Degradable Holey Palladium Nanosheets with Highly Active 1D Nanoholes for Synergetic Phototherapy of Hypoxic Tumors

Article abstract of DOI:10.1021/jacs.9b12929

Pd nanosheets (Pd NSs) have attracted extensive attention due to their promising application in photothermal therapy. However, their photodynamic properties have rarely been reported. Herein, holey Pd NSs (H-Pd NSs) with intrinsic photodynamic and hypoxia-resistant capacities are fabricated for the first time using an anisotropic oxidative etching strategy, which introduces one-dimensional nanoholes with active (100) facets on the hole walls. Gradual degradation of H-Pd NSs is observed in simulated physiological media due to the oxidative etching. In vitro and in vivo studies indicate that the single-component H-Pd NSs can act as a photothermal/photodynamic agent for imaging-guided hypoxic tumor therapy, with a high tumor inhibition rate of 99.7%. This work provides ideas for introducing active facets in metallic pore walls, broadening the application of Pd NSs and the design of biodegradable noble metal nanotheranostic agents for cancer therapy.

Full text of DOI:10.1021/jacs.9b12929

Subscriber access provided by Karolinska Institutet, University Library
Article
Degradable holey palladium nanosheets with highly active
D nanoholes for synergetic phototherapy of hypoxic tumors
1
Shanshan Li, Kai Gu, Hui Wang, Bolong Xu, Huawei Li, Xinghua Shi, Zhijun Huang, and Huiyu Liu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b12929 • Publication Date (Web): 02 Mar 2020
Downloaded from pubs.acs.org on March 2, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 9
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Degradable holey palladium nanosheets with highly active 1D
nanoholes for synergetic phototherapy of hypoxic tumors
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
†
,+
†,+
‡,+
†
‡
‡
*,⊥
Shanshan Li, Kai Gu, Hui Wang, Bolong Xu, Huawei Li, Xinghua Shi, Zhijun Huang, Huiyu
*,†
Liu
AUTHOR ADDRESS
†Beijing Advanced Innovation Center for Soft Matter Science and Engineering, State Key Laboratory of Organic-
Inorganic Composites, Bionanomaterials & Translational Engineering Laboratory, Beijing Key Laboratory of
Bioprocess, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029,
P.R. China.
‡CAS Key Laboratory of Nanosystem and Hierarchial Fabrication, CAS Center for Excellence in Nanoscience, National
Center for Nanoscience and Technology, Beijing 100190, P.R. China.
⊥
Beijing National Laboratory of Molecular Sciences, Key Laboratory of Green Printing, Institute of Chemistry, Chinese
Academy of Sciences, Beijing 100190, P.R. China.
ABSTRACT: Pd nanosheets (Pd NSs) have attracted extensive attention due to their promising application in photothermal
therapy. However, their photodynamic properties have rarely been reported. Herein, holey Pd NSs (H-Pd NSs) with intrinsic
photodynamic and hypoxia-resistant capacities are fabricated for the first time using an anisotropic oxidative etching
strategy, which introduces one-dimensional nanoholes with active (100) facets on the hole walls. Gradual degradation of H-
Pd NSs is observed in simulated physiological media due to the oxidative etching. In vitro and in vivo studies indicate that the
single-component H-Pd NSs can act as a photothermal/photodynamic agent for imaging-guided hypoxic tumor therapy, with
a high tumor inhibition rate of 99.7%. This work provides ideas for introducing active facets in metallic pore walls, broadening
the application of Pd NSs and the design of biodegradable noble metal nanotheranostic agents for cancer therapy.
INTRODUCTION
activity Pd(111) facets are the dominant exposed surfaces.
Modulating the surface facets and constructing a porous
structure to increase the specific surface area are two
Bifunctional phototherapy agents, which simultaneously
possess the intrinsic photothermal and photodynamic
functions, have shown promise for application in cancer
therapy due to their much higher efficacy than single-modal
photothermal therapy (PTT) or photodynamic therapy (PDT)
1
3,14
conventional methods to obtain efficient catalysts.
However, it is very challenging to control the exposed facets of
the pore walls of noble metal materials to further improve their
catalytic performance. In this work, we prepared holey Pd NSs
(H-Pd NSs) with highly active Pd(100) facets on the walls of
one-dimensional (1D) holes by anisotropic oxidative etching of
intact Pd NSs. These facets showed high efficiency for the
1
−3
agents.
PTT/PDT agents is highly dependent on the O
hypoxia, one of the principal features of solid tumors,
However, the PDT effect of these bifunctional
2
supply. Tumor
4,5
significantly limits the therapeutic efficiency of PDT.
Moreover, continuous O consumption and vasculature injury
during PDT might further accelerate tumor hypoxia and reduce
2 2 2 2
decomposition of H O to O and the activation of O to reactive
2
oxide species (ROS) under near-infrared (NIR) light irradiation,
which makes H-Pd NSs great candidates for PDT against
hypoxic tumors. Additionally, the degradability of H-Pd NSs
was demonstrated, which has rarely been reported to the best
of our knowledge. Moreover, in vitro and in vivo studies
suggested that H-Pd NSs can act as a tetra-functional PDT/PTT
agent with hypoxia modulation ability for imaging-guided
cancer therapy. We believe that H-Pd NSs will open up new
horizons for introducing active facets on metallic holey walls,
broadening the application of Pd NSs and furthering the design
of multifunctional single nanomaterials for cancer therapy.
6
the PDT effect in turn. Given these issues, many strategies,
7
,8
such as transporting O
generating O in situ via catalase or catalase mimics, and
increasing the tumor vessel densities by hyaluronidase
2 2
to the tumor region by O carriers,
9
2
10
(
HAase), have been developed. However, the introduction of
extra O carriers and the instability of enzyme-based
2
complexes still hinder their practical application. Hence, it is
critical to develop nanomaterials with inherent structural
multifunctionality for regulating tumor hypoxia and improving
therapeutic efficacy in cancer phototherapy.
RESULTS AND DISCUSSION
Ultrathin hexagonal palladium nanosheets (Pd NSs) with
adjustable and robust surface plasmon resonance (SPR)
absorption in the near-infrared (NIR) region are promising
Characterization of materials. H-Pd NSs were prepared by
oxidative etching of fresh Pd NSs (Figure 1A), which were
obtained by treatment under pressurized CO at 80 °C for 3 h
1
1,12
PTT agents.
However, both their intrinsic PDT and hypoxia
1
5
modulation capabilities have rarely been explored, as the low-
and washed with an ethanol/acetone mixture.
