Biomaterials 60 (2015) 62e71

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Two-dimensional magnetic WS2@Fe3O4 nanocomposite with mesoporous silica coating for drug delivery and imaging-guided therapy of cancer Guangbao Yang, Hua Gong, Teng Liu, Xiaoqi Sun, Liang Cheng, Zhuang Liu* Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, Jiangsu 215123, China

a r t i c l e i n f o

a b s t r a c t

Article history: Received 20 January 2015 Received in revised form 22 April 2015 Accepted 30 April 2015 Available online 14 May 2015

Integrating multiple imaging and therapy functionalities into one single nanoscale platform has been proposed to be a promising strategy in cancer theranostics. In this work, WS2 nanosheets with their surface pre-adsorbed with iron oxide (IO) nanoparticles via self-assembly are coated with a mesoporous silica shell, on to which polyethylene glycol (PEG) is attached. The obtained WS2-IO@MS-PEG composite nanoparticles exhibit many interesting inherent physical properties, including high near-infrared (NIR) light and X-ray absorbance, as well as strong superparamagnetism. In the mean time, the mesoporous silica shell in WS2-IO@MS-PEG could be loaded with a chemotherapy drug, doxorubicin (DOX), whose intracellular release afterwards may be triggered by NIR-induced photothermal heating for enhanced cancer cell killing. Upon systemic administration of such drug-loaded nano-theranostics, efficient tumor homing of WS2-IO@MS-PEG/DOX is observed in tumor-bearing mice as revealed by three-modal fluorescence, magnetic resonance (MR), and X-ray computed tomography (CT) imaging. In vivo combined photothermal & chemotherapy is then carried out with WS2-IO@MS-PEG/DOX, achieving a remarkably synergistic therapeutic effect superior to the respective mono-therapies. Our study highlights the promise of developing multifunctional nanoscale theranostics based on two-dimensional transition metal dichalcogenides (TMDCs) such as WS2 for multimodal imaging-guided combination therapy of cancer. © 2015 Elsevier Ltd. All rights reserved.

Keywords: Theranostics WS2 Iron oxide Mesoporous silica shell Synergistic therapeutic effect

1. Introduction While cancer has become one of major threats to human health nowadays, conventional cancer therapies have limited efficacy and severe toxic effects. Combination therapy to kill cancer by different strategies with synergistic effects has thus received significant attention in recent years [1e7]. On the other hand, theranostics, usually by integrating multiple imaging and therapeutic functions within a single platform, has been proposed as a promising approach to optimize treatment planning and thus to improve therapeutic specificity and efficiency [8e12]. Therefore, the development of multifunctional nanoscale platforms with various functionalities acting in a cooperative manner for imaging-guided combination therapy could bring new opportunities in our future

* Corresponding author. E-mail address: [email protected] (Z. Liu). 0142-9612/© 2015 Elsevier Ltd. All rights reserved.

fight against cancer [13e17]. As a new class of two-dimensional (2D) nanomaterials, transition metal dichalcogenides (TMDCs) have received tremendous attention and showed great promise in various areas including biomedicine [18e23]. TMDCs have many similar characteristics compared to their sister material, graphene, such as ultra-high surface available for efficient molecular binding and drug loading, as well as strong near-infrared (NIR) absorbance useful for photothermal tumor ablation and photoacoustic imaging [24,25]. Moreover, unlike graphene, the elementary composition of TMDCs could be easily tuned to acquire additional functionalities [26e33]. In the past two years, a number of groups including ours have explored the use of TMDCs including MoS2, WS2, and Bi2Se3 nanosheets, for biological sensing [34,35], imaging [25], drug delivery [36], and photothermal therapy [19,20], showing many encouraging results in both in vitro and in vivo experiments. In particular, WS2 nanosheets could not only serve as a photothermal agent to destroy tumor cells, but also act as a contrast agent for in vivo enhanced X-

