luminogens are capable of specifically
anchoring to mitochondria, cellular membrane and lysosome, and
effectively generating reactive oxygen species (ROS). Notably,
biological studies demonstrate that by combined usage of three
AIE photosensitizers, multiple ROS sources synchronously
derived from several organelles exhibit superior therapeutic effect
than that of single organelle under the same photosensitizers’
concentration. This strategy is conceptually and operationally
simple, providing an innovative approach and renewed
awareness of improving therapeutic effect through three-pronged
PDT.
5
generation ability. Moreover, some photosensitizers with
extended π conjugation tend to be intrinsically planar in
structure. This structural feature endows them with efficient
luminescence in dilute solution but suppressed emission in
aggregation state, which is commonly known as aggregation-
6
caused quenching (ACQ). ACQ characteristics often hamper
the practical applications of fluorescent photosensitizers,
especially for fluorescence image-guided photodynamic
therapy, which has become one of the prominent modalities
of cancer theranostics.7 In this context, the emergence of
photosensitizers with aggregation-induced emission (AIE)
characteristics has triggered state-of-the-art development of
cancer treatment. AIE luminogens (AIEgens) exhibit
enhanced emission in aggregation state due to the principle
of restriction of intramolecular motions (RIMs) that can block
the nonradiative pathway upon aggregates formation.8 In
addition, AIE photosensitizers also show boosted ROS
generation efficiency in aggregation state through promoting
Introduction
Cancer, as a leading cause of death worldwide, has aroused
great attention due to its limited early detection, rapid
9
intersystem crossing rate. Generally, an AIE photosensitizer
is introduced inside cell to specifically target a type of
subcellular organelle, and produce cytotoxic ROS upon light
exposure to destroy the subcellular functions.10 Some
subcellular organelles including mitochondria, cellular
membrane and lysosome, are wonderful cellular targeting
sites for implementing PDT,11 because these subcellular
organelles are closely related to various cellular processes
and playing indispensable roles in manipulating cellular
status.
1
malignant progression, and late-stage metastasis. In recent
years, photodynamic therapy (PDT) has been discovered to
induce apoptotic response of malignant cells through
generation of radicals or reactive oxygen species (ROS) upon
light irradiation. Since the first characterization of the
photosensitizer Haematoporphyrin Derivative (HpD) in 1960,2
PDT has been extensively explored to mediate tumor
3
destruction. Compared with surgery, radiotherapy and
chemotherapy, PDT is highly repeatable, of lower costs, less
invasive, and rarely has long term side effects. So far, PDT
has been highly recognized in clinical practice, appearing as
Notwithstanding the great significance, PDT strategy is
stereotyped in recent years. Scientists have spent too much
efforts on developing novel photosensitizers, whereas PDT
1
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
Figure 1. (A) Chemical structures of three AIEgens: TFPy, TFVP and TPE-TFPy. (B) Schematic illustration of using three AIEgens for achieving “1+1+1>3”
synergistic enhanced photodynamic therapy.
itself as a distinct strategy has been paid little attention and
remains barely exploited. As we know that the issues of
inefficient therapy and drug resistance could be elegantly
addressed by drug synergism, where equivalent therapeutic
effect can be obtained with much fewer drug dose.12 Inspired
by synergistic effect of drugs, we are wondering if similar
approach can be applied on PDT.13 That is to say, what if
multiple AIEgens are introduced into different organelles of
cancer cells simultaneously? Is it possible to get
synergistically enhanced PDT performance with lower
photosensitizers’ concentration?
emission, making them potentially AIE-active. Pyridinium ions
not only impose electronic effects, but are well known to have
targeting function as well. Compared with TFPy, TPE-TFPy
attaches an extra triphenylethylene segment at lipophilic part,
leading to more hydrophobic nature. In the case of TFVP,
linking a tail of quaternary ammonium salt to pyridine moiety
produces an elongated hydrophilic fragment, which greatly
reduces the permeation ability of TFVP through cellular
In this work, a novel strategy is put forward and explored.
