Light-Triggered Transformable Ferrous Ion Delivery System for Photothermal Primed Chemodynamic Therapy

Article abstract of DOI:10.1002/anie.202015379

Chemodynamic therapy (CDT) involves the catalytic generation of highly toxic hydroxyl radicals (^.OH) from hydrogen peroxide (H₂O₂) through metal-ion-mediated Fenton or Fenton-like reactions. Fe²⁺ is a classical catalyst ion, however, it suffers easy oxidation and systemic side-effects. Therefore, the development of a controllable Fe²⁺ delivery system is a challenge to maintain its valence state, reduce toxicity, and improve therapeutic efficacy. Reported here is a near-infrared (NIR) light-triggered Fe²⁺ delivery agent (LET-6) for fluorescence (FL) and photoacoustic (PA) dual-modality imaging guided, photothermal primed CDT. Thermal expansion caused by 808 nm laser irradiation triggers the transformation of LET-6 to expose Fe²⁺ from its hydrophobic layer, which primes the catalytic breakdown of endogenous H₂O₂ within the tumor microenvironment, thus generating ^.OH for enhanced CDT. LET-6 shows remarkable therapeutic effects, both in vitro and in vivo, achieving 100 % tumor elimination after just one treatment. This high-performance Fe²⁺ delivery system provides a sound basis for future synergistic metal-ion-mediated cancer therapy.

Full text of DOI:10.1002/anie.202015379

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Light-triggered transformable ferrous ion delivery system for
photothermal primed chemodynamic therapy
Authors: Jing Lin, Ting He, Yanyan Yuan, Chao Jiang, Nicholas
Thomas Blum, Jing He, and Peng Huang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202015379
Link to VoR: https://doi.org/10.1002/anie.202015379

10.1002/anie.202015379
Angewandte Chemie International Edition
RESEARCH ARTICLE
Light-triggered transformable ferrous ion delivery system for
photothermal primed chemodynamic therapy
Ting He†, Yanyan Yuan†, Chao Jiang, Nicholas Thomas Blum, Jing He, Peng Huang, Jing Lin*
Marshall Laboratory of Biomedical Engineering, International Cancer Center, Laboratory of Evolutionary Theranostics (LET), School of Biomedical
Engineering, Shenzhen University Health Science Center, Shenzhen 518060, China
E-mail: jingl@szu.edu.cn
Abstract: Chemodynamic therapy (CDT) has been recognized as an
emerging and alternative tumor therapeutic modality, which mainly
involved the catalytic generation of highly toxic hydroxyl radical (•OH)
from hydrogen peroxide (H2O2) through metal ions-mediated Fenton
or Fenton-like reactions. Among metal ions, ferrous ion (Fe2+) is a
classical catalyst ion, however, it suffers easy oxidation and systemic
side effects. Therefore, the development of controllable Fe2+ delivery
system is a big challenge to maintain its valence state, reduce toxicity
and improve therapeutic efficacy. Here, we report a near-infrared
(NIR) light-triggered Fe2+ delivery agent (denoted as LET-6) for
fluorescence (FL) and photoacoustic (PA) dual-modality imaging
guided photothermal primed CDT. The LET-6 was composed of
cyanine analogue (tPy-Cy-Fe) and distearoylphosphoethanolamine-
polyethylene glycol (DSPE–PEG). The tPy-Cy-Fe contains a cyanine
structure for FL/PA imaging and a chelating ligand, 4'-(amino- methyl
phenyl)-2,2':6',2"-terpyridine (tPy), for Fe2+ binding. Thermal
expansion caused by 808 nm laser irradiation triggered the
transformation of LET-6 to expose Fe2+ from its hydrophobic layer,
which primed the catalytic breakdown of endogenous H2O2 in tumor
microenvironment, thus generating abundant of •OH for enhanced
CDT. The LET-6 showed remarkable therapeutic effects under laser
irradiation, both in vitro and in vivo, achieving 100% tumor elimination
after just once treatment. This high-performance Fe2+ delivery system
provides a sound basis for future metal-ions-mediated cancer
synergistic therapy.
agent for CDT [3]. So far, amorphous Fe0 nanoparticles [4], Fe
oxides [5], ZnFe2O4 [6], Fe3O4 [7], and metal-organic frameworks
(MOFs) with Fe3+ [8] have been explored as CDT agents, triggering
cancer cell apoptosis and inhibiting tumor growth. However, the
[9]
long-term toxicity of these nanomaterials still causes concern
.