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ray computed tomography (CT) imaging for imaging-guided therapy of cancer [25]. However, there is still much room to engineer TMDC-based theranostic platform, particularly by integrating TMDCs with other functional nanostructures, to realize imagingguided combination cancer treatment. In this work, WS2 nanosheets with iron oxide nanoparticles (IONPs) self-assembled on their surface are coated with mesoporous silica and then functionalized with polyethylene glycol (PEG), obtaining a WS2-IO@MS-PEG nanoscale platform useful in multimodal imaging, drug delivery, as well as photothermal therapy. In this system, WS2 nanosheets as the core exhibit strong NIR and X-ray absorbance, which are useful for photothermal therapy and X-ray computed tomography (CT) imaging, respectively [25]. In the mean time, IONPs offer the T2 contrast in MR imaging [37,38], while the mesoporous silica shell would provide enlarged capacity for effective loading of therapeutic molecules such as doxorubicin (DOX) [39e41]. Interestingly, under the stimulation of an external NIR laser, the photothermal effect of WS2 would trigger the release of DOX loaded inside the mesoporous silica shell of WS2-IO@MSPEG, enabling intracellular drug release and thereby enhanced cancer cell killing efficiency [42e44]. Utilizing the highly enriched functionalities of WS2-IO@MS-PEG, fluorescence, MR and CT threemodal imaging is conducted on tumor-bearing mice, vividly illustrating the high tumor retention of such nano-agent. At last, in vivo combined photothermal & chemotherapy is demonstrated with WS2-IO@MS-PEG/DOX, achieving a remarkable synergistic therapeutic effect in a mouse tumor model using relatively low carrier dosage and laser power density. Therefore, our work demonstrates the great promise of TMDC-based composite nanostructures as novel theranostic platforms for imaging-guided cancer therapy. 2. Materials and methods 2.1. Materials All chemicals were purchased from SigmaeAldrich and used as received. PEG polymers were purchased from PegBio, Suzhou, China. All cell-culture related reagents were purchased from Hyclone. 2.2. Synthesis of WS2 nanosheets In a typical procedure, 0.5 g WS2 powder was immersed in 5 ml n-butyllithium (1.6 M in hexane) and stirred for 2 days inside a vacuum glove box. Following the intercalation by lithium, the WS2 sample was filtered and washed repeatedly with 50 mL hexane to remove excess lithium and other organic residues. WS2 sample was then removed immediately from glove box and ultrasonicated in water for 1 h to allow effective exfoliation, obtaining exfoliated WS2 which was then centrifuged at 4500 round-per-min (rpm) to remove unexfoliated WS2 and excess LiOH in the precipitates. The yielded WS2 nanosheets were collected and dialyzed against deionized water for 2 days to completely remove any residual lithium ions. Obtaining WS2 nanosheets were dispersed in water for future use. 2.3. Synthesis of WS2-IO Ultra-small superparamagnetic iron oxide nanoparticles were synthesized from Fe (acac)3 based on a well-established method [45]. Functionalization of IONPs was carried out by slowly adding 25 mg meso-2, 3-dimercaptosuccinic acid (DMSA) in 1 mL water into a tetrahydrofuran (THF) solution containing 20 mg of IONPs under ultrasonication of 30 min. After stirring at room temperature for 2 h, the solvent was removed by centrifugation at 14800 rpm.


The DMSA-modified IONPs could be easily dissolved in water with excellent stability. To prepare WS2-IO, DMSA-modified IONPs (10 mg) were slowly dropped into water containing 2 mg WS2 nanosheets under ultrasonication for 30 min. After stirring for 6 h, a WS2-IO solution was obtained. In order to enhance the stability of WS2-IO against salts, 10 mg of lipoic acid modified PEG (LA-PEG) synthesized following a reported protocol was added into 2 mg of WS2-IO dispersed in 2 mL water [8]. After sonication for 30 min and stirring overnight, excess LAPEG were removed by centrifugal filtration with 100 kDa MWCO filters (Millipore). The obtained PEGylated WS2-IO was highly water-soluble and stored at 4  C before future use. 2.4. Preparation of WS2-IO@MS PEGylated WS2-IO (1 mg) and cetyl trimethyl ammonium bromide (CTAB, 17.5 mg) were added into 20 mL of water containing 600 mL NaOH (0.1 M) and then ultrasonicated for 1 h to allow effective dispersion. 100 mL of TEOS was then dropwisely added into the reaction solution, which was stirred for 24 h at 50  C. The products were collected by centrifugation and washed for several times with ethanol to remove the template CTAB. 2.5. Preparation of WS2-IO@MS-PEG Our strategy to functionalize WS2-IO@MS was to firstly convert its surface to be highly lipophilic, and then coat the surface with a PEGylated amphiphilic polymer. WS2-IO@MS (1 mg) dispersed in 10 mL ethanol was added with 30 mL C18TMS. The obtained suspension was stirred for 24 h C18TMS modified WS2-IO@MS, which became highly lipophilic, was collected by centrifugation and then washed with chloroform and ethanol several times. To transfer C18TMS modified WS2-IO@MS into the aqueous phase, PEG (5 kDa) drafted poly (maleic anhydride-alt-1octadecene) (C18PMH-PEG) synthesized following the protocol reported previously was used [46]. In our experiments, 10 mg C18PMH-PEG dispersed in 10 mL chloroform was mixed with WS2IO@MS/C18TMS (1 mg) under stirring for 12 h. After evaporating the organic solvent by air blow, PEGylated WS2-IO@MS (WS2-IO@MSPEG) was obtained and dissolved in water. Excess C18PMH-PEG was removed by centrifugation. 2.6. Preparation of Cy5.5 labeled WS2-IO@MS-PEG PEGylated WS2-IO (1 mg) and Cetyl trimethyl ammonium bromide (CTAB, 17.5 mg) were added into 20 mL of water containing 600 mL NaOH (0.1 M) and then ultrasonicated for 1 h to allow effective dispersion. Then, we conjugated NHS-Cy5.5 with 3aminopropyltriethoxysilane (APTES) by mixing 1 mg NHS-Cy5.5 pre-dissolved in 0.5 mL dimethyl sulfoxide (DMSO) with 10 mL APTES. The mixture was stirred for 2 h under room temperature and then added into the reaction solution. At last, 100 mL of TEOS was dropwisely added into the reaction system, which was stirred for 24 h at 50  C before the product was collected by centrifugation. The products were collected by centrifugation and washed for several times with ethanol to remove the template CTAB. Further PEGylation was then conducted following the procedures described earlier. 2.7. Characterizations Transmission electron microscopy (TEM) images were obtained using a FEI Tecnai F20 transmission electron microscope at an acceleration voltage of 200 kV, equipped with an energy dispersive


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spectroscope (EDX). UVeviseNIR spectra were obtained with PerkinElmer Lambda 750 UVeviseNIR spectrophotometer. Fluorescence spectra were acquired on a FluoroMax 4 luminescence spectrometer (HORIBA, Jobin Yvon). The sizes of nanoparticles were measured using ZEN3690 zetasizer (Malvern, USA).