The
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 9
transmission electron microscopy (TEM) image in Figure 1B
increased slightly to about 5.1 nm (Figure S8), as deterimined
by AFM, and about 2.1 nm (Figure 1G), according to TEM
analysis. This could be attributed to the regrowth of Pd during
etching, wherein the oxidized and subsequently dissolved Pd
species were partially reduced and epitaxially grew on the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
indicates that the Pd NSs displayed a hexagonal shape. The
diagonal length was adjusted to 110−130 nm to improve tumor
targeting via the enhanced permeability and retention (EPR)
1
6
effect. The absorption by Pd NSs is presented in Figure S1 and
1
1
22
can be facilely tuned by regulating the particle size. The
surface of the Pd NSs. Both etching and regrowth increased
diagonal length could be decreased from 130−160 nm to
the roughness of the surface. The fluctuanting thickness
distribution of the H-Pd NSs can be clearly observed in Figure
1E,F and was also confirmed by the 3D AFM image in Figure S8,
which demonstrated a hill-like surface. The rough surface
provided H-Pd NSs with a large number of defects and
coordinately unsaturated atoms, which were highly active in
catalysis.
8
0−100 nm by increasing the amount of water (Figure S2).
After dispersion of the fresh Pd NSs in ethanol for 10 days
under stirring, the dark blue solution turned black and H-Pd
NSs were obtained. The typical TEM images in Figure 1C,D
suggest the existence of numerous 1D nanoholes with a width
of approximately 1.6 nm. The destructive effect of an electron
beam on metal nanostructures has been observed in previous
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
7,18
studies.
To exclude the possibility that the holes were
caused by the electron beam during the TEM experiments, the
H-Pd NSs were continuously observed with TEM for 3 min. No
obvious change in the holey structure was observed. In
contrast to the surface of H-Pd, numerous irregular holes
appeared on the Pd NSs after electron beam irradiation (Figure
S3). Although the morphology was distorted slightly and the
average hydrodynamic diameter decreased from 150 to 140
nm (Figure S4), the hexagonal shape of the fresh Pd NSs was
preserved after etching. This was critical for retaining the NIR
absorption by the H-Pds. The crystallographic structure of the
H-Pd NSs was investigated by high-resolution TEM (Figure 1D).
The lattice fringes with an interplanar spacing of ~0.21 nm
correspond to the (111) facets of fcc Pd. The structure of the H-
Pd NSs was further elucidated by powder X-ray diffraction
(
XRD, Figure S5) and selected-area electron diffraction (SAED,
Figure 1D). XRD indicated the presence of peaks at 40.2°, 46.6°,
and 68.6°, corresponding to the (111), (200) and (220) facets
of fcc Pd (JCPDS 05-0681), respectively. A similar result was
confirmed by the SAED pattern. These results were highly
consistent with the results for fresh Pd NSs reported
Figure 1. Preparation of H-Pd NSs. (A) Schematic illustration of
the synthetic process for the H-Pd NSs. TEM images of (B) Pd
NSs and (C) H-Pd NSs. (D) High-resolution TEM image and
SAED pattern of H-Pd NSs. (E) AFM image and (F) the
corresponding thickness distribution curves of H-Pd NSs. (G)
The thickness of H-Pd NSs measured by TEM.
previously, indicating that the dominant surfaces of H-Pd NSs
were (111) facets and the sidewalls were (100) facets.11 As
shown in Figure S6, the surface chemistry of H-Pd NSs was
investigated by X-ray photoelectron spectroscopy. Four
elements, C, N, O and Pd, were observed (Figure S6A). The first
three elements were mainly attributed to polyvinylpyrrolidone
Mechanism of etching. To further investigate the oxidative
etching mechanism, the etching process was monitored by
ultraviolet-visible-near-infrared (UV–vis–NIR) absorption
spectroscopy. As shown in Figure 2A, the absorption spectra
exhibited no obvious change in the initial 9 days except for the
slight intensity decrease to 88.7%. However, the absorption
intensity sharply decreased to 62.2% on the 10th day, and the
absorption peak redshifted from 1060 to 1160 nm. In addition,
the hexagonal shape and smooth surface were maintained for
(
PVP) coated on the surface of the H-Pd NSs. In addition, the
surface atoms of Pd nanomaterials could be partially oxidized
to PdO. To identify this change, two peaks were fitted
according to the Pd 3d5/2 spectrum (Figure S6B). The peak at
1
9
3
PdO.
36.5 eV was ascribed to Pd(II), indicating the existence of
2
0,21
This oxidation may reduce the stability of Pd NSs and
induce oxidative etching.
5
days (Figure 2B). By the 9th day, only slight deformation at
A few studies have reported the oxidative etching of Pd
the edge was found, while a large number of 1D nanoholes were
generated on Pd NSs on the 10th and 12th days. These
phenomena are consistent with the UV–vis–NIR results and
indicated that the etching progressed slowly in the initial 9
days and accelerated on the 10th day.
−
17,22
nanostructures by Br /O
2
pairs,
but anisotropic etching has
never been reported. In this work, most of the holes on the H-
Pd NSs were 1D nanostructures, suggesting anisotropic
etching. According to the TEM images (Figure 1C,D), these 1D
holes exhibited a uniform orientation and were parallel to the
sidewalls and the (111) lattice fringes of the H-Pd NSs. This
indicated preferential etching along the diagonal (110)
direction, leading to the formation of 1D holes with (100) facets
–
Previous studies revealed that Br plays an important role in
controlling the shape of Pd nanostructures due to its
preferential adsorption on the (100) facets of fcc Pd. Therefore,
–
2
3
we speculated that Br may play a vital role in H-Pd NS etching.
on the hole walls. The thickness and surface morphology of
the samples were investigated by atomic force microscopy
To verify this speculation, NaBr-free Pd NSs were prepared.
The newly prepared Pd NSs were dispersed in ethanol to fully
dissolve the NaBr. Acetone was then added to precipitate the
Pd NSs. The as-prepared NaBr-free Pd NSs were then aged in
ethanol with different concentrations of NaBr to study the
(
AFM). As shown in Figure S7, the Pd NSs displayed a smooth
surface and the thickness was determined to be 4.0 nm.
