Journal Pre-proofs

Construction of CuS@Fe-MOF nanoplatforms for MRI-guided synergistic

photothermal-chemo therapy of tumors

Zhaojie Wang, Wanjian Yu, Nuo Yu, Xuan Li, Yirou Feng, Peng Geng, Mei
Wen, Maoquan Li, Haijun Zhang, Zhigang Chen

PII: S1385-8947(20)32005-2
DOI: https://doi.org/10.1016/j.cej.2020.125877
Reference: CEJ 125877

To appear in: Chemical Engineering Journal

Received Date: 17 February 2020

Revised Date: 27 May 2020
Accepted Date: 11 June 2020

Please cite this article as: Z. Wang, W. Yu, N. Yu, X. Li, Y. Feng, P. Geng, M. Wen, M. Li, H. Zhang, Z. Chen,
Construction of CuS@Fe-MOF nanoplatforms for MRI-guided synergistic photothermal-chemo therapy of
tumors, Chemical Engineering Journal (2020), doi: https://doi.org/10.1016/j.cej.2020.125877

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 Construction of CuS@Fe-MOF nanoplatforms for MRI-guided

synergistic photothermal-chemo therapy of tumors

Zhaojie Wang,a,b,# Wanjian Yu,b,# Nuo Yu,b Xuan Li,b Yirou Feng,b Peng Geng,b Mei

Wen,b Maoquan Li,a Haijun Zhang,a,c Zhigang Chen*a,b

aDepartment of Interventional and Vascular Surgery, Shanghai Tenth People’s Hospital,
Tongji University School of Medicine, Shanghai 200072, China.
bCollege of Materials Science and Engineering, Donghua University, Shanghai 201620,

China.
National United Engineering Laboratory for Biomedical Material Modification,
c

Branden Biomedical Park, Qihe Advanced Science & High Technology Development
Zone, Qihe, Shandong 251100, China.

Abstract: Integrated theranostic nanoplatforms with imaging and photothermal/drug-

delivering functions have great advantages in cancer therapy, but the design and

preparation of the simple efficient nanoplatforms are still of great urgency. Herein, we

report the construction of novel core-shell CuS@Fe-based metal-organic-framework

(Fe-MOF) nanoplatforms by the co-precipitation/assembling growth of Fe-MOF shell

on the surface of CuS nanoplate. The resulting CuS@Fe-MOF nanoparticles (NPs)

consist of hexagonal-shaped CuS nanoplate core with an average size of ~85 nm and

amorphous Fe-MOF shells with an average thickness of 16 nm. CuS@Fe-MOF NPs

are then surface-modified with lipids, and they exhibit the increased NIR

*Corresponding Authors. E-mail: zgchen@dhu.edu.cn

#These authors contributed equally to this work.
1
photoabsorption and photothermal conversion efficiency (39.7%), resulting from

localized surface plasmon resonance (LSPR) effect of CuS. The presence of Fe-MOF

shell confers the efficient loading (27.5%) of doxorubicin (DOX), pH-responsive

releasing ability, and strong magnetic resonance imaging (MRI) ability. Especially, the

photothermal effect of CuS and the released DOX from CuS@Fe-MOF-DOX result in

the most efficient death of cancer cells in vitro. When CuS@Fe-MOF-DOX dispersion

was injected into the tumor, the tumor-bearing mice could be monitored by MR and

thermal imaging. Furthermore, the tumors could be inhibited and destroyed due to the

synergistic photothermal-chemo therapy, remarkably better than that from

photothermal ablation therapy or chemotherapy alone. Simultaneously, no noticeable

side-effects can be found for mice. Therefore, the present CuS@Fe-MOF-DOX can act

as a biocompatible multifunctional nanoplatform for MRI-guided synergistic

photothermal-chemo therapy of tumors.

Keywords: CuS, photothermal ablation therapy, chemotherapy, metal-organic

framework

1. Introduction

Cancer is one of the most fatal diseases, and it has seriously influenced the life

quality and health of numerous people [1]. Traditional therapy methods for cancer

include surgery, radiation therapy, chemotherapy, etc. However, these methods are the

“double-edged sword” and exhibit a lot of side effects. To treat cancer more efficiently

with low side-effects, some new methods have been discovered [2-6], such as

2
photothermal ablation therapy (PAT) [3, 5], photodynamic therapy [5], sonodynamic

therapy [4], chemodynamic therapy [6] and so on. Among them, PAT has drawn much

attention, since it employs photothermal agents to convert near-infrared (NIR) laser to

heat efficiently for rapid ablation of in vivo cancer cells [3, 7]. One of the prerequisites

for PAT is to obtain efficient photothermal agents. Several kinds of photothermal agents

have been well developed, including organic/polymer (such as ICG [8, 9], PPy [10]),

noble metal (such as Au nanorods [11]), carbon [12] and semiconductor [13]

nanomaterials. Semiconductor-based photothermal agents have attracted the increasing

interests, due to their low-price, easy synthesis/modification process, strong NIR

photoabsorption and photothermal effect. As the first semiconductor photothermal

agents, CuS nanoparticles with strong NIR photoabsorption were used to ablate cancer

cells as early as in 2010 [14]. After that, plenty of CuS nanomaterials with different

morphology (such as superstructures [15], nanoparticles [16], nanodots [17]) or surface

ligands (such as sodium citrate [18], chitosan [19] and proteins [20]) have been well

developed as efficient and biocompatible photothermal agents. Under NIR laser

irradiation, these CuS nanomaterials in tumors can efficiently ablate cancer cells in vivo.

