Thieno[3,2-b]thiophene-DPP based near-infrared nanotheranostic agent for dual imaging-guided photothermal/photodynamic synergistic therapy

Article abstract of DOI:10.1039/C8TB03185A

Diketopyrrolopyrrole (DPP) based organic molecules have drawn significant research attention as phototheranostic agents. Herein, based on thieno[3,2-b]thienyl-DPP (TT-DPP), a near-infrared small molecule photosensitizer diethyl 3,3′-((((2,5-bis(2-decyltetradecyl)-3,6-dioxo-2,3,5,6-tetrahydropyrrolo[3,4-c]pyrrole-1,4-diyl)bis(thieno[3,2-b]thiophene-5,2-diyl))bis-(4,1-phenylene))bis(7-bromo-10H-phenothiazine-10,3-diyl))(2E,2′E)-diacrylate (PDBr), with a high singlet oxygen (¹O₂) quantum yield of 67%, was developed. After nano-precipitation, the hydrophilic PDBr NPs present an encouraging photothermal conversion efficiency of 35.7% and excellent fluorescence/infrared-thermal imaging performance. In vitro studies disclosed the high phototoxicity but low dark cytotoxicity of PDBr NPs to tumor cells. Furthermore, PDBr NPs can effectively impede the tumor growth without noticeable side effects in living mice through imaging-guided synergistic photothermal/photodynamic therapy. Therefore, PDBr NPs could be a promising nanotheranostic agent for imaging-guided synergistic photothermal and photodynamic therapy in the clinic.

Full text of DOI:10.1039/C8TB03185A

View Article Online
View Journal
Journal of
Materials Chemistry B
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: X. Dong, X. Yang,
Q. Yu, N. Yang, L. Xue, J. Shao, B. Li and J. SHAO, J. Mater. Chem. B, 2019, DOI: 10.1039/C8TB03185A.
This is an Accepted Manuscript, which has been through the
Volume
4 Number 1 7 January 2016 Pages 1–178
Royal Society of Chemistry peer review process and has been
accepted for publication.
Journal of
Materials Chemistry B
Accepted Manuscripts are published online shortly after
Materials for biology and medicine
www.rsc.org/MaterialsB
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 2050-750X
PAPER
Guoping Chen et al.
Regulating the stemness of mesenchymal stem cells by tuning
micropattern features
rsc.li/materials-b

Please do not adjust margins
Page 1 of 9
Journal of Materials Chemistry B
View Article Online
DOI: 10.1039/C8TB03185A
Journal Name
ARTICLE
Thieno[3,2-b]thiophene-DPP Based Near-Infrared Nanotheranostic
Agent for Dual Imaging-Guided Photothermal/Photodynamic
Synergistic Therapy
Received 00th January 20xx,
Accepted 00th January 20xx
Xue Yang,a Qing Yu,a Nan Yang,a Lei Xue,a Jiawei Shao,a Buhong Li,b* Jinjun Shao,a* Xiaochen Donga*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Diketopyrrolopyrrole (DPP) based organic molecules have drawn significant research attention as phototheranostic agents.
Herein, based on thieno[3,2-b]thienyl-DPP (TT-DPP), a near-infrared small molecule photosensitizer Diethyl 3,3'-((((2,5-
bis(2-decyltetradecyl)-3,6-dioxo-2,3,5,6-tetrahydropyrrolo[3,4-c]pyrrole-1,4-diyl) bis(thieno[3,2b]thiophene-5,2-diyl))bis-
(4,1-phenylene))bis(7-bromo-10H-phenothiazine-10,3-diyl))(2E,2'E)-diacrylate (PDBr), with high singlet oxygen (1O2)
quantum yield of 67%, was developed. After nano-precipitation, the hydrophilic PDBr NPs present an encouraging
photothermal conversion efficiency of 35.7% and excellent fluorescence/infrared-thermal imaging performance. In vitro
studies disclose the high phototoxicity but low dark cytotoxicity of PDBr NPs to tumor cells. Furthermore, PDBr NPs can
effectively impede the tumor growth without noticeable side effects in living mice through imaging-guided synergistic
photothermal/photodynamic therapy. Therefore, PDBr NPs could be a promising nanotheranostic agent for imaging-
guided synergistic photothermal and photodynamic therapy in clinical.
clinical hyperthermia temperature (~42 °C), the tumor can be
suppressed or even eradicated by inducing cell death through
protein denaturation and DNA cross linking.13, 14 Compared
1. Introduction
Tremendous efforts have been devoted to cure malignant
neoplasm all over the world during the past decades.
Traditional cancer therapies including radiotherapy,
chemotherapy and surgery, usually suffer from their intrinsic
limitations of serious side effects, drug resistance and lack of
specificity for individual patient.1-3 Recently, phototherapy, a
light-induced non-invasive therapeutic modality with reduced
side effects, has attracted widespread interest.4-8 Generally,
phototherapy consists of photodynamic therapy (PDT) and
photothermal therapy (PTT). PDT relies on the photosensitizers
that absorb light energy to generate reactive oxygen species
with PDT or PTT alone, synergistic PDT/PTT present a better
phototherapeutic efficacy.15-18 Due to the similar illumination
procedure, great efforts have been made to integrate PTT and
PDT into one therapeutic platform. Not surprisingly, one
straightforward strategy is to combine photosensitizers, such
as Indocyanine Green (ICG) or Chlorin e6 (Ce6) with inorganic
photothermal agents (for example, gold nanorods, carbon
nanomaterials, transition metal oxides or sulfides) through
physical adsorption or chemical conjugation, which usually
requires complicated synthetic process.19-23 Besides, this kind
of PDT/PTT combined platform often claims different optical
1
(ROS, such as singlet oxygen O2) which is capable of reacting
excitation wavelengths to generate ROS and heat, respectively,
which will bring more systemic side effects to patients.24, 26
Therefore, it is of great significance to develop novel
photothermogenic photosensitizers for phototherapy to
simultaneously produce ROS and heat under single wavelength
illumination, especially with near-infrared (NIR) light excitation
wavelength to achieve deeper penetration therapy as well as
alleviated damage to normal tissues surrounding the tumors.
Compared with inorganic nanomaterials, organic
nanotheranostic agents, such as cyanine dyes encapsulated
liposomes and semiconducting polymer nanoparticles (SPN),
have been widely studied as potential alternative
nanotheranostic agents owing to their easy fine-tuning of
chemical structures and properties, low cytotoxicity and
superior biodegradability.26-29 For instance, ICG has been
approved by US Food and Drug Administration (FDA) as a
medical imaging contrast agent. Additionally, it has been
with intracellular components to induce oxidative damage to
cancer cells.9,10 Cell apoptosis and necrosis will take place if
sufficient damage is caused within a short time.11, 12 TT seeks
to convert light into heat, which can induce hyperthermia in
diseased tissue for tumor ablation by apoptosis and necrosis.