Notably, the thickness measured by TEM in previous studies
was 1.8 nm. The thickness obtained with AFM was larger than
the actual value because of the presence of capping agents on
the surface. After etching, the thickness of the H-Pd NSs
2
4
−
effect of Br on etching. Due to the poor solubility of NaBr in
–
acetone, Br could not be removed completely by washing with
ACS Paragon Plus Environment

Page 3 of 9
Journal of the American Chemical Society
ethanol/acetone mixture. As shown in Figure 2C, with
increase in the H-Pd NS solution (24.9 °C). The photothermal
conversion efficiency of the Pd NSs was calculated to be 30.9%
(Figure S11), while that of the H-Pd NSs was 35.1%. The
photothermal stability of the H-Pd NSs was also tested. After a
five-run cycling experiment, no obvious change in the heating
curves was observed (Figure S12A) and the TEM image
indicated that the edges of the H-Pd NSs only slightly curled up
(Figure S12B).
1
2
3
4
5
6
7
8
9
increasing of NaBr concentration, the aging time determined by
the sharp decrease in the UV–vis–NIR absorption intensity
–
1
increased significantly. With 0 and 1 μg mL NaBr, the Pd NSs
could be aged in 1.5 and 3 days, respectively. Rough surfaces
were observed and no holes could be formed (Figure 2D,E).
–
1
When 10 and 100 μg mL NaBr were used, the aging time
increased and a large number of 1D holes were generated
(
Figure 2F,G). Pd NSs could not be aged within 18 days when
–
1
25
the concentration of NaBr was increased to 5000 μg mL . The
edges of the Pd NSs were etched slightly and the smooth
surface was preserved (Figure 2H). This is induced by the
strong binding ability of Br to the Pd NSs, which could protect
the Pd NSs from oxidative etching. Oxidative etching in water
and N,N-dimethylformamide (DMF) was also investigated
Plasmonic nanomaterials, such as Au nanostructures,
2
6
27
MXene nanosheets and copper sulfide nanocrystals usually
exhibit both PTT and PDT properties. Pd NSs possess strong
NIR SPR absorption and excellent PTT performance, but their
PDT activity has never been reported, although Pd
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–
2
2
2
8
nanocrystals were used for the activation of O
2
in the dark. To
(
Figure S9). Irregular holes were generated, indicating that
indicate whether Pd NSs have PDT capability, the catalytic
1
solvents have a major effect on the etching behavior.
activity for the generation of O
2 2
from O was tested by electron
spin resonance (ESR). 2,2,6,6-Tetramethylpiperide was used as
1
Based on these results, an oxidative etching mechanism was
proposed (Figure 2I). First, the surface Pd atoms on the basal
2
the trapping agent to detect O . As shown in Figure 3B, the
intensities of the ESR signals from pure solvent were not
(
111) facets were oxidized to PdO molecules, which were then
obviously different before and after NIR light irradiation,
1
dissolved to a yellow soluble substance (Figure S10) and
removed from Pd NSs. This process slowed when NaBr was
added because Br could block the active Pd atoms on the
indicating that O
2
could not be generated without the PSs. The
ESR signal of the Pd NSs in the dark exhibited no obvious
increase compared with that of pure solvent. A slight
enhancement of the ESR signal was achieved after NIR light
irradiation, suggesting that the Pd NSs indeed demonstrated
some PDT properties, although the efficiency was relatively
low. The possible PDT pactivity was also investigated by dye
oxidation. The results were in agreement with those of the ESR
experiments. As exhibited in Figure S13, 9,10-
diphenylanthracene (DPA) was oxidized slowly to 9,10-
–
2
surface from oxidation by O . After etching the surface Pd
atoms, highly active facets, such as the (100) and (110) facets,
were exposed to the oxidants. Therefore, the etching rate
increased quickly. Meanwhile, the selective binding of Br–
protected the Pd(100) facets, leading to anisotropic etching
toward the diagonal (110) direction and the formation of 1D
nanoholes with (100) facets on the walls.
diphenanthraquinone dioxide (DPO
2
) in the dark with Pd NSs.
The oxidation rate increased slightly after NIR laser irradiation,
1
which could have been caused by the O
2
generated via the
2
5
transformation of energy from plasmonic Pd NSs to O
2
.
The effect of porosity on the catalytic activities of H-Pd NSs
was subsequently investigated. As shown in Figure S13A, a
rapid decrease in the DPA concentration could be observed,
suggesting the high catalytic activity of H-Pd NSs. The DPA
concentration decreased by 48.0% within 5 min, while only
21.5% of the decrease was obtained with Pd NSs under the
same conditions (Figure S13B). The high catalytic activity of
1
the H-Pd NSs could be attributed to their high O
rate.
2
generation
To clarify the facet effect on O
to the low-index facets of fcc Pd, including the (100), (110) and
111) facets, was studied by density functional theory (DFT)
calculations. The most favorable configurations of
interacting with the above three facets are displayed in Figure
3D–F. The bond lengths of the O adsorbed on Pd(100),
Pd(110) and Pd(111) were 1.420, 1.407 and 1.324 Å,
respectively. Clearly, O on Pd(111) exhibited the shortest
bond length. The binding energies of O on Pd(100), Pd(110)
2 2
activation, the binding of O
(
O
2
Figure 2. Etching process of Pd NSs. (A) Time-dependent UV–
vis–NIR absorption spectra of Pd NSs during oxidative etching.
2
(
B) Time-dependent TEM images of Pd NSs during oxidative
2
etching at time points of 5, 9, 10, and 12 days. Scale bar = 100
nm. (C) Aging time of Pd NS solutions with different NaBr
concentrations (0, 1, 10, 50, 100, and 5000 μg mL ). Oxidative
2
and Pd(111) were calculated to be –1.229, –1.070 and –0.673
eV, respectively. These results implied that the interaction
−1
etching products of Pd NSs with NaBr concentrations of (D) 0,
between O
2 2
and Pd(111) was weakest of the three and the O
−
1
(E) 1, (F) 10, (G) 100 and (H) 5000 μg mL . (I) Etching
adsorbed on Pd(100) was much more active than that
1
procedure and mechanism of Pd NSs.
