Fluorine Grafted Cu7S4-Au Heterodimers for Multimodal Imaging Guided Photothermal Therapy with High Penetration Depth

Article abstract of DOI:10.1021/jacs.8b00368

We report the multifunctional nanocomposites (NCs) consisting of ¹⁹F-moieties grafted Cu₇S₄-Au nanoparticles (NPs) for negligible background ¹⁹F-magnetic resonance imaging (¹⁹F-MRI) and computed tomography (CT) imaging guided photothermal therapy. The localized surface plasmon resonance (LSPR) absorption can be reasonably tuned to the in vivo transparent window (800-900 nm) by coupling Au (<10 nm, LSPR ～530 nm) with Cu₇S₄ (<15 nm, LSPR ～1500 nm) into Cu₇S₄-Au heterodimers. The in vivo photothermal tests show that Cu₇S₄-Au show deeper light penetration with 808 nm irradiation, better photothermal efficacy, and less damage to normal tissues than Cu₇S₄ with 1500 nm irradiation. Moreover, compared to traditional ¹H-MRI, the ¹⁹F-MRI based on these NCs demonstrates much better sensitivity due to the negligible background. This work offers a promising strategy for multimodal imaging guided photothermal therapy of deep tissue with good efficacy.

Full text of DOI:10.1021/jacs.8b00368

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Fluorine grafted Cu7S4-Au heterodimers for multimodal imaging
guided photothermal therapy with high penetration depth
Jiabin Cui, Rui Jiang, Chang Guo, Xilin Bai, Suying Xu, and Leyu Wang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b00368 • Publication Date (Web): 20 Apr 2018
Downloaded from http://pubs.acs.org on April 20, 2018
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Fluorine grafted Cu S -Au heterodimers for multimodal
imaging guided photothermal therapy with high penetration
depth
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Jiabin Cui, Rui Jiang, Chang Guo, Xilin Bai Suying Xu, and Leyu Wang*
State Key Laboratory of Chemical Resource Engineering, Beijing Advanced Innovation Center for Soft Matter Science and
Engineering, Beijing University of Chemical Technology, Beijing 100029, China
Supporting Information Placeholder
22, 34
36
35
including photocatalysis,
controlled drug delivery, and PTT,
photothermal imaging, photoꢀ
ABSTRACT: We report the multifunctional nanocomposites
37ꢀ39
1
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however, it is hard to
(
(
(
NCs) consisting of Fꢀmoieties grafted Cu S ꢀAu nanoparticles
7 4
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0
19
tune the LSPR peak of Cu2ꢀxS to transparent window. The
formation of heterodimer has been confirmed as a novel strategy
to tune the LSPR peak position.
fabricated the AuꢀAg heterodimers via growing Ag domain on Au
seeds. The absorption was enhanced, broadened and redꢀshifted to
50 nm. By growing Cu2ꢀxSe on Au seeds, Swihart synthesized
AuꢀCu2ꢀxSe heterodimers with broadened absorption centered at
120 nm. By means of Au seeds, Jiang synthesized AuꢀCu9S5
NPs) for negligible background Fꢀmagnetic resonance imaging
1
9
FꢀMRI) and computed tomography (CT) imaging guided
28, 36, 41ꢀ43
44, 45
Sun
has successfully
photothermal therapy. The localized surface plasmon resonance
(LSPR) peak can be reasonably tuned to the in vivo transparent
window (800ꢀ900 nm) by coupling Au (<10 nm, LSPR ∼530 nm)
with Cu7S4 (<15 nm, LSPR ∼1500 nm) into Cu S ꢀAu
26
6
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4
heterodimers. The in vivo photothermal tests show that Cu S ꢀAu
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46
1
show deeper light penetration with 808ꢀnm irradiation, better
photothermal efficacy and less damage to normal tissues than
Cu S with 1500ꢀnm irradiation. Moreover, compared to tradiꢀ
hybrids with LSPR peak at 1100 nm. So far, it remains largely
unexplored to get the expected LSPR around 800 nm by growing
small Au domain on Cu2ꢀxS NPs.
