Strategies to Enhance the Photosensitization: Polymerization and the Donor–Acceptor Even–Odd Effect

Article abstract of DOI:10.1002/anie.201810326

A particular challenge in the design of organic photosensitizers (PSs) with donor–acceptor (D-A) structures is that it is based on trial and error rather than specific rules. Now these challenges are addressed by proposing two efficient strategies to enhance the photosensitization efficiency: polymerization-facilitated photosensitization and the D-A even–odd effect. Conjugated polymers have been found to exhibit a higher ¹O₂ generation efficiency than their small molecular counterparts. Furthermore, PSs with A-D-A structures show enhanced photosensitization efficiency over those with D-A-D structures. Theoretical calculations suggest an enhanced intersystem crossing (ISC) efficiency by these strategies. Both in vitro and in vivo experiments demonstrate that the resulting materials can be used as photosensitizers in image-guided photodynamic anticancer therapy. These guidelines are applicable to other polymers and small molecules to lead to the development of new PSs.

Full text of DOI:10.1002/anie.201810326

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Strategies to Enhance the Photosensitization: Polymerization and
D/A Even-Odd Effect
Authors: Shunjie Liu, Haoke Zhang, Yuanyuan Li, Junkai Liu, Lili Du,
Ming Chen, Ryan Kwok, Jacky Lam, David Lee Phillips, and
Ben Zhong Tang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201810326
Angew. Chem. 10.1002/ange.201810326
Link to VoR: http://dx.doi.org/10.1002/anie.201810326
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10.1002/anie.201810326
Angewandte Chemie International Edition
COMMUNICATION
Strategies to Enhance the Photosensitization: Polymerization and
D/A Even-Odd Effect
Shunjie Liu+, Haoke Zhang+, Yuanyuan Li+, Junkai Liu, Lili Du, Ming Chen, Ryan T. K. Kwok, Jacky W.
Y. Lam, David Lee Phillips and Ben Zhong Tang*
Abstract: A particular challenge in the current design of organic
photosensitizers (PSs) with donor-acceptor (D−A) structures is based
on trial and error method rather than specific rules. Here we address
these challenges by proposing two efficient strategies to enhance the
as reduced fluorescence and singlet oxygen (1O2) production
owing to the strong π-π stacking of their rigid planar structures.
To address these issues, luminogens with aggregation-induced
emission (AIE) characteristics have recently been developed.[3]
AIE luminogens (AIEgens) emit intense fluorescence in the
aggregate state due to the mechanism of the restriction of
intramolecular motion.[4] In addition, they also exhibit enhanced
1O2 generation in the aggregate state.[5] These features make the
nanoparticles of AIEgens particularly suitable as PSs for image-
guided PDT.[6]
photosensitization
efficiency:
polymerization−facilitated
photosensitization and D/A even−odd effect. Conjugated polymers
have been found to exhibit a higher 1O2 generation efficiency than
their small molecular counterparts. In addition, PSs with A-D-A
structures show enhanced photosensitization efficiency than those
with D-A-D ones. Theoretical calculations suggest an enhanced
intersystem crossing (ISC) efficiency by these strategies. Both in vitro
and in vivo experiments demonstrate that the resulting materials can
be used as photosensitizers in image-guided photodynamic
anticancer therapy. These guidelines are applicable to other polymers
and small molecules to lead to the development of new PSs.
The common method to improve the photosensitization
efficiency of PSs is based on the enhancement of the intersystem
crossing (ISC) from the lowest excited state (S1) to the lowest
triplet state (T1).[7] Thus, approaches to promote ISC is of vital
importance for designing efficient PSs. According to the
perturbation theory, the rate constant (kISC) of ISC is given by:[8]
2
1
푘ISC ∝ < Ψ|퐻푆푂|3Ψ >/exp(∆퐸푆푇
)
(1)
̂
Owing to its spatial−temporal control and noninvasive character,
photodynamic therapy (PDT) has recently attracted considerable
attention in cancer therapy, and has surpassed the traditional
methods such as surgery, chemotherapy and radiotherapy.[1] In
PDT, the target cells or bacteria are controllably killed by reactive
oxygen species (ROS) produced by photosensitizers (PSs) under
illumination. Currently, porphyrin, BODIPY derivatives,
phthalocyanines and bacteriochlorin derivatives are the most
widely used PSs.[2] However, they exhibit several drawbacks such
1
Where < Ψ|퐻푆푂|3Ψ > is the spin-orbit coupling (SOC) matrix
̂
̂
element, 퐻푆푂 is the SOC Hamiltonian and ΔEST is the energy gap
between the singlet and triplet states. This equation suggests that
large SOC and small ΔEST can result in high kISC. Incorporation of
heavy atoms such as bromide, iodine, selenium or platinum, to
organic π−conjugated system can enhance SOC to increase
[9]
kISC
.