adsorbed on Pd(100) and Pd(110). The difference between O
and O originates from the different distribution of the two
electrons in the π* orbital. For O , the two electrons occupy two
π* orbitals. The spin directions are the same. As a result, the
2
2
Photodynamic, photothermal and catalytic properties of
H-Pd NSs. A high photothermal conversion efficiency is a
striking feature of ultrathin Pd NSs. As shown in Figure 3A, the
temperature of the Pd NS solution increased by 34.8 °C after
laser irradiation, which was higher than the temperature
2
1
spin quantum number of O
2 2
is 1. For O , two electrons occupy
the same π* orbital and the spin directions are opposite, thus,
1
2
the spin quantum number of O is 0. We characterized their
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 9
spin by calculating the projected density of states (PDOS) of O
on the three fcc Pd facets. The results in Figure 3G,H show that
the spin quantum numbers of the O adsorbed on Pd(100) and
Pd(110) were almost equal to 0, indicating that these O
molecules have gone through a spin-flip process and can be
2
different systems (H
over time and photographs of H
addition of H-Pd NSs or Pd NSs for 5 min. The most favorable
adsorption configurations of O on (D) Pd(100), (E) Pd(110)
and (F) Pd(111) facets. PDOS of O adsorbed on the (G)
2
O
2
, H
2
O
2
+ Pd NSs, and H
2 2
O + H-Pd NSs)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2 2
O
aqueous solution after the
2
2
2
2
1
easily converted into O
Pd(111), the spin state is similar to that of free O
suggesting a lower potential for the generation of
Pd(111). This is the main reason for the low O activation
2
. However, for the O
2
adsorbed on
Pd(100), (H) Pd(110) and (I) Pd(111) facets.
2
(Figure 3I),
1
O
2
on
Degradability of Pd NSs and H-Pd NSs. Although noble metal
33
nanomaterials have been widely used in biological fields,
their biodegradability has rarely been investigated.
2
3
4
activity of the Pd NSs, as they were dominantly covered by
Pd(111) facets. On the other hand, the anisotropic etching of Pd
Considering that the oxidative etching of Pd NSs may lead to the
generation of soluble Pd species, the biodegradation behavior
of Pd NSs was first studied by TEM. As shown in Figure 4A,
obvious degradation at the edges of the Pd NSs could be
observed after incubation with simulated body fluid (SBF, pH
7.4), which is similar to the oxidative etching Pd NSs at high
NaBr concentrations. The size of the Pd NSs decreased
gradually with increasing incubation time. Meanwhile, the
color of the blue Pd NS SBF solution faded and the absorption
intensity at 1160 nm decreased continuously (Figure 4B).
Unlike those of the H-Pd NSs, the degradation products of the
Pd NSs had smooth surfaces, indicating that degradation
occurred at the edge (100) planes but not at the basal (111)
planes. H-Pd NSs with more exposed (100) planes were
degraded faster, which was confirmed by the rapid decrease in
the absorption intensity of the H-Pd NSs in SBF. The TEM
images in Figure 4C demonstrate the different degradation
behavior of the H-Pd NSs. Degradation mainly started at the 1D
holes due to the active (100) facets onthe hole walls. This led to
the formation of smaller degradation products, which could
NSs resulted in 1D nanoholes with active (100) facets on the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
hole walls, which contributed to the high
2
O generation
activity of the H-Pd NSs. Moreover, it should be noted that the
capping agent might cover the active sites and significantly
29
reduce the catalytic activity. The newly produced active
facets on the H-Pd NSs contained less or no capping agent,
which may have further enhanced the catalytic performance.
The high NIR photothermal efficiency and excellent NIR
photocatalytic activity for O activation make H-Pd NSs a
2
promising candidate for PTT/PDT combined cancer therapy.
However, the efficacy could be limited by the hypoxia of solid
30,31
tumors.
rich in H
Because the tumor microenvironment is usually
2 2
O , the catalytic performances of Pd NSs and H-Pd NSs
for the decomposition of H
could not be decomposed by the Pd NSs. However, after adding
H-Pd NSs to the H aqueous solution, O was generated
rapidly (Figure 3C). The O concentration in the solution
determined by the oxygen probe increased from 8.7 to 17.3 mg
2 2 2 2 2
O to O were investigated. H O
2
O
2
2
2
−
1
35
L
within 5 min, suggesting the high catalytic activity of the H-
facilitate renal clearance. The degradation of H-Pd NSs in
1
Pd NSs. In addition, the generation of O
presence of H was also evidenced by ESR measurements. As
shown in Figure 3B, the intensity of the ESR signal increased by
59% upon the addition of H . The difference in the catalytic
2
by H-Pd NSs in the
simulated lysosomal fluid (SLF) was also investigated (Figure
4D). No obvious difference in the degradation behavior but a
slightly higher degradation rate was observed. The aciditye of
SLF (pH 4.5) could accelerate the degradation, which is
consistent with the results in Figure 4B.
2 2
O
2 2
O
activity between Pd NSs and H-Pd NSs can be ascribed to the
facet-dependent catalase-like activity of Pd. The decomposition
3
2
2 2
rate of H O was low on the Pd(111) facets, leading to the
poor catalytic performance of the Pd NSs, while the H-Pd NSs
showed high activity due to the rich active facets on the hole
walls.
Figure 4. Degradability of Pd NSs and H-Pd NSs. (A) TEM
images of Pd NSs after incubation in SBF at 37 °C for different
durations. (B) Relative absorption peak intensities at 1160 nm
after incubation of Pd NSs in SBF and H-Pd NSs in SBF or SLF
for different durations. TEM images of H-Pd NSs incubated in
(C) SBF and (D) SLF at 37 °C for different durations.
In vitro therapeutic effect of H-Pd NSs. Encouraged by the
excellent photothermal properties and high catalytic activities
1
Figure 3. Photothermal, photodynamic, and catalytic
for the generation of O and O , the in vitro therapeutic effect
2
2
properties of H-Pd NSs and Pd NSs. (A) Temperature
of the H-Pd NSs was investigated. First, to test the cellular
uptake of the H-Pd NSs, 4T1 cells were incubated with the H-Pd
−
1
−1
measurements of H-Pd NSs (50 μg mL ), Pd NSs (50 μg mL )
−
1
and pure water (control) under 808 nm laser irradiation (1 W
NSs at a concentration of 100 μg mL for 4, 12, and 24 h. After
washing with PBS, the cell nuclei and lysosomes were stained
with 4’,6-diamidino-2-phenylin-dole (DAPI) and LysoTracker
−
2
cm ). (B) ESR spectra of Pd NSs and H-Pd NSs under different
−
2
2
conditions (2 W cm for NIR groups). (C) O concentration in
ACS Paragon Plus Environment

Page 5 of 9
Journal of the American Chemical Society
Red, respectively. As shown in Figure 5A and S14, the red,
production of reactive oxygen radicals from H
absence of NIR light.
2 2
O in the
1
2
3
4
5
6
7
8
9
green and blue fluorescence represented lysosomes, H-Pd NSs
and nuclei, respectively. H-Pd NSs were observed around the
cell nuclei and located in lysosomes at 12 h and 24 h, indicating
efficient cellular uptake.