Three novel AIEgens with the same backbone were well-
tailored and used to specifically light up mitochondria, cellular
membrane and lysosome, respectively. As displayed by in
vitro and in vivo PDT experiments, when ROS is generated
from multiple areas inside cells, it can lead to more severe
cell death and prohibit tumor growth to a larger extent under
the same concentration of photosensitizers (Figure 1). This is
the first report to compare PDT efficacy between one and
multiple ROS sources, thus demonstrating a smart strategy to
improve therapeutic effect through three-pronged PDT.
0
%
95%
Results and Discussion
Figure 1a presents the molecular structures of three novel
compounds (TFPy, TFVP, and TPE-TFPy) with typical
electron-donating and -accepting (D-A) feature. Such strong
D-A interaction could facilitate intramolecular charge transfer
Figure 2. (A) Normalized absorption spectra of TFPy solution in DMSO,
TPE-TFPy solution in DMSO and TFVP aqueous solution. (B) Normalized
PL spectra of AIEgens in solid state. (C) PL spectra of TFVP (1×10- M) in
(
ICT) and thus allow longer wavelength emission. Besides,
5
TPA moiety, a propeller-shaped nonplanar structure, can
freely rotate in solution state resulting in nonradiative
relaxation, and extend the intermolecular distance between
two parallel planes in aggregates to produce enhanced
H
2
O/THF mixtures with different THF fractions (f
T
); λex: 480 nm. (D) Plots of
relative PL intensity (I/I versus the composition of different solution
mixture of AIEgens. Inset: photos of H
of TFVP under 365 nm UV light.
0
)
2 2 T
O and H O/THF mixture (f = 95%)
2
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RESEARCH ARTICLE
Scheme 1. Synthetic route to TFPy, TPE-TFPy, and TFVP.
membrane.14 It is believed that these three homologous
compounds could possess different subcellular organelle-
specific targeting behaviors. To verify these hypotheses, we
started with the synthesis and characterization. As depicted in
Scheme 1, the aldehyde intermediates 1 and 2 were obtained
through Suzuki coupling reaction. The bromo-substituted TPA
starting materials are either commercially available or
accessible through reported procedures.15 Knoevenagel
condensation reaction between aldehyde and active methyl
group was employed to produce target compounds TFPy,
TFVP, and TPE-TFPy in moderate yields. Overall, the three
AIEgens were facilely developed within a few reaction steps.
The photophysical properties of TFPy, TFVP and TPE-
TFPy were characterized by UV-Vis and photoluminescence
spectroscopies (Figure 2, Table S1). The three compounds
possess similar absorption with maximum absorption peaks
shaped cell membrane, and round or oval-shaped lysosome
were clearly visualized showing bright fluorescence and high
contrast to background signal. To further prove the targeting
specificity, three commercial fluorescent probes, MitoTracker
Green, CellMask Green, and LysoTracker Green, were
employed to costain with AIEgens respectively. The
costaining experiments showed perfect overlap as seen in the
merged images with the Pearson’s correlation coefficients of
over 90%, indicating the high targeting specificity, and
validating that subtle structural alteration can lead to
targetability variation. It was inferred that the mitochondria-
staining behavior of TFPy could be attributed to its high
efficiency of electrophoretic transmembrane migration, as well
as appropriate binding ability between positively charged
pyridinium moiety and the negatively charged interior of the
transmembrane potential of mitochondria.16 The low
permeability coefficients resulted from the quite high free
energy barrier of TFVP at membrane center could lead to its
specific accumulation.14 In the case of TPE-TFPy, it tends to
form nano-sized aggregates in culture media due to the high
hydrophobicity, and the in-situ generated aggregates can
internalize into lysosome of HeLa cells through endocytosis
and specifically light up lysosome upon photoexcitation.
Therefore, when HeLa cells were cultured with these three
AIEgens simultaneously, all of mitochondria, cell membrane
and lysosome were highly emissive (Figure 3D).