If Fe2+ was delivered directly and non-specifically as a CDT agent,
this easily cause oxidative stress throughout the whole body [9c, 10]
.
Additionally, Fe2+ is easily oxidized to Fe3+, which precipitates and
thus stops participating in the Fenton reaction [11]. Therefore, the
challenge in creating an intelligent Fe2+ delivery system is to
maintain its valence state and avoid the oxidation and leakage
during circulation.
Some organic ligands can coordinate with Fe2+, which keep the
ion valence state, thus avoiding the oxidation and preventing it
from participating in the Fenton reaction. Besides, these ligands
can be modified with different functional groups to effectively
combine diagnostic and therapeutic modalities in a single-
molecule theranostics [12]. Some cyanine molecules, for example
indocyanine green (ICG), which has been approved by the U.S.
Food and Drug Administration (FDA), have an ideal molecular
structure for this purpose. The strong near-infrared (NIR)
absorbance properties of cyanine dyes benefit for photoacoustic
(PA) imaging and photothermal therapy (PTT) [13]. Here, we report
Fe2+ contained cyanine dye-based nanoprobe (denoted as LET-
6) with light-triggered transformation to launch Fenton reaction for
synergistic photothermal-CDT. The LET-6 was composed of Fe2+
chelated 4'-(amino-methyl phenyl)-2,2':6',2"-terpyridine modified
cyanine (tPy-Cy-Fe) and distearoylphosphoethanolamine-
polyethylene glycol (DSPE-PEG). The tPy-Cy served as the
fluorescence (FL) and PA dual-modality imaging contrast agent,
photothermal transducer as well as iron chelator in case of being
oxidized and causing oxidative stress. The chelation ability of tPy-
Cy is attributed to the backbone of nitrogen atoms of terpyridine
(tPy) that confirmed strong bonding force to Fe2+. Under 808 nm
laser irradiation, the cyanine structure of LET-6 broke down, and
then transformed to small fragments, releasing Fe2+ from its
hydrophobic layer and catalyzing the breakdown of endogenous
H2O2, thus generating •OH for CDT of cancer (Scheme 1).
Introduction
Chemodynamic therapy (CDT) is an emerging and alternative
tumor therapeutic modality, which is based on the Fenton or
Fenton-like reactions generate hydroxyl radicals (•OH) from
hydrogen peroxide (H2O2), thus damaging the DNA of cells and
inducing cell apoptosis [1]. Many transition metal ions can act as
Fenton (Fe2+) or Fenton-like (Cu+, Mn2+, etc.) agents, which in
tumor microenvironments catalyze the breakdown of endogenous
H2O2 into •OH [2]. Ferrous ion (Fe2+) is the most studied Fenton
1
This article is protected by copyright. All rights reserved.

10.1002/anie.202015379
Angewandte Chemie International Edition
RESEARCH ARTICLE
Scheme 1. An illustration of a NIR light-triggered Fe2+ delivery agent (denoted as LET-6) for photothermal enhanced CDT. The LET-6 was composed of Fe2+
chelated tPy-Cy-Fe and DSPE-PEG.
days (Figure 1d). The zeta potentials of LET-6 (-19.43 mV)
showed higher than LET-6’ (-27.13 mV), due to the neutralization
of surface charge after Fe2+ binding (Figure S4). Both LET-6 and
Results and Discussion
LET-6’ had the absorbance peak at ~823 nm indicated their
potentials as PA contrast agents (Figure 1e). As shown in Figure
1f, the PA signal at 808 nm (PA808) exhibited a concentration
dependent manner with a good linear relationship in the range of
0 to 150 µM (Figure 1g). Interestingly, LET-6 emitted higher PA
amplitude than LET-6’ at a certain concentration because of Fe2+-
induced aggregation of tPy-Cy [15]. Both fluorescence of LET-6
and LET-6’ were quenched compared with free cyanine dyes due
to aggregation-caused quenching (ACQ) of cyanine (Figure 1h)
Synthesis and characterization of LET-6 nanoparticles
The synthesis route of tPy-Cy was showed in Figure S1 of the
supporting information (SI). In brief, cyanine dye IR-823 was
[14]
synthesized as the previous reference
. tPy-Cy was
synthesized via substitution of chlorine in IR-823 with tPy ligand
and was characterized in Figure S2 and S3. Due to the presence
of strong ion binging sites in tPy-Cy, the tPy-Cy-Fe was facilely
obtained by addition of Fe2+ into tPy-Cy solution. Afterwards, LET-
6 was prepared by nanoprecipitation method of tPy-Cy-Fe and
DSPE-PEG. tPy-Cy directly assembled with DSPE-PEG was
obtained as iron-free control (denoted as LET-6’). Both LET-6 and
LET-6’ showed a sphere-like morphology with average diameter
of ~50 nm (Figure 1a,b). However, the hydrodynamic diameter for
LET-6 (~ 223 nm) is larger than LET-6’ (~ 180 nm) (Figure 1c).