Previous studies revealed that Pd NSs exhibited no obvious
36
cytotoxicity. However, whether the hole structure of H-Pd
NSs can affect their biosafety is unknown. Therefore, the dark
cytotoxicity of both the H-Pd NSs and Pd NSs was examined
before in vivo experiments. 4T1 cells were incubated with Pd
NSs or H-Pd NSs for 24 h and tested by the 3-(4,5-
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
assay. As shown in Figure 5B, no obvious dark toxicity could be
observed in either the Pd NS or H-Pd NS groups, even at a
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
−1
concentration of 200 μg mL , which indicated high
biocompatibility.
Subsequently, the photoinduced killing efficacy of the H-Pd
NSs was evaluated in vitro (Figure 5C). 4T1 cells with different
treatments were stained with calcein acetoxymethyl ester
(
calcein-AM) and propidium iodide (PI). The live and dead cells
could be marked by green and red fluorescence, respectively.
Most of the cells survived in the PBS, PBS + NIR, Pd NS and H-
Pd NS groups. However, only a few living cells could be
observed in Pd NSs + NIR group, indicating the high PTT
efficacy of the Pd NSs. H-Pd NSs + NIR showed greater
therapeutic efficacy than Pd NSs + NIR, which could be
attributed to the outstanding PDT performance. The cell killing
efficiency of H-Pd NSs and Pd NSs was further quantitatively
investigated by MTT assay (Figure 5D). The cell killing efficacy
of H-Pd NSs is 92.47%, which is much higher than that of Pd
NSs (40.05%). To further investigate the hypoxia modulation
ability of H-Pd NSs in vitro, the in vitro therapeutic efficiency of
H-Pd NSs was tested under both normoxic and hypoxic
conditions. The results showed that the cancer cell killing
efficiency of H-Pd NSs showed no obvious differences between
normoxia and hypoxia (Figure 5D), suggesting that the H-Pd
Figure 5. In vitro experiments of H-Pd NSs and Pd NSs. (A)
CLSM images of 4T1 cells incubated with H-Pd NSs at 100 μg
−
1
mL for 4, 12, and 24 h. Blue, nucleus; red, lysosome; green, H-
Pd NSs. Scale bar = 25 μm. (B) Cell viability of 4T1 cells
incubated with different concentrations of Pd NSs or H-Pd NSs
−1
(
0, 6.25, 12.5, 25, 50, 100, and 200 μg mL ) (n = 5). (C) CLSM
images of 4T1 cells co-stained with calcein-AM and PI after
different treatments (PBS, PBS + NIR, Pd NSs, Pd NSs + NIR, H-
Pd NSs, and H-Pd NSs + NIR); green and red fluorescence
represent live and dead cells respectively; scale bar = 200 μm.
(
D) Viability of 4T1 cells after incubation with different
concentrations of H-Pd NSs or Pd NSs (0, 6.25, 12.5, 25, and 50
μg mL ) under hypoxic or normoxic conditions and irradiated
by an 808 nm laser with a power density of 1 W cm for 3 min
−
1
−2
2 2 2
NSs could effectively decompose H O into O and regulate
per well (n = 3). Mean values and error bars are defined as the
mean and s.d., respectively. P > 0.05, *P < 0.05, **P < 0.01, ***P
< 0.001. (E) CLSM images of ROS in 4T1 cells with different
treatments (PBS, PBS + NIR, Pd NSs, Pd NSs + NIR, H-Pd NSs,
and H-Pd NSs + NIR); scale bar = 250 μm.
tumor hypoxia.
To investigate whether the higher therapeutic efficiency of
H-Pd NSs was induced by PDT, the ROS generation rate of H-Pd
NSs and Pd NSs was tested at the cellular level. 4T1 cells were
first incubated with PBS, Pd NSs or H-Pd NSs for 24 h and then
incubated with 2,7-dichlorodihydrofluorescein diacetate
In vivo therapeutic effect of H-Pd NSs. For in vivo
experiments, the hemolytic behavior of the H-Pd NSs was first
investigated. As shown in Figure S16, only a few hemolytic
RBCs could be detected at the very high concentration of 200
(
DCFH-DA) for 30 min. After washing with PBS, the samples
were exposed to an NIR laser for 3 min. Confocal laser scanning
microscopy (CLSM) was used to observe the green
fluorescence from the oxidation products of DCFH-DA. As
shown in Figure 5E, a strong fluorescence signal could be
observed in H-Pd NSs + NIR group, indicating the efficient PDT
effect of H-Pd NSs. The fluorescence intensity was enhanced
slightly in Pd NSs + NIR and H-Pd NS groups compared with the
PBS groups. These results were consistent with those of the
ESR and dye oxidation experiments, which suggested that H-Pd
NSs could serve as PSs for cancer PDT. Notably, ROS were also
–
1
μg mL (5.2%). No obvious hemolytic RBCs (hemolysis rate <
–
1
5
%) were observed at 100 μg mL H-Pd NSs, suggesting
favorable biocompatibility. The blood circulation of the H-Pd
NSs was then investigated. The circulation half-life of the H-Pd
NSs in the bloodstream was calculated to be 1.09 h based on a
two-compartment pharmacokinetic model (Figure S17). The
accumulation of the H-Pd NSs in the tumor was measured by
photoacoustic (PA) imaging. After injection of the H-Pd NSs, a
strong PA signal from the H-Pd NSs could be clearly observed
at the tumor site 18 h post injection (Figure 6A), indicating the
effective intratumoral aggregation of H-Pd NSs based on the
typical EPR effect on passive tumor targeting and
produced in the H-Pd NS group. Considering that H-Pd without
1
laser irradiation did not produce O
2
(Figure 3B), H-Pd can also
produce other types of ROS, such as hydroxyl radicals, without
NIR irradiation. Therefore, we mixed H-Pd NSs or Pd NSs (50
3
7
–
1
accumulation. This was also indicated by quantitative
analysis with inductively coupled plasma mass spectrometry
μg mL ) with the TMB liquid substrate system at a volume
ratio of 1:10 and observed the color changes. As shown in
Figure S15, after 3 min of reaction with TMB, the solution color
changed from gray to blue rapidly in the H-Pd NSs + TMB
(
ICP-MS) (Figure S18). Before injection of the H-Pd NSs, an
obvious blue signal could be found at the tumor sites, implying
hypoxic microenvironment of the tumor. With the
a
2 2
(H O ) group, which suggested that H-Pd NSs can catalyze the
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 9
accumulation of H-Pd NSs at the tumor sites within the first 18
h, the concentration of oxygenated hemoglobin (HbO , red
