Polydopamine Coated Selenide Molybdenum: A New Photothermal

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Polydopamine Coated Selenide Molybdenum: A New Photothermal Nanocarrier for Highly Effective Chemo-photothermal Synergistic Therapy Chao Wang, Jing Bai, Yuwei Liu, Xiaodan Jia, and Xiue Jiang ACS Biomater. Sci. Eng., Just Accepted Manuscript • DOI: 10.1021/acsbiomaterials.6b00416 • Publication Date (Web): 16 Sep 2016 Downloaded from http://pubs.acs.org on September 18, 2016

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ACS Biomaterials Science & Engineering

Polydopamine Coated Selenide Molybdenum: A New Photothermal Nanocarrier for Highly Effective Chemo-photothermal Synergistic Therapy ,

†

,

†

*,†

Chao Wang† ‡, Jing Bai , Yuwei Liu† §, Xiaodan Jia and Xiue Jiang

†

State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied

Chemistry, Chinese Academy of Science, Changchun 130022, Jilin, China. ‡

§

University of the Chinese Academy of Sciences, Beijing 100049, China. Department of Materials Science and Engineering, Shenyang University of Chemical

Technology, Shenyang 110142, China.

ABSTRACT: Recently, two-dimensional transition metal dichalcogenides (TMDCs) have been widely studied in biomedicine. In this article, we developed a new photothermal nanocarrier based on polydopamine coated selenide molybdenum (MoSe2@PDA) as an effective nanocarrier for loading anticancer drug doxorubicin (MoSe2@PDA-Dox). Conjugation of PDA onto the surface of MoSe2 nanosheets can not only enhance the photothermal effect of MoSe2 nanosheets and decrease its cytotoxicity but also provide anchor points for loading Dox. The resulting MoSe2@PDA nanocomposites exhibit good biocompatibility, well stability, and high photothermal conversion efficiency. The subsequent loading of anticancer drug doxorubicin

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(Dox) creates an efficient therapeutic agent with pH- and heat-responsive drug release. In vivo experiment shows strong damage to tumor tissue, killing the tumor cell almost thoroughly. On that account, the MoSe2@PDA-Dox nanocomposites may play a key role in cancer therapy in the future. Our work reveals the great promise of combing chemical and photothermal therapy to realize synergistic effect for tumor treatment.

KEYWORDS: Selenide molybdenum, polydopamine, chemo-photothermal therapy, synergistic effect, antitumor

INTRODUCTION With the improvements of science and technology, many incurable diseases have been treated successfully, however cancer is still a harder nut to crack. Despite tremendous progress of current medicines for cancer therapy over the past decades, patients treated by conventional strategies, such as surgery, radiation therapy, and chemotherapy, commonly suffer from frequent relapses, metastases and destroying the immune system. Recent advances in nanotechnology have attracted great attention in cancer diagnosis and therapy. Among these investigations, photothermal therapy (PTT) has drawn considerable research and clinical attention as a minimally invasive approach to kill cancer cells, which converts optical energy into thermal energy based on photothermal agent, leading to thermal ablation of cancer cells. Several kinds of NIR light-absorbing nanomaterials have been developed for cancer therapy in vitro and in vivo over the recent years. Au nanostructures, such as Au nanorod,1 Au nanocage,2 Au nanoshell,3 Au nanomatryoshka,4 Au nanostar5 and other Au nanoparticles,6-8 are most-widely used for PTT of cancer cells due to their strong absorption in the NIR region. However, Au nanostructures have low photostability due to the “melting effect” and expensive price, which