Both of them remained no obvious changes after storage for 8
[16]
.
Additionally, the photothermal properties of LET-6 were
evaluated and exhibited a concentration (Figure S5a) and laser
densities (Figure S5b) dependent manner. Compared to LET-6’,
the LET-6 had an obviously higher temperature increase (Figure
S5c). The photothermal conversion efficiencies (η) of LET-6 and
LET-6’ nanoparticles were ~23.6% (Figure 1i) and ~20.4%
2
This article is protected by copyright. All rights reserved.

10.1002/anie.202015379
Angewandte Chemie International Edition
RESEARCH ARTICLE
(Figure S5d,e), respectively. These results are probably attributed
photostability of LET-6 was enhanced relative to that of LET-6’
due to the reduced electron density of the polymethine chain in
tPy-Cy by chelation with Fe2+ [19]
.
to the aggregation of tPy-Cy dye in the presence of metal ions [17]
,
which could enhance dye non-radiative transition, resulting in
better photothermal effect [18]. As shown in Figure S5f, the
Figure 1. Physical and chemical properties of LET-6 and LET-6’. TEM images of LET-6 (a) and LET-6’ (b). (c) Size distribution of LET-6 and LET-6’. (d) Size
distribution of LET-6 and LET-6’ in deionized water for 8 days. (e) UV-vis spectra of LET-6 and LET-6’. (f) PA808 images and (g) corresponding intensities of LET-6
and LET-6’ with different concentrations. (h) FL spectra of tPy-Cy-Fe, tPy-Cy, LET-6, and LET-6’. (i) Heating and cooling curve of LET-6 under 808 nm laser
irradiation (1.0 W/cm2) and determination of the photothermal conversion efficiency by applying time versus the natural logarithm of the cooling temperature change.
ratio of ligand to Fe2+ was 4:1) ligand occupancy of LET-6
Evaluation and mechanism of •OH generation
according to the mount of •OH generation. The characteristic
peak of the mixture solution of TMB (20 mM) and H2O2 (10 µL,
3%) exhibited Fe2+ concentration-dependent increase (Figure S6).
As shown in Figure 2c, the higher absorbance intensities of
unsaturated LET-6 relative to that of saturated LET-6 suggested
that the unsaturated ligand occupancy exhibited much stronger
reduction capacity, verifying that the presence of free orbitals in
iron was in favor of catalytic activity of LET-6. Furthermore, after
808 nm laser irradiation for 12 min, the absorbance at 652 nm
（A652）intensity of TMB treated unsaturated ligand occupancy in
LET-6 solution (50 μM) was markedly increased, indicating that
laser irradiation could promote the generation of •OH, resulting in
higher catalytic efficiency. Furthermore, electron spin resonance
(ESR) spectra confirmed that the similar results using 5, 5-
dimethyl-1-pyrroline N-oxide (DMPO) as a radical trapping agent
(Figure 2d). Hence, unsaturated ligand occupancy in LET-6 was
chosen for the subsequent studies. The effect of laser irradiation
on the formation of •OH exhibited laser density-dependent
increase manner (Figure 2e). In addition, the TMB oxidation
The tPy ligand of tPy-Cy provides a specific Fe2+ chelating site
for Fe2+ delivery. After coordination with tPy-Cy, Fe2+ is prevented
from oxidizing to Fe3+. X-ray photoelectron spectroscopy (XPS)
spectrum of LET-6 showed that 721.48 and 708.58 eV bands
were attributed to 2p1/2 and 2p3/2 of Fe2+ chelated with tPy-Cy,
respectively (Figure 2a). However, the pure Fe2+ were easily
oxidized to Fe3+ after 5 h according to two new bands (728.18 and
713.98 eV) in XPS spectrum which belonging to 2p1/2 and 2p3/2 of
Fe3+, respectively (Figure 2b). These results confirmed that the
coordination of organic dye strategy can enhance the stability of
Fe2+. As we known, the catalytic activity of Fe2+ mediated Fenton
[11,
reaction will be affected by the number of its chelated ligands
20]. When all six electronic orbitals of iron were occupied by the
ligands, Fe2+ would be low catalytic efficiency in the Fenton
reaction [1c, 21]. The 3,3',5,5'-tetramethylbenzidine (TMB) oxidation
reaction was employed to investigate the catalytic activities of
saturated (the ratio of ligand to Fe2+ was 1:2) and unsaturated (the
3
This article is protected by copyright. All rights reserved.