2.8. Drug loading and release For DOX loading, solutions of WS2-IO@MS-PEG (0.1 mg/mL) were mixed with different concentrations of DOX in PBS at pH ¼ 8.0. After stirring at room temperature for 24 h, Excess DOX was removed by centrifugation and washing with PBS several times. The obtained WS2-IO@MS-PEG/DOX was stored at 4  C in the dark for future use. To study the drug release, a solution of WS2-IO@MS-PEG/DOX was dialyzed against PBS with different pH values (7.4 or 5.5) under room temperature. The amounts of DOX released into the dialysis media at different time points were measured by UVevis spectra. The laser-triggered drug release experiments were performed in PBS at pH 5.5 and 7.4 at 37  C. An optical-fiber-coupled powertunable diode laser (continuous wave) with wavelengths of 808 nm (maximal power ¼ 10 W) was employed in this work. WS2-IO@MSPEG/DOX was dispersed in 2 mL of PBS solution at different pH values. At design time intervals, the samples were irradiated by the 808 nm laser with a power intensity of 0.8 W/cm2 for 5 min. As the controls, WS2-IO@MS-PEG/DOX solutions without laser irradiation were used. For each measurement, 2 mL of solution was centrifuged at 14800 rpm for 5 min. The amount of released DOX in the supernatant was determined using UVevis spectrometry.

2.9. Cellular experiments 4T1 murine breast cancer cells (4T1), HeLa human cervical cancer cells (HeLa), and 293T human embryonic kidney cells (293T) were originally obtained from American Type Culture Collection (ATCC) and cultured under recommended medium under 37  C within 5% CO2 atmosphere. For cell toxicity assay, cells were seeded into 96-well plates (1  104 per well) until adherent and then incubated with series concentrations of WS2-IO@MS-PEG/DOX. After incubation for 24 h, the standard thiazolyl tetrazolium (MTT, SigmaeAldrich) test was conducted to measure the cell viabilities relative to the untreated cells. To test the toxicity of DOX, 4T1 cells were seeded into 96-well plates until adherent and then incubated with WS2-IO@MS-PEG/DOX and free DOX for 24 h before the MTT test. For combination therapy, 4T1 cells in 96-well plates at the density of 1  104 cells/well were incubated with free DOX, WS2IO@MS-PEG and WS2-IO@MS-PEG/DOX (DOX ¼ 50 mg/mL) for 1.5 h, washed with PBS, and then irradiated by an 808-nm NIR laser at power densities of 0.1 W/cm2, 0.3 W/cm2 and 0.8 W/cm2 for 20 min. After additional incubation for 24 h, the relative cell viabilities were then measured by the MTT assay. For confocal fluorescence imaging, 4T1 cells (1  104 cells) were cultured in 24-well plates containing WS2-IO@MS-PEG/DOX (DOX ¼ 50 mg/mL) and free DOX for 1.5 h, washed with PBS, and then irradiated by an 808-nm NIR laser at power densities of 0.3 W/ cm2 for 20 min. Cells were labeled with 40 , 6-diamidino-2phenylindole (DAPI) and then imaged by a laser scanning confocal fluorescence microscope (Leica SP5). Those cells were also analyzed by flow cytometry after trypsinization and washing with PBS for 3 times. The cellular DOX fluorescence was analyzed by flow cytometry (FACS Calibur from Becton, Dickinson Company).