However, it should be noted that the therapeutic effect from PAT will cease

immediately when the NIR laser is switched off.

To compensate the limitation of PAT, the marriage of PAT and chemotherapy has

been well demonstrated to have a satisfactory treatment effect [21-25], since drugs in

tumors can continuously produce the chemo-therapeutic effect for the long duration [26,

27]. In addition, when combined with chemotherapy, PAT can be able to synergistically

3
increase the therapeutic effect, such as accumulation of the nanocarriers in the tumor

site, facilitation of cell membrane permeability and improvement of the drug cytotoxic

effect [24]. For realizing the synergistic photothermal-chemo therapy, the key is to

construct multifunctional nanomaterials with photothermal effect and controllable

drug-loading/releasing ability. Currently, there are three main kinds of construction

strategies. The first kind is to load drugs directly on the outer surface or inner cavity of

photothermal agents. For example, PEGylated MoS2 nanosheets [28] or CuS hollow

nanospheres [29] can load DOX on the surface. The second kind is to encapsulate

photothermal agents and drugs by some protein or polymers, such as CuS-DOX-

MBA@PCM NPs [30], ICG-DOX@PLGA [31]. The last kind is the use of nanocarrier

(including mesoporous SiO2, polymer) as shells of photothermal agents, such as

CuS@SiO2 [32], Au-Ag@PEG-based hydrogel [33]. Our group also reported

thermosensitive polymer nanogels which can act as the nanoreactor to prepare CuS and

as the carriers to load DOX [34]. These photothermal-core@carrier-shell

nanocomposites have high photothermal effects, good drug loading and

microenvironmental (pH/temperature)-responsive releasing abilities. When aqueous

solutions of core-shell nanocomposites are injected into the tumor-bearing mice, they

exhibit the excellent photothermal-chemo therapy effect, which is much better than

PAT or chemotherapy alone [34]. However, it should be noted that the carriers usually

have only drug-loading/release function without other important imaging functions.

Thus, it is still necessary to develop the simple synthesis strategy and novel nanocarrier

shells especially with CT/MR imaging function.

4
 It is well known that metal-organic frameworks (MOFs) can be constructed by

assembling metal ions and polydentate bridging ligands via coordination interaction,

and they usually have regular porosity and high pore volume [35, 36]. Recently, the

nanoscale MOFs have become research hotspots as a drug carrier in biomedical

applications, due to high drugs/enzymes-loading capacity, easy functionalization for

multimodal imaging, and biodegradability for avoiding long-term toxicity [37, 38]. To

enhance the functions of photothermal agent, some MOFs have also been used as

nanocarrier shells to construct core-shell nanocomposites, such as CuS@ZIF-8 (zeolitic

imidazolate framework-8) [39], Au@ZIF-8 [40], and so on. It should be noted that the

numbers of such core-shell nanocomposites are very few due to the complex

preparation, and the imaging ability of MOF should be improved.

Fe-based MOFs (such as MIL-88A, MIL-100) have been demonstrated to have

good capacity drug loading, stimuli-responsive release and especially magnetic

resonance imaging (MRI) properties [41]. To obtain simultaneously drug loading and

MRI ability for optimizing CuS nanomaterials, herein we report a simple in-situ growth

strategy for the synthesis of Fe-MOF shell on the surface of CuS nanoplate cores. The

resulting CuS@Fe-MOF nanoparticles (NPs) were surface-modified with amphiphilic

PEGylated phospholipid (DSPE-PEG). CuS@Fe-MOF NPs exhibited strong NIR

photoabsorption and photothermal conversion efficiency (39.7%). Simultaneously, Fe-

MOF shell confers good doxorubicin (DOX)-loading ability (27.5%) and pH-

responsive releasing ability. When CuS@Fe-MOF-DOX dispersion was injected into

the tumor, the tumor-bearing mice could be monitored by MR and thermal imaging.

5
Furthermore, the tumors could be inhibited and destroyed due to the synergistic

photothermal-chemo therapy, better than those from PAT or chemotherapy alone.

2. Experimental sections

2.1 Materials

Copper (II) chloride dihydrate (CuCl2·2H2O, AR), iron chlorides anhydrous

(FeCl3, AR), sulfide ammonia solution (≥17wt%), polyvinylpyrrolidone (PVP, K30),

1,3,5-Benzenetricarboxylic acid (H3BTC, AR), doxorubicin hydrochloride (DOX), and

anhydrous ethanol were purchased from Sinopharm Chemical Reagent Co., Ltd.

Amphiphilic PEGylated phospholipid (DSPE-PEG, Mw=5000) was acquired from

Shanghai Yanyi Biotechnology Corporation.

2.2 Synthesis of CuS@Fe-MOF

CuS nanoplates were prepared by a modified hydrothermal method according to

our previous reports [15, 42], and the details are supplied in supporting information.

The in-situ growth of Fe-MOF shells on CuS nanoplates was realized by a simple

coprecipitation-assembling strategy according to the synthesis of MIL-100(Fe) except

for the high-temperature hydrothermal step [43]. In a typical process, CuS nanoplates

(10 mg) were dispersed in ethanol solution (5 mL) containing FeCl3 (10 mM), and the

dispersion was stirred for 30 min. Subsequently, the above solution was added to

another ethanol solution containing H3BTC (5 mL, 10 mM), and the dispersion was

stirred at 70 °C for 30 min, conferring the in-situ growth of Fe-MOF shell. The above

dispersion was centrifuged at low speed (3000 rpm, 5 min) to remove larger

aggregations, and then the upper dispersion was centrifuged at high speed (10000 rpm,

6
10 min) to obtain CuS@Fe-MOF.

