A Water-Soluble, NIR-Absorbing Quaterrylenediimide Chromophore for Photoacoustic Imaging and Efficient Photothermal Cancer Therapy

Article abstract of DOI:10.1002/anie.201810541

Precision phototheranostics, including photoacoustic imaging and photothermal therapy, requires stable photothermal agents. Developing such agents with high stability and high photothermal conversion efficiency (PTCE) remains a considerable challenge. Her

Full text of DOI:10.1002/anie.201810541

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Accepted Article
Title: A Water-soluble, NIR-absorbing Quaterrylenediimide
Chromophore for Photoacoustic Imaging and Efficient
Photothermal Cancer Therapy
Authors: Klaus Müllen, Chang Liu, Shaobo Zhang, Jianhao Li, Jie Wei,
and Meizhen Yin
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201810541
Angew. Chem. 10.1002/ange.201810541
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10.1002/anie.201810541
Angewandte Chemie International Edition
COMMUNICATION
A Water-soluble, NIR-absorbing Quaterrylenediimide Chromophore
for Photoacoustic Imaging and Efficient Photothermal Cancer
Therapy
Chang Liu,[a] Shaobo Zhang,[a] Jianhao Li,[a] Jie Wei,[a] Klaus Müllen[b] and Meizhen Yin*[a]
Abstract: Precision phototheranostics, including photoacoustic
imaging and photothermal therapy, requires stable photothermal
agents. Developing photothermal agents with high stability and high
photothermal conversion efficiency (PTCE) remains a considerable
challenge in biomedical applications. Herein, we introduce a new
photothermal agent based on water-soluble quaterrylenediimide
(QDI) that can self-assemble into nanoparticles (QDI-NPs) in
aqueous solution. Incorporation of polyethylene glycol (PEG) into the
QDI core significantly enhances both physiological stability and
biocompatibility of QDI-NPs. These highly photostable QDI-NPs
exhibit exciting advantages including intense absorption in the near-
infrared (NIR) and high PTCE of up to 64.7 ± 4%. This is higher than
that of many other organic photothermal agents, such as graphene
or commercial indocyanine green (ICG). Their small size of
approximately 10 nm enables a sustained retention in deep tumor
sites and at the same time proper clearance from the body. QDI-NPs
allow high-resolution photoacoustic imaging and efficient 808 nm
laser-triggered photothermal therapy of cancer in vivo. The current
study opens a promising way for precision phototheranostics.
Recently, a terrylenendiimide-based photothermal agent
has been investigated under 660 nm laser irradiation.[7] However,
the wavelength of 660 nm defines a serious limitation for clinical
applications. The core-expanded quaterrylenediimide (QDI)[8]
possesses an intense absorption at a wavelength of 808 nm
which holds a great potential for deep-tissue penetration and
minimal optical interference in phototheranotics. Because of the
poor water solubility brought about by its large unpolar and rigid
π-system,[9] QDI derivatives have never been employed in
phototheranostics. Herein, we exploited the NIR-absorbing,
water-soluble QDI-cored star-macromolecule P(QDI) (Figure 1A)
containing multi-poly(ethylene glycol) (PEG) chains for
phototheranostics in vivo.
Organic molecules have been shown to assemble to
nanoparticles,[10] among which ultra-small ones (about 10 nm)
exhibited proper clearance from the body and thus furnished
high biosecurity.[11] Further, ultra-small nanoparticles display
prolonged blood circulation time together with an enhanced
permeability and retention (EPR) effect, and thus lead to deep
tumor permeation.[12] In this study, aiming at cancer
phototheranostic applications, photostable QDI-NPs offer distinct
advantages such as: i) a high PTCE of up to 64.7 ± 4%, which is
higher than the values of most organic photothermal agents,[13]
and also higher than that of most inorganic agents;[4,14] ii) a
diameter of 10.8 ± 1.4 nm, leading to an efficient tumor-targeting,
excellent metabolism, and low biotoxicity during prolonged blood
circulation; iii) the incorporation of poly(ethylene glycol) (PEG),
which is approved by Food and Drug Administration and greatly
enhances biocompatibility of QDI-NPs. Thus, QDI-NPs can
enable pthototheranostic applications including sensitive PAI
and efficient PTT in vivo.