2.10. Animal model Female Balb/c mice weighing 18e20 g were purchased from Nanjing Peng Sheng Biological Technology Co. Ltd. and used in accordance with regulations provided by Soochow University Laboratory Animal Center. 4T1 tumors were inoculated by subcutaneous injection of 5  106 cells in ~100 mL of serum-free RMPI1640 medium onto the back of each mouse. After ~6 days, the mice bearing 4T1 tumors were treated when the tumor volume reached ~60 mm3. 2.11. In vivo imaging In vivo fluorescence imaging was conducted using the Maestro in vivo fluorescence imaging system (Cri inc.). The autofluorescence was removed by the spectrum unmixing software. MR imaging was conducted by using a 3.0-T clinical MRI scanner (GE healthcare, USA) equipped with a special coil for small animal imaging. CT imaging was performed on GE discovery CT750 HD (GE Healthcare, WI) with the following parameters: beam collimation ¼ 64  0.625 mm; table speed ¼ 27 mm per rotation; beam pitch ¼ 1.25; gantry rotation time ¼ 1.0 s. For IR thermal imaging, mice injected with various materials were anesthetized and imaged under an IR thermal camera (Infrared Cameras Inc) with or without irradiation by the 808 nm laser at power densities of 0.55 W/cm2 for 10 min. 2.12. Blood circulation and biodistribution measurement Blood circulation was measured by drawing 10e15 mL of blood from the untreated side of tail vein in Balb/c mice at different timeintervals after injection of WS2-IO@MS-PEG/DOX (dose of WS2 ¼ 8.4 mg/kg, dose of DOX ¼ 7 mg/kg). The blood samples were weighted and then dissolved in cell lysis solution (2% Sodium Dodecyl Sulfonate). DOX concentrations in those samples were determined by the fluorescence spectrum of DOX. For biodistribution study, three female Balb/c mice bearing 4T1 murine breast cancer tumors were sacrificed at 24 h after i.v. injection of WS2-IO@MS-PEG/DOX (dose of WS2 ¼ 8.4 mg/kg, dose of DOX ¼ 7 mg/kg). Various organs and tissues were collected, weighed and then solubilized by aqua regia. The concentrations of W in those tissue lysate samples were measured by ICP-AES. The W levels in organs were presented in the unit of the percentage of injected dose per gram tissue (%ID/g). 2.13. Combination therapy in vivo 4T1 tumor-bearing mice were divided into five groups (n ¼ 5 per group). Each group of mice were i.v. injected with 200 mL of PBS, DOX, WS2-IO@MS-PEG, or WS2-IO@MS-PEG/DOX (dose of WS2 ¼ 8.4 mg/kg, dose of DOX ¼ 7 mg/kg). After 24 h, the tumors were treated with or without NIR light (0.55 W/cm2, 808 nm) for 10 min. Tumor sizes were monitored every 2 days for 2 weeks. The length and width of the tumors were measured by a digital caliper. The tumor volume was calculated according to the following formula: width2  length/2. 3. Results and discussion 3.1. Preparation and characterization of WS2-IO@MS-PEG/DOX The design and synthesis strategy of WS2-IO@MS-PEG platform is illustrated in Fig. 1a. We obtained single-layered WS2 nanosheets with a high-yield through the Morrison method, which broke the weak interlayer forces in bulk WS2 by lithium insertion and

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Fig. 1. Synthesis and characterization of WS2-IO@MS-PEG. (a) A procedure showing the fabrication of WS2-IO@MS-PEG/DOX theranostic nanoparticles. (b) TEM images of WS2 (left) WS2-IO (middle) and WS2-IO@MS-PEG (right). Insets are zoomed-in TEM images. (c) STEM image and HAADF-STEM-EDS mapping images of WS2-IO@MS-PEG. (d) UVeviseNIR absorbance spectra of WS2 and WS2-IO@MS-PEG in water. (e) The photothermal heating curves of pure water and WS2-IO@MS-PEG with different concentrations under 808-nm laser irradiation at the power density of 0.5 W/cm2. Inset: IR images of water and WS2-IO@MS-PEG solutions after laser irradiation for 5 min. (f) Temperature variations of the WS2IO@MS-PEG solution (0.5 mg/mL) under irradiation by the 808-nm laser at the power density of 0.8 W/cm2 for 5 cycles.

exfoliation [47,48]. Ultra-small Fe3O4 iron oxide nanoparticles (IONPs) were synthesized using the binary solvothermal method following a literature protocol [49] and then modified with meso-2, 3-dimercaptosuccinic acid (DMSA). Interestingly, we found that DMSA-modified IONPs could be self-assembled on the surface of WS2 as a single nanoparticle layer upon simple mixing, likely via sulfide chemistry between thiol groups on IONPs and defect sites on WS2 (Fig. 1b) [25]. We then ought to coat WS2-IO with mesoporous silica. Because as-made WS2-IO, although soluble in water, would aggregate in the presence of salts, we used a lipoic acid conjugated PEG (LA-PEG) to functionalize WS2-IO (via the WeS bond) in order to enhance its stability against salts, which could not

be avoided during the following fabrication steps. Next, in the presence of cetyl-methyl-ammonium bromide (CTAB), tetraethyl orthosilicate (TEOS) was injected into the solution of PEG modified WS2-IO to induce the formation of silica shell on its surface. After washing with ethanol to remove CTAB, which served as the mesostructural template, mesoporous silica coated WS2-IO (WS2-IO@MS) was then obtained. To optimize the ratio between WS2-IO and mesoporous silica in our composite nanoparticles, the reactions were performed by adding different ratios of WS2-IO and TEOS. From the transmission electron microcopy (TEM) images and the dynamic light scattering (DLS) measurement (Supporting Fig. S1a&b), the obtained nanocomposites showed