10.1002/anie.202015379
Angewandte Chemie International Edition
RESEARCH ARTICLE
reaction under different conditions was investigated (Figure 2f).
Compare to the control groups, the absorbance intensities at 652
nm of TMB oxidation in FeSO4 or LET-6 plus laser treated groups
have a comparable value, which suggested the Fenton catalysis
activity of LET-6 under laser irradiation (808 nm, 1 W/cm2) was
similar as that of free Fe2+. The underlying mechanism of light-
triggered CDT effect of LET-6 was hypothesized that the LET-6
was disassembled and decomposed under laser irradiation,
leading to the exposure of Fe2+, thus triggering the Fenton
reaction (Figure 2g) [22]. After laser irradiation, the morphology of
LET-6 changed from sphere-like to dots (Figure S7a), and the
color of the LET-6 solution changed from dark blue to maroon
(Figure S7b). The absorbance and fluorescence of LET-6 were
completely disappeared (Figure S7c,d). Obviously, many
fragment peaks were appeared in the mass spectrum of LET-6
(Figure S8), which further verified the LET-6 can be destroyed
upon laser irradiation. The above results indicated that
unsaturated ligand occupancy of Fe2+ in LET-6 shows potential
for light-triggered CDT of tumor.
Figure 2. The evaluation and mechanism of light-triggered •OH generation. XPS spectra of (a) LET-6 powder and (b) pure Fe2+ exposed in ambient condition for 5
h. (c) A652 internsity increase of TMB oxidation by saturated or unsaturated LET-6 with or without laser irradiation. (d) ESR spectra of H2O2 solutions treated with
different conditions: Control (DMPO), unsaturated LET-6+DMPO, unsaturated LET-6+Laser+DMPO, saturated LET-6+Laser. (e) A652 internsity increase of TMB
oxidation by unsaturated LET-6 with different laser densities. (f) A652 internsity of TMB oxidation in different conditions (a: TMB, b: TMB+H2O2, c: TMB+H2O2+Fe(II),
d: TMB+H2O2+LET-6, e: TMB+H2O2+LET-6+Laser. Inset: photographs of the corresponding color changes). (g) The probable mechanism of the light-triggered CDT
effect of LET-6.
Evaluation of cytotoxicity and cell apoptosis
cellular destruction than LET-6’ group, which was attributed to the
synergistic effect of photothermal enhanced CDT. Encouraged by
this excellent treatment effect in the LET-6 plus laser group, we
further explored the probable mechanism. Oxidative stress
changes in U87MG cells were evaluated using a reactive oxygen
species (ROS) probe, 2,7-dichlorofluorescein diacetate (DCFH-
DA), with or without laser irradiation. As shown in Figure 3b, the
The cytotoxicity of LET-6 was assessed by methyl thiazolyl
tetrazolium (MTT) assay. The cell viability of both LET-6 and LET-
6’ was over 83% at all tested concentrations suggesting their good
biocompatibility (Figure 3a). Interestingly, after laser irradiation
(808 nm, 1 W/cm2, 5 min), LET-6 group exhibited more significant
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202015379
Angewandte Chemie International Edition
RESEARCH ARTICLE
cells treated with LET-6 plus laser showed much stronger green
fluorescence than all other groups. This result provided direct
evidence that LET-6 produced large quantities of ROS
(particularly •OH generated by the Fenton reaction) under light
stimulation. Increased ROS levels in cells may give rise to lipid
peroxidation (LPO) of the cell membrane. More vigorous 4T1 cells
was used to conduct the LPO staining of LET-6 in FBS-free
medium to avoid own fluorescence via a radiometric fluorescent
C11-BODIPY581/591 probe shifts from red to green [23]. The LET-6
with laser treated cells had a much stronger green fluorescence
than all other groups, indicating that LET-6 successfully led to a
laser-triggered Fenton reaction within the cells (Figure 3c). As we
know, the LPO of cell membrane could lead to the cellular
apoptosis. Cellular apoptosis with different treatments were
indicated by immunofluorescent staining (green fluorescence) of
cleaved caspase-3 (Cas-3). As shown in Figure 3d, the LET-6
plus laser treated cells showed much stronger green fluorescence
than the LET-6’ with laser group, suggesting that both PTT and
CDT could induce cell apoptosis, but synergetic photothermal
enhanced CDT showed much stronger cell apoptosis than single
PTT alone. Taken together, these results indicated that LET-6 can
effectively mediate light-induced CDT in vitro.