To improve the hydrophilicity, CuS@Fe-MOF sample (10 mg) was re-dispersed

in 10 mL aqueous solution containing 50 mg DSPE-PEG. The above dispersion was

stirred overnight at 37 °C. Then, the DSPE-PEG-coated CuS@Fe-MOF nanoparticles

(abbreviated as CuS@Fe-MOF NPs) were centrifuged (10000 rpm, 10 min) and washed

with water for three times.

2.3 Characterization and photothermal test

The CuS@Fe-MOF NPs were characterized by transmission electron microscopy

(TEM, FEI Talos F200S), powder X-ray diffractometer (XRD, Bruker D4), and UV-

vis-NIR absorption spectrophotometer (Shimadzu UV-3600). The concentrations of

CuS@Fe-MOF dispersions were determined by an inductively coupled plasma atomic

emission spectroscopy (ICP-AES, Prodigy). Specific surface areas were calculated

from the results of N2 physisorption at 77 K by using the BET (Brunauere-Emmete-

Teller, Quantachrome Autosorb-iQ). In order to measure the photothermal efficiency,

CuS@Fe-MOF aqueous dispersions (0.1 mL) were exposed by a 1064 nm laser and the

temperature was recorded by an infrared camera (FLIR A300).

2.4 Drug loading and release test

DOX was used as the model of antitumor drug, and 7.5 mg DOX was added into

10 mL phosphate buffer saline (PBS, pH=7.4) containing CuS@Fe-MOF NPs (1.0 mg

mL-1). The resulting dispersion was stirred at room temperature for 48 h. Finally, the

dispersion was centrifuged (10000 rpm, 10 min) to collect the supernatant solution and

CuS@Fe-MOF-DOX precipitation. The absorbance at 480 nm of the supernatant

7
solution was tested by a UV-Vis spectrophotometer. The content of free DOX was

calculated according to the absorbance and the concentration-dependent absorbance

standard curve of DOX. The entrapment efficiency (EE w/w%) and loading content

(LC, w/w%) of DOX were evaluated from the equations: EEDOX = (DOX-loading

weight/initial weight of DOX) ×100%, LCDOX = (DOX- loading weight/weight of

CuS@Fe-MOF-DOX) ×100%.

The release of DOX from CuS@Fe-MOF-DOX was tested by using different

buffer solutions. In a typical process, CuS@Fe-MOF-DOX dispersions were added into

10 mL PBS solution (pH=7.4) or acetate buffer solution (pH=5.4), and the solutions

were stirred in dark. 0.5 mL dispersion was taken out at certain time (0-24 h) and

centrifuged. The volume of the original dispersion is gradually decreased, while the

concentration of CuS@Fe-MOF remains unchanged. The wavelengths of supernatants

were investigated at 480 nm. The release rate of DOX was calculated using the equation:

(release weight/load weight) ×100%.

2.5 Cell tests

Mouse colon cancer cells CT26 cells and human umbilical vein endothelial cells

(HUVEC) were originally purchased from Type Culture Collection of the Chinese

Academy of Sciences, Shanghai, China. CT26 cells and HUVEC were grown in

complete Dulbecco's Modified Eagle Medium (DMEM) medium at 37 °C in the

presence of 5% CO2.

Cytotoxicity test: HUVEC and CT26 cells (1×104 cells/well) were seeded in 96-

well plates and cultivated for 12 h, respectively. Afterwards, the old medium was

8
discarded and cells were washed with PBS. For HUVEC, the cells were cultured with

CuS@Fe-MOF (0-0.3 g L-1) for another 24 h. For CT26 cells, the cells were cultured

with CuS@Fe-MOF (0-0.3 g L-1) or CuS@Fe-MOF-DOX (0-0.3 g L-1) for another 24

and 48 h. At last, the cytotoxicity was assessed by the standard CCK-8 assay.

Therapy effect in vitro: CT26 cells (1×104 cells/well) were seeded in 96-well plates

and cultivated for 12 h. The plates were divided into six groups, control (I), NIR (II),

CuS@Fe-MOF (III), CuS@Fe-MOF-DOX (IV), CuS@Fe-MOF+NIR (V), CuS@Fe-

MOF-DOX+NIR (VI). After different processing, a portion of cells was washed with

PBS and the cell viability was assessed by the standard CCK-8 assay. In addition, the

other part of the cells was washed with PBS and co-stained with Calcein-AM and

propidium iodide (PI), then the fluorescent images were captured by a microscope.

DOX releasing in vitro: CT26 cells were seeded in 24-well plates (1.5×105

cells/well) and cultivated for 24 h, and then the old medium was replaced by fresh

medium with CuS@Fe-MOF-DOX (0.2 g L-1). After the incubation for 0.5, 1, 2 h, cells

were washed with PBS. The cell nuclei were stained with 4',6-diamidino-2-

phenylindole (DAPI). The cellular fluorescence was investigated by microscopy.

2.6 Animal experiments

All animal investigations conformed to the guide for the Care and Use of

Laboratory Animals by the U.S. National Institutes of Health (NIH Publication no. 86-

23, revised 1985) and performed in accordance with the protocols approved by the

Animal Welfare and Research Ethics Committee of Donghua University. BALB/c mice

(15-20 g, female) were obtained from Shanghai SLAC Laboratory Animal Center

9
(Shanghai, China). CT26 cells solution (2×106/mouse) was injected subcutaneously

into the back of each mouse to establish the tumor model.