When the temperature of tumor tissues increases beyond the
a.Key Laboratory of Flexible Electronics (KLOFE) & Institute of Advanced Materials
(IAM), Nanjing Tech University (NanjingTech), Nanjing 211800, China
*E-mail: iamjjshao@njtech.edu.cn, iamxcdong@njtech.edu.cn
b.MOE Key Laboratory of OptoElectronic Science and Technology for Medicine,
Fujian Provincial Key Laboratory for Photonics Technology, Fujian Normal
University, Fuzhou 350007, China. *Email: bhli@fjnu.edu.cn
Electronic Supplementary Information (ESI) available: See DOI: 10.1039/x0xx
00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Journal of Materials Chemistry B
Page 2 of 9
ARTICLE
Journal Name
widely taken as an off-label photothermal agent.30
Nevertheless, the shortcomings of poor photostability and low
photothermal conversion efficiency for ICG limit its further
clinical therapeutic application.31 Accordingly, it is essential to
develop predominantly photostable and NIR organic
theranostic agents.
2. Experimental Section
View Article Online
DOI: 10.1039/C8TB03185A
2.1 Synthesis
2.1.1
10-(4-bromophenyl)-10H-phenothiazine
(3)
:
Phenothiazine
1
(5.000 g, 25.00 mmol), 1,4-dibromobenzene 2
(3.0 eq., 17.690 g, 75.00 mmol), Sodium tert-butoxide (t-
BuONa) (3.0 eq., 8.410 g, 75.00 mmol), Tris-
(dibenzylideneacetone)dipalladium (3%, 0.686 g, 0.75 mmol),
Tri-tert-butylphosphine tetrafluoroborate (3%, 0.217 g, 0.75
mmol) were added to toluene (60 mL) in a two-necked round
bottom flask, which was heated to 110 °C under nitrogen
Diketopyrrolopyrrole (DPP), a traditional electron-deficient
moiety with inherent lactam structure, has been widely
exploited to construct NIR molecules for high-performance
organic optoelectronic devices such as organic photovoltaics,
due to its planar π-skeleton, high molar extinction coefficient,
good thermal-stability and photostability.32,33 Recently,
thienyl-DPP and furyl-DPP derivatives with the donor-
acceptor-donor (D-A-D) structures and intense NIR absorbance
have been widely developed as nanotheranostic agents for
imaging-guided PDT or PTT.34-36 To further enhance the
phototherapeutic efficacy, thieno[3,2-b]thiophene-DPP (TT-
DPP) derivatives come into our sight. By replacing thiophenes
or furans with more electron-rich thieno[3,2-b]thiophene (TT)
units at the periphery sites of DPP, the π-conjugation length
can be extended and the molecular co-planarity can be
promoted, thus will result in stronger intermolecular π-π
interactions and induce a more delocalized HOMO (highest
occupied molecular orbital) distribution along the backbone,
which will enhance the intramolecular charge transfer (ICT)
overnight.
After
cooling
to
room
temperature,
dichloromethane (DCM) (2 × 150 mL) was added and the
solution was washed with water (2 × 100 mL) and brine (100
mL). The solvent was removed and the residue was purified by
column chromatography on silica gel (Petroleum ether, PE) to
1
provide compound
3 as white powder (7.100 g, 80%). H NMR
(400 MHz, CDCl3): δ ppm 7.70 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4
Hz, 2H), 7.04 (dd, J1 = 7.4, J2 = 1.8 Hz, 2H), 6.88 (m, 4H), 6.24
(dd, J1 = 8.0, J2 =1.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ ppm
143.82, 140.35, 134.00, 132.05, 126.97, 122.95, 121.67,
121.12, 116.54, 77.42, 77.10, 76.78. MALDI-TOF-MS (m/z):
calcd for C18H12BrNS [M+H]+: 352.987, found 353.994.
2.1.2 10-(4-bromophenyl)-10H-phenothiazine-3-carbaldehyde
and
achieve
bathochromic
shift.37-39
Furthermore,
(4): Compound
3 (3.000 g, 8.47 mmol) and dry N,N-
phenothiazine derivatives can act as electron donors and
further increase ICT, hence functionalized phenothiazine units
are introduced onto TT-DPP to push the absorption band more
red-shifted. Furthermore, bromine atom (Br) is introduced
onto phenothiazine to facilitate the spin-orbital coupling and
enhance inter-system crossing (ISC) for higher ROS generation
and better PDT efficacy.40-43
Herein, a TT-DPP-based NIR small molecule photosensitizer
PDBr has been designed and synthesized. And the hydrophilic
PDBr nanoparticles (NPs) are prepared via nano-precipitation,
which show good singlet oxygen quantum yield of 67% and
relatively high photothermal conversion efficiency of 35.7%.
Furthermore, PDBr NPs show excellent photo-toxicity but low
dark cytotoxicity to cancer cells. The in vivo studies illustrate
that PDBr NPs are effective to destroy cancer cells via imaging-
guided dual-modal PDT/PTT and can be used as a promising
photothermogenic nanotheranostic agent (Scheme 1).
dimethylformamide (DMF) (4.0 eq, 2.6 mL, 33.88 mmol) were
dissolved in dry chloroform (20 mL), stirring under N2 for 5
min. Then Phosphorus oxychloride (POCl3) (4.0 eq., 3.1 mL,
33.88 mmol) was added slowly to the above mixture at 0 °C in
an ice bath. The solution was refluxed overnight, and then
poured into ice water, simultaneously Sodium hydroxide
(NaOH) was added to adjust the mixture to neutral. The above
mixture was extracted with DCM (2 × 50 mL), washed with
water for three times and dried over anhydrous sodium sulfate
(Na2SO4). Then anhydrous sodium sulfate was removed by
suction, and solvent was removed under reduced pressure and
the residue was purified by column chromatography on silica
gel (DCM:PE = 1:10; v/v) to afford
4 as yellow powder (2.490 g,
77%). 1H NMR (400 MHz, CDCl3): δ ppm 9.708 (s, 1H), 7.78 (d, J
= 8.4 Hz, 2H), 7.31 - 7.26 (m, 3H), 7.48 (d, J = 2.0 Hz, 1H), 7.00 -
6.97 (m, 1H), 6.87 - 6.84 (m, 1H), 6.17 (d, J = 8.4 Hz, 1H); 13C
NMR (100 MHz, CDCl3): δ ppm 189.75, 148.78, 142.24, 138.96,
132.64, 131.23, 131.23, 129.94, 127.58, 126.87, 123.07,
120.45, 119.27, 116.37, 115.00, 77.41, 77.09, 76.77. MALDI-
TOF-MS (m/z): calcd for C19H12BrNOS [M+H]+: 380.982, found
381.991.
2.1.3 Ethyl (E)-3-(10-(4-bromophenyl)-10H-phenothiazin-3-yl)
acrylate (5): To a three-neck round bottom flask, the solution
of LiCl (1.4 eq., 0.310 g, 7.34 mmol) in tetrahydrofuran (20 mL)
were added Triethyl phosphonoacetate (1.3 eq., 1.520 g, 6.80
mmol) and the mixture was stirred at room temperature for 10
min. Then 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (1.2 eq.,
0.960 g, 6.29 mmol) was dripped into the above mixture at 0
Scheme 1. Schematic illustration of Fluorescence imaging (FI)-guided synergistic
PDT/PTT for PDBr NPs.