(λabs) at around 490 nm. Due to different solubility behavior,
the AIE characteristics of TFPy and TPE-TFPy were
investigated in DMSO/toluene mixture with different toluene
fractions, whereas TFVP was measured in H
2
O/THF mixture
(
Figure 2C, 2D and S2). Taking TFVP as an example, TFVP
was barely emissive when fully dissolved in water. Upon
increasing THF fraction, fluorescence emission intensity got
boosted accordingly with a 218-time increment when THF
fraction reached 95%. In case of TFPy and TPE-TFPy, the
increment value is 12.6 and 26.4, respectively, demonstrating
typical AIE characteristics of all three compounds. Notably,
they exhibit far-red/near-infrared (FR/NIR) emission in solid
state with relatively large stokes shifts (ca. 200 nm) (Figure
Furthermore, photostability as an essential parameter to
evaluate
a
fluorescence imaging agent was carefully
investigated. Photostability assessment was carried out by
continuous irradiation and sequential scanning. After 40 times
of scan, minimal intensity loss was found for TPE-TFPy, TFPy
and TFVP, whereas three fluorescent commercial probes
especially LysoTracker Green suffered obvious fluorescence
intensity decrease, demonstrating high photobleaching
resistance of AIEgens (Figure 3E). With HeLa cell imaging
and photostability data in hand, additional cellular uptake
experiment using 4T1 cell line was performed as preliminary
study for in vivo experiment. Similar bioimaging results were
obtained, that is, TFPy, TFVP and TPE-TFPy exhibited strong
affinity towards mitochondria, cellular membrane, and
lysosome, respectively. The AIEgens exhibit high targeting
specificity which was confirmed by superb costaining
outcome with commercial probes (Figure 4A). Again, with
three AIEgens staining jointly, the mitochondria, cellular
membrane, and lysosome were well located and lighted up
concurrently (Figure 4B).
2
B).
To better understand the optical properties of the AIEgens,
density functional theory (DFT) calculations were carried out
Figure S1). The calculated natural transition orbitals (NTOs)
(
show that all three molecules feature the “electron”
delocalizing over TPA moiety and “holes” delocalizing at
pyridine fragment, exhibiting strong charge transfer character.
For all three AIEgens, the calculated decay energies of ca. 2
eV are relatively small, agreeing with their far red/NIR
emission property. Singlet-triplet energy gaps (ΔEST) are
determined to be around 1 eV due to sufficient separation of
the corresponding NTOs, potentially making them promising
PDT candidates by promoting ROS generation.
In vitro cellular imaging was carried out to evaluate their
subcellular organelle targeting property using HeLa cell as
model cell line. Thanks to the analogous maximum absorption
of three AIEgens, fluorescence images can be acquired
simultaneously using the same excitation at 488 nm. As
illustrated in Figure 3, after respective incubations with TFPy,
TFVP, and TPE-TFPy, reticulum-like mitochondria, ring-
In general, each organelle has its own specific function to
manage cellular behavior. Briefly, mitochondria is a “power
house” that can produce ATP to regulate cellular
3
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
TFPy
MitoTracker
Green
Merged
Merged
TFVP
CellMask Green
Merged
TPE-TFPy
LysoTracker
Green
Three in one
Three in one +
Hoechst 33258
Merged
20 μm
Figure 3. Co-localization test and photostability of TFPy, TFVP and TPE-TFPy. Confocal microscopic images of HeLa cells stained with A) TFPy (200 nM),
MitoTracker Green (50 nM), and their merged images; B) TFVP (500 nM), CellMask Green (500 nM), and their merged images; C) TPE-TFPy (2 μM),
LysoTracker Green (50 nM), and their merged images; D) three AIEgens (TFPy, TFVP and TPE-TFPy) altogether, three AIEgens and Hoechst 33258 (5 μM), and
their merged images. E) Loss in fluorescence of HeLa cells stained with TFPy, TFVP, TPE-TFPy, MitoTracker Green, CellMask Green and LysoTracker Green
with the number of scans of laser irradiation. Scanning rate: 22.4 s per frame. Scale bar = 20 μm.
1
7
metabolism. Plasma membrane has selective permeability
that protect the interior of cell from environment.18 Lysosome’s
acidic interior can degrade obsolete biomolecules by various
enzymes.19 All the aforementioned three organelles are of
vital importance to cellular status, therefore applying PDT to
these regions can effectively induce cancer cell ablation. We
are thereby prompted to examine PDT efficacy of three
AIEgens, and more importantly, to explore whether PDT
effectiveness will be boosted if three AIEgens are introduced
concurrently.
