A Photoinduced Nonadiabatic Decay-Guided Molecular Motor Triggers Effective Photothermal Conversion for Cancer Therapy

Article abstract of DOI:10.1002/anie.202002516

It remains highly challenging to identify small molecule-based photothermal agents with a high photothermal conversion efficiency (PTCE). Herein, we adopt a double bond-based molecular motor concept to develop a new class of small photothermal agents to b

Full text of DOI:10.1002/anie.202002516

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Accepted Article
Title: Photoinduced Nonadiabatic Decay-guided Molecular Motor
Triggers Effective Photothermal Conversion for Hyperthermia
Cancer Therapy
Authors: Jen-Shyang Ni, Xun Zhang, Guang Yang, Tianyi Kang,
Xiangwei Lin, Menglei Zha, Yaxi Li, Lidai Wang, and Kai Li
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202002516
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Photoinduced Nonadiabatic Decay-guided Molecular Motor
Triggers Effective Photothermal Conversion for Hyperthermia
Cancer Therapy
Jen-Shyang Ni,† Xun Zhang,† Guang Yang, Tianyi Kang, Xiangwei Lin, Menglei Zha, Yaxi Li, Lidai
Wang, and Kai Li*
Abstract: Photothermal agents, which can release nonradiative heat
by strongly twisted intramolecular charge transfer (TICT) state
and/or molecular motions in aggregates, have been implemented in
photothermal therapy for treating diseases. To achieve enhanced
nonradiative decay, long alkyl-chains and bulky substituents have
been proposed to be introduced into the large conjugation structure,
which always require complicated synthetic procedures. Thus, it
remains highly challenging to strategically explore small molecule-
based photothermal agents with high photothermal conversion
efficiency (PTCE). Herein, we adopt a double bond-based molecular
motor concept to develop a new class of small photothermal agents
to break the current design bottleneck. As the double-bond is twisted
by strong TICT upon irradiation, the excited agents can deactivate
nonradiatively through the conical intersection (CI) of internal
conversion, which is called as photoinduced nonadiabatic decay.
Such agents thus possess a high PTCE of ~90.0%, facilitating low-
temperature photothermal therapy in the presence of a heat shock
protein 70 inhibitor. In addition, the behaviors and mechanism of NIR
laser-triggered molecular motions for generating heat via the
nonradiative CI pathway have been further understood by theoretical
and experimental evidence, providing a feasible design principle to
synthesize highly efficient photothermal and photoacoustic agents.
molecular motions in aggregates, as well as long-conjugated
system to extend the absorption to NIR-region. As a result,
these materials not only require complex synthesis but also
encounter potential biodegradation problem when used for in
vivo studies. Thus, the new design strategy and/or mechanism
to synthesize small-molecular photothermal agents with high
PTCE holds great potential to promote further biomedical
applications.
Molecular motor with an imino-rotary axis exhibits
photochemical rotation around the C=N bond (C=N rotation) and
thermal nitrogen-inversion (N-inversion) under irradiation, as a
typical light-driven imine-based molecular motion (Scheme S1).[4]
Theoretically, the molecular motions via photoisomerization can
release the excitation energy as heat through nonradiative
pathway including conical intersection (CI), which is defined as
photoinduced nonadiabatic decay (PIND). This indicates that the
excited molecules can easily pass through the nonradiative CI
pathway and return to the ground state as the twisted double-
bond has a vertical angle (~90°). Such PIND-guided materials
thus have significant potential to serve as the advanced
photothermal and photoacoustic contrast agents. Inspired by this
concept, we developed the molecular motor-based photothermal
agents
by
one-step
condensation
synthesis,
using
dialkylaminophenyl-donor and 1,3-bis(dicyanomethylidene)indan
(BDCI) acceptor bridged by a imino-double bond (Scheme S2).