Figure 3. Evaluation of cytotoxicity, LPO, and cell apoptosis of LET-6. (a) Cell viability of U87MG cells treated with LET-6’ or LET-6 at various concentrations with
or without laser irradiation (808 nm, 1 W/cm2, 5 min). ***P < 0.001 (b) ROS generation fluorescence images of LET-6’ or LET-6 (20 μM) in U87MG cells. Scale bar
= 100 µm. (c) C11-BODIPY581/591-stained Fluorescence images (Scale bar = 100 μm) and (d) immunofluorescent stained images (green fluorescence) of cleaved
Cas-3, (Scale bar = 50 μm) of LET-6’ or LET-6 with or without laser irradition.
In vivo imaging
tumor-bearing mice. Based on FL/PA imaging results, the 808 nm
laser irradiation for 10 min (0.5 W/cm2) was originated at 8 h post-
injection of LET-6’ or LET-6. The tumor temperature for LET-6
treated mice increased to approximately 50 °C after 5 min and
remained constant during the irradiation, whereas that of LET-6’
treated mice only increased to 43°C after 5 min and then gradually
decreased (Figure 5a,b). Tumor growth was recorded every two
days in each of the groups following laser irradiation treatment
and tumor growth curves were plotted (Figure 5c). Tumors in the
LET-6 plus laser group were eliminated and showed no
recurrence. However, there were no obvious suppressive effects
on tumors in the other treatment groups. The relative body
weights of all groups were unaffected during the treatment (Figure
5d). After 14 days treatment, the recorded ex vivo tumor size and
weight verified synergetic photothermal primed CDT of LET-6
plus laser treated group had well-marked tumor suppression
compared with mono PTT or CDT (Figure 5e,f). Hematoxylin and
In vivo FL/PA dual-modal imaging was performed in U87MG
tumor-bearing mice. After tail vein injection of LET-6, the FL signal
of tumor regions gradually increased over time (Figure 4a), finally
reached a plateau at 8 h (Figure 4b). After 24 h monitoring, the
mice were euthanized and dissected. The ex vivo FL images and
quantitative results of the relative fluorescence intensity showed
that the fluorescence signal of tumor is strongest in all organs
suggesting high accumulation of LET-6 (Figure 4c,d). Such
phenomenon was also confirmed by PA imaging (Figure 4e,f).
These results provided a meaningful guidance for in vivo therapy.
In vivo therapy
Encouraged by in vitro results, in vivo therapy was administered
to evaluate the synergetic photothermal primed CDT on U87MG
5
This article is protected by copyright. All rights reserved.

10.1002/anie.202015379
Angewandte Chemie International Edition
RESEARCH ARTICLE
eosin (H&E) stained image of tumor in the LET-6 plus laser group
showed serious membrane leakage and chromosome fusion,
indicating necrosis and apoptosis (Figure 5g). However, no
significant damage in other groups. More importantly, the
biochemical analysis of blood and the H&E stained images
showed no obvious changes in all groups (Figure S9). These
results demonstrated that LET-6 has good biocompatibility and
theranostic capacity for tumor management.
Figure 4. In vivo FL/PA imaging of LET-6. (a) FL images of U87MG tumor-bearing mice after intravenous injection of LET-6. (b) The corresponding FL intensity of
(a). (c) FL images of ex vivo tumors and other organs after 24 h monitoring. (d) The corresponding FL intensity of (c). (e) PA images of U87MG tumor-bearing mice
after intravenous injection of LET-6. (f) The corresponding PA intensity of (e).