utilized as an indicator. Upon white light irradiation (4.2
mW·cm ), absorption peak of ABDA at 378 nm gradually
-2
decreased along with irradiation time in the presence of
photosensitizers, while no obvious change was found for
control group (Figure 5A and S3). Ce6 and Rose Bangel
(RB), two well-known commercially available standard
photosensitizers, were engaged as comparison. Both TFPy
and TFVP exhibiting similar ROS generation efficacy
performed better than Ce6, but not as efficient as RB. In
addition, a sharp decline of absorbance intensity was found
for TPE-TFPy, suggesting the superior ROS generation
performance and great potential for PDT application. Besides,
the ROS generation of “three in one” group suits well with
linear combination of each individual AIEgen, suggesting that
ROS generation of AIEgen is independent of each other
Preliminary study was conducted by evaluating capability of
ROS generation of three AIEgens, where 9,10-
Anthracenediyl-bis-(methylene)-dimalonic acid (ABDA) was
TFPy
MitoTracker Green
Merged
Merged
Merged
(
Figure S3). The singlet oxygen quantum yield was calculated
using RB as a relative standard (Figure S4).
Cytotoxicity of photosensitizer is a non-negligible factor to
take into consideration. Desired photosensitizer should exhibit
minimal cytotoxicity under dark condition, but produce
efficient ROS to induce cell death upon light irradiation.
Consequently, quantitative evaluation of PDT effect was
applied on both HeLa Cell and 4T1 cell line through standard
methylthiazolyldiphenyltetrazolium bromide (MTT) assay.
Each AIEgen and an experimental group named “three in
one” were evaluated. The “three in one” group was comprised
of one third concentration of each AIEgen (1/3 TFPy, 1/3
TFVP, and 1/3 TPE-TFPy) to assure the overall concentration
as same as other experimental groups. As illustrated in
Figure 5B and 5D, after incubation for 24 h, negligible cellular
viability reduction was found for HeLa cell with the
concentration as high as 2.5 μM. In the case of 4T1 cell, the
viability maintained 100 % at 5 μM, suggesting little dark
toxicity of these AIEgens towards both cell lines. However,
upon 20 min light irradiation, HeLa cell suffered severe
viability loss with only 10 % remaining when the “three in one”
group was at 2.5 μM (Figure 5C). Meanwhile, each individual
AIEgen only exhibited moderate PDT efficacy. As for 4T1 cell,
cell viability of “three in one” group started to decline at 2.5
μM, and almost complete cell death was induced at 5 μM
TFVP
CellMask Green
TPE-TFPy
LysoTracker Green
Three in one
Three in one +
Hoechst 33258
Merged
2
0 μm
(
Figure 5E). Nevertheless, the individual AIEgen hardly
displayed any therapeutic effect at 2.5 μM, and more than
0% cell viability still remained at 5 μM. Interestingly, ROS
Figure 4. Co-localization test of AIEgens. Confocal microscopic images of
T1 cells stained with A) TFPy (1 μM), MitoTracker Green (500 nM), and
4
their merged images; TFVP (5 μM), CellMask Green (500 nM), and their
merged images; TPE-TFPy (2 μM), LysoTracker Green (500 nM), and their
merged images; B) three AIEgens (TFPy, TFVP and TPE-TFPy)
altogether, three AIEgens and Hoechst 33258, and their merged images
with bright field. Scale bar = 20 µm
6
generation degree of “three in one” group was not as much as
TPE-TFPy, but it caused more cell death. Both intracellular
4
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Angewandte Chemie International Edition
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RESEARCH ARTICLE
Figure 5. A) Normalized absorbance intensity of ABDA at 380 nm after photodecomposition by ROS upon white light irradiation. Cell viability of HeLa cell stained
with different concentrations of AIEgens in the B) absence and C) presence of white light irradiation. Cell viability of 4T1 cell stained with different concentrations
of AIEgens in the D) absence and E) presence of white light irradiation. IC50 values of “three in one” for HeLa and 4T1 cell are 2.72 and 1.40 µmol/L, respectively.
ROS generation detection by DCFH-DA and live/dead
staining experiment assessed by FDA/PI supported the
strong PDT effect of three in one group (Figures S5 and
S6).The above results not only quantitatively demonstrated
ROS generation ability and in vitro PDT effect of three
AIEgens, but provided strong evidence that three-pronged
PDT deriving out of multiple organelles can induce enhanced
therapeutic effect as well.