Phototheranostics has attracted considerable attention as a
compelling platform in cancer photoacoustic imaging (PAI) and
photothermal therapy (PTT).[1] Due to the deep penetration and
minimal invasiveness through tissue, near-infrared (NIR, 690-
900 nm) light has been considered as ideal source to trigger a
photothermal effect.[2] Therefore, NIR-absorbing agents have
been widely investigated in cancer phototheranostics.[3] However,
the design of highly efficient photothermal agents still faces
many challenges.[4] NIR-absorbing organic agents are made
from extended conjugated π-systems and suffer from oxidative
decomposition, resulting in photobleaching and subsequent
insufficient photothermal conversion efficiency (PTCE).[5] Current
The QDI molecule was synthesized from perylene
monoimide in a four-step process by bromination, Suzuki cross-
coupling, and cyclodehydrogenation under basic conditions
according to the literature[15] (Figure S4 in the supporting
information (SI)). Subsequently, bromination of QDI with an
excess of molecular bromine afforded the hexabrominated QDI-
1 (Figure 1A). Then, phenoxylation with 4-(2-hydroxyethyl)
phenol occurred at the four most reactive bromides closest to
inorganic photothermal agents
,
apart from unknown
degradation pathways, raise serious biosafety concerns.[6]
Therefore, it is of vital significance to develop new NIR-
absorbing photothermal agents.
[a]
[b]
C. Liu, S. Zhang, J. Li, Prof. J. Wei, Prof. M. Yin
Beijing Advanced Innovation Center for Soft Matter Science and
Engineering, BAIC-SM, Beijing Laboratory of Biomedical
Materials, Beijing University of Chemical Technology, Beijing,
100029 (China)
the
imide
positions
of
QDI-1,
resulting
in
the
tetra(hydroxyethylphenoxy) substituted QDI-2. QDI-2 was further
subjected to fourfold esterification with carboxy-functionalized
PEG2000 (MnPEG ≈ 2000) to obtain the targeted macromolecule
P(QDI).
P(QDI) with a high water-solubility (>7.5 mg·mL-1) self-
assembled into QDI-NPs in aqueous solutions (Figure 1A). The
morphology of QDI-NPs was first studied by high-resolution
transmission electron microscopy (HRTEM), which exhibited
well-defined spherical particles (Figure 1B). The HRTEM images
provided an average diameter of the QDI-NPs as 10.8 ± 1.4 nm.
E-mail: yinmz@mail.buct.edu.cn
Prof. K. Müllen
Max Planck Institute for Polymer Research; Institute of Physical
Chemistry, Johannes Gutenberg University Mainz, Duesbergweg
10-14, Mainz, D-55128 (Germany)
Supporting information for this article is given via a link at the end
of the document.
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10.1002/anie.201810541
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COMMUNICATION
Figure 1. Preparation and characterization of QDI-NPs. (A) Synthesis of the targeted product P(QDI) and the self-assembly of P(QDI) to form QDI-NPs in
aqueous solution. (B) HRTEM images of QDI-NPs. The inset shows a simulated illustration and a magnified image. (C) DLS profile of QDI-NPs. The inset
presents a photograph of QDI-NPs in water. (D) Vis-NIR absorption spectrum of QDI-NPs in water.
This finding could be confirmed by dynamic light scattering
(DLS) (Figure 1C). The sizes of QDI-NPs were monitored by
DLS in phosphate buffered saline (PBS) and deionized water,
respectively. No obvious changes in their size and precipitation
behavior were observed in both solutions after storage at 4 °C
for two weeks, confirming the good chemical and physiological
stability of QDI-NPs in aqueous solutions (Figure S6). This is
essential forreducing risks of adverse effects in vivo. The
absorption spectrum of QDI-NPs in water (Figure 1D) revealed a
high molar extinction coefficient (about 1.3*105 M-1·cm-1)
suggesting a pronounced capability to absorb light energy in NIR.
Weak fluorescence emission at 830 nm and low reactive
oxygen species generation of QDI-NPs were detected after
excitation (Figure S7 and S8) which suggested that vibrational
relaxation may play a major role thus furnishing a useful
photothermal effect. This was tested under NIR laser (808 nm)
irradiation. The solution temperature of QDI-NPs at different
concentrations regularly increased under irradiation as recorded
by thermal images. A high value of 61.7 °C could be recorded in
300 s (Figure 2A and 2B). Furthermore, the solution of QDI-NPs
at a given concentration (150 g·mL-1) was irradiated at different
laser power densities (0.1~1 W·cm-2) revealing significant
temperature increases (Figure S9). Moreover, a steady-state
temperature was recorded through the heating and cooling
Figure 2. Photothermal and photoacoustic properties of QDI-NPs. (A)
Temperature curves of QDI-NPs in PBS solutions at different concentrations.
profiles (Figure S10). The PTCE (η) of the QDI-NPs was
calculated to be 64.7 ± 4% which is higher than the values of
most reported organic photothermal agents.[13] The high PTCE
value of QDI-NPs may be attributed to their tight π-π interactions
thus favoring energy relaxation in nanostructures.[16] Besides,
QDI-NPs maintained an undiminished ability of heating,
unchanged absorption and nanosize after cyclic laser irradiation
(Figure S11) indicating their excellent photostability in water.