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limit their widespread application. Alternatively, carbon-based nanomaterials, such as graphene,9 carbon nanocube10 and fullerene,11 have showed great potential for photothermal therapy of cancer due to their good photostability, relatively low cost, and strong NIR light absorption. However, some shortcomings including poor dispersibility and complicate preparation and modification greatly hinder their biomedical application. To meet the severe demands of PTT in future, it is essential to develop facile strategy for preparing efficient photothermal agents with high photostability, high photothermal conversion performance and low cost. Recently, semiconductor nanostructures, such as CuS,12 MoS2,13 WS214 and Bi2S3,15 have become the rising stars as photothermal agents, with the advantages of high photothermal conversion efficiency, low cost and good photothermal stability. However, completely destructing tumor tissues by PTT alone is difficult due to the light scattering and absorption in biological tissues. Therefore, the combination of PTT with chemotherapy or photodynamic therapy is attractive for enhanced anticancer efficacy. As loading platform, two-dimensional (2D) nanomaterials have excellent loading efficiency for multifunctional application.16,17 From this point, 2D transition-metal dichalcogenides (TMDCs) is more attractive as multifunctional platform than 0D copper chalcogenide semiconductors because their ultrahigh surface area is available for high cargo loading on both sides, and the abundant elemental compositions enable the precise tuning of their functions. For instance, Liu et al. have developed a new generation of photothermal theranostic agent based on WS2 nanosheets for in vivo photothermal killing of tumor. And the WS2 nanosheets can serve as a bimodal contrast agent for CT and PAT imaging, respectively.18 Cheng et al. have demonstrated the potential of TiS2 nanosheets for in vivo photothermal therapy of tumor. Moreover, TiS2 nanosheets can be used as strong contrast in photoacoustic imaging.19 Zhao et al. have reported a simple approach to prepare MoS2


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nanosheets, and these MoS2 nanosheets have been developed as a chemotherapeutic drug nanocarrier for near-infrared (NIR) photothermal-triggered drug delivery, facilitating the combination of chemotherapy and photothermal therapy into one system for cancer therapy.20 Selenide molybdenum (MoSe2) is also a class of TMDCs, and has been widely used in electronic devices or as a hydrogen-storage material.21,22 In a recent work, Wang et al. synthesized ultrasmall size MoSe2 nanodots with significant NIR absorption for efficient photothermal therapy of cancer cells.23 However, due to their smaller size, MoSe2 nanodots are not suitable for the delivery of the therapeutic agent and cannot achieve multifunctional treatment of cancer. With ultrahigh specific surface area and excellent photothermal property, the 2D MoSe2 nanosheets could serve as an ideal photothermal agent and nanocarrier for drug loading for nearinfrared chemo-photothermal therapy. Despite of the excellent properties of the TMDCs, a major challenge for their chemical instability in vitro and in vivo for the biomedical applications still exists. In order to improve the physiological stability and biocompatibility of these materials, the coating method is often used for surface modification of nanomaterials to form core-shell structure24-26, which can segregate the nanomaterials from the external environment and thereby improve the chemical stability and biocompatibility. In this case, polydopamine (PDA) possesses unique features such as good biocompatibility, biodegradability, strong NIR absorption ability and with abundant functional groups on the surface, which make it highly suitable to be shell materials for the surface modification of nanomaterials, and it can be used as a photothermal agent for in vivo cancer therapy simultaneously. More recently, Messersmith et al. have reported PDA-coated gold nanorods (NRs) that not only decreases the cytotoxicity of gold NRs but also provides binding


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sites on gold NRs for further modification.27 Therefore, PDA can enhance the PTT efficiency of semiconductor nanomaterials as appropriate polymer conjugation.

Scheme 1. Schematic representation for synthetic process and therapeutic mechanism of MoSe2@PDA-Dox nanocomposites. In this work, we report an efficient PTT agent based on PDA-coated MoSe2 nanosheets (MoSe2@PDA) with strong NIR absorbance. PDA was conjugated onto the surface of MoSe2 nanosheets through the polymerization of dopamine molecules under alkaline aqueous conditions, which significantly enhances the photothermal effects of MoSe2 nanosheets and decreases its cytotoxicity (Scheme 1). Furthermore, the PDA shells provide anchor points for the conjugation of anticancer drug doxorubicin (Dox) by π–π stacking and hydrophobic interaction (MoSe2@PDA-Dox). The as-obtained MoSe2@PDA-Dox nanostructures as a bifunctional agent show high chemo-photothermal therapy efficiency for tumor cells (Scheme 1). As far as we know, this is the first report on MoSe2@PDA-Dox nanostructures as therapeutic platform for the