Alternatively, extending the conjugation length in
platinum−containing polymer can also enhance the SOC.[10]
However, the presence of heavy atoms may lead to dark toxicity
in biological applications.[11] According to Equation (1), another
approach to increase kISC is to reduce ΔEST, which has been
proved by our group and others in designing fluorescent
materials with pure organic room-temperature phosphorescence
or thermally-activated delayed fluorescence.[12] This way is quite
propitious for achieving efficient PSs but has received scant
attention owing to the large ΔEST of the most organic molecules.
Recently, strategies of combining different D and A units in
conjugated molecules were developed to minimize ΔEST. This
method relies on trial and error discovery of a promising motif
[*] Dr. S. Liu, Dr. H. Zhang, Dr. Y. Li, Mr. J. Liu, Dr. M. Chen, Dr. R. T. K.
Kwok, Dr. J. W. Y. Lam, Prof. B. Z. Tang
Department of Chemistry, Hong Kong Branch of Chinese National
Engineering Research Center for Tissue Restoration and econstruction,
Institute for Advanced Studgy and Department of Chemical and
Biological Engineering, The Hong Kong University of Science and
Technology, Clear Water Bay, Kowloon, Hong Kong, China
and
HKUST-Shenzhen Research Institute, No.9 Yuexing 1st RD, South
Area, Hi-tech Park, Nanshan, Shenzhen 518057, China
E-mail: tangbenz@ust.hk
followed by extensive tuning of the electronic properties of the
D/A units.[9d,
13]
Thereby, a convenient yet efficient chemical
Prof. B. Z. Tang
design strategy to enhance ISC is fascinating and practical.
Herein, we established two strategies to effectively enhance
the efficiency of PSs, namely polymerization−facilitated
photosensitization[14] and D/A even−odd effect. As shown in
Figure 1, several AIEgens based on electron-donating
triphenylamine (T) and electron-accepting benzothiadiazole (B)
units were synthesized and well characterized (Supporting
Information, Scheme S1−S7). To study the conjugation effect, TB,
dimer of TB, namely TBTB, was prepared (Figure 1A). For further
comparison, polymer P1 was prepared. Analysis of the polymer
by gel permeation chromatography gave a molecular weight of
2000 g mol-1, suggesting the existence of 5 repeating TB units in
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)
Dr. L. Du, Prof. D. L. Phillips
Department of Chemistry, The University of Hong Kong, Pokfulam Road,
Hong Kong SAR, China.
Dr. L. Du
Institute of Life Sciences, Jiangsu University, Zhenjiang 212013, China
[+] These authors contributed equally to this work
Supporting information for this article is given via a link at the end of the
document.
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10.1002/anie.201810326
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COMMUNICATION
one polymer chain. Such a length is believed to be longer than
the effective conjugated one.[10] On the other hand, to investigate
the even−odd effect, four compounds with different relative
amount of D and A units were designed and abbreviated as TBT
with D-A-D structure, BTB with A-D-A structure, TBTBT with D-
A-D-A-D structure and BTBTB with A-D-A-D-A structure (Figure
1B).
The effect of D-A even-odd effect on the photosensitization is
shown in Figure 1D. BTB (A-D-A) and BTBTB (A-D-A-D-A)
exhibit an increased photosensitization efficiency (Φo = 8.7% and
10.8%) but a decreased fluorescence quantum yield (Φf = 21%
and 10%) than TBT (D-A-D) and TBTBT (D-A-D-A-D) (Φo = 5.6%
and 7.0%; Φf = 45% and 11%). This result indicates that when a
luminophore has more A unit than D unit, it shows an enhanced
ISC process at the expense of fluorescence quantum yield.[10]
Given the widespread use of D-A-D or A-D-A−type luminophores,
our finding provides a valuable information for molecular design:
fluorescent materials with D-A-D structures show a higher
quantum yield, while their A-D-A counterparts are more suitable
to serve as efficient PSs. It is noticeable that the improved
photosensitization efficiency is independent of the size and shape
of these nanoparticles (Figure S9). Furthermore, the same trend
in Φo variation was observed even when other nanoparticle
preparation methods were employed (Figure S10).