In this work, we first synthesized a pair of imino- and vinyl-
based molecular motors (Scheme 1). In comparison with the
vinyl-based molecular motor (CCTI; Figure S1), the imino-based
one has almost no fluorescence in either solution or solid state,
which is attributed to easier intramolecular motions via double-
bond torsion causing PIND effect. Interestingly, owing to the
strong TICT effect, its absorption can be red-shifted to the NIR-
region, further benefiting photothermal conversion under laser
irradiation of 808 nm. The maximum PTCE of C6TI in the
aggregation state thus can reach ~90.0%, which is greatly
higher in comparison with most reported photothermal agents
including ICG (Table S1).[2b, 3a, 5] Thanks to its excellent PTCE,
Photothermal therapy (PTT) using near-infrared (NIR) light-
absorbing agents to locally generate heat for tumor ablation has
received considerable interest in recent years.[1] Taking
advantage of the minimal invasiveness, convenient operation,
low toxicity and quick recovery, PTT using NIR laser-triggered
photothermal agents has been intensively investigated in the
field of phototheranostics.[2] To obtain ideal agents with high
photothermal conversion efficiency (PTCE), one of the key
points is to acquire effective nonradiative transition.[3] In view of
this, some organic small molecules based on strong twisted
intramolecular charge transfer state (TICT) or intramolecular
motion-induced photothermy (iMIPT) properties have been
developed. However, those molecular structures usually involve
long-branch alkyl-chains and/or bluky subsituents to support
[*]
Prof. J.-S. Ni, X. Zhang, Dr. T. Kang, Dr. G. Yang, M. Zha, Y. Li,
Prof. K. Li
Department of Biomedical Engineering, SUSTech Academy for
Advanced Interdisciplinary Studies, Southern University of Science
and Technology (SUSTech), Shenzhen 518055, China
E-mail: lik@sustech.edu.cn
Prof. J.-S. Ni
HKUST-Shenzhen Research Institute, Shenzhen 518057, China
Dr. X. Lin, Prof. L. Wang
City University of Hong Kong Shenzhen Research Institute,
Shenzhen 518057, China
[†]
These authors contributed equally to this work
Supporting information for this article is given via a link at the end of
Scheme 1. Design strategy for highly efficient photothermal agent.
the document.
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C6TI serves as a NIR-triggered PTT agent that can locally heat
the tumor region to 53.4 °C and further induce complete cell
necrosis (Figures S2-4). Nevertheless, the high-temperature
ablation may cause heating damage of normal organs adjacent
to the tumor due to heat diffuse (Figure S3).[1d] To address this
concern of side effects in conventional PTT, we employed a heat
shock protein 70 (HSP70) inhibitor, apoptozole (Apo), that can
against thermotolerance of tumor cells upon laser irradiation.
The combination of Apo and C6TI can realize synergistic PTT in
the hyperthermia region (43 °C) upon laser irradiation,[6] which
actively avoided collateral damage to normal tissues in the
traditional photothermal treatment at a high temperature (over
50 °C). Overall, these insights into the working mechanism of
such molecular motor and its successful implementation in
biomedical practice can open a new door to explore highly-
effective PTT agents for advanced tasks.
First of all, the imino-molecular motor (C1TI) shows a broad
absorption profile covering from visible to NIR region, peaked at
740 nm with an intense tail extended to 1000 nm (Figure 1a). Its
bathochromic absorption is contributed from the electron-rich
nitrogen atom and strong TICT property. The results of
theoretical calculations (Figures S5-6 and Tables S2-3) reveal
that the ground-state (S0) geometries of chiral P- and M-helical
C1TI molecules have similar optimized energies, oscillator
strengths (f) and dihedral angles between dimethylaminophenyl-
donor and BDCI-acceptor, indicating the feasibility of chiral
switch in C1TI molecules upon light irradiation. In addition, the
excited C1TI molecule in the strong TICT state shows an almost
vertical donor-acceptor twisting behavior (87.0°), leading to the
ineffective overlap of molecular orbitals with zero f value in the
emissive transition.[7] This is the reason why the C1TI molecule
does not emit in solution at room temperature (298 K) (Figure
1b).
As shown by the excited-state double-bond reorganization
(ESDBR) guided potential energy surface (Figure 1c),[8] twisting
around the imino-double bond can yield a highly polar TICT
state and CI in the torsional angle between -10° and 0°. This
reveals that the excited C1TI molecule can be efficiently
deactivated to S0//S1 state through the CI pathway of
nonradiative internal conversion, followed by the vibrational
relaxation to its original S0 state or chiral isomer (Figure 1d).[9]
The total de-excited processes are designated as PIND. By
contrast, as the donor-acceptor twisting is below 87.0°, the
excitons for the local excited-state (LE) of C1TI molecule can
deactivate through the radiative decay pathway in the light of
RIM mechanism at a low temperature of 77 K, making it
emissive upon irradiation (Figure 1b).[3c] On the contrary, it
shows negligible emission at room temperature (298 K). This
suggests that the imino-molecular motor (C1TI) provides an
effective approach passing through photoinduced excited-state
nonadiabatic process upon irradiation with NIR laser at room
temperature. In addition, the nanoaggregates of C6TI
substituted with the longest alkyl-chains have the highest PTCE
(90.0%) in comparison to the ones with shorter alkyl-chains
(C1TI, C2TI and C4TI) (Figures S7-8). According to the iMIPT
mechanism,[3c] the substituent with long alkyl-chains is
conducive to molecular motions in the aggregation state.[3b]
Specifically, such PIND-guided materials thus will befittingly
serve as advanced photothermal agents.