signal) at the tumor sites increased significantly, while the
HbO concentration decreased with the decrease in H-Pd NSs at
4 h (Figure 6A), suggesting the decomposition of H to O in
vivo. Moreover, the hypoxic environment of the tumor was
further studied by a hypoxia-inducible factor (HIF)-1α staining
assay. As shown in Figure S19, the hypoxia status in the H-Pd
NSs and H-Pd NSs + NIR groups was significantly modulated by
H-Pd NSs compared with that in the other four groups. The
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
2
2
2
O
2
2
2 2
decomposition of H O in vivo can overcome the hypoxia of
tumors and improve the PDT efficiency.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Considering the potential hypoxia-resistant PTT/PDT
efficacy demonstrated above, the antitumor efficacy of H-Pd
NSs was further investigated. Female Balb/c mice bearing 4T1
breast tumors were randomly divided into six groups (n=5) (I,
PBS; II, PBS + NIR; III, Pd NSs; IV, Pd NSs + NIR; V, H-Pd NSs; VI,
H-Pd NSs + NIR). Each group was treated with different
procedures, as outlined in the experimental section. Guided by
PA imaging, groups II, IV, and VI were exposed to an 808 nm
−
2
laser (1 W cm ) for 5 min after administration for 18 h. The
temperature of the tumor sites was monitored by an infrared
thermal mapping apparatus (FLIR Systems) during irradiation
(
Figure 6B and S20). The temperature reached 48.1 and 49.8 °C
in the H-Pd NSs + NIR and Pd NSs + NIR groups, respectively,
indicating the high PTT abilities of Pd NSs and H-Pd NSs. The
mice were sacrificed after therapy and the tumors were
collected and stained with hematoxylin and eosin (H&E)
(
Figure S21). The obvious therapeutic efficiency of the H-Pd
NSs + NIR and Pd NSs + NIR groups could be visually confirmed
by the small tumor volumes (Figure 6C). The therapeutic
efficiency of H-Pd NSs + NIR was much better than that of Pd
NSs + NIR, although the H-Pd NSs exhibited slightly fewer
thermal effects during therapy. The tumors in the H-Pd NSs +
NIR group became very small or even disappeared. The tumor
volumes were also monitored by photographing the mice in
different groups during the 14-day therapeutic period (Figure
Figure 6. In vivo therapy of mice bearing 4T1 breast tumors.
(A) PA imaging of mice before and after H-Pd NS injection via
the tail vein. Green, H-Pd NSs; red, HbO
2
; blue, Hb. (B) IR
thermal images of mice injected with PBS, H-Pd NSs or Pd NSs
−
1
−2
6
D). Obvious tumor inhibition was observed in the H-Pd NSs +
(10 mg kg ) after exposure to an 808 nm laser (1 W cm ). (C)
Photographs of tumors from different groups after 14 days of
therapy. (D) Photographs of mice from different groups after
therapy for 0, 4, 8 and 14 days. Tumor volume (E) and body
weight (F) of different groups during the 14-day therapeutic
period. I, PBS; II, PBS + NIR; III, Pd NSs; IV, Pd NSs + NIR; V, H-
Pd NSs; VI, H-Pd NSs + NIR for (B)–(F) (n = 5). Mean values and
error bars are defined as the mean and s.d., respectively. P >
0.05, *P < 0.05, **P < 0.01, ***P < 0.001.
NIR group. The changes in tumor volume were quantified by
measuring the tumor sizes every two days (Figure 6E). The
tumor volume in the H-Pd NSs + NIR group decreased
continuously. The tumor inhibition rate reached 99.7%.
However, obvious tumor regrowth was observed in the Pd NSs
+
NIR group after 6 days of therapy. This strongly suggested the
positive effect of the PDT activity of H-Pd NSs. The biosafety of
the H-Pd NSs was also confirmed by weighing the mice (Figure
6
F). No obvious weight loss was observed. Additionally, to
investigate the in vivo degradability, the amount of palladium
in urine and feces was detected after injection of the H-Pd NSs
(Figure S22). The results show that palladium could be
excreted in both urine and feces but mainly in urine. The
palladium content in urine and feces increased significantly at
CONCLUSION
In conclusion, holey Pd nanosheets, called H-Pd NSs, which can
be used for imaging-guided PTT/PDT of hypoxic tumors, were
successfully fabricated. The anisotropic oxidative etching of Pd
NSs results in 1D nanoholes with hole walls covered by active
(100) facets. The high catalytic activity of H-Pd NSs for the
3
−6 h and 6−8 h post injection, respectively. The degradation
rate in vivo was higher than that in vitro, which may be caused
by the complex internal environment in vivo. These results
strongly suggested that H-Pd NSs can be degraded in vivo. The
main tissues in each group were collected and stained with
H&E after the therapeutic period (Figure S21). No obvious
damage could be observed, which confirmed the great
potential of H-Pd NSs for cancer therapy.
1
generation of O
2
from O
2
is reported, indicating their potential
can be decomposed into O by H-Pd
as PSs for tumor PDT. H
2
O
2
2
NSs, which modulate the hypoxic environment of the tumors.
The oxidative etching also enables the degradation of H-Pd NSs
in simulated physiological media. H-Pd NSs inherit the
photothermal and imaging properties of Pd NSs. In vitro and in
vivo studies suggest that H-Pd NSs demonstrate excellent
photothermal stability, biocompatibility and tumor-specific
accumulation. A 99.7% in vivo tumor inhibition rate was
ACS Paragon Plus Environment

Page 7 of 9
Journal of the American Chemical Society
reached with the H-Pd NSs under NIR laser irradiation. This
[7] Tang, W.; Zhen, Z. P.; Wang, M. Z.; Wang, H.; Chuang, Y. J.; Zhang,
W. Z.; Wang, G. D.; Todd, T.; Cowger, T.; Chen, H. M.; Liu, L.; Li, Z. B.;
Xie J. Red blood cell-facilitated photodynamic therapy for cancer
treatment. Adv. Funct. Mater. 2016, 26, 1757–1768.
1
2
3
4
5
6
7
8
9
work opens the door to fabricate porous metal nanocrystals
with pore walls covered by active facets, reveals the PDT
activity of Pd nanostructures, and provides a reference for the
design biodegradable noble metal nanotheranostic agents for
cancer therapy.
[
8] Sharma, A.; Arambula, J. F.; Koo, S.; Kumar, R.; Singh, H.; Sessler,
J. L.; & Kim, J. S. Hypoxia-targeted drug delivery. Chem. Soc. Rev.
2019, 48, 725–964.