B
A
BTB (A-D-A)
TBT (D-A-D)
TB (D-A)
TBTBT (D-A-D-A-D)
TBTB (D-A-D-A)
BTBTB (A-D-A-D-A)
0.6
0.4
0.2
0.0
15
12
9
P1 (D-A)n
A
B
D-A even-odd effect
Conjugation effect
16
12
8
100
80
60
40
20
0
12
9
50
40
30
20
10
0
D
C

f
o
f

nT-nB = 1
nB-nT =1
nT = nB
6
6
nT = nB




nB-nT = 1
nT-nB =1
4
3
3
2
3
4
5
6
7
8
9
10
2
3
4
5
6
7
8
9
10
Number of buliding block
Number of building block
0
0
TB
P1
TBT
BTB
TBTB
C
TBTBT
BTBTB
Figure 1. Molecular structures of the new materials and their photosensitization
properties. (A and B) Chemical structures. 1O2 quantum yield and fluorescence
quantum yield of (C) TB, TBTB and P1 and (D) TBT, BTB, TBTBT and BTBTB.
The photophysical data of all compounds are summarized in
Table S1. P1 shows a redder absorption (456 nm) and
photoluminescence (PL) (610 nm) in THF than its monomer TB
(416 and 550 nm), suggestive of its higher conjugation (Figure
S1)[15] and potential biological applications. On the other hand,
TBT and TBTBT represent D>A systems and display red-shifted
absorption and PL in THF than their A>D counterparts, such as
BTB and BTBTB (Figure S2). Moreover, all the new molecules
show blue-shifted but stronger emission in 90% aqueous mixture
than in pure THF, demonstrating a twisted intramolecular charge
transfer characteristic (Figure S3-S5).[16]
Figure 2. The polymerization and even-odd effect. Dependence of (A) ΔEST and
(B) Φo on the number of building block. (C) Enhanced photosensitization for
application in PDT. Abbreviation: nT = number of donor unit, (T); nB = number of
acceptor unit, (B).
Due to the fact that phosphorescence is not detected in these
molecules, it was necessary to apply time-dependent density
functional theory (TD-DFT) calculations to estimate the triplet
energy. In particular, triplet formation via ISC has an impact on
the efficiency of photosensitization.[7] According to Equation (1),
we take both ΔEST and SOC into consideration to study the ISC.
First, we investigate the effect of ΔEST on SOC. The ΔEST
decreases progressively by extending the π-conjugation as the
energy of the higher-lying Tn and Sn states decreases gradually to
make them get closer to the low-lying state (T1 and S1) (Figure
S11, Table S2, S3). The increased Φo with enhanced conjugation
well accounts for the drop in ΔEST. The decrease of Φf from TB to
P1 is partially due to the promotion of the ISC,[10] despite the
interchain interactions may play also an important role in
fluorescence quenching[17]. Similarly, BTB and BTBTB exhibit a
1
To investigate the ability of these AIEgens to generate O2,
the 1O2 quantum yield (Φo) of their nanoparticles in water was
determined using a chemical trapping method by monitoring the
absorption of 9,10-anthracenediyl-bis(methylene)dimalonic acid
at 378 nm (Figure S6-S8). Interestingly, as shown in Figure 1C,
with an increase in conjugation from TB to TBTB and then to P1,
the Φo increases from 3.8% to 8.9% and then to 14%,
accompanying a decreased fluorescence quantum yield (Φf)from
87% to 15% and then to 7%. The inverse correlation between Φo
and Φf suggests that the increasing conjugation by polymerization
is an effective way to enhance the ISC.[10]
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10.1002/anie.201810326
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lower ΔEST than their D>A counterparts. On the other hand, the
SOC effect should also be taken into consideration. However, the
calculated SOC constants of these molecules are all small (Table
S4), which is a common phenomenon observed in pure organic
materials.[12a] Collectively, the decrement of ΔEST plays a major
role in improving the ISC efficiency and also Φo. To probe the
triplet excited state, nanosecond transient absorption experiment
was carried out. Polymer P1 displays a triplet absorption lifetime
of 2.68 µs, whereas no data can be obtained from small molecule
AIEgens like TB, TBT and BTB (Figure S12). This further
suggests the improved ISC by conjugation.[9c, 18]
A
C
I
E
G
B
D
F
H
J
5
8
12
11.0
10.5
10.0
9.5
50
40
30
20
10
0
45
10.1
6.2
3.9
6
4
2
0
4
3
2
1
8





4
12
1.5
1.5
0.9
0
9.0
3000
6000
9000
12000
PTP
TPT
MAQM
P3
TCNT
P2
MAQM
AQMAQ
Mn (g mol-1)
Figure 3. Chemical structures of (A) TCNT and P2, (C) MAQM and P3, (E) polymer P3a-c, (G)TPT and PTP and (I) MAQM and AQMAQ, and (B, D, F, H and J)
their respective Φo
Extension of the conjugation length or variation of the relative
amount of D and A unit plays the same role in improving the
photosensitization efficiency. To obtain a full picture, we tried to
integrate these two methods into one rule. As shown in Figure 2A,
in general, the Φo of the same series increases with the extension
of conjugation. When the total number of building blocks is even,
the Φo monotonously increases with increasing the conjugation
length. However, in the odd system, the Φo depends on the
relative amount of D and A unit and AIEgens with more A unit, i.