MRI in vivo: The MR imaging tests were conducted by an NMR Analyzing and

Imaging system and a 3.0 T clinical MRI instrument (GE Signa 3.0 T) with a special

coil for small animal imaging. To evaluate the in vitro MRI ability, CuS@Fe-MOF

aqueous dispersions with different concentrations (Fe: 0-0.8 mM, 0.5 mL) were tested.

In addition, CT26 tumor-bearing mice were anesthetized and monitored by the MR

scanner, and then the CuS@Fe-MOF dispersion (0.2 g L-1, 100 μL) was intratumorally

injected in the mice and the signals after injection were monitored.

Therapeutic effect in vivo: CT26 tumor-bearing mice were randomly divided into

five groups (six mice/group), the groups I-V were saline-injection (I), saline+NIR (II),

CuS@Fe-MOF-DOX (III), CuS@Fe-MOF+NIR (IV), CuS@Fe-MOF-DOX+NIR (V),

respectively. The mice in groups (I, II), (IV) and (III, V) were intratumorally injected

with saline, CuS@Fe-MOF (0.2 g L-1, 100 μL) and CuS@Fe-MOF-DOX (0.2 g L-1,

100 μL), respectively. After 0.5 h, mice in groups II, IV and V were irradiated by 1064

nm laser (1.0 W cm-2, 10 min). After 24 h, one mouse in each group was sacrificed and

the tumors were collected, the hematoxylin and eosin (H&E) staining assay was

employed to analyze the histological changes of tumors. The remaining mice were

observed for 20 days, the weight of mice and the tumor volumes (length × width2/2)

were monitored. For histological examinations, main organs in groups (I and V) were

harvested and fixed with a formalin solution, then cut into slices for staining H&E assay.

2.7 Statistical Analysis

10
 The data were expressed as the mean value ± standard deviation (SD), and

statistical analysis was analyzed by using the Student’s two-tailed t-test. *p < 0.05

(significant), **p < 0.01 (moderately significant), and ***p < 0.001 (highly significant).

3. Results and discussion

3.1 Synthesis and characterization of CuS@Fe-MOF

CuS@Fe-MOF NPs were synthesized through the co-precipitation/assembling growth

of Fe-MOF shell layer on the surface of CuS nanoplates, as shown in Fig.1a. CuS

sample was firstly synthesized by a modified hydrothermal method [42], and it was

mainly composed of hexagonal-shaped nanoplates with an average size of ~85 nm,

accompanying some triangular-shaped nanoplates (Fig. 1b,c). High-resolution TEM

(HRTEM) image shows that single CuS nanoplate has a clear lattice fringe of ~0.19 nm

(Fig. 1b), which is corresponding to the (110) plane of covellite CuS (JCPDS card no.

06-0464). Subsequently, Fe-MOF shells were grown on CuS nanoplates by assembling

FeCl3 with H3BTC. After the shell growth, the size and morphology of CuS@Fe-MOF

sample were further investigated. TEM image (Fig. 1d) at low magnification reveals

that CuS@Fe-MOF sample consists chiefly of hexagonal nanoplates with a small

amount of triangular nanoplates, and these nanoplates have relatively indistinct edges,

resulting from the presence of amorphous shell. A typical TEM image (the inset in Fig.

1d) of single CuS@Fe-MOF nanoplate at high magnification confirms the clear

structure with hexagonal-shaped CuS nanoplates as core and amorphous Fe-MOF layer

as shell. Size distribution analysis(Fig. 1e) reveals that CuS@Fe-MOF nanoplates have

11
the average size of ~117 nm, with an increase of ~32 nm compared with that (~85 nm)

of CuS nanoplates, which suggests that the average thickness of Fe-MOF shell should

be ~ 16 nm, matching with the thickness distribution of Fe-MOF shells (Fig. S1a). EDS

pattern illustrates that there are Cu, S, Fe, C and O elements in CuS@Fe-MOF sample

(Fig. S1b), where Cu and S elements should emanate from CuS, while Fe, C and O

elements originate from Fe-MOF. HAADF-STEM image of CuS@Fe-MOF single

particle exhibits the clear core-shell structure, where the core is hexagonal CuS

nanoplate and the shell is amorphous Fe-MOF (Fig. 1f). Elemental mapping images

(Fig. 1f) and the corresponding line scan (Fig. S1c) further demonstrate that Cu and S

elements are homogeneously distributed within the nanoplate core, while Fe element is

distributed throughout the entire amorphous shell layer. In addition, the weight ratio of

Fe and Cu in the final sample was determined to be ~6.2 wt% and ~39 wt% by ICP-

AES. The above results confirm the well construction of CuS@Fe-MOF with a core-

shell structure.

Fig. 1 (a) Synthesis scheme of CuS@Fe-MOF. TEM image (b) and size distribution (c)

12
of CuS. TEM image (d), size distribution (e) and HRTEM, HAADF-STEM images and
elemental mappings (f) of CuS@Fe-MOF.

Fig. 2 XRD pattern (a) and nitrogen adsorption-desorption curve (b) of CuS@Fe-MOF.