6
This article is protected by copyright. All rights reserved.

10.1002/anie.202015379
Angewandte Chemie International Edition
RESEARCH ARTICLE
Figure 5. In vivo therapeutic efficacy of LET-6. (a) Thermal images of mice intravenously injected with LET-6 and LET-6’ (808 nm, 0.5 W/cm2, 10 min). (b) The
corresponding temperature at different time points of (a). (c) Relative tumor growth curves (mean ± SD, n = 5, **P < 0.01), (d) body weights, (e) tumor weights
(mean ± SD, n = 5, ***P < 0.001), and (f) photographs of ex vivo tumors after different treatments. (g) H&E stained images of tumor sections (scale bar = 100 μm).
[4]
C. Zhang, W. Bu, D. Ni, S. Zhang, Q. Li, Z. Yao, J. Zhang,
H. Yao, Z. Wang, J. Shi, Angew. Chem. Int. Ed. Engl. 2016,
55, 2101-2106.
Conclusion
In summary, we develop a NIR light-triggered unsaturated
ligand occupancy of Fe2+ delivery system for FL/PA dual-modality
imaging guided photothermal enhanced CDT. The FL/PA signals
of LET-6 can be used as indicators for in vivo monitoring. Upon
laser irradiation, the disassembly and decomposition of LET-6
promoted the exposure of Fe2+, thus enabling the catalytic
breakdown of endogenous H2O2 in tumor microenvironment and
the formation of •OH for enhanced CDT. Both in vitro and in vivo
experiments confirmed the remarkable therapeutic effects of LET-
6 on U87MG cells and U87MG tumor-bearing mice. Only once
treatment can achieve 100% tumor elimination. The LET-6 has
simple component, good biocompatibility, NIR light-triggered
transformation, FL/PA dual-modality imaging ability, and efficient
photothermal-CDT synergistic therapy. Our findings provided a
controllable metal ions delivery strategy for future metal-ions-
mediated cancer synergistic therapy.
[5]
[6]
[7]
Z. Wang, Y. Ju, Z. Ali, H. Yin, F. Sheng, J. Lin, B. Wang, Y.
Hou, Nat. Commun. 2019, 10, 4418-4430.
H. Bi, Y. Dai, P. Yang, J. Xu, D. Yang, S. Gai, F. He, B. Liu,
C. Zhong, G. An, J. Lin, Small 2018, 14, e1703809.
a) M. Huo, L. Wang, Y. Chen, J. Shi, Nat. Commun. 2017,
8, 357-369; b) Z. Zhao, W. Wang, C. Li, Y. Zhang, T. Yu, R.
Wu, J. Zhao, Z. Liu, J. Liu, H. Yu, Adv. Funct. Mater. 2019,
29, 1905013.
D. W. Zheng, Q. Lei, J. Y. Zhu, J. X. Fan, C. X. Li, C. Li, Z.
Xu, S. X. Cheng, X. Z. Zhang, Nano Lett. 2017, 17, 284-
291.
a) F. Peng, M. I. Setyawati, J. K. Tee, X. Ding, J. Wang, M.
E. Nga, H. K. Ho, D. T. Leong, Nat. Nanotechnol. 2019, 14,
279-286; b) S. Sharifi, S. Behzadi, S. Laurent, M. L. Forrest,
P. Stroeve, M. Mahmoudi, Chem. Soc. Rev. 2012, 41,
2323-2343; c) C. R. Keenan, R. Goth-Goldstein, D. Lucas,
D. L. Sedlak, Environ. Sci. Technol. 2009, 43, 4555-4560.
a) C. S. Lim, N. D. Vaziri, Kidney Int. 2004, 65, 1802-1809;
b) Y. J. Yauger, S. Bermudez, K. E. Moritz, E. Glaser, B.
Stoica, K. R. Byrnes, J. Neuroinflamm. 2019, 16, 41-56.
N. Kishimoto, T. Kitamura, M. Kato, H. Otsu, J. Water
Environ. Tech. 2013, 11, 21-32.
a) W. Xuan, Y. Xia, T. Li, L. Wang, Y. Liu, W. Tan, J. Am.
Chem. Soc. 2019, 142, 937-944; b) J. Zhang, L. Ning, J.