Both the strong photothermal effect and excellent photostability
highlight the potential of QDI-NPs for PTT.
(B) Optical photographs and thermal images of QDI-NPs in PBS solutions
after laser irradiation. (C) Photoacoustic spectra of QDI-NPs in PBS solutions.
(D) Photoacoustic images of QDI-NPs as a function of the concentration in a
normalized phantom mold. (E) In vivo photoacoustic images of tumor tissue
(arrows) at different times (left) and the 3D-images (right) at 36 h after the
intravenous injection of QDI-NPs. Scale bars: 3 mm.
Our QDI-NPs were then employed for photoacoustic
diagnosis and visualization of cancer. The photoacoustic spectra
of QDI-NPs were plotted in a normalized phantom mold (Figure
2C). The detected photoacoustic intensities at 800 nm indicate
superior photoacoustic (NIR) properties of QDI-NPs in aqueous
phase (Figure 2D).
A
linear relationship between the
concentrations and the mean photoacoustic signals (R2 = 0.985)
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10.1002/anie.201810541
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COMMUNICATION
was calculated (Figure S12). The positive photoacoustic
property in phantom motivated us to explore the PAI in vivo,
aiming to visualize the location, shape, and size of solid tumors.
Thus, we inspected PAI in 4T1 (murine breast cancer) tumor-
bearing BALB/c mice, and the high-resolution photoacoustic
images were recorded in a time-dependent protocol after
intravenous injection of QDI-NPs (Figure 2E, left). The results
revealed that QDI-NPs passively permeated into the deep tumor
region and reached the highest accumulation at approximately
36 h post-injection during a blood circulation time. The 3D
images of the tumor at 36 h further verified the precision PAI
capability of QDI-NPs (Figure 2E, right). The photoacoustic
intensities of QDI-NPs in the tumor region were determined
(Figure S13). Taking advantage of the intrinsic photothermal
effect, the QDI-NPs can be used as photoacoustic contrast
agents for an efficient visualization of cancer in vivo.
NPs display no cytotoxicity and thus hold promise in PTT
applications. Under laser irradiation for 5 min (808 nm, 1 W·cm-
2), the viability of cancer cells decreased with the increase of
QDI-NPs concentration. A quite low IC50 of 1.7 g·mL-1
demonstrated an efficient PTT of QDI-NPs (Figure 3A).
Live/dead staining further supported the PTT results in vitro
(Figure S15), in which live and dead 4T1 cells were
differentiated by co-staining with PI (red fluorescence; dead
cells) and calcein AM (green fluorescence; living cells) after the
same laser irradiation. Almost all the cells were positive for red
fluorescence after combination of the QDI-NPs and laser
irradiation, thus indicating the cancer cell extinction. The
superior biocompatibility and efficient PTT again characterize
QDI-NPs as remarkable photothermal agents.
The pharmacokinetics and pharmacodynamics of QDI-NPs
were checked in 4T1 tumor-bearing mice. After intravenous (i.v.)
injection of QDI-NPs (5 mg·kg-1), tissue distribution studies
demonstrated that the highest concentrations of QDI-NPs were
detected during 24~48 h in the tumor region, suggesting high
tumor accumulation (Figure 3B). QDI-NPs were mainly taken up
by liver and spleen, but were barely cleared through urinary
excretion due to the size of QDI-NPs above the kidney filtration
threshold (ca. 5.5 nm)[17] (Figure S16).The remaining
concentrations of QDI-NPs in each organ were quite low at 288
h post-injection, indicating that QDI-NPs can be properly cleared
from the body.
