D-A-D structured selenadiazolesbenzothiadiazole-based near-infrared dye for enhanced photoacoustic imaging and photothermal cancer therapy

Article abstract of DOI:10.1016/j.cclet.2021.02.017

Near-infrared (NIR) small molecular organic dyes as photothermal agents for cancer photothermal therapy (PTT) have attracted considerable research attention. Herein, two donor-acceptor-donor (D-A-D) structured NIR dyes, BBTT and SeBTT, are rationally designed, where the only difference is one heteroatom within the acceptor unit varying from sulfur to selenium (Se). More importantly, SeBTT NPs exhibit stronger NIR absorbance and higher photothermal conversion efficiency (PTCE ≈ 65.3%). In vivo experiments illustrate that SeBTT NPs can be utilized as a high contrast photoacoustic imaging (PAI) agent, and succeed in tumor suppression without noticeable damage to main organs under NIR photoirradiation. This study presents an effective molecular heteroatom surgery strategy to regulate the photothermal properties of NIR small molecules for enhanced PAI and PTT.

Full text of DOI:10.1016/j.cclet.2021.02.017

Chinese Chemical Letters 32 (2021) 1580–1585
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
D-A-D structured selenadiazolesbenzothiadiazole-based near-infrared
dye for enhanced photoacoustic imaging and photothermal cancer
therapy
a
a
a
a
a
a,
Zijin Cheng , Tian Zhang , Weili Wang , Qing Shen , Ying Hong , Jinjun Shao *,
a
b,
a,c
Xiaoji Xie , Zhenghao Fei *, Xiaochen Dong
Key Laboratory of Flexible Electronics (KLOFE) and Institute of Advanced Materials (IAM), Nanjing Tech University, Nanjing 210009, China
Applied Chemistry & Environmental Engineering, Yancheng Teachers University, Yancheng 224051, China
a
b
c
School of Chemistry and Materials Science, Nanjing University of Information Science & Technology, Nanjing 210044, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Received 15 January 2021
Received in revised form 7 February 2021
Accepted 9 February 2021
Available online 11 February 2021
Near-infrared (NIR) small molecular organic dyes as photothermal agents for cancer photothermal
therapy (PTT) have attracted considerable research attention. Herein, two donor-acceptor-donor (D-A-D)
structured NIR dyes, BBTT and SeBTT, are rationally designed, where the only difference is one
heteroatom within the acceptor unit varying from sulfur to selenium (Se). More importantly, SeBTT NPs
exhibit stronger NIR absorbance and higher photothermal conversion efficiency (PTCE ꢀ 65.3%). In vivo
experiments illustrate that SeBTT NPs can be utilized as a high contrast photoacoustic imaging (PAI)
agent, and succeed in tumor suppression without noticeable damage to main organs under NIR
photoirradiation. This study presents an effective molecular heteroatom surgery strategy to regulate the
photothermal properties of NIR small molecules for enhanced PAI and PTT.
Keywords:
Photothermal
Near-infrared dye
Cancer therapy
Donor-acceptor
Selenadiazolesbenzothiadiazole
© 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Photothermal therapy (PTT) is an emerging effective cancer
treatment for various tumorous diseases; it has recently attracted
ever-increasing research attention due to its inherent advantages
of high tumor eradication efficacy, low side effects as well as the
auxiliary real-time diagnosis function for the theranostic platform
contrast agent for PAI can achieve a high signal-to-noise ratio on
account of the low signal attenuation. Both PAI and PTT are highly
dependent on the photothermal conversion performance of the
agents; as a result, considerable research attention has been
focused on the development of NIR nanotheranostic agents with
high photothermal conversion efficiency for PAI-guided PTT for
cancer treatment [11–16].