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quite uniform morphology without noting free silica nanoparticles when the mass ratio of WS2-IO and TEOS reached 10:1, which was chosen in our further experiments. As revealed by TEM imaging, a mesoporous silica shell with a thickness of ~10 nm was noted on the surface of WS2-IO@MS (Fig. 1b). This kind of nanostructure would facilitate the mass transportation between the inner and outer surfaces of the silica coating to allow drug loading and releasing. The surface area and average pore diameter of WS2-IO@MS were determined to be 568.03 m2 g1 and 2.48 nm, respectively, by BrunauereEmmetteTeller (BET) measurement (Supporting Fig. S2a). The multi-component structure of WS2-IO@MS-PEG was further confirmed by the high-angle annular dark field scanning TEM (HAADF-STEM) images (Fig. 1c), which showed the overlapping of Fe and W signals, as well as the uniform coating of silica on WS2-IO. Besides the C and Cu elements from the TEM grid, only peaks of W, S, Fe, O and Si were detected in the energy dispersive X-ray spectroscopy (EDS) pattern (Supporting Fig. S2b). As-synthesized WS2-IO@MS nanoparticles, which were soluble in water, would rapidly aggregate in the presence of salts and thus were not stable in physiological solutions, even though WS2-IO was pre-PEGylated before silica coating (Supporting Fig. S3a). To enhance the physiological stability of WS2-IO@MS, we modified WS2-IO@MS subsequently with octadecyltrimethoxysilane (C18TMS) and then PEG-grafted poly (maleic anhydride-alt-1octadecene) (C18PMH-PEG). After PEGylation, the obtained WS2IO@MS-PEG was well dispersed in water, saline, and serum without any noticeable agglomeration after 24 h (Supporting Fig. S3b). UVeviseNIR absorbance spectra of WS2 showed strong NIR absorbance, which was not affected after coating with mesoporous silica and functionalization with PEG (Fig. 1d). The mass extinction coefficient of WS2 nanosheets at 800 nm was calculated to be 23.8 L g1 cm1 [25]. As expected, when irradiated by an 808 nm NIR laser (0.5 W/cm2), the WS2-IO@MS-PEG solution exhibited an obvious concentration-dependent heating effect (Fig. 1e), allowing it to be effectively used as a photothermal agent. Notably, it was found that WS2-IO@MS-PEG remained to be a rather robust photothermal heater after five cycles of NIR-induced heating (808 nm laser at 0.8 W/cm2, 3 min laser irradiation for each cycle), demonstrating its excellent photothermal stability (Fig. 1f). We next studied the drug loading ability of WS2-IO@MS-PEG using doxorubicin (DOX), a commonly used anti-cancer drug [50], as a model drug molecule. For drug loading, WS2-IO@MS-PEG (0.1 mg/mL) was mixed with different concentrations of DOX in phosphate buffered saline (PBS) at pH 8.0 overnight in dark. Excess unbound DOX molecules were removed by centrifugation at 14800 rpm for 5 min and washed with water for several times. The UVeVis absorption spectra of WS2-IO@MS-PEG/DOX were then recorded (Supporting Fig. S4a). Based on the DOX characteristic peak at 490 nm, the drug loading capacities on WS2-IO@MS-PEG were determined. The DOX loading increased with increasing amounts of added DOX and reached the maximal level at the DOX concentration of 0.5 mg/mL (Supporting Fig. S4b). The drug release behaviors of WS2-IO@MS-PEG/DOX were then studied. Similar to many other DOX-loaded nanocarriers [51e53], our WS2-IO@MS-PEG/DOX exhibited pH dependent drug release behavior, with accelerated release under slightly acidic pH owing to the protonation of amino group in the DOX molecule (Fig. 2a). Moreover, to test whether the photothermal effect of WS2 can be utilized to induce DOX release from the nanocarrier, WS2-IO@MSPEG/DOX in PBS at pH 5.5 and 7.4 were irradiated under 808 nm NIR laser (0.8 W/cm2, 5 min for each pulse). It was found that the stimulation of NIR light could obviously trigger drug release from WS2-IO@MS-PEG/DOX (Fig. 2b), similar to the behaviors of many other mesoporous silica coated photothermal nano-carriers

[1,54,55]. Interestingly, the NIR light responsiveness of our nanocarrier was particularly sensitive within the acidic environment. Such behavior may enable light-triggered drug release inside cells after WS2-IO@MS-PEG/DOX enters cell endosomes and lyosomes with acidic pH. 3.2. In vitro experiments We then tested the cytotoxicity of WS2-IO@MS-PEG towards different types of cells. Cell viability test based on the standard methyl thiazolyl tetrazolium (MTT, Sigma Inc.) assay showed that WS2-IO@MS-PEG exhibited no obvious toxicity to different types of cells including 4T1 murine breat cancer cells, HeLa human cervical cancer cells and 293T human embryonic kidney cells, even at high concentrations of nanoparticles up to 200 mg/mL (Supporting Fig. S5a). DOX loaded WS2-IO@MS-PEG, on the other hand, was able to kill cancer cells by a concentration-dependent manner (Supporting Fig. S5b). Next, we wondered whether the NIR light triggered drug release of WS2-IO@MS-PEG/DOX could also be realized inside cells (Fig. 2c). By covalently doping a NIR dye, Cy5.5, into the MS shell during its formation (Fig. 1a, see method section for detailed protocol), Cy5.5 labeled WS2-IO@MS-PEG was obtained for in vitro experiments. After being incubated with Cy5.5 labeled WS2-IO@MS-PEG/DOX at 37  C for 1.5 h, 4T1 cells were washed with PBS to remove free nano-carriers and then irradiated by the 808 nm laser at the power intensity of 0.3 W/cm2 for 20 min. Since the DOX fluorescence is largely quenched in the Cy5.5 labeled WS2-IO@MS-PEG/DOX formulation (Supporting Fig. S6), its fluorescence recovery could serve as an indicator of drug release. As revealed by confocal fluorescence images, it was found that DOX fluorescence inside cells was significantly enhanced after laser irradiation (Fig. 2d), suggesting the NIR light triggered release of DOX from Cy5.5 labeled WS2-IO@MS-PEG/DOX inside the cells. Since Cy5.5 was doped inside the MS shell during its formation, no significant change of Cy5.5 fluorescence was found after laser irradiation. Notably, while Cy5.5 fluorescence mainly located in the cytoplasm of cells, the fluorescence of DOX, which inserts into the helix of double-strand DNA to inhibit cell proliferation, was found to be inside cell nuclei. The absence of co-localization between signals from drug molecules and carriers might be attributed to the fact that DOX fluorescence was greatly quenched in the WS2-IO@MSPEG/DOX formulation before being released and thus only released DOX instead of loaded DOX could be observed under confocal fluorescence microscope. Consistent results were also observed from flow cytometry data, which revealed the enhanced cellular DOX fluorescence after laser exposure (Fig. 2e). The above results thus evidenced that the intracellular release of DOX from WS2IO@MS-PEG/DOX could indeed be triggered by NIR light. The combined therapeutic effect of photothermal with chemotherapy delivered by WS2-IO@MS-PEG/DOX was then studied at the cellular level. In our experiments, 4T1 cells were incubated with WS2-IO@MS-PEG/DOX or free DOX with the same DOX concentration for 1.5 h, washed with PBS to remove free nanoparticles, transferred into fresh cell culture, and then treated with or without an 808-nm NIR laser at different power densities for 20 min. After incubation for another 24 h, the relative cell viabilities were measured by the MTT assay (Fig. 2f). WS2-IO@MS-PEG without DOX loading was also used as the control. It was found that the cancer cell killing efficiency of WS2-IO@MS-PEG/DOX without laser irradiation was similar to that of free DOX, likely because of the enhanced cellular uptake of DOX in our WS2-IO@MS-PEG/DOX formulation (Supporting Fig. S7), despite the slower release of DOX from the nano-carrier in dark. It was also indicated that WS2IO@MS-PEG/DOX treated cells showed remarkably reduced

