A Phototheranostic Strategy to Continuously Deliver Singlet Oxygen in the Dark and Hypoxic Tumor Microenvironment

Article abstract of DOI:10.1002/anie.201914384

Continuous irradiation during photodynamic therapy (PDT) inevitably induces tumor hypoxia, thereby weakening the PDT effect. In PDT-induced hypoxia, providing singlet oxygen from stored chemical energy may enhance the cell-killing effect and boost the therapeutic effect. Herein, we present a phototheranostic (DPPTPE?PEG-Py NPs) prepared by using a 2-pyridone-based diblock polymer (PEG-Py) to encapsulate a semiconducting, heavy-atom-free pyrrolopyrrolidone-tetraphenylethylene (DPPTPE) with high singlet-oxygen-generation ability both in dichloromethane and water. The PEG-Py can trap the ¹O₂ generated from DPPTPE under laser irradiation and form a stable intermediate of endoperoxide, which can then release ¹O₂ in the dark, hypoxic tumor microenvironment. Furthermore, fluorescence-imaging-guided phototherapy demonstrates that this phototheranostic could completely inhibit tumor growth with the help of laser irradiation.

Full text of DOI:10.1002/anie.201914384

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
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Accepted Article
Title: A simple phototheranostics strategy to continuously deliver
singlet oxygen in dark and hypoxic tumor microenvironment
Authors: Jianhua Zou, Jianwei Zhu, Zhen Yang, Ling Li, Wenpei Fan,
Liangcan He, Wei Tang, Liming Deng, Jing Mu, Yuanyuan
Ma, Yaya Cheng, Wei Huang, Xiaochen Dong, and Xiaoyuan
Chen
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201914384
Angew. Chem. 10.1002/ange.201914384
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10.1002/anie.201914384
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A simple phototheranostics strategy to continuously deliver
singlet oxygen in dark and hypoxic tumor microenvironment
Jianhua Zou, Jianwei Zhu, Zhen Yang*, Ling Li, Wenpei Fan, Liangcan He, Wei Tang, Liming Deng, Jing
Mu, Yuanyuan Ma, Yaya Cheng, Wei Huang, Xiaochen Dong*, Xiaoyuan Chen*
Abstract: Continuous irradiation during photodynamic therapy (PDT)
process inevitably induces tumor hypoxia, thereby weakening the
PDT effect. In the PDT induced temporary hypoxia, sustainably
providing singlet oxygen from stored chemical energy may enhance
the cell killing effect and boost the phototheranostics. Herein, we
present a phototheranostics (DPPTPE@PEG-Py NPs) by using 2-
extremely low. Thus, O2 shortage in tumors is responsible for
significantly reduced antitumor efficacy of PDT, especially in
those cases that require continuous treatment. Therefore, the
hypoxia of tumor microenvironment (TME) is universally
considered as the “Achilles’ heel” of PDT. [11,12]
To reverse the deficiency of oxygen in TME for sustainable
PDT, considerable efforts were made to find efficient and safe
strategies to refuel O2 in TME to boost the PDT efficacy, such as
delivering oxygen saturated perfluorocarbons to TME, fabricating
inorganic nanoenzymes (such as MnO2 nanoparticles and
nanosheets) to generate oxygen in the acidic TME. However,
some concerned issues hinder their practical applications in the
clinic. For example, for the fluorocarbons system, the inevitable
oxygen leakage from fluorocarbons during the longtime blood
circulation usually induces inefficient oxygen delivery. Although
the nanoenzymes could produce oxygen effectively in the tumor
region, the superfluous metal ion release may bring about acute
toxicity, oxidative stress and oxidative damage to main organs. By
looking back on the application of PDT in the clinic, fractionated
PDT provides time for the replenishment of cellular oxygen and
minimize photoinduced hypoxia.[13-15] In continuous PDT, the
chemically collecting and then sustained releasing of partial
singlet oxygen from photosensitized generation may enhance the
cell killing effect in the PDT induced temporary hypoxia and boost
the phototheranostics.
pyridone based diblock polymer (PEG-Py) to encapsulate
a
semiconducting heavy atom free pyrrolopyrrolidone-
tetraphenylethylene (DPPTPE) with high singlet oxygen generation
ability both in dichloromethane and water. In the phototheranostics,
the designed PEG-Py can trap the 1O2 generated from DPPTPE under
laser irradiation and form a stable intermediate of endoperoxide,
which can then chemically release 1O2 in both dark and hypoxic tumor
microenvironment. In comparison with DSPE-PEG encapsulated
DPPTPE (DPPTPE@DSPE-PEG), much lower half maximum
inhibitory concentration (IC50) was observed in four types of cancer
cell lines, including HeLa, HCT-116, A549 and MCF-7 under laser
irradiation after being uptaken by DPPTPE@PEG-Py NPs.