[9] Chen, H. C.; Tian, J. W.; He, W. J.; Guo, Z. J. H
2 2
O -activatable and
ASSOCIATED CONTENT
Supporting Information.
This material is available free of charge via the Internet at
http://pubs.acs.org.
O
2
-evolving nanoparticles for highly efficient and selective
photodynamic therapy against hypoxic tumor cells. J. Am. Chem.
Soc. 2015, 137, 1539–1547.
[10] Gong, H.; Chao, Y.; Xiang, J.; Han, X.; Song, G. S.; Feng, L. Z.; Liu,
J. J.; Yang, G. B.; Chen, Q.; Liu, Z. Hyaluronidase to enhance
nanoparticle-based photodynamic tumor therapy. Nano Lett. 2016,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Materials and methods and additional experimental data
PDF)
(
1
6, 2512–2521.
[11] Huang, X. Q.; Tang, S. H.; Mu, X. L.; Dai, Y.; Chen, G. X.; Zhou, Z.
AUTHOR INFORMATION
Y.; Ruan, F. X.; Yang, Z. L.; Zheng, N. F. Freestanding palladium
nanosheets with plasmonic and catalytic properties. Nat.
Nanotechnol. 2011, 6, 28–32.
[12] Tang, S. H.; Chen, M.; Zheng, N. F. Sub-10-nm Pd nanosheets
with renal clearance for efficient near-infrared photothermal
cancer therapy. Small 2014, 10, 3139–3144.
+
These authors contributed equally.
Corresponding Author
*
hzj@iccas.ac.cn
*liuhy@mail.buct.edu.cn.
[13] Strasser, P.; Gliech, M.; Kuehl, S.; Moeller, T. Electrochemical
processes on solid shaped nanoparticles with defined facets. Chem.
Soc. Rev. 2018, 47, 715–735.
Notes
[
14] Zhu, B. E.; Xu, Z.; Wang, C. L.; Gao, Y. Shape evolution of metal
nanoparticles in water vapor environment. Nano Lett. 2016, 16,
628–2632.
15] Gu, K.; Pan, X. T.; Wang, W. W.; Ma, J. J.; Sun, Y.; Yang, H. L.; Shen,
The authors declare no competing financial interests.
2
[
ACKNOWLEDGMENT
This work was financially supported by the National Natural
Science Foundation of China (No. 21822802, 51772018,
H. Y.; Huang, Z. J.; Liu H. Y. In situ growth of Pd nanosheets on g-
C3N4 nanosheets with well-contacted interface and enhanced
catalytic performance for 4-nitrophenol reduction. Small 2018, 14,
1801812.
5
1572271), the National Basic Research Program of China
under Grant No. 2016YFA0201500, and the Fundamental
Research Funds for the Central Universities (No. XK1901,
buctrc201915, XK1802-8), as well as Fundamental Research
Funds for the Central Universities and research projects on
biomedical transformation of the China-Japan Friendship
Hospital (No. PYBZ1825).
[16] Chen, Q.; Feng, L. Z.; Liu, J. J.; Zhu, W. W.; Dong, Z. L.; Wu, Y. F.;
2 2 2
Liu, Z. Intelligent albumin-MnO nanoparticles as pH-/H O -
responsive dissociable nanocarriers to modulate tumor hypoxia
for effective combination therapy. Adv. Mater. 2016, 28, 7129–
7
136.
[17] Jiang, Y. Y.; Zhu, G. M.; Lin, F.; Zhang, H.; Jin, C. H.; Yuan, J.; Yang,
D.; Zhang, Z. In situ study of oxidative etching of palladium
nanocrystals by liquid cell electron microscopy. Nano Lett. 2014,
14, 3761–3765.
[18] Wu, J. B.; Gao, W. P.; Yang, H.; Zuo, J. M. Dissolution kinetics of
oxidative etching of cubic and icosahedral platinum nanoparticles
revealed by in situ liquid transmission electron microscopy. ACS
Nano 2017, 11, 1696–1703.
[19] Zhu, W. J.; Zhang, L.; Yang, P. P.; Hu, C. L.; Luo, Z. B.; Chang, X.
X.; Zhao, Z. J.; Gong, J. L. Low-coordinated edge sites on ultrathin
palladium nanosheets boost carbon dioxide electroreduction
performance. Angew. Chem. Int. Ed. 2018, 130, 11718–11722.
[20] Nilsson, J.; Carlsson, P. A.; Fouladvand, S.; Martin, N. M.;
Gustafson, J.; Newton, M. A.; Lundgren, E.; Grönbeck, H.; Skoglundh,
M. Chemistry of supported palladium nanoparticles during
methane oxidation. ACS Catal. 2015, 5, 2481–2489.
REFERENCES
[1] Kumar, A.; Kumar, S.; Rhim, W. K.; Kim, G. H.; Nam, J. M.
Oxidative
nanopeeling
chemistry-based
synthesis
and
photodynamic and photothermal therapeutic applications of
plasmonic core-petal nanostructures. J. Am. Chem. Soc. 2014, 136,
1
6317–16325.
[2] Mohamed, M. S.; Veeranarayanan, S.; Maekawa, T.; Kumar, D. S.
External stimulus responsive inorganic nanomaterials for cancer
theranostics. Adv. Drug. Deliver. Rev. 2019, 138, 18–40.
[
3] Wang, S. H.; Riedinger, A.; Li, H. B.; Fu, C. H.; Liu, H. Y.; Li, L. L.;
Liu, T. L.; Tan, L. F.; Barthel, M. J.; Pugliese, G.; Donato, F. D.;
D'Abbusco, M. S.; Meng, X. W.; Manna, L.; Meng, H.; Pellegrino, T.;
Plasmonic copper sulfide nanocrystals exhibiting near-infrared
photothermal and photodynamic therapeutic effects. ACS Nano
2015, 9, 1788–1800.
[21] Li, F. M.; Shao, Q.; Hu, M. C.; Chen, Y.; Huang, X. Q. Hollow Pd–
Sn nanocrystals for efficient direct H O synthesis: The critical role
[
4] Yang, Y.; Zhu, W. J.; Feng, L. Z.; Chao, Y.; Yi, X.; Dong, Z. L.; Yang,
2
2
K.; Tan, W. H.; Liu, Z.; Chen, M. W. G-quadruplex-based nanoscale
coordination polymers to modulate tumor hypoxia and achieve
nuclear-targeted drug delivery for enhanced photodynamic
therapy. Nano Lett. 2018, 18, 6867–6875.
of Sn on structure evolution and catalytic performance. ACS Catal.