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Fig. 2. NIR-triggered intracellular drug release. (a) DOX release from WS2-IO@MS-PEG/DOX nanoparticles overtime in buffers at the different pH values (5.5 and 7.4). (b) The NIR irradiation triggered release of DOX from WS2-IO@MS-PEG/DOX at different pH values (5.5 and 7.4). Arrows point to the time points at which NIR irradiation was applied (0.8 W/ cm2, 5 min). (c) A scheme showing NIR-triggered drug release from WS2-IO@MS-PEG/DOX inside cells. (d) Confocal images of 4T1 cells incubated with Cy5.5 labeled WS2-IO@MSPEG/DOX with or without laser irradiation (808 nm, 0.3 W/cm2, and 20 min). Blue, green and red colors represent DAPI stained nuclear, Cy5.5 and DOX fluorescence, respectively. (e) Flow cytometry measurements of cellular Cy5.5 and DOX fluorescence in (d). The recovery of DOX fluorescence of cells incubated with Cy5.5 labeled WS2-IO@MS-PEG/DOX after laser irradiation indicated drug release inside cells. (f) Relative viabilities of 4T1 cells after various treatments indicated. NIR laser irradiation could significantly enhance cancer cell killing induced by WS2-IO@MS-PEG/DOX. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

viabilities as the increase of laser power intensities, while the cytotoxicity of free DOX was not affected by NIR laser exposure. Simple photothermal heating induced by WS2-IO@MS-PEG without chemotherapy appeared to be not as effective compared to the combination therapy. Therefore, the combined photothermal & chemotherapy could offer obviously better therapeutic effect at the cellular level compared to mono-therapies. 3.3. In vivo imaging We next would like to study the behaviors of WS2-IO@MS-PEG in animals by in vivo imaging. Multimodal imaging has become the important direction in the current development of biomedical imaging as it could overcome limitations of each single imaging modality [56e58]. Since our WS2-IO@MS-PEG is able to offer contrast under a number of different imaging modalities, three modal, fluorescence, MR, and X-ray CT imaging are conducted on 4T1 tumor-bearing mice after intravenous (i.v.) injection of WS2IO@MS-PEG.

NIR fluorescence imaging is a widely used small animal imaging approach that can be easily operated. Cy5.5 labeled WS2-IO@MSPEG was used for in vivo fluorescence imaging (Fig. 3a). The tumor contrast, which already showed up at early time points post i.v. injection of Cy5.5 labeled WS2-IO@MS-PEG, became rather strong at 24 h post injection (p.i.), suggesting efficient retention of nanomaterials in the tumor, which was also confirmed by ex vivo fluorescence imaging (Supporting Fig. S8). Owing to the presence of IONPs inside the nanocomposite, our WS2-IO@MS-PEG could act as a T2 contrast agent for MR imaging. T2-weighted MR images of WS2-IO@MS-PEG solutions using a 3T MR scanner revealed a concentration-dependent darkening effect, showing a high transverse relaxivity (r2) of 121.5 mM1s1 (Fig. 3b). After i.v. injection of WS2-IO@MS-PEG into 4T1 tumorbearing mice, remarkably darkened appearance was observed in the tumor region of mice from in vivo MR imaging, again demonstrating high tumor accumulation of those nanoparticles after systemic administration (Fig. 3c). In our previous work, it has been demonstrated that tungsten in