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synergistic anti-tumor effects. Our results demonstrate a simple approach to fabricate a new photothermal material that is able to deliver antitumor drug for cancer treatment and enhance the therapeutic efficacy. METHODS Reagents and apparatus. Dopamine hydrochloride (DA-HCl) was purchased from Aladdin Reagent Co. NaBH4 was purchased from Sinopharm Chemical Reagent Co. Doxorubicin hydrochloride (Dox) was purchased from Beijing Huafeng United Technology Co. Dimethyl sulfoxide (DMSO), selenide (Se), 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-Htetrazolium bromide (MTT), calcein acetoxymethyl ester (calcein AM), propidium iodide (PI) and Na2MoO4·2H2O were purchased from Sigma-Aldrich. Dulbecco’s modified eagle medium (DMEM), penicillin, fetal bovine serum (FBS) and streptomycin were purchased from Beijing Dingguo Biotechnology Co. Other reagents were all purchased from Beijing Chemicals Co. Phosphate buffered saline (PBS) purchased from Invitrogen was used as balanced salt solution in cell culture. PBS used in other experiments was prepared by mixing stock solutions of NaH2PO4 and Na2HPO4. All the chemical reagents were used directly without further purification. All solutions were freshly prepared with deionized water using the Millipore Milli-Q system. The dynamic light scattering (ZEN 3600, Malvern Instrument, UK) was used to measure the zeta potential and hydrodynamic size of the as-synthesized materials. LAMBDA 25 spectrometer (PerkinElmer) was applied to measure UV-vis absorption spectra. Fourier transform infrared (FTIR) spectra were recorded by a Nicolet 520 FTIR spectrometer equipped with a KBr beam splitter, a germanium attenuated total reflection (ATR) accessory, and a DTGS detector (Bruker Co., German). Transmission electron microscopy (TEM) images were got from HITACHI H8100EM (Hitachi, Tokyo, Japan), a H-600 electron microscope operating with 75 keV. SEM


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images were obtained by using a Hitachi S-4800 FE-SEM. The X-ray photoelectron spectroscopy (XPS) measurements were performed on an ESCALAB 250 X-ray photoelectron spectrometer with a monochromated X-ray source (AlKαhυ = 1486.6 eV). The 808-nm laser was exported in a power density of 2 W/cm2 by the laser device (Changchun New Industries Optoelectronics Technology, China). A digital thermometer with a thermocouple probe (Pyrometer Instrument Company, USA) was used to detect the temperature of the irradiated solution or aqueous dispersion. The cells were imaged through a confocal laser scanning fluorescence microscope (CLSM, Leica TCS SP2, Leica Microsystems, Mannheim, Germany). Preparation of MoSe2@PDA. The MoSe2 nanosheets were prepared by a hydrothermal synthesis method.28 Briefly, the Se powder was added into 5 mL of NaBH4 (3 mM) aqueous solution under stirring at the concentration of 1 mM, and kept stirring for 15 min. After that, Na2MoO4·2H2O (0.5 mM) was added into the reaction solution with another 30 min stirring. Finally the mixture was transferred into a Teflon-lined autoclave, keeping at 180 ºC for 24 h, and cooled to room temperature naturally. The black precipitates were obtained and centrifuged at 11000 rpm for 15 min, then washed with distilled water for 5 times. The obtained MoSe2 nanosheets (30 mg) were dispersed in the Tris-HCl buffer solution (10 mM, pH 8.5, 50 mL). Then dopamine (3 mg) was added to the mixture followed stirring over night at room temperature. After the reaction, the product was washed with distilled water for several times and dispersed in distilled water to obtain 1.0 mg/mL of dispersion. Photothermal performance of the materials. To measure the photothermal performance of MoSe2 and MoSe2@PDA nanocomposites, the sample solution (1 mL) was added into the quartz cuvette and then irradiated with the 808-nm laser at 2.0 W/cm2. In the process, the MoSe2 and MoSe2@PDA nanocomposites with different concentrations (i.e., 0, 0.1,