e. nB-nT = 1, show higher values than their counterparts with
higher D fraction, i. e. nT-nB = 1. It is noteworthy that the ΔEST
values obtained by calculation are in good agreement with the
experimental data (Figure 2B). This insight provides a design
criteria for the selection of PSs to apply in image-guided PDT
(Figure 2C).
photosensitization efficiency. The Φo increases gradually by
increasing Mw from 3800 to 11000 g mol-1 (Figure 3E and 3F).
Thus, the polymerization method can precisely increase the
photosensitization efficiency of PSs.
Next, we examine the D/A odd effect on the photosensitization
efficiency. As shown in Figure 3G, AIE-active TPT with D-A-D
structure has been successfully used for through−skull
three−photon fluorescence imaging of mouse.[20] According to our
strategy, PTP with an A-D-A structure was designed. As expected,
PTP exhibits a high Φo of 45%, being 2.7-fold higher than that of
TPT (12%) (Figure 3H). We further varied both the D and A units,
as displayed in Figure 3I and 3J, AQMAQ with an A-D-A structure
showed Φo of 3.9%, which was higher than its MAQM counterpart
(1.5%). Clearly, the D/A conjugated AIEgens demonstrate a
stronger photosensitization efficiency when there is more A unit
in the molecular structure. Overall, by using this strategy, the Φo
of low efficient PSs becomes higher and that of high efficient PSs
To prove the versatility of the present strategy, different
polymers and D/A molecules were designed and examined
(Figure 3 and S13-S21, Scheme S8−S16). As shown in Figure 3A, turns into excellent.
TCNT is an AIE−active near−infrared emitting dye for organic
light−emitting diode.[19] The Φo was enhanced from 0.9% to 6.2%
when it was polymerized into polymer P2 corresponding to a 5.8-
fold enhancement (Figure 3B). In addition, if we change both the
types of D and A units, the present strategy still works well. For
example, P3 (Φo = 10.1%) shows a 5.7-fold enhancement in Φo
than its small molecule counterpart (Φo = 1.5%) (Figure 3C and
The significantly enhanced photosensitization ability and easy
synthesis of conjugated polymer P1 encourages us to evaluate its
image-guided PDT of tumor. Due to its hydrophobic character, P1
is encapsulated by amphiphilic DSPE-PEG2000 to endow the
resulting nanoparticles (PNPs) with good water dispersibility
(Figure S22). Analysis of dynamic light scattering and
transmission
electron
microscopy
reveals
the
good
3D). On the other hand, the high molecular weight of P3 (Mw
=
monodispersity of PNPs with a hydrodynamic diameter of about
120 nm (Figure S22). To examine whether the assembled PNPs
11000 g mol-1) motivates us to study the effect of Mw on the
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10.1002/anie.201810326
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COMMUNICATION
can effectively enter cells, we evaluate the uptake ability of the
HeLa cells using a confocal laser scanning microscope. The
observation of reticulum-like fluorescence image of HeLa cells
suggests the dye may locate at mitochondria (Figure S23).[21] To
prove this, colocalization experiment with MitoTracker Green
(MTG), a commercial mitochondria-specific imaging agent, was
performed. As depicted in Figure 4A, the regions stained with
PNPs overlap well with those stained by MTG. The Pearson’s
coefficient was calculated to be 0.92, indicating the high specificity
of PNPs to mitochondria. Moreover, the mitochondrial membrane
will be damaged by sensitized 1O2 during PDT and the
consequent dysfunction of mitochondria will induce cell apoptosis.