°C. After stirring for 10 min, compound
4 (2.370 g, 5.24 mmol)
was slowly added. Then the resulting mixture was allowed to
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 3 of 9
Journal of Materials Chemistry B
Journal Name
ARTICLE
ambient, stirring for 20 min until the reaction was complete was removed by suction, and then remove the orVgieawnAicrtiscloelOvnelinnet
DOI: 10.1039/C8TB03185A
(monitored by thin layer chromatography, TLC). Followed by under reduced pressure, the residue was purified by column
completion, the reaction was quenched with ice water and chromatography on silica gel (DCM:PE = 1:5; v/v) to give PD as
extracted with ethyl acetate (EA) (3 × 50 mL). The organic dark green powder (0.120 g, 40%). 1H NMR (400 MHz, CDCl3): δ
extracts were washed with brine, dried over anhydrous Na2SO4. ppm 9.45 (s, 2H), 7.90 (d, J = 8.4 Hz, 1H), 7.60 (s, 2H), 7.48 (d, J
Then sodium sulfate was removed by suction, and the solvent = 15.6 Hz, 2H), 7.43 (d, J = 8.4 Hz, 4H), 7.20 (d, J = 2 Hz, 2H),
was evaporated under reduced pressure to give the crude 7.04 - 6.70 (m, 4H), 6.89 - 6.86 (m, 4H), 6.28 - 6.22 (m, 6H),
product. The residue was purified by column chromatography 6.42 (d, J = 1.6 Hz, 4H), 4.23 (m, 4H), 4.11 (d, J = 7.2 Hz, 4H),
on silica gel (EA:PE = 1:15; v/v) to yield
5 as yellow powder 2.03 - 2.00 (m, 2H), 1.60 - 1.21 (m, 84H), 0.86 - 0.83 (m, 12H).
(2.130 g, 90%). H NMR (400 MHz, CDCl3): δ ppm 7.76 (d, J = 13C NMR (100 MHz, CDCl3): δ ppm 167.18, 161.61, 149.44,
8.8 Hz, 1H), 7.78 (d, J = 16.0 Hz, 1H), 7.28 - 7.26 (m, 2H), 7.17 145.44, 143.08, 143.02, 140.64, 140.10, 139.87, 134.23,
(d, J = 2.0 Hz, 1H), 7.01 - 6.96 (m, 1H), 6.88 - 6.82 (m, 3H), 6.23 131.21, 129.16, 128.32, 127.74, 127.50, 127.11, 126.92,
1
(d, J = 16.0 Hz, 1H), 6.15 - 6.14 (m, 2H), 1.34 - 1.30 (m, 3H). 13
C
125.96, 123.32, 121.00, 119.94, 116.47,116.02, 115.81, 108.59,
NMR (100 MHz, CDCl3): δ ppm 167.16, 143.34, 142.94, 139.42, 77.36, 77.04, 76.73, 60.42, 31.95, 30.21, 29.73, 29.70, 29.65,
134.34, 132.66, 129.10, 127.48, 126.87, 125.92, 123.27, 29.42, 29.40, 26.30, 22.72, 14.36, 14.15. MALDI-TOF-MS (m/z):
122.60, 120.61, 119.55, 116.13, 116.08, 115.64, 77.42, 77.10, calcd for C112H138N4O6S6 [M]+, 1826.894, found 1827.187.
77.79, 60.43. MALDI-TOF-MS (m/z): calcd for C23H18BrNO2S
[M+H]+: 451.024, found 452.031.
2.1.6 Diethyl 3,3'-((((2,5-bis(2-decyltetradecyl)-3,6-dioxo-
2,3,5,6-tetrahydropyrrolo[3,4-c]pyrrole-1,4-diyl)bis(thieno
2.1.4
dioxaborolan-2-yl)phenyl)-10H-phenothiazin-3-yl)
(6): To a solution of compound (0.850 g, 2.00 mmol) in dry (0.050 g, 0.03 mmol) and dichloromethane (10 mL) were
Ethyl
(E)-3-(10-(4-(4,4,5,5-tetramethyl-1,3,2- [3,2b]thiophene-5,2-diyl))bis(4,1-phenylene))bis(7-bromo-
acrylate 10H-phenothiazine-10,3-diyl))(2E,2'E)-diacrylate (PDBr)
:
PD
5
DMF (15 mL) at room temperature was added Potassium added to a 100 mL two-necked round bottom flask. After
acetate (KOAc) (3.0 eq., 0.590 g, 6.00 mmol) followed by stirring for 5 min at room temperature, N-Bromosuccinimide
bis(pinacolate)diboron (1.2 eq., 6.100 g, 2.40 mmol) and (NBS) (2.2 eq, 0.010 g, 0.07 mmol) was added in two portions
Bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)Cl2) at 0 °C. The reaction was slowly warmed to room temperature
(5%, 0.070 g, 0.10 mmol) under nitrogen atmosphere. The and stirred until the reaction completed (monitored by TLC),
reaction mixture was stirred at 80 oC for overnight and quenched with water and the product was extracted with DCM
extracted with EA (2 × 50 mL), washed with brine, dried over (2 × 50 mL). The combined organic layer was washed with
anhydrous Na2SO4. Then sodium sulfate was removed by brine, dried over anhydrous Na2SO4. Then sodium sulfate was
suction, and the solvent was removed under vacuum. The removed by suction, and the solvent was evaporated under
residue was purified by column chromatography on silica gel reduced pressure to give the crude product for purification by
(EA:PE = 1:15; v/v) to get
6
as yellow powder (0.680 g, 70%). 1H column chromatography on silica gel (DCM:PE = 1:5; v/v) to
1
NMR (400 MHz, CDCl3): δ ppm 8.05 (d, J = 8.4 Hz, 2H), 7.46 (d, J give PDBr as dark green powder (0.040 g, 70%). H NMR (400
= 16 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 2.0 Hz, 1H), MHz, CDCl3): δ ppm 9.37 (d, J = 2.0, 2H), 7.90 (d, J = 8.4 Hz,
7.00 - 6.97 (m, 1H), 6.94 (dd, J1 = 8.4, J2 = 2.0 Hz, 1H), 6.82 - 4H), 7.62(s, 2H), 7.51 (d, J = 3.6 Hz, 2H), 7.46 (d, J = 8.0 Hz, 4H),
6.80 (m, 2H), 6.21 (s, 1H), 6.14 - 6.12 (m, 2H), 1.59 (s, 12H), 7.07 (t, J = 3.4 Hz, 4H), 6.92 - 6.86 (m, 4H), 6.35 (d, J = 8.4 Hz,
1.31 (t, J = 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ ppm 6H), 4.26 - 4.11 (m, 4H), 3.19 (d, J = 4.8 Hz, 4H), 2.07 - 2.00 (m,
167.14, 145.45, 143.10, 137.35, 129.37, 128.74, 127.36, 2H), 1.57 (s, 2H), 1.34 - 1.21 (m, 86H), 0.86 - 0.84 (m, 12H).
126.61, 125.72, 122.95, 120.32, 119.28, 116.19, 115.71, 84.13, MALDI-TOF-MS (m/z): calcd for C112H136Br2N4O6S6 [M]+:
77.31, 76.99, 76.68, 60.28, 24.85, 14.28. MALDI-TOF-MS (m/z): 1982.715, found: 1983.015.
calcd for C29H30BNO4S [M]+: 499.1989, found 499.2337.
2.2 Preparation of nanoparticles (NPs)
2.1.5 Diethyl 3,3'-((((2,5-bis(2-decyltetradecyl)-3,6-dioxo- Briefly, PDBr (2.0 mg) was dissolved in tetrahydrofuran (1 mL),
2,3,5,6
[3,2b]thiophene-5,2-diyl))bis(4,1-phenylene))
phenothia-zine-10,3-diyl)) (2E,2'E)-diacrylate (PD): A 50 mL system was removed by nitrogen bubbling (30 min). PDBr NPs
two-necked round bottom flask was charged with (0.200 g, were obtained at a concentration of 200 μg/mL.