To investigate the PTT of cancer in vivo, four groups were
randomly established from 4T1 tumor-bearing mice, as follows:
G (i) PBS administration (i.v. injection), G (ii) only QDI-NPs
administration (i.v. injection, 5 mg·kg-1), G (iii) only laser
irradiation administration (808 nm, 1 W·cm-2, 10 min), and G (iv)
QDI-NPs administration (i.v. injection, 5 mg·kg-1) combined with
laser irradiation. We established the 36 h post-injection as the
optimum treatment time, according to the accumulation
concentration detection of QDI-NPs in the tumor region (Figure
3B). At 36 h post-injection, the mice from G (iii) and G (iv) were
dealt with laser irradiation. The mice of G (iv) displayed a rapid
temperature increase to 69.7 °C. In the control group of G (iii),
the temperature increased to 41.1 °C under the same irradiation
condition without QDI-NPs (Figure S17). A thermal imaging
camera recorded the treating process every two minutes,
indicating that the QDI-NPs could efficiently induce
a
Figure 3. The pharmacokinetics of QDI-NPs, and PTT in vitro and in vivo. (A)
Relative viability of 4T1 cells, MCF-7 cells and HeLa cells co-incubated with
different concentrations of QDI-NPs for 24 h. Cells treated with PBS combined
with laser irradiation were used as controls. (B) Tissue distribution of QDI-NPs
in mice determined by the concentration in each organ. (C) Thermal images of
4T1 tumor-bearing mice during the therapeutic process. (D) Tumor volume
growth curves of tumors in different groups after laser irradiation. (E) Photos of
stark tumors collected from the mice in different groups at the end of PTT. (F)
The H&E-stained images of tumor after PTT. 808 nm laser irradiation was at 1
W·cm-2 for 10 min. Error bars, mean ± SD (two-tailed Student’s test), Scale bar:
100 μm.
temperature increase for PTT of cancer in vivo (Figure 3C).
During the subsequent 20-day observation period the tumor
volumes of the four groups were recorded every other day
(Figure 3D). There was no tumor outburst after initial elimination
in G (iv). In contrast, the tumors from the other three groups
showed consistently high growth rates, suggesting that the PTT
induced by QDI-NPs can significantly eliminate the cancer
(Figure S18). The anatomized tumor displayed eradication and
the lowest values in size and weight in group (iv) than those in
the other three groups (Figure 3E and S19). The bioactivity of
residual tumor tissues was further verified through a pathological
examination by hematoxylin and eosin (H&E) staining (Figure
3F). High extermination of malignant cells was observed from G
(iv), including cell shrinkage, separation and fragmentized nuclei.
Importantly, during the 20-day observation period, there were no
abnormalities of the treated mice in the daily behaviors and the
monitored body weight values were steady (Figure S20), thus,
suggesting the QDI-NPs displayed no adverse effects during
PTT in vivo. Altogether, the QDI-NPs can passively accumulate
Photothermal agents must possess low cytotoxicity in dark
and efficient PTT against cancer cells under light irradiation. The
potential cytotoxicity of the QDI-NPs was investigated by a
standard cell counting kit-8 (CCK-8) assay in three cancer cell
lines: 4T1 cells, human breast cancer (MCF-7) cells, human
cervical carcinoma (HeLa) cells and two non-cancer cell lines:
L929 cells, rat bone marrow stromal (BMSC) cells. No
cytotoxicity was detected after co-incubation with high-
concentration (1000 g·mL-1) solutions of QDI-NPs for 24 h and
prolonged 48 h (Figure S14). These results imply that the QDI-
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10.1002/anie.201810541
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a
control, respectively. The
histopathological studies through the H&E staining method
revealed no noticeable damage or inflammation in the organs
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for the QDI-cored star-macromolecule P(QDI) with multi-PEG
chains for phototheranostic applications. P(QDI) shows strong
NIR absorption and can assemble into QDI-NPs with ultra-small
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passively target tumors and visualize the tumor outline with high
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photothermal agent after appropriate chemical modification.
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phototheranostics and to act as useful therapeutic systems in
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Acknowledgements
The National Natural Science Foundation of China (21774007,
21574009, 51873009 and 51573012), Fundamental Research
Funds for the Central Universities (PT1811), Beihuazhongri United
Fund (PYBZ1822), and the Max-Planck-Society are acknowledged
for financial support and the Joannes-Gutenberg University for a
scholarship from the Gutenberg Research College.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: NIR-absorption • quaterrylenediimide • photoacoustic
imaging • photothermal conversion efficiency • pharmacokinetics
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C. Liu, S. Zhang, J. Li, J. Wei, K. Müllen,
M. Yin*
Page No. – Page No.
Title: A Water-soluble, NIR-absorbing
Quaterrylenediimide Chromophore for
Photoacoustic Imaging and Efficient
Photothermal Cancer Therapy
Entry for the Table of Contents
Text for Table of Contents:
A water-soluble NIR-absorbing photothermal agent for phototheranostics has been developed
based on quaterrylenediimide (QDI). The poly(ethylene glycol)-functionalized QDI can self-
assemble into QDI-nanoparticles (QDI-NPs) with sizes of approximate 10 nm in aqueous
solution. QDI-NPs exhibit high-resolution photoacoustic imaging and efficient photothermal
cancer therapy at 808 nm NIR laser irradiation.
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