7
4
1
19
tional HꢀMRI, the FꢀMRI based on these NCs demonstrates
much better sensitivity due to the negligible background. This
work offers a promising strategy for multimodal imaging guided
photothermal therapy of deep tissue with good efficacy.
In another aspect, magnetic resonance imaging (MRI) is one of
the most popular imaging techniques,
imaging deep tissues with negligible injury. However, the
conventional H MRI suffers from low signalꢀtoꢀnoise ratio
47, 48
which can be used for
1
4
(
SNR) due to the high content of water in body. Recently,
19
fluorineꢀ19 ( F) MRI with a higher SNR has drawn wide
attention, because F displays almost equivalent sensitivity to that
of H (0.83 relative to H) and owns negligible endogenous
background interference, which complements the wealth of
information provided by conventional H MRI.
challenge of F MRI is to increase the number of F atoms per
probe and simultaneously retain the molecular mobility, otherwise
the F MRI signal will be attenuated by the reduced solubility of
probes with increased restriction of F molecular mobility while
grafting more Fꢀatom onto one particle.
1ꢀ3
19
Multimodal imagingꢀguided photothermal therapy (PTT) has
been extensively considered as a promising and minimally
invasive strategy for cancer therapy. One of the essential
requirements in the imagingꢀguided PTT is the high penetration
depth of irradiation and imaging. Due to the high content of water
1
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1
49ꢀ51
19
The major
19
4,
5
in live body (50ꢀ80% in weight),
the major challenge to
19
increase the penetration depth is designing the nanoprobes which
can effectively dodge the influence of water. In recent years,
19
6
ꢀ8
9ꢀ
19
38, 52, 53
plasmonic nanostructures including gold nanorods, nanocages,
hollow spheres,
Compared to
1
1
12, 13
14ꢀ16
and core/shell nanoparticles (NPs)
with
MRI, computed tomography (CT) is sensitive with a high spatial
5
4ꢀ56
localized surface plasmon resonance (LSPR) peak in the
resolution,
but is limited by the associated radiation burden
1
7, 18
57
transparent window (800ꢀ900 nm)
have been recognized as
and lack of tissue characterization. Simultaneous CTꢀMRI has
potentials to address individual limitations of each imaging
modality and enable synergistic physiological and morphologic
imaging. Therefore, the CT/ FꢀMRI guided PTT will be highly
desirable imagingꢀguided ablation strategy but faces challegening.
1
, 2, 19
20ꢀ24
promising agents for PTT.
Despite of great progresses,
it
is still urgent to get the strong LSPR absorption in the transparent
window, high photothermal conversion efficiency and longꢀtime
stability.
19
2
5
26, 27
In addition to noble metal nanostructures, chalcogenide
Herein, we report a facile strategy to get the strong LSPR
absorption around ∼808 nm by growing a small Au domain (7.3 ±
1.5 nm, LSPR at ∼530 nm) on a heavily doped Cu S domain (14
± 0.8 nm, LSPR at ∼1500 nm) to form a Cu S ꢀAu heterodimer
(detailed synthesis procedures presented in Supporting
Information and Table S1). Then, the FꢀMRI singal molcules
were grafted onto the heterodimer via click chemistry (Figure S1)
to form Cu S ꢀAu@PSIꢀ F/PEG nanocomposites (termed as
NCs) (Scheme 1). These NCs were successfully utilized for
28
and metalꢀoxide nanocrystals also exhibit LSPR features in near
infrared (NIR) and midꢀinfrared (MIR) regions via doping, the
process of introducing foreign atoms or impurities into a host
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29, 30
lattice.
In contrast to LSPR in metals, which is attributed to
19
oscillation of free electrons, the LSPR in doped semiconductors
31
arises from free holes as a result of cation vacancies. The holeꢀ
19
density and thus LSPR peak can be readily tuned by varying the
7 4
32, 33
doping level.