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Fig. 3. In vivo multimodal imaging. (a) In vivo fluorescence imaging of 4T1 tumor-bearing mice taken at different time points post i.v. injection of Cy5.5 labeled WS2-IO@MS-PEG. Dashed circles highlight the tumor. (b) T2-weighted MR images of WS2-IO@MS-PEG solutions recorded using a 3T MR scanner revealed a concentration-dependent darkening effect. (c) In vivo T2-wighted MR imaged of a mouse taken before injection (left) and 24 h post injection (right). Obvious darkening effect showed up in the tumor after i.v. injection of WS2IO@MS-PEG. (d) CT images and HU values of WS2-IO@MS-PEG solutions with different concentrations. (e) CT images of mice before and 24 h after i.v. injection with WS2-IO@MSPEG (2 mg/mL, 200 mL). The CT contrast was obviously enhanced in the tumor area (highlighted by dashed circles).

WS2 could absorb X-ray and offer strong contrast in CT imaging. CT images of WS2-IO@MS-PEG solutions (Fig. 3d) revealed the linear increase of the Hounsfield unit (HU) values with the increasing concentrations of WS2-IO@MS-PEG. The slope of the HU values of WS2-IO@MS-PEG was measured to be 31.9 HU L/g. In vivo CT imaging was then conducted for 4T1 tumor-bearing Balb/c mice after they were i.v. injected with WS2-IO@MS-PEG (2 mg/mL, 200 mL). Obvious CT contrast was also observed in the tumor at 24 h p.i., consistent to the previous fluorescence and MR imaging results (Fig. 3e). 3.4. In vivo behavior of WS2-IO@MS-PEG/DOX To understand the observed high tumor accumulation of nanoparticles as revealed by three-modal in vivo imaging, the blood circulation and biodistribution of WS2-IO@MS-PEG/DOX (dose of WS2: 8.4 mg kg1, dose of DOX: 7 mg kg1) after i.v. injection into tumor-bearing mice were then studied (Supporting Figure S9a). Based on the measurement of DOX fluorescence from blood samples collected at different time points p.i., the blood circulation half-life was determined to be 4.77 h, which appeared to be quite long compared to many different drug delivery nanocarriers. The mice i.v. injected with WS2-IO@MS-PEG were scarified at 24 h. Major organs of mice (n ¼ 3) were collected and solubilized by aquaregia for inductively-coupled plasma atomic-

emission spectroscopy (ICP-AES) measurement of W element. Apart from high retention in the liver and spleen, which were reticuloendothelial systems known for the clearance of foreign nanoparticles from blood, a relatively high level of W was also found in the tumor at 24 h p.i. (Supporting Fig. S9b). The high tumor uptake of WS2-IO@MS-PEG/DOX could be attributed to its long blood circulation half-life, which is favorable for tumor passive homing of nanoparticles via the enhanced permeability and retention effect of cancerous tumors [3,59e61]. At last, we ought to demonstrate the combination therapy with WS2-IO@MS-PEG/DOX in animal experiments. When the tumor sizes reached about 60 mm3, Balb/c mice bearing 4T1 tumors were divided into five groups with 5 mice per group: untreated (Group 1), free DOX þ 808-nm light (Group 2), WS2-IO@MS-PEGþ808-nm light (Group 3), WS2-IO@MS-PEG/DOX (Group 4), WS2-IO@MSPEG/DOX þ 808-nm light (Group 5). The therapeutic agents with the same equivalent WS2 and DOX doses (WS2: 8.4 mg kg1, DOX: 7 mg kg1) were i.v. injected into those mice. At 24 h p.i., their tumors were irradiated by the 808 nm laser at a moderate power density of 0.55 W/cm2 for 10 min. An IR thermal camera was used to monitor the tumor temperature (Fig. 4a&b). It was found that the tumor surface temperatures of mice treated with WS2-IO@MS-PEG and WS2-IO@MS-PEG/DOX rapidly increased and maintained at ~48  C during laser irradiation. In contrast, the mice treated with PBS and free DOX showed no significant heating in the tumor

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Fig. 4. WS2-IO@MS-PEG/DOX for in vivo combination therapy. (a) IR thermal images of 4T1 tumor-bearing mice recorded by an IR camera. The doses WS2-IO@MS-PEG and DOX were 8.4 mg/kg and 7 mg/kg, respectively. (b) Temperature changes of tumors monitored by the IR thermal camera in different groups during laser irradiation. (c) The growth of 4T1 tumors in different groups of mice after various treatments indicated. The relative tumor volumes were normalized to their initial sizes. (d&e) Average weights (d) and photographs (e) of tumors collected from mice at the end of treatments (day 14). The predicted addictive effect was calculated by multiplying the tumor growth inhibition ratios between group 3 (photothermal therapy) and group 4 (chemotherapy). (f) H&E-stained tumor slices collected from mice post various treatments indicated (scale bar ¼ 100 mm). P values in (c) and (d) were calculated by Tukey's post-test (***p < 0.001, **p < 0.01, or *p < 0.05).