The phase structure and Brunauer-Emmett-Teller (BET) surface area of CuS@Fe-

MOF sample were studied by X-Ray diffractometer (XRD) and nitrogen

adsorption/desorption isotherms. XRD pattern (Fig. 2a) indicates that there are seven

main diffraction peaks at 27.68°, 29.30°, 31.80°, 32.87°, 47.98°, 52.72° and 59.36°,

corresponding to (101), (102), (103), (006), (110), (108) and (116) planes of hexagonal

phase covellite CuS (JCPDS 06–0464). No obvious peaks can be found for Fe-MOF,

revealing the weak signal strength and amorphous nature of Fe-MOF. In addition,

nitrogen adsorption/desorption isotherms (Fig. 2b) illustrate that CuS@Fe-MOF

sample has a specific surface area (42.634 m2/g), and its pore size distribution is

centered at ~5 nm. These facts confirm the presence of hexagonal phase covellite CuS

and amorphous Fe-MOF in CuS@Fe-MOF with large surface area and porosity.

To confer high hydrophilicity, CuS@Fe-MOF NPs were further surface-modified

by amphiphilic DSPE-PEG molecules according to the previous report [7]. DSPE-PEG-

coated CuS@Fe-MOF can be well dispersed in aqueous solution (Fig. S2). The aqueous

13
dispersions of DSPE-PEG-coated CuS@Fe-MOF exhibit strong black-green color and

high dispersity, and no obvious precipitations can be found within 10 days (Fig. S2).

Subsequently, the optical properties of aqueous dispersions containing DSPE-PEG-

coated CuS@Fe-MOF (0.075-0.3 g L-1) were measured by UV-Vis-NIR spectra (Fig.

3a). These absorption spectra of CuS@Fe-MOF are similar to that of CuS

superstructures [15] and CuS@polymer [34]. All spectra demonstrate the short-

wavelength absorption with edges at ~580 nm due to the bandgap absorption of CuS

semiconductor. Then the absorbance goes up with the increased wavelength from 650

to 1000 nm, and this kind of the increased NIR absorbance has been a characteristic of

covellite, resulting from strong localized surface plasmon resonances (LSPR) effect due

to high Cu defect concentration in covellite [15]. Furthermore, the entire absorption

spectra are enhanced with the increased CuS@Fe-MOF concentration, revealing the

concentration-dependent photoabsorption.

Fig. 3 (a) UV-vis-NIR spectra of CuS@Fe-MOF dispersions (0.075-0.3 g L-1). (b)

14
Temperature elevation curves of CuS@Fe-MOF (0-0.5 g L-1) under 1064 nm laser
irradiation. (c) Temperature curve of CuS@Fe-MOF with laser on/off. (d) Time
constant (τs) of CuS@Fe-MOF.

Due to the excellent photoabsorption at NIR-II window (1000-1350 nm), herein,

1064 nm laser was used as the NIR optical source to investigate the photothermal

effects of CuS@Fe-MOF. The temperature of CuS@Fe-MOF dispersions with different

concentrations (0-0.5 g L-1) was recorded by a thermal imaging camera (Fig. 3b). Under

1064 nm laser irradiation (1.0 W cm-2), pure water shows a very slow temperature

increase from 21.0 °C to 25.4 °C during 400 s, with an inconspicuous temperature

elevation (ΔT=4.4 °C). On the contrary, the temperature of CuS@Fe-MOF dispersions

shows the rapid elevation during 0 to 120 s of irradiation, and then exhibits a relative

slow increase to 400 s. The ΔT at 400 s with different concentrations is exhibited in

Fig. S3. With the increase of CuS@Fe-MOF concentration from 0 to 0.5 g L-1, ΔT

exhibits approximately lineal enhancement from 4.4 to 44.3 °C, confirming the

concentration-dependent photothermal performances of CuS@Fe-MOF.

To further evaluate the photothermal conversion efficiency, CuS@Fe-MOF

dispersion (100 μL) was illuminated by 1064 nm laser. When the temperature was

increased to the maximum (Tmax = 48.2 °C) and remained an equilibrium at 510 s, the

laser was turned off and then the temperature went down to the original temperature

(Tsurr = 20.2 °C) (Fig. 3c). The photothermal conversion efficiency was calculated by a

modified method according to Roper’s report [44].

ℎ𝐴(𝑇𝑚𝑎𝑥 ― 𝑇𝑠𝑢𝑟𝑟) ― 𝑄𝑑𝑖𝑠
𝜂𝑇 = ―𝐴1064 (1)
𝐼(1 ― 10 )

where h, A, and I are the heat transfer coefficient, the surface area of the container and
15
the laser power (250 mW). The absorbance (A1064) is calculated to be 0.55. The hA can

be calculated from equation (2) as:

𝑚H2O𝐶H2O
𝜏𝑠 = ℎ𝐴
(2)

Where τs is the system time constant (122 s, Fig. 3d); mH2O and CH2O present the mass

(0.1 g) and the heat capacity (4.2 J g-1) of deionized water. Qdis can be tested

independently to be 16.02 mW by using water under same conditions. Thus, the

photothermal conversion efficiency of CuS@Fe-MOF (ηT) is determined to be 39.7%,

which is close to CuS-Au heterostructures (36.5%) [42], and Bi2Se3 (34.6%) [45].

3.2 Loading and pH-sensitive release of DOX

Large surface area and porosity of Fe-MOF shell confer CuS@Fe-MOF NPs

potential application as drug delivery vehicles for chemotherapy function. Herein, with

DOX as the model of anticancer drug, we evaluated the DOX loading and releasing

ability of CuS@Fe-MOF (Fig. 4a). The optical properties of the aqueous solution

containing free DOX, CuS@Fe-MOF or CuS@Fe-MOF-DOX were firstly investigated

by UV-vis-NIR absorption spectrophotometer. The free DOX solution shows a typical

absorption peak at ~480 nm, and CuS@Fe-MOF aqueous dispersion shows typical

band-gap absorption and the increased LSPR absorption in the NIR region from CuS.