0.18 mmol) and (2.2 eq., 0.200 g, 0.40 mmol) in toluene (10
mL) under N2. Then aqueous Potassium carbonate (K2CO3) (5.0 2.3 In Vitro Photothermal Effect
eq., M, mL), Tetrakis(triphenylphosphine)palladium Aqueous solution of PDBr NPs (3 mL, 150 μg/mL) was put into
tetrahydropyrrolo[3,4-c]pyrrole-1,4-diyl)bis(thieno and then the solution was quickly injected into DI water (10
bis(10H- mL) with ultrasonic. After 10 min, the organic solvent in the
7
6
1
1
(Pd(PPh3)4) (10%, 0.020 g, 0.02 mmol) and Methyl trioctyl a quartz cuvette (10 mm path length) and irradiated by 660-
ammonium chloride (5%, 0.004 g, 0.01 mmol) were added. The nm laser (1.0 W/cm2) while monitor the temperature with a
resulting solution was heated to 110 °C under N2 for 18 h, and time step of 20 seconds. The laser was switched off when the
then the reaction mixture was allowed to cool to room temperature reached a plateau and the thermal cooling profile
temperature, extracted with DCM (2 × 50 mL) and brine (100 was recorded thereafter. The same heating-cooling cycle was
mL). After drying over anhydrous Na2SO4. Then sodium sulfate measured for deionized water. Other tests (different
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Journal of Materials Chemistry B
Page 4 of 9
ARTICLE
Journal Name
concentration: 50, 75, 100, 125, 150 μg/mL, respectively; formula: Cell viability (%) = (mean of absorbance VoiefwtArretiacltemOnelinnet
different laser power density: 0.2, 0.4, 0.6, 0.8, 1.0 W/cm2, group) / (mean of absorbance of control group) × 100.
DOI: 10.1039/C8TB03185A
respectively.) were carried out under the same condition. The
temperature change is recorded by an infrared camera E5.
2.8 Cell staining and migration assays
HeLa cells were seeded into two 6-well plates at a density of
5000 cells per well and incubated in the culture media (2 mL)
2.4 Singlet oxygen generation of PDBr
The singlet oxygen generation of PDBr was detected with DPBF at 37 °C (5% CO2 atmosphere) for 24 h. Then these cells
1
as the O2 probe in DCM. In other words, DPBF (20 mM in incubated with PDBr NPs in DMEM media (100 μg/mL, 200 μL
DCM) was mixed with PDBr in DCM, and the maximum per well) for another 24 h in darkness. Then one of these 6-
absorption intensity of DPBF was around 1.05-1.20. The well plates was irradiated under 660 nm laser (1.0 W/cm2) at
absorbance maximum of PDBr was adjusted to be 0.2-0.3. room temperature for 8 min and the others are still in
Then the above mixture was irradiated with 660 nm laser (0.6 darkness. Immediately after illumination, these cells were
W/cm2). The absorbance change of DPBF at 412 nm was treated with trypan blue (0.1%, 100 μL) for another 3~5 min,
monitored by UV-Vis-NIR spectrophotometer over time.
the images were gathered by high-power microscope.
2.5 Cell culture
2.9 Animals and tumor model
HeLa cell (cervical cancer), A549 (lung cancer), HCT-116 (colon Female athymic nude mice (4-weeks old, Permit number:
cancer) and A2780 (ovarian cancer) are provided by the SCXK(Su)2012-0004) used in this study were bought from
Institute of Biochemistry and Cell Biology, SIBS, CAS (China). Comparative Medicine Centre of Yangzhou University. All
They are cultured in Dulbecco’s modified Eagle’s medium animal experiments conformed to the NIH guidelines for the
(DMEM, Gibco) containing 10% fetal bovine serum (FBS) under care and use of laboratory animals approved by School of
5% CO2 at 37 °C.
Pharmaceutical Sciences, Nanjing Tech University. The
subcutaneous xenograft model of cervical cancer was built by
injecting 3 ×
106 HeLa cells in 100 mL PBS solution
2.6 Cellular uptake and intracellular ROS detection in vitro
Hela cells incubated with PDBr NPs in PBS (100 μg/mL, 2 mL) in subcutaneously into the left flank near the front armpit of the
a confocal dish at 37 °C under 5% CO2 for additional 24 h. After mice. After the tumor volumes were around 300 mm3, mice
removing these media, the cells were washed with PBS were randomly employed for imaging and phototherapy.
solution and further incubated with DCFH-DA for 20 min and
DAPI for 3 min in the dark, respectively. Then the cells were 2.10 In vivo Imaging and therapy
rinsed thrice with PBS solution and illuminated using Xenon 2.10.1 In vivo fluorescence Imaging: PDBr NPs (100 μg/mL) is
lamp for 8 min. After that, the fluorescence images of the cells injected through the tail vein into HeLa tumor xenografted
were obtained using a confocal laser scanning microscope nude mice anesthetized using 2% isoflurane in oxygen. After
(Olympus IX 70 inverted microscope). PDBr NPs are excited at injection, fluorescence images of the mice were performed
600 nm and collect the fluorescence from 630 nm to 900 nm. using IVIS spectrum imaging system. Mice were later sacrificed
For DAPI detection, it is excited at 405 nm, and the and tumor, liver, spleen, heart, lung, kidney were harvested
fluorescence from 420 nm to 500 nm was collected. For DCF for ex vivo fluorescence imaging to estimate the
detection, it is excited at 488 nm, and the fluorescence from biodistribution of PDBr NPs.
500 nm to 600 nm was collected.
2.10.2 In vivo photothermal images: PDBr NPs (100 μg/mL) or
2.7 Cell viability studies
PBS is injected through the tail vein into HeLa cell xenografted
To explore the cytotoxicity of PDBr NPs, its PBS suspension is nude mice anesthetized using 2% isoflurane in oxygen.
diluted to various concentrations by DMEM. Meanwhile, HeLa, Photothermal images were recorded by an E50 infrared
A549, HCT-116, and A2780 cells were seeded into two 96-well camera when the tumor sites are irradiated with 660 nm laser
plates at a density of 5000 cells per well, respectively, and (0.6 W/cm2) at different time points after 8 h post-injection of
incubated in the culture media (200 μL) at 37 °C under a 5% PDBr NPs.
CO2 atmosphere for 24 h. Then these cells are incubated with
various concentrations of PDBr NPs in DMEM media (200 μL 2.10.3 In vivo synergistic therapy: HeLa tumor xenografted
per well) for another 24 h in darkness. Subsequently, one of nude mice are randomly divided into three groups (PBS with
the 96-well plates was irradiated under 660-nm laser (1.0 W irradiation, PDBr NPs without irradiation, PDBr NPs with
/cm2) at room temperature for 8 min. After illumination, these irradiation, 660 nm laser, 1.0 W/cm2). For each group, mice
96-well plates were incubated for additional 24 h, and then are injected with PDBr NPs (150 μg/mL, 100 μL, dose 0.75
MTT (100 μg/mL, 20 μL) solution in PBS was added to each mg/kg) in PBS or PBS through the tail vein, respectively. 8 h
well and incubated for another 4 h. After removing the later, mice are irradiated with laser for 8 min. The body
medium, these cells were treated with DMSO (150 μL) and the weights and tumor sizes of each mice are supervised every two
absorption was measured at 490 nm by a Microplate Reader. days. Tumor volumes are calculated by the commonly used
The cell viability values were calculated by the following equation: volume = 0.5 × (length × width2).