Furthermore, the fluorescence imaging guided phototherapy study
demonstrates that our designed phototheranostics could completely
inhibit the tumor growth with the help of laser. This study provides a
paradigm to develop highly efficient photosensitizers with
photodynamic and photothermal capability for personalized cancer
therapy.
Photodynamic therapy (PDT) is a promising strategy which can
transform nontoxic oxygen to toxic reactive oxygen species
(ROS) for cancer treatment. As a result, great efforts have been
devoted to advance PDT owing to its unique features, including
the lack of initiating resistance, low systemic toxicity, and minimal
invasiveness.[1-5] To date, a majority of existing PDT systems
In recent years, semiconducting materials have been widely
used for biomedical applications, including imaging and
therapy.[16-20] For example, Li et al. designed an organic
semiconducting pro-nanostimulant for NIR photoactivatable
cancer immunotherapy.[16] In addition, a semiconducting polymer
based pro-nanoenzyme was fabricated to improve therapeutic
specificity.[17] 2-Pyridone group is able to react with singlet oxygen
to form endoperoxides of 2-pyridone. The resulting product can
undergo thermal cycloreversion to release singlet oxygen in vivo,
re-producing 2-pyridone module. Thus, the strategy of using 2-
pyridone based polymer to encapsulate photosensitizer (PS)
could be an attractive approach to fabricating desirable enhanced
PDT regents (scheme 1). In this study, we developed an
intelligent phototheranostics with the capability of enhanced PDT.
The phototheranostics (DPPTPE@PEG-Py NPs) was obtained
by nanoprecipitation of a 2-pyridone based amphiphilic diblock
polymer (PEG-Py) and a newly synthesized semiconducting
pyrrolopyrrolidone-tetraphenylethylene (denoted as DPPTPE)
with a high 1O2 quantum yield of 69%. PEG-Py contains abundant
2-pyridone pendants for capturing and then releasing singlet
oxygen in the dark cycle. Since DPPTPE is a heavy atom free PS,
it would have negligible dark toxicity in vivo. As a result, the
photodynamic process of DPPTPE@PEG-Py NPs keeps
producing 1O2 under the laser irradiation even when O2 supply is
depend highly on O2 concentration and involves
a huge
consumption of O2. [6-10] Unfortunately, due to insufficient O2 in
blood supply in the tumor region and aggressive proliferation of
cancer cells, O2 concentration, however, varies from different
locations in solid tumors, with some interior regions being
[*]
Dr. J. Zou, Dr. J. Zhu, Prof. W. Huang, Prof. X. Dong
Key Laboratory of Flexible Electronics (KLOFE) & Institute of Advanced
Materials (IAM), Nanjing Tech University (NanjingTech), 30 South Puzhu
Road, Nanjing, 211800, China. E-mail: iamxcdong@njtech.edu.cn
Dr. J. Zou, Dr Z. Yang, Dr W. Fan, Dr L. Li, Dr. L. He, Dr W. Tang, Dr Y.
Cheng, Dr L. Deng, Dr J. Mu, Dr Y. Ma, Dr. X. Chen
Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National
Institute of Biomedical Imaging and Bioengineering (NIBIB), National
Institutes of Health (NIH), Bethesda, MD 20892, USA. Email:
zhen.yang3@nih.gov; shawn.chen@nih.gov
Prof. W. Huang
Shaanxi Institute of Flexible Electronics (SIFE), Northwestern Polytechnical
University (NPU), 127 West Youyi Road, Xi'an 710072, China
1
stopped. The chemical storage of O2 was also demonstrated in
the light as well as dark cycles. The DPPTPE@PEG-Py NPs also
showed
photothermal
effect,
providing
synergistic
Supporting information for this article is given via a link at the end of the
document.