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0.2, and 0.5 mg/mL) were exposed to the laser irradiation for 10 min, and the temperature of the solution was recorded every 30 s. To detect the thermal stability of MoSe2@PDA nanocomposites, the samples were cyclically irradiated and cooled for six times, and the temperature was recorded every 30 s. Loading and release of Dox. The 4 mg of MoSe2@PDA nanocomposites was mixed into Dox buffer solution (4 mL, 0.1 mg/mL, pH 8.5) with stirring for 24 h in dark. The product was centrifuged and washed for 5 times to remove the free Dox in supernatant and then the MoSe2@PDA-Dox nanocomposites were obtained. To calculate the Dox loading efficiency (DLE), the content of the original Dox and the residual Dox in the supernatant was determined by UV-vis absorption spectroscopy using the intensity at the wavelength of 480 nm, which is the characteristic absorption of free Dox. The DLE was calculated by eq. (1)

DLE % =

ODox − RDox × 100% ODox

(1)

where ODox and RDox represent the contents of the original and residual Dox in solution, respectively. Here, the mass of ODox and RDox is 0.40 mg and 0.04 mg. According to eq. (1), the DLE can reach 90%. To analyze the controlled release of Dox, the MoSe2@PDA-Dox nanocomposites (2.0 mg) were dispersed in three kinds of PBS (2 mL) with pH 7.4, pH 5.5 and pH 5.5 particularly with laser irradiation for 10 min. The suspensions were then shaken in constant temperature oscillator at 37℃ and 150 rpm. At selected time intervals, the PBS was taken out by centrifuging to test the concentration of released Dox in the supernatant. All the data were recorded within 48 h. MTT assay. The cell viability was measured by MTT assay. HeLa cells were cultured in DMEM that includes 100 mg/mL streptomycin, 10% FBS, and 100 units/mL penicillin in a humid incubator with 5% CO2 at 37 ºC. In the MTT assay, HeLa cells at a density of 1×104


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cells/well were seeded in 96-well plate, and cultured in 5% CO2 at 37 ºC for 24 h. Thereafter, the cell samples were either exposed to MoSe2@PDA nanocomposites dispersed in the culture medium at a series of concentrations (0~1000 µg/mL) for biocompatibility analysis assay or exposed to free Dox (10 µg/mL), MoSe2@PDA nanocomposites (100 µg/mL) and MoSe2@PDA-Dox nanocomposites (100 µg/mL, the concentration of loaded Dox was 10 µg/mL) for the chemo-photothermal assay for 24 h. For the chemo-photothermal assay, the cells were irradiated with 808-nm NIR laser at 2.0 W/cm2 for 5 min and re-incubated for another 12 h. Then, the culture media with nanocomposites or not was removed and 0.1 mL of MTT solution (0.5 mg/mL) was added into each well, incubating for another 4 h. Finally, the culture media was removed and each well was added with DMSO (100 µL) to dissolve the formazan crystals, and the microplate reader was used to measure its spectrophotometric absorption (at 570 nm). Confocal fluorescence imaging analysis. Before the confocal microscopy study, HeLa cells were seeded in a 20-mm tissue culture dish and cultured for 24 h. The dishes were washed with PBS for 3 times, followed by being incubated with MoSe2@PDA nanocomposites (1mL, 0.1 mg/mL) or MoSe2@PDA-Dox nanocomposites (1mL, 0.1 mg/mL, the concentration of Dox was 10 µg/mL) suspension in DMEM at 37 ºC and 5% CO2 for 24 h. After incubation, the corresponding culture dishes were irradiated for 5 min by 808-nm NIR laser for photothermal elimination. Then, the dishes were washed 3 times with PBS, and calcein AM and PI were used to stain the cells for 15 min. Finally, the living cells were imaged using a confocal laser scanning fluorescence microscope with 20 × objective. In vivo photothermal therapy. Animal care and handing procedures were reached an agreement with national guidelines and approval of the regional ethics committee for animal experiments. The U14 cells (5 × 106) were suspended in 10 mL of PBS and injected


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subcutaneously into the right shoulder of male Kunming mice at the injection amount of 0.1 mL/animal. When the tumor volume reached about 50 mm3, the mice were divided into 4 groups randomly (n=3 per group). Saline solution (Group I, 0.9%), Dox (Group II, 10 µg/mL), MoSe2@PDA (Group III, 0.1 mg/mL) and MoSe2@PDA-Dox (Group IV, 0.1 mg/mL, and the concentration of Dox was 10 µg/mL) were locally injected into the tumors of the mice. After 2 h of injection, the 808-nm NIR laser was used to irradiate the location of the tumors in the Group III and IV at a power density of 2.0 W/cm2 for 5 min. The dimension of tumors was measured every two days by a caliper, and volume of tumor was calculated by the following formula: V=L×W 2/2