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 5 of 9
Journal of Materials Chemistry B
Journal Name
ARTICLE
therapeutic window and can be used for in vivoVfieluwoArrteicsleceOnnlicnee
imaging.
3. Results and discussion
DOI: 10.1039/C8TB03185A
3.1 Synthesis and characterization of PDBr and PDBr NPs
As shown in Scheme 2, the synthesis started from Buchwald-
3.2 In Vitro Photothermal Effect
Hartwig reaction between phenothiazine
dibromobenzene in toluene to give in 80% yield, which was
later treated with Vilsmeier-Haack condition (POCl3/DMF) to
introduce an aldehyde group to afford in a good yield of
77%.44,45 Then
was reacted with triethyl phosphonoacetate
via a modified Witting-Horner reaction to afford in 90%
yield.46 Later, compound
was prepared by Miyaura
1
and 1,4-
To investigate the photothermal behaviour of PDBr NPs, the
temperature changes of the aqueous dispersion at various
concentrations (50, 75, 100, 125, 150 μg/mL) were
quantitatively measured by using 660 nm laser (1.0 W/cm2). As
depicted in Fig. 2A, the temperature gradually rises and
reaches the plateau after 10 min laser irradiation. Notably, the
eventual temperature plateau depends on the concentration
of NPs. Furthermore, Fig. 2B shows the obvious laser power
density dependence for the photothermal behaviour of PDBr
NPs at the concentration of 100 μg/mL. In addition, the
temperatures of PDBr NPs and pure water upon exposure to
660 nm laser irradiation were compared. The temperature
2
3
4
4
5
6
borylation reaction.47, 48 PDBr was synthesized through Pd-
catalyzed Suzuki coupling and then treated with N-
50
bromosuccinimide (NBS).49,
The chemical structures and
purity of all these compounds were confirmed by H NMR, 13C
1
NMR and MALDI-TOF mass spectroscopy (Fig. S9-S19).
o
elevation (ΔT) of PDBr NPs is ~17.6 C, whereas pure water
shows little increase of 1.4 oC only under the same condition of
laser irradiation, implying the excellent photothermal
conversion property of PDBr NPs (Fig. 2D). According to the
method reported, the photothermal conversion efficiency (η)
of PDBr NPs is calculated to be 35.7%, which is higher than
most of reported photothermal agents.53,54 Interestingly, the
temperature elevation after five alternate heating and cooling
cycles was nearly unchanged, reflelcting a good photothermal
stability of PDBr NPs (Fig. 2C). Additionally, the UV-vis
absorption profiles of PDBr NPs showed almost no change
after five-cycles irradiation in contrast to that before
irradiation (Fig. S2, ESI†). These results suggest that PDBr NPs
could be a promising candidate as an efficient photothermal
agent.
Scheme 2. Synthetic routes for PDBr.
1.0
12
PDBr
PDBr NPs
0.8
0.6
0.4
0.2
0.0
10
8
3.3 Singlet oxygen generation of PDBr
6
4
As known to all, singlet oxygen quantum yield (ΦΔ) is the key
factor for PDT. In this contribution, ΦΔ was assessed by
monitoring the absorbance decrease of the trapping reagent
1,3-diphenyl-isobenzofuran (DPBF) at 412 nm under 660-nm
laser irradiation, and Methylene Blue (MB, ΦΔ = 0.57 in DCM)
was employed as the reference (Fig. S3).55 As shown in Fig. 3A,
the absorbance at 412 nm of DPBF remarkably decreased in
the presence of PDBr under laser irradiation (660 nm, 0.6
W/cm2). The degradation slope of DPBF in the presence of
PDBr is determined to be 0.011 with the absorbance ranging
from 0.8 to 1.0 (R2 = 0.998), indicating a linear degradation
process (Fig. 3B). Singlet oxygen quantum yield of PDBr is
calculated to be 67%, which is comparable to many NIR
organic photodynamic agents.7,10,56 The result suggests that
PDBr can produce sufficient singlet oxygen under laser
illumination.
2
0
0
50
100
150
200
250
400
500
600
700
800
900
1000
Size (nm)
Wavelength (nm)
Fig. 1 (A) Dynamic light scattering (DLS) size distribution of PDBr NPs. Inset:
transmission electron microscopy (TEM) image of PDBr NPs. Scale bar: 200 nm.
(B) Normalized absorbance of PDBr in DCM and PDBr NPs in water.
PDBr NPs were synthesized via nano-precipitation that can
form stable multimeric species in water.51, 52 As revealed by
transmission electron microscopy (TEM) image and dynamic
light scattering (DLS), PDBr can take shape into spherical NPs
and the average diameter of PDBr NPs is approximate 100 nm
(Fig. 1A). As shown in Fig. 1B, the absorption maximum of
PDBr in DCM is peaked at 588 nm and 635 nm, with the
absorption onset at around 680 nm. Nevertheless, the
maximum absorption peaks for PDBr NPs are 602 nm and 650
nm, showing a slight red-shift of around 15 nm as compared
with that of PDBr owing to the intermolecular π-π interaction
of the aggregated PDBr molecules. Upon excitation at 600 nm,
PDBr NPs demonstrate three broad emission peaks at 676 nm,
730 nm and 820 nm (Fig. S1A), which locate within the NIR
3.4 Cellular uptake and cellular ROS detection
To investigate the cellular uptake and singlet oxygen
generation of PDBr NPs in vitro, HeLa cells were incubated
with PDBr NPs in PBS (20 μg/mL, 20 μL) and ROS probe 2’,7’-
dichlorofluorescein diacetate (DCFH-DA). As depicted in Fig.
3C, it is interesting to note that PDBr NPs could be uniformly
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Journal of Materials Chemistry B
Page 6 of 9
ARTICLE
Journal Name
localized in cytoplasm according to the confocal images of 3.5 Cytotoxicity assay and preliminary in vitro study
View Article Online
HeLa cells. After 5 min laser irradiation (660 nm, 0.6 W/cm2),
strong green fluorescence from as-produced 2’, 7’-
dichlorofluorescein (DCF) can be clearly observed throughout
the cells (excited at 488 nm), as suggests that ROS could be
efficiently generated by PDBr NPs under irradiation. This
phenomenon shows that PDBr NPs could effectively enter
cells, locating in cytoplasm, and generate intracellular ROS
upon suitable irradiation, which indicates PDBr NPs could be a
promising nanotheranostic agent for PDT.