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10.1002/anie.201914384
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photothermal/photodynamic
therapy.
The
enhanced
phototheranostic effect was demonstrated by four different cancer
cell lines (HeLa, HCT-116, A549 and MCF-7). Furthermore,
thanks to the large Stokes shift of DPPTPE, in vivo fluorescence
imaging with low background guided the phototherapy experiment,
in which the tumors treated with DPPTPE@PEG-Py NPs were
completely inhibited without any adverse effects to main organs,
such as heart, kidneys, liver, lung and spleen. This study
demonstrates that DPPTPE@PEG-Py NPs can be a powerful
candidate for enhanced phototherapy and also provides a
paradigm to develop highly efficient PSs.
Figure 1. (a) Normalized absorbance and fluorescence spectra of DPPTPE in
THF and NPs in water; (b) TEM and DLS of DPPTPE@PEG-Py NPs; (c) Singlet
oxygen generation of DPPTPE in DCM with DPBF as a probe; (d) Singlet
oxygen generation of DPPTPE@PEG-Py NPs with SOSG as a probe.
Then, we demonstrated the continuous PDT property of
DPPTPE@PEG-Py NPs by investigating the reversible singlet
oxygen capture and release process under different conditions,
including normoxia and hypoxia. For the DPPTPE@DSPE-PEG
group under normoxic condition, the fluorescence intensity of
SOSG increased by 3-fold after 1 min irradiation, indicating
effective 1O2 generation. While in the dark, negligible fluorescence
enhancement was observed (figure S12). In contrast, the
fluorescence intensity of SOSG after irradiation of
DPPTPE@PEG-Py for 1 min continued to increase over time in
the dark even without irradiation (figure 2a and 2b). This can be
explained by the fact that singlet oxygen can be captured by the
2-pyridone to form an endoperoxide during light irradiation and is
then chemically released without irradiation (scheme 1). PEG-Py
with abundant benzene groups is able to reduce the π-π stacking
of DPPTPE more efficiently than DSPE-PEG, thereby reducing
the ACQ. The amount of generated 1O2 of DPPTPE@PEG-Py
NPs is more than that of DPPTPE@DSPE-PEG NPs. Negligible
fluorescence enhancement was observed after 45 min, indicating
the complete release of 1O2 (half-life of 1O2 release was
approximately 1.8 min). In addition, we studied whether the
DPPTPE@PEG-Py NPs can still generate 1O2 under hypoxic
condition. Thus, the experiment was conducted by irradiating
such solution for 1 min. Then the solution was purged with N2 for
45 min. Compared with DPPTPE@DSPE-PEG, DPPTPE@PEG-
Py NPs still showed 1O2 generation when the oxygen was
insufficient (figure 2c and 2d), indicating that the DPPTPE@PEG-
Py NPs could release 1O2 under hypoxic condition, as well ( half-
life of 1O2 release was 1.6 min).
Scheme 1. Schematic of light responsive PEG-Py with 1O2 capture and release
ability for phototheranostics.
General synthetic routes of DPPTPE and PEG-Py are shown in
supporting information (figure S1, S2). DPPTPE was prepared
through a C-H activation reaction by reacting DPP and Br-
substituted tetraphenylethylene in the presence of anhydrous
K2CO3 and PivOH with Pd(OAc)2 as the catalyst in anhydrous
DMA solution.[26] The reversible addition fragmentation chain
transfer (RAFT) polymerization method was used for the
synthesis of the chlorinated groups based copolymers. Then 2-
pyridone was conjugated onto the polymer with the catalysis of
hexaoxacyclooctadecane and K2CO3 in DMF to form PEG-Py.
The structure of DPPTPE was characterized by 1HNMR, 13CNMR
and mass spectroscopy (figure S3-S7).
DPPTPE in THF exhibited maximum absorbance at 576 and
618 nm while a red shift was observed after the PEG-Py coated
DPPTPE was dispersed in water (589 and 640 nm).