(2)

where V, L and W respectively represent the volume, length and width of tumor. The relative tumor volume was calculated by V/V0, where V0 is the initial tumor volume. Histology study. All the mice were killed after 15 days. The fresh tumor tissues of different groups were fixed in 4% neutral-buffered formalin, and then processed routinely into paraffin for haematoxylin and eosin (H&E) assay. They were examined under a digital microscope (Olympus). RESULTS AND DISCUSSION Characterization of MoSe2@PDA nanocomposites. The MoSe2 nanosheets were prepared by hydrothermal method, and the MoSe2@PDA nanocomposites were prepared via room-temperature chemical polymerization of DA monomers under alkaline condition. To intuitively observe the surface morphology of MoSe2 and MoSe2@PDA nanocomposites, TEM was used to characterize the as-prepared nanomaterials (Figure 1A and Figure 1B). The TEM images show that the size of as-synthesized MoSe2 nanosheets is about 200 nm (Figure 1A). After conjugation of PDA on the surface of MoSe2 nanosheets, core-shell nanostructure of


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MoSe2@PDA nanocomposites with an inner MoSe2 core and outer PDA shell was observed in Figure 1B. This preliminarily proves the load of PDA on the MoSe2 nanosheets. SEM was also used to observe the surface morphology of MoSe2 and MoSe2@PDA nanocomposites (Figure S1). The as-synthesized materials agree well with that in TEM images in morphology and size, and typical sheet structure can be observed. Furthermore, the presence of PDA on the surface of MoSe2 nanosheets was confirmed by XPS. The survey spectrum of the MoSe2@PDA (Figure 1C) clearly shows a new peak at 399.2 eV attributed to N 1s, demonstrating successful formation of PDA layer on the surface of MoSe2. The DLS size of as-prepared MoSe2 and MoSe2@PDA are about 255 nm and 314 nm, and mean zeta potential are 45.6 mV and -20.2 mV, respectively (Figure 1D). Thus, the MoSe2@PDA nanocomposites are composited by the electrostatic interaction of the deprotonated phenolic group of DA at pH 8.529 with the positively charged surface of MoSe2, together with the hydrophobic interaction between them.30 Correspondingly, the increase of hydrodynamic diameter confirms the coating of PDA polymer onto the surface of MoSe2. After 7 days, the DLS size of the as-prepared MoSe2@PDA keeps nearly unchanged (Figure S2), suggesting the good stability. Figure 1E shows UV-vis spectra of MoSe2 and MoSe2@PDA aqueous suspensions. The UV-vis spectrum of MoSe2 shows a peak at 211 nm with NIR absorption, while the near infrared absorption was further enhanced for the MoSe2@PDA nanocomposites, suggesting that the MoSe2@PDA nanocomposites are superior to single MoSe2 nanosheets in photothermal effect and PTT. The UV-vis spectrum of MoSe2@PDA keeps nearly unchanged in different time and temperature (Figure S3) as well as in serum (Figure S4). The successful coating of PDA was further characterized by FTIR. The FTIR absorption shows N-H


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scissoring at 1480 cm-1 and phenoxy C-O stretching at 1270 cm-1, which are the signatures of the coated PDA.

Figure 1. TEM images of MoSe2 (A) and MoSe2@PDA nanocomposites (B), XPS survey spectrum of MoSe2@PDA nanocomposites (C), the size distribution and zeta potential (D), the UV-vis (E) and the FTIR (F) spectra of MoSe2 and MoSe2@PDA nanocomposites. Photothermal properties of MoSe2@PDA nanocomposites. To investigate the photothermal properties of MoSe2@PDA nanocomposites, the aqueous dispersions of MoSe2 and MoSe2@PDA nanocomposites with different concentrations (0.1-0.5 mg/mL) were illuminated by 808-nm laser at the power density of 2.0 W/cm2 and the time-dependent temperature was recorded for both suspensions under the irradiation (laser on) and followed by natural cooling to