To analysis the synergistic phototherapeutic efficacy of
DOI: 10.1039/C8TB0P31D8B5Ar
NPs,
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide (MTT) assay was carried out. High photo-toxicity and
low dark cytotoxicity are the key requirements of
nanotheranostic agent for in vivo phototherapy, and four kinds
of cancer cell lines (HeLa, A549, HCT-116, and A2780) were
treated with PDBr NPs at different concentrations for MTT
test. Fig. 4A and 4B show the cytotoxicity of PDBr NPs to HeLa
cells and A549 cells. Upon laser irradiation (660 nm, 1.0
W/cm2), the cell viability decreases obviously with PDBr NPs
concentration increasing, and IC50 (half-maximal inhibitory
concentration) values for HeLa and A549 cell lines are 35
μg/mL and 40 μg/mL, respectively. Moreover, PDBr NPs show
low dark toxicity with a cell viability of nearly 95% even at a
high concentration. In addition, PDBr NPs also perform high
photo-cytotoxicity but low dark toxicity to HCT-116 and A2780
cell lines (Fig. S4A and S4B). Such good biocompatibility and
high phototoxicity of PDBr NPs make it desirable for
phototherapy.
150 g/mL
1.0 W
12
9
20
16
12
8
125 g/mL
100 g/mL
75 g/mL
50 g/mL
Water
0.8 W
0.6 W
0.4 W
0.2 W
6
3
4
0
0
0
100
200
300
400
500
600
0
100
200
300
400
500
600
Time (s)
Time (s)
20
16
12
8
750
600
450
300
150
0
y
= 368.78x - 13.51
PDBr NPs
Water
R2 = 0.997
16
12
8
To visualize the therapeutic effect, the trypan blue (TB)
exclusion assay was carried out. It is widely acknowledged that
membrane-impermeable molecule TB can interact with
intracellular proteins when entering the cells with incomplete
cell membranes, which will render the cells a blue colour,
while live cells with intact membranes will not be coloured.
0.0
0.4
0.8
1.2
1.6
2.0
-ln()
4
4
0
0
0
1200
2400
3600
4800
6000
0
200
400
600
800
1000
Time (s)
Time (s)
Therefore, the TB exclusion assay allows for
a direct
Fig. 2 (A) Temperature changes of PDBr NPs aqueous dispersion at various
concentration upon laser irradiation (660 nm, 1.0 W/cm2). (B) Temperature
changes of PDBr NPs (100 μg/mL) upon laser irradiation with different power
densities. (C) Photothermal stability of PDBr NPs (150 μg/mL) under laser
irradiation for five alternate on-off cycles. (D) Temperature curves of water and
PDBr NPs in water (150 μg/mL) with laser irradiation in a procedure of laser-on
for 10 min and off for 10 min (660 nm, 1.0 W/cm2). Inset: linear cooling time
data versus -Ln(θ) obtained from the cooling period of (C).
identification and enumeration of live (unstained) and dead
(blue) cells in a given population. Following treatment of cells
with PDBr NPs for 24 h, the cells were then exposed to laser
irradiation (660 nm, 0.6 W/cm2), and subsequently treated
with TB immediately. It can be clearly seen that the cells
appeared blue which suggested they undergone cell death.
However, the cells without irradiation still remained
transparent (Fig. 4C), which also demonstrates the low toxicity
of PDBr NPs. Noteworthy is that the light induces the dramatic
temperature increase and singlet oxygen generation, which
lead to the cell death. In addition, PDBr NPs can inhibit tumor
cells migration as depicted in wound healing assay (Fig. S4C).
1.00
0.96
0.92
0.88
0.84
0.80
0 s
4 s
8 s
1.2
0.9
0.6
0.3
0.0
y
= -0.011x + 1.19
R2 = 0.998
12 s
16 s
18 s
20 s
22 s
24 s
29 s
33 s
3.6 Fluorescence imaging and photothermal imaging in vivo
300
350
400
450
500
18
21
24
27
30
33
Time (s)
Wavelength (nm)
Motivated by the excellent photothermal conversion and high-
efficiency singlet oxygen generation of PDBr NPs, xenograft
HeLa tumor-bearing mouse model is used for fluorescence
imaging to real-time monitor the dynamic accumulation of
PDBr NPs in tumor. At 0 h, almost no fluorescence signal could
be detected from the blood vessels before PDBr NPs injection.
After 2 h of intravenous injection, the fluorescence intensity at
tumor site gradually increases, suggesting the increasing
accumulation of PDBr NPs in the tumor region due to the
enhanced permeability and retention (EPR) effect. The
fluorescence signals at tumor site reached the maximum at 8 h
post-injection (Fig. 5A). Subsequently, the fluorescence
intensity became weaker because of the clearance of PDBr
NPs. After 24 h, the main organs were collected to study the
biodistribution of PDBr NPs, the fluorescence intensity was
Bright field
DAPI
DCF-DA
Merge
Bright field
DAPI
PDBr NPs
Merge
Fig. 3 (A) The absorbance degradation of DPBF under 660-nm laser irradiation in
the presence of PDBr in DCM. (B) Linear fitting of the degradation of DPBF. (C)
Confocal images of cellular uptake of PDBr NPs and DCFH-DA stained HeLa cells.
Scale bar: 10 μm
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 7 of 9
Journal of Materials Chemistry B
Journal Name
ARTICLE
mainly observed in liver and spleen, this is due to the fact that contrast, the temperature in the tumor region of HeLa tumor
View Article Online
DOI: 10.1039/C8TB03185A
both Liver and spleen contain reticuloendothelial system (RES) xenograft mouse with PBS injection showed just a little
which would capture heterologous substance, thus high temperature increase (Fig. 5B, S6). According to the
accumulation of PDBr NPs can be observed in the liver and photothermal images, PDBr NPs can absorb the NIR light to
spleen. Meanwhile, liver is the main detoxification system, and generate heat which can lead to the in vivo temperature
it is supposed that the nanoparticles would be metabolized by increase at tumor site.
liver.57,58 Furthermore, 8 h post-injection is the optimized time
3000
point for fluorescence imaging and PTT treatment of tumor.
Saline with irradiation
NPs without irradiation
NPs with irradiation
2500
2000
1500
1000
500
100
80
60
40
20
0
100
80
60
40
20
0
without irradiation
with irradiation
0
without irradiation
with irradiation
0
4
8
12
16
20
Time (day)
0
10
20
30
40
50
60
0
20
30
40
50
60
Concentration (g/mL)
Concentration (g/mL)
22
20
18
16
14
Saline with irradiation
NPs without irradiation
NPs with irradiation
without irradiation
with irradiation
0
4
8
16
20
Time (d1a2y)
Fig. 4 Cell viability tested by MTT assay of (A) HeLa cells and (B) A549 cells
incubated with PDBr NPs at different concentration with and without irradiation.
(C) Bright field images of HeLa cells incubated with PDBr NPs treated with trypan
blue in (i) the absence, and (ii) presence of irradiation. Scale bars: 50 μm.
Max
0 h
2 h
4 h
8 h
Fig. 6 (A) Tumor growth curves for control, no illumination and illumination groups
during the treatment. (B) Body weight change for the three groups. (C) Photographs of
tumor-bearing mice after different treatment. (D) H&E stained images of tumor tissues
after different treatment. Scale bars: 100 μm.