Simultaneously, DPPTPE@PEG-Py NPs showed a large Stokes
shift (163 nm) and strong NIR fluorescence, which is helpful for in
vivo NIR fluorescence imaging (figure 1a). Transmission electron
microscope (TEM) and dynamic light scattering (DLS) indicated
that size distribution of DPPTPE@PEG-Py NPs was from 52 to
128 nm (figure 1b), which is similar to that of DPPTPE@DSPE-
PEG NPs (figure S8). High 1O2 generation is the indispensable
property for a PS to achieve effective PDT. The 1O2 quantum yield
(QY) of DPPTPE in dichloromethane (DCM) was quantified by
using the commercial PDT agent methylene blue (MB) as a
standard substance (ΦΔ = 57% in DCM). The 1O2 QY of DPPTPE
was calculated to be as high as 69% (figure 1c, S9 and S10). To
investigate the singlet oxygen generation ability of
DPPTPE@PEG-Py NPs, singlet oxygen sensor green (SOSG)
was used in the experiments (figure 1d, S11). With laser
irradiation, the fluorescence intensity of SOSG in the presence of
DPPTPE@PEG-Py NPs increased rapidly while that of SOSG
alone was negligible.
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Figure 2. Singlet oxygen capture and release of DPPTPE@PEG-Py NPs with
irradiation for 1 min and then in dark for 44 min: (a-b) under normoxia condition;
(c-d) under hypoxia condition with N2 bubbling after 1 min irradiation.
Combining PDT with photothermal therapy (PTT) is
considered to be
a
superior way to achieve better
phototherapeutic efficacy. Photothermal conversion efficiency
was investigated by heating and cooling DPPTPE@PEG-Py NPs
(figure S13a, 13b). A temperature elevation of 17.6 oC can be
observed with laser irradiation, promising the potential for mild
photothermal therapy of DPPTPE@PEG-Py NPs. The
photothermal conversion efficiency of such NPs is calculated to
be 30.6%. A concentration dependent temperature elevation can
be observed (figure S13c). The repeated photothermal
conversion experiments were performed to investigate the
thermal stability (figure S13d). It is worth pointing out that such
NPs exhibit excellent photothermal stability after being repeated
for at least 5 cycles and no decay was observed in the
absorbance spectra (figure S14).
High singlet oxygen generation ability and photothermal
conversion efficiency contribute to the high cytotoxicity of PS.[27]
To further confirm the phototherapy efficacy of DPPTPE, four
different cell lines, HeLa, HCT-116, A549 and MCF-7 were tested.
The cellular uptake of NPs was performed by CLSM. Enhanced
ROS generation with DCF as a probe can be detected for
DPPTPE@PEG-Py NPs due to the enhanced fluorescence
intensity, compared with that of DPPTPE@DSPE-PEG (figure 3a,
3b). Furthermore, MTT assay indicated neither DPPTPE@DSPE-
PEG nor DPPTPE@PEG-Py NPs was toxic as the cell viabilities
of the four groups were similar to those of the control groups
without light irradiation (figure S15). In contrast, considerably high
phototoxicity of DPPTPE@PEG-Py NPs can be detected on the
four different cell lines with laser irradiation (figure 3c-3f), which is
superior to those treated with DPPTPE@DSPE-PEG (figure 3c-
3f). These results suggest that heavy atom free DPPTPE with
high singlet oxygen generation ability are capable of inhibiting cell
proliferation. Meanwhile, DPPTPE@PEG-Py NPs with singlet
oxygen capture and release ability are superior to
DPPTPE@DSPE-PEG, indicating that DPPTPE@PEG-Py NPs
are more suitable for cancer treatment.
Figure 3. Cellular uptake of (a) DPPTPE@DSPE-PEG; (b) DPPTPE@PEG-Py
NPs in HeLa, HCT-116, A549 and MCF-7 cells, scale bar: 10 μm; MTT assay
of (c) HeLa; (d) HCT-116; (e) A549 and (f) MCF-7 with treatment of
DPPTPE@DSPE-PEG and DPPTPE@PEG-Py NPs with laser irradiation (660
nm, 0.1 W/cm2). (**p＜0.01 and ***p＜0.001 compared with the control group)
Fluorescence
imaging
was
used
to
monitor
DPPTPE@PEG-Py NPs accumulation in HeLa tumor for
phototheranostics (Figure 4b). The fluorescence intensity of
tumor increased after injection of DPPTPE@PEG-Py NPs and
reached the peak at 6 h post-injection (figure S16). After imaging
study, the mice were sacrificed, followed by the measurement of
the intensity of tumor, heart, liver, spleen, lung and kidneys. It was
found that these NPs still accumulated in the tumor even at 24 h
after injection and the fluorescence intensity of the tumor
remained to be the strongest, followed by liver and kidneys (figure
S17).