After the loading of DOX, the resulting CuS@Fe-MOF-DOX dispersion exhibits all

characteristic absorption peaks from DOX and CuS (Fig. 4b). Furthermore, the DOX

encapsulation efficiency (EEDOX, w/w%) is determined to be 50.8%, and loading

content (LCDOX, w/w%) is 27.5% (Fig. 4b). The high loading efficiency of DOX into

CuS@Fe-MOF is similar to the PPy@MIL-100(Fe) [46], which can be attributed to

16
their porosity and electrostatic adsorption between the negative charge of Fe-MOF shell

[47] and the positive charge of DOX [48]. These facts suggest the efficient DOX-

loading capacity of CuS@Fe-MOF.

The release ability of DOX from CuS@Fe-MOF-DOX was further tested in

phosphate buffer saline (PBS, pH=7.4) and acetate buffer (pH=5.4). The cumulative

drug release profiles were exhibited in Fig. 4c. Both solutions exhibit a rapid release in

the initial 2 hour and then slow release in 2-6 h, and they reach to a plateau in 6-24 h.

In neutral PBS solution (pH=7.4), 19.7% of DOX is released at 24 h from CuS@Fe-

MOF-DOX. Importantly, for acid buffer solution (pH=5.4), the cumulative release of

DOX increases quickly from 0 to 35.3% at 2 h, followed by a slow increase to 47.9%

at 24 h. Obviously, the cumulative release (47.9%) at pH=5.4 is 2.4 times than that

(19.7%) at pH=7.4. These results prove that CuS@Fe-MOF-DOX has pH-dependent

drug-release behavior, which results from the change of the electrostatic attraction

between the Fe-MOF and DOX under different pH conditions.

17
Fig. 4 (a) pH-sensitive release scheme. (b) UV-vis-NIR absorbance spectra of the
dispersions containing free DOX, CuS@Fe-MOF, CuS@Fe-MOF-DOX. (c)
Cumulative release of DOX from CuS@Fe-MOF-DOX at different pH values (n=3).

3.3 Cytotoxicity test and photothermal-chemo therapy in vitro

Good biocompatibility is one of the prerequisites for biomedical application.

Firstly, HUVEC was used as a normal cell line to evaluate the cytotoxicity of CuS@Fe-

MOF via standard CCK-8 assay. As shown in Fig. S4, the cell viability was higher than

85% after 24 h incubation with CuS@Fe-MOF (0-0.3 g L-1), which reveals the low

cytotoxicity of CuS@Fe-MOF. Because of the good biocompatibility, the cancer cell-

killing effect of CuS@Fe-MOF-DOX was further investigated. CT26 cells were

incubated with CuS@Fe-MOF and CuS@Fe-MOF-DOX for 24 and 48 h, respectively

(Fig. 5a, S5). Obviously, after cultivating for 24 h, there is no obvious difference in cell

proliferation in the absence (control) or presence of CuS@Fe-MOF or CuS@Fe-MOF-

DOX at a series of concentrations (0-0.05 g L-1), and the viabilities are determined to

be >85%. When the concentration reaches 0.15, 0.2, and 0.3 g L-1, the average
18
viabilities respectively go down to 76%, 68%, and 59% for CuS@Fe-MOF-DOX group

which are lower at the significant difference (**p < 0.01) compared with that for the

CuS@Fe-MOF group, due to the antitumor activity of the released DOX. In addition,

when cultivation time extends to 48 h, the average viabilities of CT26 for CuS@Fe-

MOF-DOX group decrease significantly (***p < 0.001) in comparison to that for

CuS@Fe-MOF group at the concentration of 0.2 g L-1 (Fig. S5). Therefore, these results

indicate that CuS@Fe-MOF has low cytotoxicity, and the loading of DOX confers the

chemotherapy function.

Fig.5 (a) Cytotoxicity tests of CuS@Fe-MOF and CuS@Fe-MOF-DOX. (b)

Fluorescent images of cells incubated with CuS@Fe-MOF-DOX for different time.

To investigate the DOX release in cancer cells, CT26 cells were incubated with

CuS@Fe-MOF-DOX (0.2 g L-1) for different time and then observed by fluorescence

microscope (Fig. 5b). The blue fluorescence originates from the DAPI which is usually

employed to label cell nuclei. The red fluorescence comes from the loaded DOX, and

it can be used to evaluate the release of DOX. Blue and red fluorescence images are

also merged. In the initial 0.5 h, red fluorescence is few and weak, demonstrating that

only a few DOX release in cancer cells. With the increase of incubation time from 0.5

19
to 1 and 2 h, red fluorescence become stronger in the cytoplasm, revealing that more

DOX uptake in cancer cells. Therefore, these results imply that CuS@Fe-MOF-DOX

can be efficiently endocytosed by live cancer cells, resulting in a high release of DOX.

Fig.6 Relative viabilities (a) and fluorescence images (b) of CT26 cells after different
treatments. Relative viabilities (c) and fluorescence images (d) of CT26 cells under
various illumination time (1.0 W cm-2, 0-10 min).