Among these nanocrystals, selfꢀdoped copper
chalcogenide has been harnessed for many new applications
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19
simultaneous CT/ FꢀMR imaging guided PTT with negligible
background and high penetration depth.
interface and high crystallinity of Cu S ꢀAu. The lattice fringes
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with a measured interplanar spacing of 0.193 nm in the semiconꢀ
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ductor domain, correspond to the (0 16 0) planes of the Cu S .
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In metal domain, an interplanar distance of 0.236 nm is consistent
with the (111) lattice spacing of faceꢀcentered cubic (fcc) Au. The
HAADFꢀSTEM micrograph (Figure 1e) clearly shows that Cu S ꢀ
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Au NPs are heterodimers (the brighter contrast demonstrates Au)
instead of Cu S @Au core/shell nanostructures. The energyꢀ
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dispersive spectroscopy (EDS) elemental maps shown in Figure
1f and Xꢀray photoelectron spectroscopy (XPS) analysis (Figure
S2) further confirm the composition of heterodimers. The heteroꢀ
structure of Cu S ꢀAu was further confirmed by the powder Xꢀray
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diffraction (XRD) patterns in Figure S3.
Figure 2. (a) LSPR absorption spectra of these NPs. (b) Photoꢀ
thermal images of mouse liver injected with Cu S ꢀAu (left) and
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Cu S (right) NPs before (Top) and after (bottom) irradiation with
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Scheme 1. Schematic illustration for the fabrication and CT/ Fꢀ
808ꢀnm (left) and 1500ꢀnm (right) light after passing through 1.7ꢀ
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MR imaging guided PTT of Cu S ꢀAu@PSIꢀ F/PEG.
cmꢀthick tissue (initial irradiation: 0.5 W/cm ; 5 min).
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As shown in Figure 2a, after the formation of Cu S ꢀAu, the
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visible absorption of Au (LSPR at ∼530 nm) slightly weakened
and the NIR absorption of Cu S (LSPR ∼1500 nm) showed slight
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enhancement. Interestingly, in the NIR region of 700ꢀ1500 nm,
the LSPR absorption was greatly enhanced, which was as strong
as that at 1500 nm. It is noteworthy that, for the LSPR spectrum
test, the concentration of Au and Cu S in solution was kept idenꢀ
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tical to that in Cu S ꢀAu colloids, respectively. We also checked
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the influence of Au size on the LSPR of Cu S ꢀAu. As shown in
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Figure S4, if the Au size was 3.1 ± 0.5 nm, no obvious changes of
absorption around 800 nm was observed. When the size was inꢀ
creased to 9.8 ± 1.2 nm, a broad and increased absorption was
obtained (Figure S5) as that of Cu S ꢀAu with Au size of 7.3 ± 1.5
7
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nm. As a control, we could not observe any new absorption enꢀ
hancement around 800 nm from the physical mixture (Figure S6)
of Au (7.3 ± 1.5 nm) and Cu S NPs (14 ± 0.8 nm), suggesting
7
4
that this new absorption around 800 nm arisen from the coupling
of these two domains in a heterodimer.
The evolution of LSPR could be mainly attributed to the
changes of free carrier concentration, particle size, as well as the
31, 32
refractive index variation of surrounding medium.
It is known
that the LSPR of Au is attributed to oscillation of free electrons
and the LSPR of heavily doped semiconductors (Cu S ) arises
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58
from free holes. The formation of Cu S ꢀAu heterodimers would
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Figure 1. TEM images of Cu S ꢀAu (a), Au (b) and Cu S (c)
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result in charge neutralization, accordingly redꢀshift of LSPR for
individual domains. Here the enhancement of absorption around
808 nm should be mainly attributed to the redꢀshift of LSPR of
Au domain. With respect to LSPR of Cu S domain, the reduction
NPs. HRTEM (d), STEM (e) images and (f) HAADFꢀSTEM
image as well as corresponding elemental maps of Cu S ꢀAu.
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Figure 1a shows the typical transmission electron microscope
TEM) image of Cu S ꢀAu heterodimers obtained by depositing
Au (7.3 ± 1.5 nm, Figure 1b) on Cu S (14 ± 0.8 nm, Figure 1c).