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room temperature (laser off), as shown in Figure 2A. As a blank test, the temperature of pure water was also recorded under the same condition, but it only increased by nearly 3 ºC from the room temperature under the irradiation. As the concentration of nanomaterials increased from 0.1 mg/mL to 0.5 mg/mL, the temperature could be elevated up to 15-24 ºC for MoSe2 nanosheets, while to 24-30 º C for MoSe2@PDA nanocomposites under NIR irradiation for 10 min, indicating the synergetic effect in the enhancement of photothermal efficiency due to the coating of PDA. Then the photothermal conversion efficiency (η) of MoSe2 and MoSe2@PDA nanocomposites was calculated according to the model reported previously.31 The η value of MoSe2 nanosheets is 32.8% via calculation, while it is significantly increased to 44.5% for MoSe2@PDA nanocomposites due to the synergistic effect of MoSe2 and PDA (Figure 2B). The MoSe2@PDA nanocomposites at 1 W/cm2 also show reasonable photothermal properties (Figure S5). The result suggests that the MoSe2@PDA is a kind of good photothermal nanomaterial. Furthermore, we also studied the photothermal stability of the MoSe2@PDA nanocomposites under irradiation of 808-nm NIR laser. The time-dependent temperature of the MoSe2@PDA nanocomposites aqueous dispersion (0.5 mg/mL) was measured with NIR exposure cycles for six times, and almost no noticeable attenuation could be observed in the temperature-time curve after six cycles (Figure 2C). On the other hand, whether before or after irradiation, UV-vis spectrum curves of MoSe2@PDA suspension have no significant changes, which indicates the great photothermal stability of the material (Figure 2D). The high photothermal conversion efficiency and the great photothermal stability suggest that the MoSe2@PDA nanocomposites can be well used in the photothermal therapy field.


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Figure 2. (A) The photothermal properties of the obtained nanomaterials as reflected by timetemperature curves of MoSe2 and MoSe2@PDA nanocomposites. (B) Linear relationship between time and -lnθ obtained from the cooling time of 0.2 mg/mL MoSe2 and 0.2 mg/mL MoSe2@PDA. (C) Photothermal stability curve of MoSe2@PDA nanocomposites and (D) the UV-vis spectra of MoSe2@PDA before and after laser irradiation. Loading and release of Dox. Except for photothermal therapy, the MoSe2@PDA nanocomposites can also be applied to drug delivery. It is well known that the dropping of pH will decrease the solubility of Dox due to the protonation of the amino group.32,33 Thus, in our experiment, Dox was loaded on the surface of MoSe2@PDA nanocomposites in Tris-HCl buffer solution (pH 8.5). An absorption peak can be observed at 480 nm in the UV-vis spectrum of free Dox, which could be ascribed to the π→π* electron transition of the conjugated naphthacenedione moiety in Dox, while the broadened band of Dox appears at around 502 nm in the UV-vis spectrum of the MoSe2@PDA-Dox suspension, the red shift of the peak position indicates the formation of π-π stacking interaction between Dox and PDA (Figure 3A). The binding of the drug molecules onto the nanocarriers could be also via hydrophobic interaction


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between Dox and PDA.34 All the results demonstrate that Dox molecules have been successfully loaded onto MoSe2@PDA nanocomposites. And the drug loading content was 0.1 mg Dox mg-1 MoSe2@PDA nanocomposites.

Figure 3. UV-vis absorption spectra of MoSe2@PDA, free Dox and MoSe2@PDA-Dox nanocomposites dispersed in water (A), the release profiles of Dox from MoSe2@PDA-Dox nanocomposites at pH 7.4, pH 5.5, and pH 5.5 with 808-nm laser irradiation (B). Meanwhile, we also studied the release profiles of Dox in different conditions (Figure 3B). The release amount of Dox in different environments was calculated by the UV-vis absorption spectroscopy at 480 nm. It was reported that the micro-environment of tumor keeps balance at a mildly acidic environment (pH 5.8-7.1) and it is more acidic in the intracellular environment with a pH 5.0.35,36 To study the controllable drug release from the surface of MoSe2@PDA-Dox nanocomposites, the release rate of Dox in PBS with pH 5.5 and 7.4 was measured, respectively. The Dox release was quite quick within the first 4 h, while it became a slow and continuous process thereafter (Figure 3B). The release rate of Dox at pH 5.5 was nearly double than that at pH 7.4, and it could be further improved upon irradiation with 808-nm laser. These results indicate that the acidic environment and the laser irradiation can promote the release of Dox. It