12 h
16 h
20 h
24 h
3.7 Synergistic PTT/PDT in vivo
Min
To clarify the PTT/PDT synergistic therapeutic efficacy of PDBr
NPs in vivo, 15 xenograft HeLa tumor-bearing nude mice were
randomly divided into three groups (n = 5).59-60 Group I was
treated with PBS (100 μL) and exposed to laser. While group II
was only injected with PDBr NPs (150 μg/mL, 100 μL, dose 0.75
mg/kg) without laser irradiation. Group III was injected with
PDBr NPs (150 μg/mL, 100 μL, dose 0.75 mg/kg) with laser
irradiation. The in vivo antitumor efficacy of the three groups
was studied by monitoring the tumor volume and body weight
for 20 days. As demonstrated in Fig. 6A, the treatment for
group I was totally invalid to stop the tumor growth as
compared to that of group III, indicating PBS with irradiation
possesses no effect on the tumor growth. In addition, the
tumor growth kinetics for mice in group II is similar to that of
group I, suggesting that PDBr NPs without irradiation failed to
prohibit the tumor growth. In other words, both group I (PBS
injection, irradiation) and group II (PDBr NPs injection, without
irradiation) show negligible antitumor activity. Remarkably,
the average tumor volume for group III reduced after the
second treatment (Fig. 6A). After 12-days treatment, the
tumor completely disappeared, suggesting the distinguished
0 min
1 min
3 min
5 min
7min
Max
Min
PBS
NPs
Fig. 5 (A) In vivo fluorescence images of a subcutaneous HeLa tumor in mice at
various time after tail intravenous injection of PDBr NPs. (B) In vivo
photothermal images of HeLa tumor-bearing mice after tail intravenous injection
of PBS and PDBr NPs PBS suspension under laser irradiation (660 nm, 1.0
W/cm2).
Referred to fluorescence imaging, infrared thermal imaging is
further explored after 8 h post-injection of PDBr NPs in HeLa
tumor-bearing mice with 660-nm laser. The temperature at
tumor site continuously increased along with the extended
irradiation time, and finally reached ~48 oC after 7 min
illumination. In the organism, the blood vessels within the
tumor tissues can be destroyed when the temperature reaches
42 oC or even higher to afford the therapeutic effects. In
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
Journal of Materials Chemistry B
Page 8 of 9
ARTICLE
Journal Name
6
7
8
9
A. Kamkaew, S. H. Lim, H. B. Lee, L. V. Kiew, L. Y. Chung and
K. Burgess, Chemical Society Reviews, 2013, 42, V7ie7w-8A8rt.icle Online
B. R. Smith and S. S. Gambhir, Chem.DROeIv: .1,0.21003197/,C18T1B70,3918051A-
986.
Z. Zhou, J. Song, L. Nie and X. Chen, Chemical Society
Reviews, 2016, 45, 6597-6626.
B. Kalyanaraman, Redox Biology, 2013, 1, 244-257.
PTT/PDT therapeutic effect of PDBr NPs against tumor.
Meanwhile, the body weight for group III increases gradually
(Fig. 6B and 6C), which indicates the good bio-compatibility
and low side effect of PDBr NPs. These results manifest that
PDBr NPs is
a promising nanotheranostic agent for
photothermal and photodynamic therapy in vivo.
10 A. W. Girotti, Journal of Photochemistry and Photobiology B-
Biology, 2001, 63, 103-113.
11 K. Plaetzer, T. Kiesslich, C. B. Oberdanner and B. Krammer,
Current Pharmaceutical Design, 2005, 11, 1151-1165.
12 M. Lam, N. L. Oleinick and A. L. Nieminen, Journal of
Biological Chemistry, 2001, 276, 47379-47386.
13 S. Lal, S. E. Clare and N. J. Halas, Accounts Chem. Res., 2008,
41, 1842-1851.
14 W. I. Choi, J.-Y. Kim, C. Kang, C. C. Byeon, Y. H. Kim and G.
After in vivo treatment, all mice were sacrificed and the tumor
and main organs were collected to stain with haematoxylin
and eosin (H&E) for histopathological examination, so as to
understand the therapeutic effect at the tissue level. Fig. 6E
recorded the photograph of the tumor histologic section for
group I and group II, while the nuclei of tumor cells are in good
condition. In addition, the H&E stained images of major organs
(heart, liver, spleen, lung, and kidney) disclosed that the nuclei
of the normal cells remained almost unchanged (Fig. S8),
indicating excellent biocompatibility and low side effect of
PDBr NPs to living mice.
Tee, ACS Nano, 2011, 5, 1995-2003.
15 J. Wang, G. Zhu, M. You, E. Song, M. I. Shukoor, K. Zhang, M.
B. Altman, Y. Chen, Z. Zhu and C. Z. Huang, ACS Nano, 2012,
6
, 5070-5077.
16 W.-S. Kuo, Y.-T. Chang, K.-C. Cho, K.-C. Chiu, C.-H. Lien, C.-S.
Yeh and S.-J. Chen, Biomaterials, 2012, 33, 3270-3278.
17 D. Chen, Q. Tang, J. Zou, X. Yang, W. Huang, Q. Zhang, J. Shao
4. Conclusions
In summary, a small molecule NIR photosensitizer PDBr has
been synthesized and serves as an outstanding theranostic
agent for in vivo synergistic photothermal and photodynamic
and X. Dong, Advanced Healthcare Materials, 2018,
1701272.
7,
18 W. Xiao, P. Wang, C. Ou, X. Huang, Y. Tang, M. Wu, W. Si, J.
Shao, W. Huang and X. Dong, Biomaterials, 2018, 183, 1-9.
19 T. Yang, Y. a. Tang, L. Liu, X. Lv, Q. Wang, H. Ke, Y. Deng, H.
Yang, X. Yang and G. Liu, ACS Nano, 2017, 11, 1848-1857.
20 M. Li, X. Yang, J. Ren, K. Qu and X. Qu, Advanced Materials,
2012, 24, 1722-1728.
21 L. Jing, X. Liang, Z. Deng, S. Feng, X. Li, M. Huang, C. Li and Z.
Dai, Biomaterials, 2014, 35, 5814-5821.
22 W. Wang, L. Wang, Z. Li and Z. Xie, Chemical
Communications, 2016, 52, 5402-5405.
23 A. De La Zerda, C. Zavaleta, S. Keren, S. Vaithilingam, S.
Bodapati, Z. Liu, J. Levi, B. R. Smith, T.-J. Ma and O. Oralkan,
Nature Nanotechnology, 2008,
24 Q. Jia, J. Ge, W. Liu, S. Liu, G. Niu, L. Guo, H. Zhang and P.
Wang, Nanoscale, 2016, , 13067-13077.
25 D. Zhang, M. Wu, Y. Zeng, N. Liao, Z. Cai, G. Liu, X. Liu and J.
Liu, Journal of Materials Chemistry B, 2016, , 589-599.
therapy. PDBr
, with high stability and biocompatibility,
presents a high singlet oxygen quantum yield of 67%. And
PDBr NPs demonstrate a high photothermal conversion
efficiency of 35.7% and fluorescence imaging property without
noticeable in vivo toxicity. Due to the combined merits, PDBr
NPs can significantly inhibit the tumor growth in living mice
through imaging-guided photothermal and photodynamic
therapy. Therefore, PDBr NPs is a promising multi-functional
organic nanoparticle for clinical application.
3, 557.
8
Conflicts of interest
The authors declare no conflict of interest.
4
26 R. J. Paproski, A. Forbrich, E. Huynh, J. Chen, J. D. Lewis, G.
Zheng and R. J. Zemp, Small, 2016, 12, 371-380.
27 A. Jana, K. S. P. Devi, T. K. Maiti and N. P. Singh, Journal of
the American Chemical Society, 2012, 134, 7656-7659.
28 Y. Cai, W. Si, W. Huang, P. Chen, J. Shao and X. Dong, Small,
2018, 1704247.