To assess the photothermal-chemo therapeutic effects in vitro, DMEM mediums

containing CuS@Fe-MOF or CuS@Fe-MOF-DOX (0.2 g L-1) were used to incubate

CT26 cells for 4 h, and part of groups were then irradiated under 1064 nm laser with

the safe intensity of 1 W cm-2 for 10 min. The cell viabilities in different groups (control

(I), NIR (II), CuS@Fe-MOF (III), CuS@Fe-MOF-DOX (IV), CuS@Fe-MOF+NIR (V)

and CuS@Fe-MOF-DOX+NIR (VI)) were evaluated by CCK-8 and microscope (Fig.

6). In groups I-III, the cell viabilities are calculated to be as high as >85% (Fig. 6a).

However, for CuS@Fe-MOF-DOX (IV) group, the cell viability decreases to 58.4%

due to the chemotherapy effects of CuS@Fe-MOF-DOX. After 1064 nm laser

irradiation, the cell viability in CuS@Fe-MOF+NIR (V) group is determined to be

20
22.1%, confirming the good PAT of CuS@Fe-MOF. More importantly, CuS@Fe-

MOF-DOX+NIR (VI) group shows the lowest cell viability of 5.5%, which should

come from the synergistic chemotherapy effects of the released DOX and PAT of CuS

cores. To further evaluate the viability vividly, the six groups were stained with

Calcein-AM/PI to distinguish live (green fluorescence) and dead (red fluorescence)

cells (Fig. 6b). Cells in groups I-III show nearly whole green fluorescence. From group

IV to group VI, the green fluorescence areas decrease while red fluorescence areas go

up quickly, which indicates that the viabilities of cancer cells decrease. Especially,

CuS@Fe-MOF-DOX+NIR group (VI) shows the majority of red fluorescence from

dead cells. These facts confirm that CuS@Fe-MOF-DOX+NIR group (VI) has good

synergistic photothermal-chemo therapy, which is better than either single

chemotherapy effect (group IV) or PAT effect (group V).

For CuS@Fe-MOF-DOX+NIR group (VI), we further tested the effect of laser

illumination time (0-10 min) on cell viability (Fig. 6c). Obviously, with the increased

time from 0 to 10 min, the cell viability goes down rapidly from 100% to 5.5%.

Similarly, in the fluorescence images, green fluorescence decreases while red

fluorescence increases with the illumination time, and almost all the cells dead (Fig.

6d). The results indicate that the synergistic photothermal-chemo treatment

effectiveness can be tuned by the illumination time of 1064 nm laser.

3.4 Multimodal imaging and PAT in vivo

It is well known that iron-based materials possess good magnetic properties and

can be used as MRI agents [49, 50]. The transverse relaxation time (T2) of CuS@Fe-

21
MOF aqueous dispersions with different concentrations (Fe: 0-0.8 mM) was measured

to explore their MRI ability (Fig. 7a). With the increase of concentration, the color of

T2-weighted MRI images changes from bright to dark, and the T2 signal intensity

decreases with the increase of Fe concentration, which illustrates the concentration-

dependent MR effect. By plotting the transverse relaxation (1/T2) as a function of the

Fe concentration, the r2 of CuS@Fe-MOF is calculated to be 19.6 mM-1 s-1. To further

analyze the MRI effect in vivo, CuS@Fe-MOF dispersions (100 μL, 0.2 g L-1) were

intratumorally injected into the tumor bearing mice, and the T2-weighted MRI images

were captured before and after the injection (Fig. 7b). The color of MRI image of the

tumor site before injection is bright. Importantly, after injection, the intensity of tumor

area goes down remarkably. The above results indicate that CuS@Fe-MOF can serve

as an efficient MRI agent.

Fig.7 T2-weighted MRI images and signal intensity (a) with various Fe concentration.
(b) MR images of mice pre-and post-injection with CuS@Fe-MOF.

Due to their good photothermal-chemo therapeutic effects in vitro, CuS@Fe-

MOF-DOX may have a great potential for the therapy of tumors in vivo (Fig 8a). CT26

tumor-bearing mice were intratumorally injected with saline (100 μL), CuS@Fe-MOF

(100 μL, 0.2 g L-1) or CuS@Fe-MOF-DOX dispersion (100 μL, 0.2 g L-1). At 0.5 h

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post-injection, tumors of part of mice were illuminated by 1064 nm laser for 10 min,

and the mice can be divided to five groups (saline (I), saline+NIR (II), CuS@Fe-MOF-

DOX (III), CuS@Fe-MOF+NIR (IV) and CuS@Fe-MOF-DOX+NIR (V)). During the

laser illumination process for groups (II, IV, V), the tumor temperatures and the thermal

images of mice were real-time monitored by IR camera (Fig 8b,c). For group (II,

saline+NIR), the tumor surface temperature goes up slowly from ~35 °C to ~38 °C with

a very low elevation (ΔT = ~3°C) during 10 min irradiation, and the color of the tumor

site keeps rose-pink. Importantly, for group (IV, CuS@Fe-MOF+NIR) and group (V,

CuS@Fe-MOF-DOX+NIR), the tumor surface temperature increases rapidly from ~35

°C at 0 s to 53 °C at 100 s ， and remain ~57 °C during 300-600 s, yielding a high

elevation (ΔT = ~22°C). Correspondingly, the color of the tumor site changes from

rose-pink to bright yellow. The above results confirm that both CuS@Fe-MOF and

CuS@Fe-MOF-DOX injected in the tumor remain good and similar photothermal

effects, which can thermally ablate the nearby cancer cells in vivo.