Aiming to figure out whether combination enhanced PDT
can be applied above cellular level, in vivo therapy
experiment was conducted based on 4T1 breast tumor model.
Tumor-bearing mice were divided into five groups, with one
control group injecting PBS alone and four experimental
groups (namely TFPy, TFVP, TPE-TFPy, and “three in one”)
injecting photosensitizers’ aqueous solution (10-4 M, 100 μL).
As depicted in Figure S7, after intratumor injection, intense
fluorescence signals were captured at the tumor site in each
case. At 24 h post-injection, tumor fluorescence was still
visualized, indicating the remarkable tumor retention property
of these AIEgens. Notably, when TFPy was injected
individually, the accumulation in brain was detected by
fluorescence signal. In “three in one” group, such
fluorescence signal in brain region was insignificant,
indicating TFPy may be trapped by other two AIEgens in the
mixture. In the following study, tumor sites were exposed to
white light irradiation for 10 min. As the treatment proceeded,
tumor sizes were measured and evaluated every three days.
It was found that all the four experimental groups were able to
inhibit cancer cell proliferation in comparison with control
group. It is worthy to note that the “three in one” group again
manifested stronger hindrance of tumor growth than each
photosensitizer alone, making combination enhanced PDT a
convincing strategy to improve anti-tumor efficacy (Figure 6A).
Moreover, body weight was monitored for each group to
assess the toxicity. As shown in Figure 6B, no obvious body
weight loss or difference was observed among different
groups, owing to minimal toxicity of PDT approach. After 15
days of treatment, mice were sacrificed and major organs
were sliced for histological hematoxylin and eosin (H&E)
staining. All the tissue sections including heart, kidney, liver,
lung, and spleen were evaluated, where no pathological
change was observed (Figure S8). The body weight and H&E
result above thus indicate that the photosensitizers, either
individual or combined, were highly biocompatible.
Conclusion
To sum up, three homologous AIEgens with the same
backbone were elaborately designed and facilely synthesized
to specifically target three crucial subcellular organelles,
mitochondria, cellular membrane and lysosome. All the
AIEgens exhibited strong emission in far-red/NIR region, and
preformed well in ROS generation. Both in vitro and in vivo
PDT evaluations demonstrated that the treatment by three
AIEgens together was capable of producing far superior
therapeutic effect to each single AIEgen under the same total
concentration due to the three-pronged attack towards cancer
*
Figure 6. A) Tumor growth curves and B) body weight changes of mice in
different treatment groups. * represents P < 0.05, in comparison between
three in one group and other treatment groups.
5
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RESEARCH ARTICLE
cells, clearly suggesting "1+1+1>3" synergistic photodynamic
therapy. To the best of our knowledge, the distinctive
therapeutic protocol represents the first report of three-
pronged PDT by concurrently working on multiple subcellular
organelles. This study thus provides useful insights into
achieving the variation of organelle targetability by subtle
structural alteration, and offers an unprecedented strategy to
inspire scientists to reconsider PDT from a different angle and
study the mechanism behind.
Kwok, J. W. Y. Lam, F. Xu, D. Wang, B. Z. Tang, Mater. Chem.
Front. 2019, 3, 1454-1461; d) D. Wang, M. M. S. Lee, W. Xu, R. T.
K. Kwok, J. W. Y. Lam, B. Z. Tang, Theranostics 2018, 8, 4925-
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This work was partially supported by the Natural Science
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8
(
JCYJ20160229205601482 and JCYJ20170818113538482),
and the Innovation and Technology Commission (ITC-
CNERC14SC01 and ITCRD/17-9). Animal experiments were
approved by the China Committee for Research and Animals
Ethics in compliance with the law on experimental animals.
Keywords: "1+1+1>3" Effect • Synergistic PDT• Aggregation-
induced emission • Specific organelle-targeting
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Angewandte Chemie International Edition
10.1002/anie.202000740
RESEARCH ARTICLE
Entry for the Table of Contents
Three-pronged attack causes more damage: a synergistic
enhanced photodynamic therapy (PDT) strategy is put
forward for the first time by concurrently working on multiple
subcellular organelles. Under the same photosensitizers’
concentration, synchronous PDT treatment by three
aggregation-induced emission luminogens (AIEgens) exhibits
superior therapeutic effect than that of single AIEgen.
7
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