region when irradiated by the laser. The tumor sizes and body weights were then measured every the other day (Fig. 4c, Supporting Fig. S10) for two weeks. At day 14, tumors from all groups of mice were collected and weighed (Fig. 4e&d, Supporting Fig. S11). Compared to treatment with free DOX, WS2-IO@MS-PEG/DOX without laser irradiation showed improved therapeutic effect, likely owing to the enhanced tumor uptake of DOX in the later formulation by the EPR effect. However, the tumor growth was still only partially delayed by chemotherapy alone delivered by WS2-IO@MS-PEG/DOX. Similarly, for mice injected with WS2-IO@MS-PEG and exposed to laser irradiation, the tumor development was also only slightly delayed after the mild photothermal heating. In marked contrast, the tumor growth in the combination therapy group (WS2-IO@MS-PEG/DOX þ laser irradiation) was almost completely inhibited. Notably, the therapeutic efficacy achieved in our combination therapy group appeared to be obviously stronger than the predicted addictive effect (Fig. 4d), suggesting the obvious synergistic effect by combined photothermal & chemotherapy. In addition, Hematoxylin and eosin (H&E) staining of tumor slices (Fig. 4f) further confirmed that while

cells in control groups of tumors largely retained their normal morphology with distinctive membrane and nuclear structures, most tumor cells were severely damaged in the group receiving WS2-IO@MS-PEG/DOX injection and NIR laser irradiation. The potential side effect of our combination therapy with WS2IO@MS-PEG/DOX was looked into at last. In our experiments, animals after various treatments showed no obvious body weight drop. Histology examination of H&E stained organ slices harvested from healthy mice and WS2-IO@MS-PEG/DOX treated mice (with light exposure, 14 days p.i.) was conducted (Supporting Fig. S12). No noticeable organ damage or abnormality was observed for all major organs including liver, spleen, kidney, heart, and lung, indicating that our WS2-IO@MS-PEG/DOX exhibited no obvious toxic side effect to the mice. Our study presents a new design of WS2-based multifunctional nanoscale theranostic platform for multimodal imaging guided combination therapy of cancer. Three-modal fluorescence, MR, and CT imaging has been realized using WS2-IO@MS-PEG as the contrast agent in our study. Fluorescence imaging is a quite sensitive modality suitable for small animal imaging. The quenching of


G. Yang et al. / Biomaterials 60 (2015) 62e71

fluorescence signals in the complicated biological tissues, the autofluorescence background, as well as the limited tissue penetration by light, are the limitations of this imaging modality. On the other hand, MR and CT imaging, which both enable whole-body imaging with high spatial resolution and provide anatomy information, however exhibit lower sensitivity towards contrast agents. Those three imaging modalities with their respectively advantages and limitations taken together could provide valuable information for planning and guiding therapeutic actions. As far as therapy is concerned, the dramatic synergistic effect achieved by combined photothermal & chemotherapy delivered by WS2-IO@MS-PEG/DOX may be explained by two mechanisms. Firstly, in previous studies and also uncovered in our own experiments (Supporting Fig. S13), the mild photothermal heating could increase the cell membrane permeability and thus enhance the intracellular delivery of drugs [62e64]. In the meanwhile, the NIRtriggered drug release from WS2-IO@MS-PEG/DOX, particularly under the acidic condition inside cells, could further promote the cell killing efficacy of chemotherapeutics. 4. Conclusion In summary, we have fabricated mesoporous silica coated, iron oxide decorated WS2 nanosheets as a theranostic platform for modal imaging guided cancer combination therapy. With excellent physiological stability and low cytotoxicity, such WS2-IO@MS-PEG nanostructure could act as a drug carrier for efficient loading of chemotherapeutics such as DOX, whose release on the other hand may be triggered by external NIR light via photothermal effect. Utilizing inherent physical properties of our composite nanoparticles, three modal fluorescence, MR and CT imaging are carried out on tumor-bearing mice, evidencing efficient retention of nanoparticles in the tumor after systemic administration. With an obvious in vivo synergistic therapeutic effect, effective inhibition of tumor growth is realized after the combined photothermal & chemotherapy delivered by WS2-IO@MS-PEG/DOX, which in the mean time shows no obvious toxic effect to the treated animals. Our work develops a novel approach to construct multifunctional nanoscale platforms based on two-dimensional TMDCs, promising for cancer theranostics. Moreover, the chemistry and materials design strategies presented here may be of great interests to researchers in other fields of TMDC research. Acknowledgment This work was partially supported by the National Basic Research Programs of China (973 Program) (2012CB932600, 2011CB911002), the National Natural Science Foundation of China (51222203, 51132006), a Jiangsu Natural Science Fund for Distinguished Young Scholars, the Jiangsu Key Laboratory for CarbonBased Functional Materials & Devices, and a Project Funded by the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// References [1] Y. Wang, K. Wang, J. Zhao, X. Liu, J. Bu, X. Yan, et al., Multifunctional mesoporous silica-coated graphene nanosheet used for chemo-photothermal synergistic targeted therapy of glioma, J. Am. Chem. Soc. 135 (2013) 4799e4804. [2] Q. Xiao, X. Zheng, W. Bu, W. Ge, S. Zhang, F. Chen, et al., A core/satellite multifunctional nanotheranostic for in vivo imaging and tumor eradication by
























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Two-dimensional magnetic WS2@Fe3O4 nanocomposite with mesoporous silica coating for drug delivery and imaging-guided therapy of cancer.

Integrating multiple imaging and therapy functionalities into one single nanoscale platform has been proposed to be a promising strategy in cancer the...
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