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Fig. 8 (a) Scheme of PAT process. Temperature elevation curves in the tumor site (b)
and the corresponding thermographic images (c) of mice intratumorally injected with
CuS@Fe-MOF, CuS@Fe-MOF-DOX dispersion or saline solution, under the
irradiation of 1064 nm laser.

To compare the long-time therapeutic effects in these five groups, the body weight

and tumor volumes of mice were periodically monitored for 20 days. As vividly shown

in Fig 9a, the body weight in all five groups exhibit a slight increase, and no obvious

difference can be found, which indicates that the treatment processes have no obvious

side effect for mice. In addition, tumor volumes in group (I, saline) and group (II,

saline+NIR) go up rapidly (Fig 9b), due to the absence of therapeutic effects from saline

and NIR light. For group (III, CuS@Fe-MOF-DOX) and group (IV, CuS@Fe-

MOF+NIR), the tumor volumes also increase, while they are lower than those from

group (I), indicating that the tumor growth can be significantly inhibited by the

chemotherapy effect of the released DOX from CuS@Fe-MOF-DOX (versus control

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group, **p <0.01) or the PAT effect of CuS@Fe-MOF with NIR laser (versus control

group, ***p <0.001). Importantly, the tumor volumes in group V (CuS@Fe-MOF-

DOX+NIR) shrink gradually and even disappear after 20 days (versus control group,

***p < 0.001), which suggest the good growth-inhibiting ability resulting from the

synergistic photothermal-chemo therapeutic effects. After 20 days, the tumors were

taken out from the sacrificed mice. The tumors in groups I-IV show relatively large

sizes. On the contrary, the tumors in group V become small or disappear (Fig 9c).

To further observe the histological changes, the tumor slices at 24 h post-treatment

were stained with Haematoxylin and eosin (H&E) staining assay. The H&E staining

images of groups (I, II) exhibit no obvious change in cell sizes, shape, or necrosis (Fig.

9d). The cells in groups (III, IV) exhibit partly change (such as cell morphology change

and damage). Interestingly, there are maximum cytolysis and the loss of cell

morphology for group (V), suggesting the good photothermal-chemo therapeutic

effects. This photothermal-chemo therapeutic effects from CuS@Fe-MOF-DOX+NIR

can be explained as follow. The photothermal effect from CuS can confer high

temperature of tumor, which results in the ablation of cancer cells in vivo. At the same

time, CuS@Fe-MOF-DOX can release DOX under the acidic microenvironment of

tumors, and thus the released DOX can also kill continuously cancer cells in vivo.

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Fig. 9 Changes of body-weights (a) and relative tumor volumes (b) of mice from
different groups during 20 days treatment. (c) Representative photos of tumors on the
20th day. (d) H&E-stained images of the tumors from different groups at 24 h post-
treatment.

Fig. 10 H&E-stained images of major organs from mice in group (I, saline) and group
(V, CuS@Fe-MOF-DOX+NIR) on the 20th day.

After the photothermal-chemo therapy of tumors, we further evaluated the

potential in vivo toxicity induced by CuS@Fe-MOF-DOX with NIR irradiation. On the

20th day, the major organs were taken out from the sacrificed mice and stained with

H&E (Fig. 10). Major organs (heart, liver, spleen, lungs, and kidneys) of the mice from

the control group (I, saline) show the normal structure and morphology. For the

photothermal-chemo therapy group (V, CuS@Fe-MOF-DOX+NIR), the mice also

26
exhibit the similar structure and morphology compared to those from the control group,

and there is no obvious abnormality/damage for pathological tissue. These facts

confirm that CuS@Fe-MOF-DOX NPs have no appreciable in vivo toxicity.

4. Conclusions

In summary, we report the design and preparation of CuS@Fe-MOF-DOX as

integrated theranostic nanoplatforms. CuS@Fe-MOF-DOX nanoparticles exhibit

strong NIR photoabsorption, photothermal conversion efficiency (39.7%), DOX-

loading (27.5%), pH-responsive releasing and MRI abilities as well as good

biocompatibility. Importantly, both in vitro and in vivo experiments demonstrate that

cancer cells can be efficiently killed by CuS@Fe-MOF-DOX due to the synergistic

photothermal-chemo therapy which is better than single PAT or chemotherapy.

Therefore, CuS@Fe-MOF-DOX can act as biocompatible multifunctional MRI

contrast and photothermal-chemotherapeutic agent. For future practical clinical

application, CuS@Fe-MOF-DOX can be further optimized, for example, by modifying

with target biomolecules and/or analyzing the therapeutic effects after the intravenous

injection to mice.

ACKNOWLEDGEMENTS

This work was financially supported by National Natural Science Foundation of

China (51972056, 51773036), Shanghai Shuguang Program (18SG29), Natural Science

Foundation of Shanghai (18ZR1401700), Major Science and Technology Innovation

27
Project of Shandong Province (2019JZZY011108), Innovation Program of Shanghai

Municipal Education Commission (2017-01-07-00-03-E00055), the Fundamental

Research Funds for the Central Universities, and DHU Distinguished Young Professor

Program.

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Highlights

 In-situ growth of Fe-MOF shell on CuS nanoplates.

 Strong NIR photoabsorption and photothermal conversion efficiency

(39.7%) due to CuS core.

 High drug loading efficiency (27.5%), pH-responsive releasing ability and

MR imaging ability due to Fe-MOF shell.

33
 Efficiency treatment of tumors by synergistic photothermal-chemo therapy

of CuS@Fe-MOF.

Declaration of Interests
The authors declare that they have no known competing financial interests or
personal relationships that could have appeared to influence the work reported in this
paper.

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