To further confirm the heterostructure, both high resolution
transmission electron microscopy (HRTEM) and highꢀangle annuꢀ
lar darkꢀfield scanning transmission electron microscopy
of holeꢀdensity results in the simultaneously depressed and broadꢀ
ened absorption spectrum. Meanwhile, given that the refractive
index of Cu S is higher than that of Au, and thus, the formation
(
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of Cu S ꢀAu heterodimer would lead to redꢀshift for the LSPR of
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Au domain and blueꢀshift for the LSPR of Cu S domain. Judging
7
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from the experimental observation, the effect of refractive index is
dominant for the LSPR change in Cu S domain.
(
HAADFꢀSTEM) analyses have been carried out. As shown in
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Figure 1d, the inhomogeneous contrast within each nanoparticle
shown on the HRTEM image indicates the heterostructure.
HRTEM image also reveals the intimate metalꢀsemiconductor
As aforementioned, we focus on the ∼800 nm region because
this special NIR light can effectively dodge the absorption of
tissues, blood, and especially water (Figure S7), and thus results
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in efficient PTT. In order to understand the influence of irradiaꢀ
tion wavelength on the photothermal efficacy, in vivo phototherꢀ
plots of the tumor size after photothermal treatment without (line
1) and with (line 2) NCs injection.
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mal imaging was conducted. The Cu S and Cu S ꢀAu were inꢀ
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jected into liver of the dissected mice first and then the irradiation
light passed through 1.7ꢀcm thick tissue from the backside to irraꢀ
diate the liver with 1500ꢀnm and 808ꢀnm laser, respectively. As
Encouraged by the aforementioned promising results, we carꢀ
ried out the in vivo imagingꢀguided PTT evaluation. As shown in
Figure 3a, the tumor with NCs displayed a much bright CT image
(HU values before and after injection of NCs were shown in Figꢀ
ure S18). However, in the control mouse without NCs, the tumor
was unobservable. In MRI tests, both before and after the injecꢀ
tion of NCs, it is hard to clearly delineate the boundary of tumor
2
shown in Figure 2b, after a 5ꢀmin irradiation (0.5 W/cm ), the
photothermal image of liver was clearly observed in the mouse
injected with Cu S ꢀAu under irradiation of 808ꢀnm light, sugꢀ
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gesting an obvious photothermal effect. On the contrast, the liver
of Cu S ꢀinjected mouse demonstrated no observable temperature
1
from surrounding normal tissues in HꢀMRI. As expected, a disꢀ
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increment after exposure to 1500ꢀnm light (0.5 W/cm , 5 min),
although the absorbance of Cu S ꢀAu at 808ꢀnm is almost equal to
tinct difference can be observed in FꢀMRI before and after adꢀ
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ministration of NCs (Figure 3b). Additionally, photothermal propꢀ
erties were examined by irradiation with NIR light (808ꢀnm) at
different time intervals. The tumor site displayed a much brighter
photothermal image compared with the surroundings (Figure 3c).
The temperature at the tumor sites quickly increased from 30 to
51.5 °C within 10 min (Figure 3d), which is highly desirable for
PTT. After photothermal treatment, the changes of tumors with
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that of Cu S at 1500ꢀnm, which is in agreement with the temꢀ
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perature evolution plot (Figure S8). These in vivo photothermal
imaging results indicate that the 1500ꢀnm is not suitable for deep
tissue irradiation due to the serious absorption by water, blood and
biological tissues, which was further confirmed by the obvious
damage of skin caused by the 1500ꢀnm irradiation (Figure S9).
3
initial volume (∼200 mm ) were tracked (Figure S19). As shown
To explore the bioapplications, the Cu S ꢀAu NPs were encapꢀ
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in Figure 3e, the tumors completely disappeared after 2 weeks.
Meanwhile, the weight of mice increased normally (Figure S20).