2018, 8, 3418–3423.
[22] Li, Y.; Wang, W. X.; Xia, K. Y.; Zhang, W. J.; Jiang, Y. Y.; Zeng, Y.
W.; Zhang, H.; Jin, C. H.; Zhang, Z.; Yang, D. Ultrathin two-
dimensional Pd-based nanorings as catalysts for hydrogenation
with high activity and stability. Small 2015, 11, 4745–4752.
[23] Yin, X.; Liu, X. H.; Pan, Y. T.; Walsh, K. A.; Yang, H. Hanoi tower-
like multilayered ultrathin palladium nanosheets. Nano Lett. 2014,
14, 7188–7194.
[24] Guo, S. J.; Zhang, S.; Sun, S. H. Tuning nanoparticle catalysis for
the oxygen reduction reaction. Angew. Chem. Int. Ed. 2013, 52,
8526–8544.
[5] Song, X. J.; Feng, L. Z.; Liang, C.; Gao, M.; Song, G. S.; Liu, Z.
Liposomes co-loaded with metformin and chlorin e6 modulate
tumor hypoxia during enhanced photodynamic therapy. Nano Res.
2
017, 10, 1200–1212.
[6] Qian, C. G.; Yu, J. C.; Chen, Y. L.; Hu, Q. Y.; Xiao, X. Z.; Sun, W. J.;
Wang, C.; Feng, P. J.; Shen, Q. D.; Gu, Z. Light-activated hypoxia-
responsive nanocarriers for enhanced anticancer therapy. Adv.
Mater. 2016, 28, 3313–3320.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 9
[
25] Vankayala, R.; Sagadevan, A.; Vijayaraghavan, P.; Kuo, C. L.;
[31] Dang, J. J.; He, H.; Chen, D. L.; Yin, L. C. Manipulating tumor
hypoxia toward enhanced photodynamic therapy (PDT). Biomater.
Sci. 2017, 5, 1500–1511.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Hwang, K. C. Metal nanoparticles sensitize the formation of singlet
oxygen. Angew. Chem. Int. Ed. 2011, 50, 10640–10644.
[
26] Liu, G. Y.; Zou, J. H.; Tang, Q. Y.; Yang, X. Y.; Zhang, Y. W.; Zhang,
Q.; Huang, W.; Chen, P.; Shao, J. J.; Dong, X. C. Surface modified Ti
mXene nanosheets for tumor targeting
[32] Fang, G.; Li, W. F.; Shen, X. M.; Perez-Aguilar, J. M.; Chong, Y.;
Gao, X. F.; Chai, Z. F.; Chen, C. Y.; Ge, C. C.; Zhou, R. H. Differential Pd-
nanocrystal facets demonstrate distinct antibacterial activity
against Gram-positive and Gram-negative bacteria. Nat. Commun.
2018, 9, 129.
[33] Yu, M. X.; Xu, J.; Zheng, J. Renal clearable luminescent gold
nanoparticles: From the bench to the clinic. Angew. Chem. Int. Ed.
2019, 131, 4156–4172.
3 2
C
photothermal/photodynamic/chemo synergistic therapy. ACS
Appl. Mater. Interfaces 2017, 9, 40077–40086.
[
27] Lu, Y.; Li, L. H.; Lin, Z. F.; Wang, L. P.; Lin, L. J.; Li, M.; Zhang, Y.;
Yin, Q. S.; Li, Q.; Xia, H. A new treatment modality for rheumatoid
arthritis: Combined photothermal and photodynamic therapy
using Cu7.2
S
4
nanoparticles. Adv. Healthc. Mater. 2018, 7, 1800013.
[34] Miao, Z. H.; Chen, S.; Xu, C. Y.; Ma, Y.; Qian, H. S.; Xu, Y. J.; Chen,
H. J.; Wang, X. W.; He, G.; Lu, Y.; Zhao, Q. L.; Zha, Z. B. PEGylated
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
[28] Long, R.; Mao, K. K.; Ye, X. D.; Yan, W. S.; Huang, Y. B.; Wang, J.
Y.; Fu, Y.; Wang, X. S.; Wu, X. J.; Xie, Y.; Xiong, Y. J. Surface facet of
palladium nanocrystals: A key parameter to the activation of
molecular oxygen for organic catalysis and cancer treatment J. Am.
Chem. Soc. 2013, 135, 3200–3207.
rhenium nanoclusters:
a
degradable metal photothermal
nanoagent for cancer therapy. Chem. Sci. 2019, 10, 5435–5443.
[35] Jin, C.; Zhang, H.; Zou, J. M.; Liu, Y.; Zhang, L.; Li, F. J.; Wang, R.
W.; Xuan, W. J.; Ye, M.; Tan, W. H. Floxuridine homomeric
oligonucleotides “Hitchhike” with albumin in situ for cancer
chemotherapy. Angew. Chem. Int. Ed. 2018, 57, 8994–8997.
[36] Chen, M.; Chen, S. Z.; He, C. Y.; Mo, S. G.; Wang, X. Y.; Liu, G.;
Zheng, N. F. Safety profile of two-dimensional Pd nanosheets for
photothermal therapy and photoacoustic imaging. Nano Res. 2017,
10, 1234–1248.
[37] Chen, M.; Tang, S. H.; Guo, Z. D.; Wang, X. Y.; Mo, S. G.; Huang, X.
Q.; Liu, G.; Zheng, N. F. Core-shell Pd@Au nanoplates as theranostic
agents for in-vivo photoacoustic imaging, CT imaging, and
photothermal therapy. Adv. Mater. 2014, 26, 8210–8216.
[
29] Quinson. J.; Neumann, S.; Wannmacher, T.; Kacenauskaite, L.;
Inaba, M.; Bucher, J.; Bizzotto, F.; Simonsen, S. B.; Kuhn, L. T.; Bujak,
D.; Zana, A.; Arenz, M.; Kunz, S. Colloids for catalysts: A concept for
the preparation of superior catalysts of industrial relevance.
Angew. Chem. Int. Ed. 2018, 130, 12518–12521.
[
30] Fan, W. P.; Yung, B.; Huang, P.; Chen, X. Y. Nanotechnology for
multimodal synergistic cancer therapy. Chem. Rev. 2017, 117,
13566–13638.
ACS Paragon Plus Environment

Page 9 of 9
Journal of the American Chemical Society
TOC Graphic
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
9
ACS Paragon Plus Environment