To date, photothermal materials mainly include inorganic
nanomaterials [17–19] and organic nanomaterials [20–23]. In
spite of the wide employment of inorganic materials for PTT,
these nanomaterials bear the inherent shortcomings of poor
biosafety. Hence, it prompts us to expand the library of organic
dyes for PTT, such as indocyanine green (ICG) with superior
biocompatibility. As a matter of fact, ICG has been approved as a
clinical contrast agent by the USA Food and Drug Administration
(FDA), and it has already been intensively studied as an off-label
phototherapeutic agent [24,25]. Nonetheless, ICG possesses its
own limitations of photobleachability and poor photothermal
behavior, as needs to be addressed before it is widely employed in
PTT. Therefore, many small molecular organic NIR dyes have been
rationally developed as photothermal agents to replace ICG
[
1–3]. In PTT, photothermal materials should convert the absorbed
photons to thermal energy to induce local hyperthermia for tumor
ablation. To achieve high therapeutic performance, near-infrared
(
NIR) photothermal agents are highly desired owing to minimized
photon scattering and diminished tissue auto-fluorescence, thus
achieving deeper tissue penetration depth and less photo-damage
to the living human body. Accordingly, it is significant to exploit
novel NIR photothermal agents for cancer phototheranostics [4–8].
Besides, PTT associated with photoacoustic imaging (PAI) has
gained extensive attention by virtue of the intrinsic benefits [9,10].
The integration of diagnosis and phototherapy in a single
nanoplatform not only can improve the therapeutic efficiency
but also accurately probe tumor location. Moreover, the NIR
*
Corresponding authors.
[
26,27]. Although different types of organic NIR dyes as photo-
E-mail addresses: iamjjshao@njtech.edu.cn (J. Shao), feizhenghao@163.com
(
Z. Fei).
thermal agents based on diketopyrrolopyrrole (DPP) [28–31],
https://doi.org/10.1016/j.cclet.2021.02.017
001-8417/© 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
1

Z. Cheng, T. Zhang, W. Wang et al.
Chinese Chemical Letters 32 (2021) 1580–1585
Boron dipyrromethane (BODIPY) [32–36] or benzo[c][1,2,5]-
thiadiazole [37,38], have emerged and achieved remarkable
progress in recent years, it is still an urgent demand to continue
to pursue origin small molecular organic NIR dyes with the merits
of fine structure/property tuning, well-defined chemical struc-
tures, and good repeatability, that have high photothermal
conversion efficiency and high stability [39–42].
Selenium (Se), coming from the VIA group, is a semi-metallic
element. Besides, it is an essential element in the organism which
fulfills many significant biochemical functions. Se-containing
molecules can facilitate the immune-cell activity to impede tumor
growth by regulating the reactive oxygen species (ROS) level to
balance the redox equilibrium in the human body [43,44]. And a
family of Se-containing small molecules has been developed as the
redox trigger for smart drug delivery systems [45–47]. Besides,
owing to the special electronegativity and atomic radius of Se, Se-
selenium dioxide (SeO
yield of 69% [60]. BBTT was successfully prepared by treating 5
with N-thionylaniline (PhNSO) and trimethylchlorosilane (TMSCl)
2
) in THF to produce SeBTT with a moderate
ꢁ
in pyridine for annulation at 80 C in 68% yield [61]. The two
flanked thiophene units were incorporated as an electron donor
(D) onto the electron acceptor (A) core to generate the D-A-D
scaffold in both SeBTT and BBTT to facilitate intramolecular charge
transfer (ICT), thus resulting in a pronounced bathochromic shift
[62,63]. The chemical structures of SeBTT and BBTT were verified
1
13
by
H
NMR,
C NMR and MALDI-TOF mass spectroscopy
(Supporting information). Besides, the frontier molecular orbital
profiles of SeBTT and BBTT were simulated by time-dependent
density functional theory (TD-DFT at B3LYP/6-31G**) calculations
(Fig. S1 in Supporting information). The calculated HOMO/LUMO
energy levels were À5.01/À3.47 eV and À4.99/À3.52 eV for SeBTT
and BBTT, respectively; Thus, the bandgap is 1.39 eV for SeBTT,
and 1.53 eV for BBTT. Additionally, both HOMOs and LUMOs are
spread over the molecular backbones, which is beneficial for
efficient ICT [2].
containing
gaps and unique chemical photophysical behaviors. Benzobisthia-
diazole (BBT), a 14 -electron system with a hypervalent S atom, is
p-conjugated systems demonstrate narrow energy
p
one of the most robust electron-withdrawing building blocks for
low bandgap compounds construction since its first report by
Yamashita et al. in the 1980s [48–50]. By replacing the S with Se in
the BBT heterocycles to get its analog selenadiazolesbenzothia-
diazole (SeBT), a narrower energy gap and pronounced red-shift
can be observed, because electrons of Se in the valence band can be
populated to the conduction band under photoirradiation [51–53].