As a control, if the mouse was treated with light irradiation but
without NCs, the tumor grew into a big one after 2 weeks and the
weight lost quickly. These observations demonstrate that the
sulated with PSIOAmꢀN3 and then conjugated with 2, 2, 2ꢀtrifluoroꢀ
Nꢀ2ꢀpropynꢀ1ꢀylacetamide via click chemistry (Figure S1). These
multifunctional NCs were characterized via TEM, dynamic light
scattering (DLS), Fourier transform infrared (FTIR) techniques
19
(
Figure S10). After Fꢀgrafting, the particle size (Figure S10) and
19
Cu S ꢀAu@PSIꢀ F/PEG NCs hold potentials as platforms for
LSPR absorption (Figure S11) have no obvious change. Both
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multimodal imagingꢀguided PTT with deep penetration.
FTIR and FꢀNMR with a single and sharp peak at 75.4 ppm
19
confirmed the F grafting (Figure S10). In addition, the tests of
In summary, we report the multifunctional Cu S ꢀAu@PSIꢀ
F/PEG for the CT/ FꢀMR imagingꢀguided photothermal ablaꢀ
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9
19
19
pH and temperature influence on FꢀNMR signals of NCs (Figure
S12) demonstrate the good stability of NCs. The photothermal
efficiency investigation also reveals a satisfied performance of
tion of tumors with deep penetration. By coupling small Au with
Cu S NPs, the LSPR peak of the Cu S ꢀAu heterodimers was
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64.4% for Cu S ꢀAu NPs at 808ꢀnm irradiation (Figure S13). The
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reasonably tuned to the in vivo transparent window (∼800 nm),
which greatly enhances the photothermal efficacy and decrease
the optical damage to normal tissues. The grafted fluorine moieꢀ
cytotoxicity evaluation (Figure S14) confirms the good biocomꢀ
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patibility. Before CT and FꢀMR imaging applications, phantom
studies were performed. As shown in Figure S15a, strong CT
signals were observed from the colloidal solution, and the CT
19
ties render these NCs FꢀMRI ability with negligible background
and good sensitivity. Meanwhile, the gold domains enable the
NCs CT imaging capability with high spatial resolution. The in
signal intensity was proportional to the concentration of NCs
19
19
(
CNCs) (Figure S15b). The FꢀMRI was carried out (Figure S16a),
vivo test results suggest that the CT/ FꢀMRI multimodal imagingꢀ
guided photothermal ablation may become an invaluable tool for
fundamental understanding, diagnostics and therapy of tumors.
This work paves the way for the rational design of multifunctional
nanoplatforms for deep nonꢀinvasive imagingꢀguided phototherꢀ
mal ablation.
19
and the FꢀMRI signal intensity was proportional to the concenꢀ
tration of fluorine atoms (C ) (Figure S16b and Figure S17). All
F
the results suggested the great potential of these NCs for both CT
19
and FꢀMR imaging.
ASSOCIATED CONTENT
Supporting Information
Detailed experiments, Table S1, and Figures S1−S20. This mateꢀ
rial is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
lywang@mail.buct.edu.cn.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This research was supported by the National Natural Science
Foundation of China (21725501, 21475007, 21675009 and
Figure 3. (a) CT images of tumorꢀbearing mouse before and after
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the injection of NCs; (b) In vivo Hꢀ and Fꢀ MRI of the tumorꢀ
bearing mice before and after the injection of NCs; (c) phototherꢀ
mal images and (d) temperature evolution profile of the mouse
2
1505003), and the Fundamental Research Funds for the Central
Universities (buctrc201706 and buctrc201720). We thank Prof. X.
19
2
Zhang at Xiamen University for the help on the F MRI and CT
under 808ꢀnm irradiation (1.0 W/cm ) for 0ꢀ10 min; (e) evolution
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experiments. We also thank
Recruited Talents of Beijing University of Chemical Technology”.
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Multifunctional Cu S ꢀAu@PSIꢀ F/PEG nanoprobes are reported for CT/ FꢀMR dualꢀmodal imagingꢀguided photothermal
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