To further investigate the PDT and PTT synergistic
therapeutic efficacy of DPPTPE@PEG-Py NPs in vivo, 20 nude
mice bearing HeLa tumors were divided into four groups as PBS
+ laser, DPPTPE@DSPE-PEG, DPPTPE@PEG-Py NPs and
DPPTPE@PEG-Py NPs + laser groups. To characterize the
photothermal ability of DPPTPE@PEG-Py NPs in vivo, the
tumors were irradiated with laser and the thermal images were
captured by an IR camera at 6 h post-injection of DPPTPE@PEG-
Py NPs or DPPTPE@DSPE-PEG(figure S18a). The temperature
of the group treated with DPPTPE@PEG-Py NPs only increased
slightly compared to that of DPPTPE@DSPE-PEG (figure S18b).
Then the mice were observed for 18 days and the survival was
shown in figure S19. The tumor volume of the group treated with
DPPTPE@PEG-Py NPs is similar to that of the control group,
indicating the negligible dark toxicity of DPPTPE@PEG-Py NPs
(figure 4c). In contrast, the tumor volume, however, has been
significantly suppressed for the illumination groups. And the tumor
volume of the group incubated with DPPTPE@PEG-Py NPs is
much smaller than that of DPPTPE@DSPE-PEG, suggesting the
high phototoxicity of the NPs. It is worth noting that the tumors
Furthermore, UV-Vis spectrometry was applied to study the
pharmacokinetics after intravenous administration of NPs.[27] The
mean plasma concentration-time profiles of DPPTPE@PEG-Py
NPs and DPPTPE@DSPE-PEG NPs (figure 4a) were used to
calculate the main pharmacokinetic parameters by a non-
compartmental model (Table 1). The values of the AUC(0-t)/AUC(0-
over 80% suggested that the blood collection time point was
∞)
suitable for the pharmacokinetic study. The data showed that the
DPPTPE@DSPE-PEG was eliminated much more quickly than
DPPTPE@PEG-Py NPs, with terminal elimination half-lives (T1/2
)
being 4.31 for DPPTPE@DSPE-PEG and 12.13 for
h
h
DPPTPE@PEG-Py, respectively. The CLz of DPPTPE@DSPE-
PEG NPs was 0.043 L/h/kg while the value of DPPTPE@PEG-Py
NPs was 0.018 L/h/kg, showing that the DPPTPE@PEG-Py NPs
were eliminated more slowly than DPPTPE@DSPE-PEG NPs.
These results demonstrate that the PEG-Py could extend the
residence time and promote its treatment effects.
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10.1002/anie.201914384
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even disappeared after treatment with DPPTPE@PEG-Py NPs
Table 1 Non-compartmental pharmacokinetic parameters of
DPPTPE@DSPE-PEG or DPPTPE@PEG-Py NPs in rat plasma
after a single intravenous administration at a dose of 5 mg/kg
(n=6/group)
1
plus laser, indicating that continuous delivery of O2 show better
phototherapy efficacy. Afterwards, all the mice were further
observed for another 10 days, no recurrence of the tumor was
observed. The mouse body weight was recorded every two days
and no significant change in three groups was observed,
demonstrating the biosafety of NPs treatment (figure 4d). The
hematoxylin and eosin (H&E)- staining showed that the tumor
cells subjected to the DPPTPE@PEG-Py NPs suffered from the
largest extent of apoptosis and necrosis (figure 4e-g). After the
treatment, all the mice were sacrificed and the tumors were
collected as well as the normal organs, including heart, spleen,
liver, lung and kidneys. According to the H&E staining images, no
abnormal cell morphology can be found between control and
DPPTPE@PEG-Py NPs or DPPTPE@DSPE-PEG NPs treated
groups in the normal organs (figure S20). In addition, the blood
index, renal function and liver function of the mice injected with
DPPTPE@PEG-Py NPs or DPPTPE@ DSPE-PEG NPs were the
same as those in the control group (Table S1). The results
indicated that DPPTPE@PEG-Py NPs could inhibit tumor growth
effectively without side effects towards normal organs, suggesting
Parameter
DPPTPE@DSPE-PEG-
DPPTPE@PEG-Py
T1/2
4.31
12.13
484.4
542.2
9.55
AUC(0-t)
AUC(0-∞)
MRT(0-t)
VZ
226.9
230.9
4.22
0.27
0.32
CLZ
0.043
0.018
T1/2: terminal elimination half-life; AUC(0−t): the area under the
curve from zero to the last measurable plasma concentration
point; AUC(0-∞): the area under the curve from zero to infinity;
MRT(0-t)
: mean residence time; VZ: apparent volume of
distribution; CLz: systemic clearance.