To achieve a bathochromic shift of SeBT derivative and push the
absorption band more redshifted, the donor (D)-acceptor (A)
structural design strategy is commonly employed for the NIR
molecule construction [54–57].
Herein, two small molecular organic NIR dyes BBTT and SeBTT
with D-A-D scaffold, were rationally developed as photothermal
agents for PTT (Scheme 1). The chemical structures of the two NIR
dyes are the same except for one heteroatom difference of S and Se.
Through nano-precipitation, hydrophilic NPs were obtained. The
absorption of both NPs showed pronounced red-shift, and SeBTT
NPs showed a higher photothermal conversion efficacy of 65.3%
than BBTT NPs of 55.1%, which is probably due to the polar effect of
the heavier atom Se. Moreover, SeBTT NPs can efficiently kill HeLa
cells with a half-maximal inhibitory concentration of as low as
The absorbance and photoluminescence (PL) spectra of SeBTT
and BBTT in toluene were measured to explore the heteroatom
substitution effect on their photophysical behaviors. As shown in
Fig.1b and Fig. S3 (Supporting information), both dyes showed two
prominent absorption bands, the one between 300 nm and 400 nm
is ascribed to the electronic transitions of both n-
p* and p-p*
within the -conjugated system; and the other covering from
p
550 nm to 1000 nm is attributed to the significant ICT effect from
periphery electron-rich thiophene units to the central electron-
deficient core. SeBTT presents two absorption peaks at 350 nm and
380 nm, as well as a broad band ranging from 600 nm to 1000 nm
À1
À1
peaked at 825 nm (e= 6780 L mol cm ), and the optical
onset
absorption edge (
l
abs
) is estimated to be 948 nm. While BBTT
shows a similar absorption profile with peaks at 338 nm, 355 nm,
À1
À1
onset
abs
and 730 nm (
thus, the optical band gap (E
SeBTT, and 1.44 eV for BBTT, according to equation E
e
= 6830 L mol cm ), and with
l
at 858 nm,
opt
g
) was determined to be 1.31 eV for
opt
g
= 1240/l
(eV). In addition, the pronounced red-shift of 90 nm from BBTT to
SeBTT is due to the polar effect of the selenium atom. The maximal
photoluminescence peak of SeBTT and BBTT in toluene is
respectively located at 925 nm and 850 nm, resulting in a large
20
m
g/mL. In vivo studies demonstrate that upon 808 nm NIR
Stokes shift (n) of 100 nm and 120 nm, respectively.
photoirradiation, SeBTT NPs can accomplish PAI-guided PTT,
without noticeable side effect on the major organs.
As shown in Fig. 1a, compound 1 was synthesized according to
the previous report [58]. Intermediate 2 was synthesized by
Hydrophilic SeBTT NPs and BBTT NPs were fabricated through
the simple nano-precipitation method. Both NPs can disperse well
in water, and the solutions with high transparency are green-
yellow for SeBTT NPs and green color for BBTT NPs. As exhibited in
Fig. 1c, the dynamic light scattering (DLS) measurement of SeBTT
NPs reveals a hydrodynamic mean diameter of 76 nm, slightly
larger than that transmission electron microscopy (TEM) result of
50 nm. Meanwhile, BBTT NPs showed similar diameters. For BBTT
NPs, the average hydrodynamic diameter is 70 nm, which is a little
larger than the result of TEM (40 nm). In addition, after a few
months storage under ambient condition, the solutions still kept
high transparency, indicating excellent dispersibility of these NPs.