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means that the MoSe2@PDA-Dox nanocomposites are extraordinarily efficient nanoplatform for chemical-photothermal synergistic therapy of tumors. Cytotoxicity study and confocal fluorescence imaging analysis. To evaluate biocompatibility of the drug-delivering material in vitro, the viabilities of HeLa cells incubated with MoSe2@PDA suspensions at a series of concentrations were measured by MTT assay. The MTT assay can provide a viable parameter for reporting metabolic activity by a colorimetric method. The cell viability was maintained at about 97% with a high concentration of MoSe2@PDA at 1000 µg/mL (Figure 4A), suggesting low cytotoxicity and well biocompatibility of MoSe2@PDA nanocomposites. To investigate the therapy efficacy of MoSe2@PDA-Dox nanocomposites in vitro, the comparative studies on the inhibition effectiveness of HeLa cells were conducted (Figure 4B). As expected, the cellular viability reaches about 91% upon exposure to MoSe2@PDA nanocomposites without irradiation, while the value drops to less than 65% under irradiation with power density higher than 1 W/cm2 (Figure S6), indicating the low toxicity and the excellent photothermal therapy effect of the MoSe2@PDA nanocomposites. The cells incubated with MoSe2@PDA-Dox nanocomposites without irradiation are more easily to survive than that incubated with equal free Dox (10 µg/mL), which should be attributed to less release of Dox from MoSe2@PDA-Dox nanocomposites and low cytotoxicity of the nanocomposites. However, after NIR laser irradiation, the cytotoxicity of the MoSe2@PDA-Dox nanocomposites increased almost quintuple with a cell viability of 17%, suggesting the superior therapy efficiency of drugdelivering photothermal nanocomposites. The cytotoxicity of the control group and the free Dox group had no significant change under NIR irradiation. Obviously, the highest cytotoxicity of MoSe2@PDA-Dox nanocomposites under the laser irradiation is attributed to the combination of


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the good photothermal effect and improved heating-triggered drug release. We believe that the MoSe2@PDA-Dox nanocomposites can be efficiently used in the chemo-photothermal synergistic therapy of tumors.

Figure 4. (A) The viability of HeLa cells incubated with the MoSe2@PDA nanocomposites at different concentrations. (B) Cell viabilities of HeLa cells incubated with DMEM as control, free Dox, MoSe2@PDA, and MoSe2@PDA-Dox either under or no irradiation. Error bars were collected based on the standard deviations (STDEV) of six parallel samples. CLSM of Calcein AM and PI stained HeLa cells incubated with DMEM medium without (C) or with (D) laser irradiation, treated with MoSe2@PDA (E) or MoSe2@PDA-Dox (F) with laser irradiation for 5 min. Scale bar = 100 µm. To further verify the chemo-photothermal synergistic therapy effect, CLSM was used to visually present the viability of HeLa cells upon incubation with the MoSe2@PDA


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nanocomposites and MoSe2@PDA-Dox nanocomposites under NIR irradiation. The living cells can be stained with calcein AM and show green fluorescence, and the dead cells can be stained with PI and show red fluorescence. No significant difference can be observed from the control group with or without laser irradiation. The green fluorescence decreases and red fluorescence increases when the cells were incubated with MoSe2@PDA nanocomposites and exposed to 808nm laser at a power density of 2.0 W/cm2 for 5 min, indicating a good photothermal cell-killing effect. The fluorescence almost disappears when the cells were exposed to the MoSe2@PDADox nanocomposites group with the irradiation, which suggests that the MoSe2@PDA-Dox nanocomposites show a synergistic effect combining chemotherapy and photothermal therapy. In vivo chemo-photothermal therapy. To investigate therapeutic efficacy of the MoSe2@PDA-Dox nanocomposites in vivo, comparative studies of inhibiting tumor growth have been carried out in living animals. Twelve female Kunming mice taking cervical cancer model were divided into four groups randomly: the Control group, Dox group, MoSe2@PDA+NIR group and MoSe2@PDA-Dox+NIR group. The mice were injected with corresponding materials and irradiated with laser every two days. The tumor volumes and the weight of mice were then measured at an interval of 2 days. The mice were killed after 15 days and the tumors were excised. Photographs of the test mice and the tumors in each group after the treatment on the 15th day were shown in Figure 5A. The weight of mice and the size of tumors were plotted as a function of time in Figure 5B and 5C, respectively. It can be observed that the mice treated only with 0.9% NaCl solution exhibit rapidly increasing tumor volumes. Compared with control group, there is only a slight inhibition of tumor growth in the group treated with free Dox, indicating its poor efficacy in inhibiting tumor growth. For the group treated with the MoSe2@PDA nanocomposites under NIR light, an obvious inhibition of tumor growth can be