In summary,
a semiconducting heavy atom free DPPTPE
compound with high singlet oxygen generation ability and large
Stokes shift of 163 nm has been designed and prepared. 2-
pyridione functionalized PEG-Py has been fabricated to
encapsulate DPPTPE for reversible capture and release of 1O2 for
continuous PDT. In the light cycle, the endoperoxide of 2-pyridone
can be generated accompanied by singlet oxygen. In the dark
cycle, the endoperoxide undergoes thermal cycloreversion to
deliver singlet oxygen, regenerating the 2-pyridone module. The
as-prepared DPPTPE@PEG-Py NPs work under both normoxic
and hypoxic conditions and are more efficacious in tumor killing
than that of DPPTPE@DSPE-PEG NPs. Furthermore, in vivo
their good biocompatibility[28-39]
.
fluorescence
imaging
guided
phototherapy
suggests
DPPTPE@PEG-Py NPs with high phototoxicity as well as low
dark toxicity are potential candidates for phototheranostics.
Acknowledgements
The work was supported by the NNSF of China (61525402,
61775095, 21704043, 81872255), Jiangsu Provincial key
research and development plan (BE2017741), Six talent peak
innovation team in Jiangsu Province (TD-SWYY-009, WSW041),
the NSF of Jiangsu Province (BK20170990, 17KJB150020), Key
medical talents fund of Jiangsu Province (2016KJQWZDRC-03)
and the China Scholarship Council and intramural research
program of the National Institute of Biomedical Imaging and
Bioengineering (NIBIB), National Institutes of Health (NIH).
Figure 4. (a) Mean plasma time dependent drug concentration curves of
DPPTPE@PEG-Py NPs or DPPTPE@DSPE-PEG NPs after single
a
intravenous administration at a dose of 5 mg/kg in rat; (b) In vivo fluorescence
imaging of HeLa tumor bearing mouse for different period of time; (c) Tumor
volume change (*p < 0.05, **p < 0.01 and ***p < 0.001 compared with the control
group); (d) Body weight change during the treatment. H&E stained pictures of
Conflict of interest
The authors declare no conflict of interest.
the tumor cells. (e) PBS
DPPTPE@DSPE-PEG + laser. Scale bar: 100 μm.
+ laser; (f) DPPTPE@PEG-Py NPs; (g)
Keywords: heavy atom free • DPPTPE • continuous PDT;
theranostics
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10.1002/anie.201914384
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Continuous
Photodynamic
therapy：The “marriage”
Jianhua Zou, Jianwei Zhu,
Zhen Yang*, Ling Li,
Wenpei Fan, Liangcan He,
Wei Tang, Liming Deng,
Jing Mu, Yuanyuan Ma,
Yaya Cheng, Wei Huang,
Xiaochen Dong*, Xiaoyuan
Chen*
of
a heavy atom free
DPPTPE (ΦΔ = 69%) and
PEG-Py with 2-pyridone
for reversibly capturing
and releasing 1O2 can
improve the lifetime of 1O2
under both normoxic and
hypoxic conditions, thus
improve the phototherapy
Page No. – Page No.
A
simple
phototheranostics
strategy to continuously
deliver singlet oxygen in
dark and hypoxic tumor
microenvironment
efficacy
of
DPPTPE@PEG-Py NPs,
compared with that of
DPPTPE@DSPE-PEG
NPs as control.
This article is protected by copyright. All rights reserved.