The absorbance and fluorescence spectra of both NPs appear
slightly broader than that in toluene (Fig. 1c, Figs. S3 and S4 in
Supporting information). SeBTT NPs display a broad and intensive
absorbance in the NIR regime covering 650À1050 nm with the peak
at 905 nm and the absorption edge at 1021 nm, exhibiting a red-shift
of 80 nm than that in toluene. Meanwhile, BBTT NPs show a
maximum absorption peak at 785 nm with the absorption edge at
3 3 3
nitration of 1 with an acid mixture of fuming HNO and CF SO H,
followed by Stille coupling with 3 to afford 4 in 75% yield [23]. The
n-hexyl hydrocarbon chain attached to the thiophene ring was
introduced to improve the solubility and processability. Later, 4
was reduced by iron dust in acetic acid to give the air-stable di-
amine 5 [59]. Later, 5 was directly employed for annulation with
1021 nm, and a red-shift of 60 nm compared to that in toluene canbe
observed.ItisnoteworthythatbothSeBTTNPsandBBTTNPsshowed
very weak fluorescence signals in an aqueous solution than in
toluene. This is consistent with the aggregation-caused quenching
(
ACQ) effect, which can facilitate the non-radiative decay for heat
Scheme 1. Schematic illustration of NIR SeBTT NPs for photoacoustic/photothermal
imaging-guided PTT.
generation and promote photothermal performance.
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Z. Cheng, T. Zhang, W. Wang et al.
Chinese Chemical Letters 32 (2021) 1580–1585
Fig. 1. (a) Synthetic route for SeBTT and BBTT. (b) Normalized UV–vis-NIR absorption spectra for BBTT and SeBTT in toluene and their corresponding NPs in water. (c) DLS size
distribution and TEM image (inset) for SeBTT NPs.
The photothermal conversion properties for both SeBTT NPs
and BBTT NPs were quantitatively evaluated. The photothermal
effect was studied by monitoring the temperature change of SeBTT
Additionally, both SeBTT NPs and BBTT NPs (100 mg/mL) were
exposed to 808-nm laser at various power densities (1.10, 0.90,
2
0.77, 0.44 and 0.10 W/cm ) for 10 min. The temperature for both
NPs and BBTT NPs at various concentrations (150, 125, 100, 50, and
NPs elevated along with the rise of the laser power densities,
implying the power intensity dependence manner of the photo-
thermal behavior for both NPs (Fig. 2b and Fig. S5). The
photothermal conversion efficiency (PTCE) was calculated to be
65.3% and 55.1% for SeBTT NPs and BBTT NPs, respectively. SeBTT
NPs showed higher PTCE; this is probably on account of polar effect
of Se atom in SeBTT molecule. Also, the high PTCE of both NPs are
among the best NIR organic photothermal agents [64–66].
Photostability and photothermal stability are of great impor-
tance for PTT in vivo. Both NPs in water show excellent photo-
thermal stability. The photothermal stability of both NPs was first
evaluated for five alternate photoirradiation ON/OFF cycles; And
2
25
m
g/mL) under 808 nm photoirradiation (1.10 W/cm , 10 min)
(
Fig. 2 and Fig. S5 in Supporting information). As shown in Fig. 2a,
with the increase of NPs concentration, the solution temperature
gradually rises under photoirradiation, indicating the significant
concentration-dependent characteristics of photothermal conver-
sion. When the concentration of SeBTT NPs is 150
m
g/mL, the
ꢁ
temperature increase reaches up to ꢂ30 C within 10 min,
manifesting the outstanding photothermal activity of SeBTT NPs.
In comparison, the aqueous BBTT NPs show a temperature increase
ꢁ
of 24 C under the same condition. While water, taken as a control,
ꢁ
just showed
a
slight temperature change of 2.0 C only.