Huang, C. Zhang, K. Pu, Chem. Sci. 2020, 618-630; c) Y.
Jiang, J. Huang, X. Zhen, Z. Zeng, J. Li, C. Xie, Q. Miao, J.
Chen, P. Chen, K. Pu, Nat Commun 2019, 10, 10; d) Y.
Jiang, X. Zhao, J. Huang, J. Li, P. K. Upputuri, H. Sun, X.
Han, M. Pramanik, Y. Miao, H. Duan, K. Pu, R. Zhang, Nat.
Commun. 2020, 11, 1857; e) J. Huang, J. Li, Y. Lyu, Q.
Miao, K. Pu, Nat. Mater. 2019, 18, 1133-1143.
[8]
[9]
[10]
[11]
[12]
Acknowledgements
This work is financially supported by National Key R&D Program
of China (2018YFA0704000, 2020YFA0908800), the Guangdong
Province Natural Science Foundation of Major Basic Research
and Cultivation Project (2018B030308003), the Basic Research
Program
JCYJ20180507182413022,
Shenzhen Science
of
Shenzhen
(JCYJ20200109105620482,
JCYJ20170412111100742),
[13]
a) X. Mu, Y. Lu, F. Wu, Y. Wei, H. Ma, Y. Zhao, J. Sun, S.
Liu, X. Zhou, Z. Li, Adv. Mater. 2020, 32, e1906711; b) X.
Gao, G. Ma, C. Jiang, L. Zeng, S. Jiang, P. Huang, J. Lin,
Anal. Chem. 2019, 91, 7112-7117; c) S. He, J. Li, Y. Lyu, J.
Huang, K. Pu, J. Am. Chem. Soc. 2020, 142, 7075-7082; d)
J. Huang, K. Pu, Angew. Chem. Int. Ed. Engl. 2020, 59,
11717-11731; e) L. Zeng, G. Ma, J. Lin, P. Huang, Small,
2018, 14, e1800782; f) S. Wang, J. Lin, T. Wang, X. Chen,
P. Huang, Theranostics, 2016, 6, 2394-2413.
and
Technology
Program
(KQTD20190929172538530) We thank Instrumental Analysis
Center of Shenzhen University (Lihu Campus).
Keywords: Chemodynamic therapy • Ferrous ion delivery • Dual
modality imaging • Synergistic therapy • Fenton reaction
[14]
[15]
L. Zeng, G. Ma, H. Xu, J. Mu, F. Li, X. Gao, Z. Deng, J. Qu,
P. Huang, J. Lin, Small 2019, 15, e1803866.
References:
a) K. Klehs, C. Spahn, U. Endesfelder, S. F. Lee, A.
Fürstenberg, M. Heilemann, Chem. Phys. Chem. 2014, 15,
637-641; b) C. Gude, W. Rettig, J. Phys. Chem. A 2000,
104, 8050-8057; c) S. Upadhyayula, V. Nunez, E. M.
Espinoza, J. M. Larsen, D. Bao, D. Shi, J. T. Mac, B. Anvari,
V. I. Vullev, Chem. Sci. 2015, 6, 2237-2251.
a) B. Andreiuk, A. Reisch, M. Lindecker, G. Follain, N.
Peyrieras, J. G. Goetz, A. S. Klymchenko, Small 2017, 13,
1701582-1701595; b) D. Hu, C. Liu, L. Song, H. Cui, G. Gao,
P. Liu, Z. Sheng, L. Cai, Nanoscale 2016, 8, 17150-17158;
c) M. A. Sowers, J. R. McCombs, Y. Wang, J. T. Paletta, S.
W. Morton, E. C. Dreaden, M. D. Boska, M. F. Ottaviani, P.
T. Hammond, A. Rajca, J. A. Johnson, Nat. Commun. 2014,
5, 5460.
C. Sun, B. Li, M. Zhao, S. Wang, Z. Lei, L. Lu, H. Zhang, L.
Feng, C. Dou, D. Yin, H. Xu, Y. Cheng, F. Zhang, J. Am.
Chem. Soc. 2019, 141, 19221-19225.
K. Zhang, H. Y. Li, J. Y. Lang, X. T. Li, W. W. Yue, Y. F. Yin,
D. Du, Y. Fang, H. Wu, Y. X. Zhao, C. Xu, Adv. Funct. Mater.
2019, 29, 1905124.