Figure 1. The photophysical properties and mechanism for imino-molecular
motor (C1TI). (a) UV-vis-NIR absorption spectrum of C1TI in THF (10 μM). (b)
PL spectra of C1TI in toluene at 77 and 298 K upon excitation at 700 nm. (c)
The potential energy surfaces of C1TI geometries in the excited state (S1) as
a function of the torsional angles. S0//S1 is the ground state (S0) projected
vertically by S1. (d)
A proposed model of photoinduced excited-state
nonadiabatic process for C1TI molecule. The inserts are its S0 and S1
geometries. The angles are the planar included angles between the
dimethylaminophenyl-donor (blue plane) and BDCI-acceptor (green plane).
Abs: absorption. CI: conical intersection. TICT: twisted intramolecular charge
transfer. Er: energy relaxation. LEE: local excited-state emission.
However, through nanoprecipitation (Figures S9-10),[10] only
C6TI-loaded nanoparticles (NPs) formed stable dispersion in
phosphate buffered saline (PBS) at a high concentration. By
contrast, the other NPs precipitated from the suspensions due to
their serious intermolecular aggregation (Figure S11). To further
evaluate the photothermal performance of C6TI NPs in PBS, the
solution temperatures were recorded at different concentrations
under laser irradiation of 808 nm at 1 W cm-2 (Figure 2b). The
solution temperatures with the increased concentrations of C6TI
NPs from 0 to 100 μg mL-1 regularly rose under laser irradiation.
A highest value of 76.4 °C can be recorded at 100 μg mL–1 after
continuously irradiated for 8 min. In particular, it exhibited a
steady-state temperature variation through 5 cycles of heating
and cooling measurements (Figure 2c), whereas ICG showed
serious photothermal un-stability. Additionally, the PTCE of C6TI
NPs was measured to be 89.3% (Figure S12). As a result, the
formulated C6TI NPs inherit the intrinsic photothermal
converting ability of C6TI aggregates. On the contrary, the PTCE
of ICG was only 32.0% measured under the same condition
(Figure S13), owing to the fact that the excited ICG can pass the
emissive pathway and return back to the ground state besides
nonradiative heat release.[11] Our non-emissive C6TI NPs thus
have a significantly higher photothermal conversion performance
in comparison with most recently reported organic photothermal
3b, 3c, 5d]
agents.[2b,
Specifically, the excitons for the molecular
motor-based materials (C6TI NPs) will mainly be deactivated
through the nonradiative CI pathway to perform the perfect
photothermal conversion for PTT.
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(Figure 2f). The Apo inhibitor release ratio from NPs was ca.
49.5% upon laser irradiation at 43 °C in 1h (Figure S18). These
results collectively confirm that C6TI/Apo-Tat NP is a promising
nanomedicine for PTT at a relatively low temperature via
thermoresistance suppression by HSP70 inhibitor.
Additionally, the intense NIR-absorbance of C6TI molecules
can facilitate photoacoustic imaging. In vivo results suggest that
the photoacoustic signal intensity of tumor region at 8 h post
intravenous injection exhibited the maximum value (Figure S19),
attributed from passive targeting effect of NPs.[15] We thus
assigned this time point for PTT treatment to realize optimized
outcome. At 8 h post intravenous injection of C6TI/Apo-Tat NPs,
the tumor-bearing region was irradiated by an 808 nm laser for
25 min (0.5 W cm-2) and its photothermal heating profile was
recorded by an IR thermal imaging system (Figure S20). The
temperature of the tumor site promptly increased to 43 °C after
continuous irradiation for 3 min and then remained stable. On
the other hand, a higher laser power density (1 W cm-2) was
required to maintain the similar temperature of tumor region of
mice injected with ICG/Apo-Tat NPs, due to the lower PTCE of
ICG-loaded NPs (17.6%; Figures S21-22). To thoroughly
investigate the efficacy of our low-temperature PTT approach,
six groups were randomly established from 4T1 tumor-bearing
Figure 2. The photothermal properties and in vitro experiments of C6TI-based
NPs. (a) Normalized UV-vis-NIR absorption spectra of C6TI in THF and C6TI
NPs in PBS. (b) Time-dependent temperature changes of C6TI NPs in PBS
with various concentrations (0−100 μg mL-1) under laser irradiation (808 nm, 1
W cm-2). (c) Temperature changes of C6TI NPs and ICG (100 μg mL-1) over
five laser-on/off cycles under 808 nm irradiation (1 W cm-2). (d) Cytotoxicity of
C6TI-Tat and C6TI/Apo-Tat NPs in 4T1 cells treated at 37 °C and 43 °C,
respectively. (e) The HSP70 expression efficacy after different treatments
as determined by western blot, and (f) the relative HSP70 quantification, using
PBS-treated group as the control. Statistical significance: **p ˂ 0.002.