2
Fig. 2. (a) Temperature change plots of different concentrations of SeBTT NPs upon 808-nm laser irradiation (1.10 W/cm , 10 min). (b) Photothermal response of SeBTT NPs
2
and BBTT NPs in water under photoirradiation of 1.10 W/cm at the same concentration (150
various concentrations with/without photoirradiation.
mg/mL). Cell viability after treatment with (c) SeBTT NPs and (d) BBTT NPs at
1582

Z. Cheng, T. Zhang, W. Wang et al.
Chinese Chemical Letters 32 (2021) 1580–1585
the temperature changes of SeBTT NPs or BBTT NPs presented
almost no change (Fig. S6 in Supporting information). Simulta-
neously, the absorption spectra and apparent colors after five
cycles of alternate heating and cooling under irradiation show
almost no change. Under Xe lamp irradiation for 2 h, a decompo-
sition of less than 5% can be observed for both NPs, while around
injection, and then started to decrease. The real-time in vivo
photoacoustic intensity extracted from the tumor regions for
SeBTT NPs confirmed that the increased photoacoustic signals
were generated from SeBTT NPs accumulation, and SeBTT NPs
could be real-time monitored over a prolonged period for clinical
application. The results of PAI manifest the efficient accumulation
of SeBTT NPs in the tumor tissue via enhanced permeability and
retention (EPR) effect, and also suggest that 6 h post-injection is
the optimized time spot for PAI-guided photothermal cancer
treatment.
7
6
0% of Fluorescein spoiled under the same circumstances for only
0 min (Fig. S7 in Supporting information). Besides, there was no
precipitation or aggregates observed after photoirradiation for
both NPs, suggesting their outstanding photostability. These
results provide solid confirmation that SeBTT NPs and BBTT NPs
are equipped with excellent photothermal stability and photo-
stability.
Infrared thermal images were collected as well to monitor the
hyperthermia of the tumor site at 6 h post-injection of SeBTT NPs in
2
mice with 808 nm photoirradiation (1.10 W/cm ). As shown in
To explore the in vitro photothermal effect, 3-(4,5-dimethylth-
iazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay was
carried out to study the cytotoxic effect and biocompatibility for
both NPs on HeLa cell lines. Two groups of HeLa cells were
incubated with SeBTT NPs or BBTT NPs at various concentrations
Fig. S10 (Supporting information), the temperature in the tumor
region continually rises along with the irradiation time increasing,
and reaches up to 54 C upon irradiation for 8 min after intravenous
ꢁ
tail injection. On the contrary, the group treated with PBS only
exhibits little temperature elevation after 8 min light exposure,
indicating that photoirradiation alone would have a negligible
effect on tumor inhibition. As demonstrate that SeBTT NPs can
induce quick temperature increase at tumor sites upon 808-nm
photoirradiation, rendering it an efficient nanotheranostic agent
for PTT.
To further explore PTT efficacy, SeBTT NPs were next
validated with the xenograft HeLa tumor-bearing mouse model.
All animal experiments were conducted under the Guide for the
Care and Use of Laboratory Animals, approved by the Animal
Experimentation Ethics Committee of Nanjing Tech University.
The mice that randomly divided into three groups (n = 5) were
named Group I (PBS + Laser irradiation), Group II (SeBTT NPs only
without Laser), and Group III (SeBTT NPs + Laser). Mice in Group I
were injected with PBS, while Group II and Group III were
(
0, 5, 10, 15, 20, 25, 30, 35, and 40 mg/mL) for 24 h, and then
subjected for laser irradiation. The other two groups, incubated
SeBTT NPs or BBTT NPs, were kept from irradiation. As presented in
Fig. 2, the cell viability under 808 nm laser irradiation is presented
to follow
inhibitory concentration (IC50) of 20
g/mL for BBTT NPs, respectively. Furthermore, it can also be
noticed that the cell viability remained over 88% when treating
HeLa cells with the NPs at a high concentration of 40 g/mL under
a
dose-dependent manner with
a half-maximal
m
g/mL for SeBTT NPs and
25 m
m
dark. These results reveal the predominant photothermal effect,
inconsiderable dark cytotoxic effect, and superb biocompatibility
of both NPs on HeLa cells. In addition, the cancer ablation
performance of SeBTT NPs is superior to that of BBTT NPs. As a
result, SeBTT NPs was taken as the representative to execute the
subsequent experiments.
treated with SeBTT NPs (150 mg/mL, 100 mL) via tail vein injection.