Acknowledgements
The work was supported by the NNSF of China (61604071,
61525402, 61775095, 61520106015), Jiangsu Provincial key
research and development plan (BE2017741), Natural Science
Foundation of Jiangsu Province (BK20161012), and Six talent
peak innovation team in Jiangsu Province (TD-SWYY-009).
29 G. Liu, J. Zou, Q. Tang, X. Yang, Y. Zhang, Q. Zhang, W. Huang,
P. Chen, J. Shao and X. Dong, ACS Applied Materials &
Interfaces, 2017, 9, 40077-40086.
30 H. S. Jung, J.-H. Lee, K. Kim, S. Koo, P. Verwilst, J. L. Sessler, C.
Kang and J. S. Kim, Journal of the American Chemical Society,
2017, 139, 9972-9978.
31 Y. Li, T. Wen, R. Zhao, X. Liu, T. Ji, H. Wang, X. Shi, J. Shi, J.
Wei, Y. Zhao, X. Wu and G. Nie, ACS Nano, 2014, 8, 11529-
Notes and references
11542.
32 M. Kaur and D. H. Choi, Chemical Society Reviews, 2015, 44
,
1
2
3
4
5
D. Ding, K. Li, B. Liu and B. Z. Tang, Accounts Chem. Res.,
2013, 46, 2441-2453.
P. Carmeliet and R. K. Jain, Nature Reviews Drug Discovery,
2011, 10, 417-427.
D. Peer, J. M. Karp, S. Hong, O. C. Farokhzad, R. Margalit and
R. Langer, Nature Nanotechnology, 2007, 2, 751.
L. Cheng, C. Wang, L. Feng, K. Yang and Z. Liu, Chem. Rev.,
2014, 114, 10869-10939.
W. Fan, P. Huang and X. Chen, Chemical Society Reviews,
2016, 45, 6488-6519.
58-77.
33 Y. Li, P. Sonar, L. Murphy and W. Hong, Energy
&
Environmental Science, 2013, 6, 1684-1710.
34 K. Pu, J. Mei, J. V. Jokerst, G. Hong, A. L. Antaris, N.
Chattopadhyay, A. J. Shuhendler, T. Kurosawa, Y. Zhou, S. S.
Gambhir, Z. Bao and J. Rao, Advanced Materials, 2015, 27
,
5184-5190.
35 Y. Cai, W. Si, Q. Tang, P. Liang, C. Zhang, P. Chen, Q. Zhang,
W. Huang and X. Dong, Nano Research, 2017, 10, 794-801.
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 9 of 9
Journal of Materials Chemistry B
Journal Name
36 P. Liang, Y. Wang, P. Wang, J. Zou, H. Xu, Y. Zhang, W. Si and
ARTICLE
View Article Online
DOI: 10.1039/C8TB03185A
X. Dong, Nanoscale, 2017, 9, 18890-18896.
37 S. Qu and H. Tian, Chemical Communications, 2012, 48
,
3039-3051.
38 G. Lin, Y. Qin, J. Zhang, Y.-S. Guan, H. Xu, W. Xu and D. Zhu,
Journal of Materials Chemistry C, 2016, 4, 4470-4477.
39 N. Shi, Y. Shi, J. Shao, X. Yang, X. Zhang, Y. Zhang, U. F.
Warsame, J. Shao and X. Dong, Dyes and Pigments, 2019,
160, 683-691.
40 W. Adam, G. Fragale, D. Klapstein, W. M. Nau and J. Wirz,
Journal of the American Chemical Society, 1995, 117, 12578-
12592.
41 J. Karpinska, B. Starczewska and H. P. Tarasiewicz, Analytical
Sciences, 1996, 12, 161-170.
42 S. P. Massie, Chem. Rev., 1954, 54, 797-833.
43 J. Zhao, W. Wu, J. Sun and S. Guo, Chemical Society Reviews,
2013, 42, 5323-5351.
44 Y.-J. Cheng, S.-Y. Yu, S.-C. Lin, J. T. Lin, L.-Y. Chen, D.-S. Hsiu,
Y. S. Wen, M. M. Lee and S.-S. Sun, Journal of Materials
Chemistry C, 2016, 4, 9499-9508.
45 Y. Hua, L. T. L. Lee, C. Zhang, J. Zhao, T. Chen, W.-Y. Wong,
W.-K. Wong and X. Zhu, Journal of Materials Chemistry A,
2015, 3, 13848-13855.
46 M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S.
Masamune, W. R. Roush and T. Sakai, Tetrahedron Letters,
1984, 25, 2183-2186.
47 T. Ben Halima, W. Zhang, I. Yalaoui, X. Hong, Y.-F. Yang, K. N.
Houk and S. G. Newman, Journal of the American Chemical
Society, 2017, 139, 1311-1318.
48 W. Shao, S. J. Kaldas and A. K. Yudin, Chemical science, 2017,
8
, 4431-4436.
49 A. L. Antaris, H. Chen, K. Cheng, Y. Sun, G. Hong, C. Qu, S.
Diao, Z. Deng, X. Hu and B. Zhang, Nature materials, 2016,
15, 235.
50 Y. Sun, C. Qu, H. Chen, M. He, C. Tang, K. Shou, S. Hong, M.
Yang, Y. Jiang and B. Ding, Chemical Science, 2016, 7, 6203-
6207.
51 M. Hamidi, A. Azadi and P. Rafiei, Advanced drug delivery
reviews, 2008, 60, 1638-1649.
52 C. Szymanski, C. Wu, J. Hooper, M. A. Salazar, A. Perdomo, A.
Dukes and J. McNeill, The Journal of Physical Chemistry B,
2005, 109, 8543-8546.
53 Y. Yan, Q. Yang, J. Wang, H. Jin, J. Wang, H. Yang, Z. Zhou, Q.
Tian and S. Yang, Journal of Materials Chemistry B, 2017, 5,
382-387.
54 Y. Cao, H. Dong, Z. Yang, X. Zhong, Y. Chen, W. Dai and X.
Zhang, ACS Applied Materials & Interfaces, 2017, 9, 159-166.
55 L. Xia, X. Kong, X. Liu, L. Tu, Y. Zhang, Y. Chang, K. Liu, D.
Shen, H. Zhao and H. Zhang, Biomaterials, 2014, 35, 4146-
4156.
56 K. Ding, Y. Zhang, W. Si, X. Zhong, Y. Cai, J. Zou, J Shao, Z.
Yang and X. Dong, Appl Mater Interfaces. 2018, 10, 238-247.
57 X. J. Song, R. Zhang, C. Liang, Q. Chen, H. Gong and Z. Liu,
Biomaterials, 2015, 57, 84-92.
58 Y. Xu, M. Zhao, L. Zou, L. Wu, M. Xie, T. Yang, S. Liu, W.
Huang and Q. Zhao, ACS Appl Mater Interfaces, 2018, 10
44324-44335.
,
59 Q. Miao, C. Xie, X. Zhen, Y. Lyu, H. Duan, X. Liu, J. V. Jokerst,
K. Pu, Nature Biotechnology, 2017, 35, 1102-1110.
60 P. Liang, X. Huang, Y. Wang, D. Chen, C. Ou, Q. Zhang, J.
Shao, W. Huang, X. Dong, ACS Nano, 2018, 12, 11446-11457.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
Please do not adjust margins