Although the traditional PTT with laser-induced high local
temperature over 50 °C can induce complete cell necrosis in
tumor tissues (Figure S4), it will also threaten the adjacent
healthy cells and tissues due to the inevitable heat diffusion
(Figure S3). To address this problem, we proposed an
alternative approach to realize PTT for tumor ablation at a
relative low temperature. C6TI/Apo-Tat NPs were prepared
through co-encapsulation of the photothermal agent (C6TI) and
HSP70 inhibitor (Apo),[12] followed by conjugation with Tat
peptides for cell penetrating abiity[13] (Figures S9, S10c and S14-
15). The potential cytotoxicity of C6TI-based NPs was
investigated by a standard cell counting kit-8 (CCK-8) assay in
4T1 cells (Figures 2d and S16). Upon co-incubation with a high
concentration (C6TI at 100 μg mL-1) of C6TI-based NPs at 37 °C
for 24 h, no obvious cytotoxicity was detected. By contrast,
through the additional PTT treatment at 43 °C for 1 h, the
viability decreased to 56.8 ± 10.6% and 70.9 ± 5.1% for cells
treated by C6TI/Apo-Tat and C6TI-Tat NPs, respectively.
According to the cell apoptosis analysis by flow cytometry
(Figure S17), the percentage of apoptotic cells increased to
23.4% upon treatment with C6TI/Apo-Tat NP at 43 °C for 1 h,
whereas the control groups treated with PBS at 37 °C and 43 °C
only showed slight apoptosis of 5.1% and 7.8%, respectively.
This confirms that the obvious apoptosis-inducing ability
originates from the suppressed thermotolerance of cancer cells
by Apo. According to the result of western blot analysis (Figures
2e-f),[14] the cells with mild thermal treatment (PBS@43 °C)
displayed an up-regulated HSP70 expression in comparison with
the cells in control group (PBS@37 °C), indicating that the
Figure 3. The in vivo experiments for C6TI-cored NPs in low-temperature
PTT treatment. (a) Growth profiles of tumors and (b) changes of body
weights after different treatments. Statistical significance: 0 ˂ #p ˂ 0.0005,
0.2 < *p < 0.25. (c) A photograph of the excised tumors from all groups. (d)
TUNEL and immunofluorescence staining of tumor slices from the
representative mice of different groups. Scale bars: 100 μm.
operating temperature induced the heating stress and further up-
12b]
regulated HSP70 expression.[12a,
Meanwhile, for the cells
treated with Apo-loaded NPs (C6TI/Apo-Tat NP@43 °C and
Apo-Tat NP@43 °C), the HSP70 expression was significantly
reduced and down-regulated by the released Apo molecules
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mice for the following treatments: (i) PBS, (ii) PBS with NIR laser
(808 nm, 0.5 W cm-2, 1 h), (iii) C6TI-Tat NPs, (iv) C6TI-Tat NPs
with NIR laser, (v) C6TI/Apo-Tat NPs, and (vi) C6TI/Apo-Tat
NPs with NIR laser. After the different treatments, their tumor
sizes and body weights were periodically monitored (Figures 3a-
b and S23). The tumors in PBS groups and all other groups
without light irradiation grew quickly during 14 days. As a clear
contrast, the tumor growth in the group treated with C6TI-Tat
NPs and NIR light irradiation was restrained within day 4 post-
treatment but reoccurred after day 6. The limited therapeutic
efficiency is attributed to the fact that the sole PTT at 43 °C is
feeble for effective tumor ablation. Among all the six groups,
PTT with C6TI/Apo-Tat NPs plus laser irradiation exhibited the
maximized inhibition efficiency on tumor growth, attributing to
the surmounted HSP-induced thermotolerance by the released
Introducing the imino-based double-bond into a strong TICT
framework can achieve UV-vis-NIR absorption as well as
complete nonradiative release upon laser excitation. Particularly,
owing to the effective molecular motions in aggregates and
complete nonradiative energy release as heat via CI-deactivated
pathway, C6TI nanoaggregates and nanoparticles have
excellent PTCE of up to ~90.0%. These results indicate the
priority of C6TI as a photothermal agent than the commercial
ICG and other recently reported synthetic agents (Table S1).