In addition, a cell migration assay was performed on HeLa cells
further to examine the photothermal therapeutic efficacy of SeBTT
NPs (Fig. S9 in Supporting information). The photograph of the cell
migration was recorded at different time spots. It is found that
HeLa cells were efficiently inhibited from moving in and filling the
open gap at 24 h after wounding. This result shows that SeBTT NPs
can efficaciously prevent cells from transferring.
As excellent photothermal conversion property in vitro, SeBTT
NPs were further employed as photoacoustic imaging (PAI) agents
to investigate the accumulation tendency of the NPs in living
The in vivo anti-tumor efficacy of all groups through PTT was
investigated through examination of the tumor volumes for a
period of 16 days. It is presented that the treatment of Group I
invalidly suppresses the tumor growth as compared to Group III,
suggesting that PBS + Laser irradiation possesses no effect of
stopping the tumor from growing. Also, the tumor growth kinetics
from Group II is also similar to Group I, which suggests that SeBTT
NPs fail to impede the tumor growth in the absence of an 808-nm
laser. In other words, only PBS with irradiation or SeBTT NPs itself
has negligible active behavior against cancer (Figs. 4a and d).
Remarkably, the average tumor volumes of Group III show changes
from day 0 that expresses the tremendous anti-tumor efficacy of
SeBTT NPs. Then the tumor volumes decrease in the following days
(Figs. 4a and c).
bodies. After systemic administration of SeBTT NPs (150
mg/mL,
1
00 L) into xenograft HeLa tumor-bearing nude mice, the
m
photoacoustic images were clearly delineated and quantified at
each post-injection time spot. As depicted in Fig. 3, the photo-
acoustic intensity is very weak at the start of 0 h (pre-scan), which
is owing to the NIR absorption from endogenous melanin and
hemoglobin. And then, the photoacoustic intensity at tumor sites
increased over time and reached the maximum at 6 h post-
After 6-days treatment, the tumors of mice in Group III
disappeared, suggesting distinguished cancer cells ablation with
808 nm laser illumination. Meanwhile, the bodyweight of mice in
Group III gained gradually (Fig. 4b), indicating the excellent
Fig. 3. (a) Photoacoustic imaging of tumor at various times after intravenous tail injection of SeBTT NPs. (b) Photoacoustic intensity in the tumor region against the post-
injection time.
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Z. Cheng, T. Zhang, W. Wang et al.
Chinese Chemical Letters 32 (2021) 1580–1585
Fig. 4. (a) Tumor growth and (b) bodyweight changes of three groups with different treatments. (c) Photographs of three groups tumor-bearing mice after treatment. (d) The
mice tumors collected with Group I and Group II. (e) H&E stained images of the tumor tissues after treatment. Scale bar: 100 m.
m
biosafety and low side toxic effect of SeBTT NPs. All the results
demonstrate that SeBTT NPs can serve as an excellent nano-agent
for PTT. After 16-days treatment in vivo, the mice in all groups were
executed, and the tissues of tumor and main organs were collected
for histopathological examination using hematoxylin and eosin
to the High-Performance Computing Center in Nanjing Tech
University for supporting the computational resources.
Appendix A. Supplementary data
(
H&E) staining to comprehend the therapeutic efficacy at cellular
Supplementarymaterialrelatedtothisarticlecanbefound, inthe
online version, at doi:https://doi.org/10.1016/j.cclet.2021.02.017.
level. Fig. 4e records the photographs of the tumor histologic
section of Group I and Group II. It is found that the tumor cells are
arranged closely, and the nuclei of tumor cells are in good order.
Moreover, the H&E staining of main organs from different
treatment groups illustrates that there is no noticeable damage
of histological morphology of the groups with SeBTT NPs injection,
comparing to the PBS injection group (Fig. S11 in Supporting
information). The photography of the organs shows that the cells’
nuclear remains almost unchanged. All results indicate that SeBTT
NPs are equipped with a high bio-compatibility without any
noticeable side effects to living mice in vivo.
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Declaration of competing interest
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