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observed, which demonstrates that the MoSe2@PDA can inhibit tumor growth in vivo under the NIR laser irradiation. When the mice treated with MoSe2@PDA-Dox+NIR, however, the inhibition efficiency of tumor growth was further improved, and no tumor regrowth was observed in this group over the course of 15 days. The mean relative tumor volume in MoSe2@PDA-Dox+NIR group is 0.42, which is significantly smaller than control group (10.87), Dox group (3.46), and the MoSe2@PDA+NIR group (0.88), as shown in Figure 5B. During treatments, significant body weight drop was not observed in all groups (Figure 5C), which implies that the toxic side effects of treatments are not severe.

Figure 5. (A) Representative photos of mice and tumors after various treatments. (B) Tumor growth curves of different groups after treatment. The tumor volumes were normalized by comparing with their initial sizes. (C) Mice weights of each group. The different treatments on tumors were evaluated by histology studies. H&E staining demonstrates that tumor tissue treated with MoSe2@PDA-Dox+NIR shows obvious necrosis,


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such as nuclear condensation, cell shrinkage to lost contact, and the disappearance of the tumor extracellular matrix. Tumor tissues treated with MoSe2@PDA+NIR or Dox, however, shows slight necrosis compared to the tissue of control group (Figure 6). These results clearly demonstrate that the synergistic effect of chemo-photothermal therapy based on the MoSe2@PDA-Dox nanocomposites is quite efficient in inhibition of tumor growth.

Figure 6. H&E stained images of tumor tissues after different treatments. Control group (A), Dox group (B), MoSe2@PDA+NIR group (C) and MoSe2@PDA-Dox+NIR group (D). CONCLUSIONS In this article, the MoSe2@PDA-Dox nanocomposites were successfully fabricated and showed to be applicable for multimodal chemotherapy and photothermal treatment. The MoSe2@PDADox nanocomposites showed high loading efficiency and pH-responsive Dox release effect, which can be enhanced by laser irradiation. It was demonstrated in this study that the synergistic therapy is highly efficient for cancer treatment, and in vitro experimental results showed significant suppression for cell viability. Through in vivo tumor model, the tumor was effectively inhibited by the NIR-induced local hyperthermia and accelerated drug release from


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MoSe2@PDA-Dox nanocomposites. These results may indicate a potential platform of MoSe2@PDA-Dox nanocomposites for biomedical application. ASSOCIATED CONTENT Supporting Information The supporting information is available free of charge on the ACS Publications website: Details on the SEM images, DLS size in aqueous over a long time, photothermal properties, and MTT assay. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGMENT The authors gratefully thank Ms. Meiye Li, for SEM analysis; Ms. Yunchun Zhou, for TEM analysis and Dr. Xinglin Li, for XPS analysis. They are all from National Analytical Research Center of Electrochemistry and Spectroscopy. Financial funding was provided from the National Science Foundation for Excellent Young Scholar of China (21322510), Science and Technology Innovation Foundation of Jilin Province for Talents Cultivation (Grants 20150519014JH), and the Youth Foundation of China (21505130). REFERENCES


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BRIEFS (For Table of Contents Use Only)

Polydopamine Coated Selenide Molybdenum: A New Photothermal Nanocarrier for Highly Effective Chemo-photothermal Synergistic Therapy Chao Wang, Jing Bai, Yuwei Liu, Xiaodan Jia and Xiue Jiang


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Polydopamine Coated Selenide Molybdenum: A New Photothermal

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