Combined with a HSP70 inhibitor (Apo), C6TI/Apo-Tat NPs can
suppress the thermotolerance of tumor cells and realize the low-
temperature PTT upon laser irradiation for effective tumor
ablation with minimized damage to adjacent normal tissues.
Noteworthy is that we demonstrate a new strategy to develop
highly-efficient small molecular photothermal agents through the
excited-state PIND process, which offers a more feasible
approach in comparison with the traditional design principle of
PTT/PA agents by introducing long alkyl-chains and bulky
substituents. As such, this investigation not only successfully
introduces PIND-guided molecular motor concept to advance
NIR-triggered photothermal agents, but also expands effective
therapeutic systems for biomedical applications.
Apo as
a HSP70 inhibitor to promote the tumor-killing
efficacy.[12c] Meanwhile, all treated groups did not display
significant drop of body weights (Figure 3b), indicating the good
tolerance of our formulations in the mice model. At day 14 post
treatment, the representative photographs of excised tumors
demonstrated a prominent tumor inhibition effect for C6TI/Apo-
Tat NPs upon NIR laser irradiation (Figures 3c and S24).
Nevertheless, this therapeutic efficacy via low-temperature PTT
is more excellent than the reported results,[16] owing to the fact
that Apo can efficiently prevent the cytoprotective pathway of the
dominant HSP factor, HSP70.[12]
Experimental Section
Through histological analysis of terminal deoxynucleotidyl
transferase dUTP nick end labeling (TUNEL) staining,
significantly large apoptotic/necrotic areas in the tumor tissues
treated by the C6TI/Apo-Tat NPs and NIR laser was observed
(Figure 3d). By contrast, C6TI NPs with NIR laser-treated group
had evident un-killed tumor tissues while no obvious
apoptotic/necrotic tissues were observed in the PBS control
group. As expected, the immunofluorescence analysis results
imply that the HSP expression for C6TI/Apo-Tat NPs group was
dramatically inhibited with less HSP70-expression, in
comparison with that for C6TI-Tat NP-treated group upon laser-
irradiation. And the sample from PBS group displayed negligible
HSP70-expression (Figure 3d). These results further
demonstrate the high efficacy of C6TI/Apo-Tat NPs for
restrained cytoprotection of HSP70, leading to enhanced
apoptosis combined with tumor photothermal ablation. In the
hematoxylin and eosin (H&E) stained histological images (Figure
S25), no obvious pathological difference was found when
comparing the major organs after individually treated. In addition,
the blood circulation half-life of NPs was estimated to be ~24 h
and they mainly accumulated in liver, spleen and tumor as
passively targeted NPs, employing fluorescent molecule-doped
NPs as the indicator (Figures S26-27). The analysis of red blood
cells lysis, blood biochemistry and blood routine examinations at
day 14 post NPs injection confirm that the liver and kidney
functions were not affected by C6TI/Apo-Tat NPs (Figures S28-
30). These results collectively confirm their good biocompatibility
and circulation half-life, which are of high importance in in vivo
therapeutic applications.
The experimental details were described in the supporting
information.
Acknowledgements
The authors are grateful to the National Natural Science
Foundation of China (31870991), the Science and Technology
Plan of Shenzhen (JCYJ20180306174918294), and High Level
Special Funds of SUSTech (G02386301 and G02386401) for
financial support. The authors also acknowledge the Center for
Computational Science and Engineering at SUSTech for
theoretical calculation support and SUSTech Core Research
Facilities for technical support. All in vivo procedures have been
approved by the Animal Ethics Committee of the Center for
Experimental Animal Research of SUSTech, China.
Keywords: HSP70 • conical intersection • imine • photothermal
therapy • NIR
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10.1002/anie.202002516
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RESEARCH ARTICLE
The molecular motor-liked agents
with excellent photothermal
conversion performance, attributed
from high-efficiently deactivating
through nonradiative conical
Jen-Shyang Ni,† Xun Zhang,† Guang
Yang, Tianyi Kang, Xiangwei Lin,
Menglei Zha, Yaxi Li, Lidai Wang, and
Kai Li*
Page No. – Page No.
intersection (CI) pathway, combined
with a HSP70 inhibitor for low-
temperature photothermal therapy.
Photoinduced Nonadiabatic Decay-
guided Molecular Motor Triggers
Effective Photothermal Conversion
for Hyperthermia Cancer Therapy
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