[1]
a) J. Imlay, S. Linn, Science 1988, 240, 1302-1309; b) Z.
Tang, Y. Liu, M. He, W. Bu, Angew. Chem. Int. Ed. Engl.
2019, 58, 946-956; c) Z. Ren, S. Sun, R. Sun, G. Cui, L.
Hong, B. Rao, A. Li, Z. Yu, Q. Kan, Z. Mao, Adv. Mater.
2020, 32, e1906024; d) Y. Wang, L. Shi, Z. Ye, K. Guan, L.
Teng, J. Wu, X. Yin, G. Song, X.-B. Zhang, Nano Lett. 2019,
20, 176-183.
[16]
[2]
a) T. Wang, H. Zhang, H. Liu, Q. Yuan, F. Ren, Y. Han, Q.
Sun, Z. Li, M. Gao, Adv. Funct. Mater. 2019, 30, 1906128;
b) L.-H. Fu, Y.-R. Hu, C. Qi, T. He, S. Jiang, C. Jiang, J. He,
J. Qu, J. Lin, P. Huang, ACS Nano 2019, 13, 13985-13994;
c) C. Yang, M. R. Younis, J.Zhang, J. Qu, J. Lin, P. Huang,
Small 2020, 16, e2001518; d) T. He, X. Qin, C. Jiang, D.
Jiang, S. Lei, J. Lin, W.-G. Zhu, J. Qu, P. Huang,
Theranostics 2020, 10, 2453-2462; e) Y. Zhang, Y. Wan, Y.
Liao, Y. Hu, T. Jiang, T. He, W. Bi, J. Lin, P. Gong, L. Tang,
P. Huang, Sci. Bull. 2020, 65, 564-572.
[17]
[18]
[19]
[3]
a) X. Chen, H. Zhang, M. Zhang, P. Zhao, R. Song, T. Gong,
Y. Liu, X. He, K. Zhao, W. Bu, Adv. Funct. Mater. 2019, 30,
1908365; b) S. He, Y. Jiang, J. Li, K. Pu, Angew. Chem. Int.
Ed. Engl. 2020, 132, 10633-10638.
a) B. Li, M. Zhao, F. Zhang, ACS Mater. Lett. 2020, 2, 905-
917; b) T. Hirayama, H. Nagasawa, J. Clin. Biochem. Nutr.
2017, 60, 39-48.
7
This article is protected by copyright. All rights reserved.

10.1002/anie.202015379
Angewandte Chemie International Edition
RESEARCH ARTICLE
[20]
E. Graf, J. R. Mahoney, R. G. Bryant, J. W. Eaton, J. Biol.
Chem. 1984, 259, 3620-3624.
[21]
S. Wang, G. Yu, Z. Wang, O. Jacobson, L. S. Lin, W. Yang,
H. Deng, Z. He, Y. Liu, Z. Y. Chen, X. Chen, Angew. Chem.
Int. Ed. Engl. 2019, 58, 14758-14763.
[22]
[23]
a) A. P. Gorka, R. R. Nani, J. Zhu, S. Mackem, M. J.
Schnermann, J. Am. Chem. Soc. 2014, 136, 14153-14159;
b) S. J. Yang, H. Tian, H. M. Xiao, X. H. Shang, X. D. Gong,
S. D. Yao, K. C. Chen, Dyes Pigments 2001, 49, 93-101.
L. S. Lin, T. Huang, J. Song, X. Y. Ou, Z. Wang, H. Deng,
R. Tian, Y. Liu, J. F. Wang, Y. Liu, G. Yu, Z. Zhou, S. Wang,
G. Niu, H. H. Yang, X. Chen, J. Am. Chem. Soc. 2019, 141,
9937-9945.
8
This article is protected by copyright. All rights reserved.

10.1002/anie.202015379
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
A light-triggered transformable ferrous ion (Fe2+) delivery agent (denoted as LET-6) was developed photothermal primed chemodynamic therapy
(CDT). Thermal expansion caused by 808 nm laser irradiation triggered the transformation of LET-6 to expose Fe2+, which primed the catalytic
breakdown of endogenous H2O2 in tumor microenvironment, thus generating abundant of •OH for enhanced CDT. This high-performance Fe2+
delivery system provides a sound basis for future metal-ions-mediated cancer synergistic therapy.
9
This article is protected by copyright. All rights reserved.