As expected, the cell viability decreases with increasing the
irradiation time (Figure S24). Importantly, the PNPs show
negligible dark toxicity because its non-cationic character to
cause no any depolarization of the mitochondrial membrane. This
aspect is of importance to avoid the side effect of PSs.[22] To
confirm that the cell death is induced by ROS, we used the 2’, 7’-
dichlorofluorescin diacetate (DCFH-DA) as the indicator to detect
the ROS generation in situ. Under white-light irradiation, the
DCFH-DA decomposes into dichlorofluorescein (DCF). The
fluorescence of the DCF increases and the morphology of the cell
changes with the irradiation time (Figure S25). At the same time,
we detect ROS generation in HeLa cells after irradiation with 488
nm laser (Figure S26). The signal of ROS increases dramatically
at the irradiated part but remains low outside this region. These
results suggest that PNPs are promising as PSs for PDT.
Before studying the in vivo image−guided PDT ability of PNPs,
we first investigate their use for in vivo fluorescence imaging by
intravenous injection of the nanoparticles to xenograft 4T1 tumor-
bearing balb/c mice. The fluorescence is gradually strengthened
at the tumor site and the fluorescence signal at 24 h is higher than
that of the tumor background owing to the enhanced permeability
and retention effect (Figure 4B and S27).[23] The tumor is then
irradiated with white light for 30 min after 24 h intravenous
injection. As control, the mice are administrated with PNPs in dark
environment or treated with saline. Results show that the growth
of tumor is partly inhibited by treated with PNPs in the presence
of light irradiation, indicating the efficient PDT ability of PNPs
(Figure 4C). The body weight of mice treated with PNPs + light
exceeds that of the control groups due to the efficient PDT (Figure
4D).
To investigate the potential toxicity of PNPs, a single dose of
PNPs was injected into mice via veil tail. During a one-month
period, the body weight of the treated group increases gradually
in a manner similar to that of the control group (Figure S28). After
30 days, the whole blood and liver function are analyzed and no
significant difference between the treated and control groups was
observed (Figure S29). Although the PNPs mainly accumulate in
mononuclear phagocyte system such as liver and spleen[24]
(Figure S30), the H&E stain suggests that there is no noticeable
tissue damage and inflammatory lesion in these tissues (Figure
S31). All the results manifest that the PNPs own good
biocompatibility in dark environment and are powerful
photosensitizers for photodynamic therapy.
In summary, we have developed two efficient strategies to
increase the O2 generation of PSs by enhancing the ISC. The
A
PNPs
MTG
Merged
Corelation
1
singlet oxygen quantum yield of the AIEgens can be increased by
5.8-fold and 2.7-fold via using the polymerization method and D/A
even-odd effect, respectively. The observation of polymerization-
facilitated photosensitization and D/A even-odd effect in the
R=0.92
AIEgens provides insight into establishing
a new design
B
1 h
3 h
8 h
24 h
255
framework for PSs. Theoretical analyses demonstrate that the
enhanced ISC process mainly results from the lowest singlet state
to the low-lying triplet states. By using these strategies, the low
efficient PSs become the higher ones and the high efficient PSs
turn into excellent ones. The obtained polymer P1 is promising for
application in image-guided photodynamic anticancer therapy.
This strategy thus provides an efficient platform for the
development of PS for PDT.
0
C
D
4
3
2
1
0
1.15
1.10
1.05
1.00
0.95
Control
Control
PNPs-dark
PNPs-light
PNPs-dark
PNPs-light
Experimental Section
0
4
8
12
16
0
4
8
12
16
Time (day)
Time (day)
Experimental Details please see supporting information.
Figure 4. Colocalization with mitochondria-targeting dye MTG. (A)
Fluorescence image of HeLa cells stained with PNPs, MTG and Merged image
of PNPs, MTG and Hoechst 33258, a nucleus-targeting commercial dye. Scatter
plot indicates the overlap coefficient of the cell image stained by PNPs and MTG.
Inset: calculated Pearson’s correlation coefficient. Excitation: 405 nm (Hoechst
33258) and 488 nm (PNPs and MTG); Emission: 420-450 (Hoechst 33258),
490-530 (MTG) and 570-700 (PNPs) with filter: 530-570 nm. (B)Tumor imaging
of mouse after intravenous injection of PNPs at different time. (C) Tumor growth
curves and (D) body weight changes of mice in different treatment groups.
Acknowledgements
We are grateful for financial support from the National Science
Foundation of China (21788102, 21490570 and 21490574), the
Research Grants Council of Hong Kong (16308116, 16308016,
C2014-15G,
C6009-17G,
N-HKUST604/14
and
A-
HKUST605/16), the Innovation and Technology Commission
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Keywords: Fluorescence • aggregation-induced emission •
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