AgInS2-Coated Upconversion Nanoparticle as a Photocatalyst for

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AgInS2‑Coated Upconversion Nanoparticle as a Photocatalyst for Near-Infrared Light-Activated Photodynamic Therapy of Cancer Cells Swarup Kumar Maji*,†,‡ and Dong Ha Kim*,†,§ †

Department of Chemistry and Nano Science, Division of Molecular and Life Sciences, College of Natural Sciences, Ewha Womans University, Seoul 03760, Korea ‡ Department of Chemistry, Khatra Adibasi Mahavidyalaya, Khatra, West Bengal 722140, India § State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai 200433, China ACS Appl. Bio Mater. Downloaded from pubs.acs.org by REGIS UNIV on 10/20/18. For personal use only.

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ABSTRACT: The development of high-performance near-infrared (NIR) photocatalysts with long-term stability and the elucidation on the working mechanism along with multifunctional activity toward biomedical applications have not been explored sufficiently. Herein, a novel hybrid material of an upconversion nanoparticle (NaYF4/Yb3+,Er3+) (UCN) coated with a ternary semiconductor (AgInS2, AIS) has been synthesized by a simple and robust two-step solvothermal route for NIR light active photocatalysis. Preparation of oleic acid-capped spherical UC nanoparticles (NPs) (∼25 nm) followed by solvothermal decomposition of two precursor complexes Ag(acda) and In(acda)3 resulted in the formation of well-defined NaYF4/ Yb3+,Er3+@AgInS2 core−shell nanoparticles (UCN@AIS NPs) (∼90 nm). It has been found that effective energy transfer occurred from NaYF4/Yb3+,Er3+ to AgInS2 by a nonradiative luminescence resonance energy transfer process. Superior photocatalytic decomposition activity was validated in terms of the degradation of methylene blue dye under the exposure of 980 nm NIR laser light with the presence of a UCN@AIS NP catalyst. The degradation process was mediated primarily owing to the formation of a cytotoxic reactive oxygen species (ROS) by the hybrid material under NIR light irradiation, in which UCN performs as a transducer to sensitize AIS and trigger the ROS generation. In vitro cancer cell imaging potentiality of the UCN@ AIS NPs was then studied on cervical cancer cells (HeLa cells). The UCN@AIS NPs induced in vitro cervical cancer cell death (photodynamic therapy) with ∼27% efficiency as measured by the MTT assay and thus proved to be a decent candidate for NIR active photocatalysts for biomedical applications. KEYWORDS: upconversion nanoparticle, ternary semiconductor (AgInS2), near-infrared photocatalysis, photodynamic therapy, bioimaging

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INTRODUCTION Solar light-driven generation of cytotoxic reactive oxygen species (ROS) [superoxide radical anion (O2−̇ •), hydroxyl radicals (•OH), and singlet oxygen (1O2)] from the photosensitizer is an effective and fascinating approach for the degradation of environmental organic pollutants from wastewater.1−3 Meanwhile, light-driven effective killing of cancerous cells, which is commonly known as photodynamic therapy (PDT) driven by generated cytotoxic ROS, has attracted enormous attention due to lesser side effects and minimal systemic toxicity compared to the traditional chemotherapy and radiation therapy. Thus, PDT has been considered as an emerging and pioneering cancer therapeutic modality.4−6 Although, the UV−visible light harvested photocatalysts are © XXXX American Chemical Society

the promising candidates for toxic organic chemicals redemption; however, their use in biomedical science is greatly hindered due to a low penetration depth in tissue sites.7 Thus, it is intentionally appreciable to tune the optical exposure to the biological NIR window (700−1000 nm) region.8 Besides, the commonly used organic photosensitizers for PDT, like Ce6, ZnPc, ICG, etc., are experiencing difficulties of photobleaching, stability, as well as quick circulation in body and, therefore, further hinders their biomedical applications.9,10 In this context, inorganic semiconductor photocatalysts are one of Received: August 27, 2018 Accepted: October 9, 2018

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DOI: 10.1021/acsabm.8b00467 ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX

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ACS Applied Bio Materials

Scheme 1. Schematic Illustration of the Superior NIR Active Photocatalytic Activity of UCN@AIS for Waste Water Treatment and Photodynamic Therapy of Tumor Cells

shown numerous promises in terms of photocatalytic generation of a significant amount of ROS, to effectively degrade hazardous organic waste and kill tumor cells by NIRtriggered PDT. Meanwhile, the in vitro cellular imaging property of this novel hybrid material was also investigated (Scheme 1) for in-depth bioimaging purposes.

the alternative candidates for the generation of ROS under broad-band light irradiation.11,12 Until now, several semiconductor nanomaterials (such as TiO2, ZnS, CdS, AgInS2, ZnS-AgInS2, etc.) and noble metals (viz. Au, Ag, etc.) have been widely used as suitable semiconductor photocatalysts for the degradation of toxic organic chemicals under UV to visible light illumination.13−18 More intensely, anatase TiO2 has been employed as a PDT agent for the generation ROS to kill tumor cells under UV light because of its superior activity, good stability, low cost, excellent biocompatibility, as well as long retention time.19,20 Though, the inherent UV light activity due to relatively high band gap energy (∼3.2 eV) has greatly restricted its application for more dipper therapy in the body.21 Thus, NIR light-triggered semiconductor photocatalysts have been proposed as the most suitable and desirable PDT photosensitizing agents. A recently developed upconversion process, in which lower energy NIR light is converted to higher energy UV or visible light through an anti-Stokes emission pathway, has been shown a new route for in-depth biomedical applications for its emerging inherent properties, such as, low toxicity, negligible auto fluorescence, and sharp absorption in the NIR region, etc.22−26 In maximum cases of upconversion nanomaterials, βNaYF4 has been chosen as the utmost efficient host material with the appropriate selection of dopants lanthanide ions, which could act as an activator (Tm3+, Er3+, and Ho3+) or sensitizer (Yb3+) based on the necessity.27,28 In recent years, increasing efforts have been made to associate this upconversion process with semiconductor materials to synthesize UCN-based semiconductor nanocomposites, including UCN/TiO2,29−36 UCN/ZnO,37,38 UCN/CdS,39 UCN/Fe2O3,40 UCN/CdSe,41 UCN/ZnxCd1−xS,42 UCN/ CuS,43 etc., for the effective generation of ROS in the field of solar energy conversion, degradation of organic hazarders, and PDT-based tumor therapy. In our previous work, we have tailored the upconversion process with β-NaYF 4 / Yb3+,Tm3+,Gd3+ as an NIR active UC material and carbondoped mesostructured TiO2 as the UV light active semiconductor for the decomposition of nitrobenzene, as a representative organic waste.44 However, still it a challenging field to design a suitable and effective NIR active photocatalyst with a greater stability, biocompatibility, and low cost material for organic chemical redemption and PDT therapy. In this work, we promoted a novel hybrid core−shell nanomaterial (NaYF4/Yb3+,Er3+@AgInS2) through the proper selection of an NIR active upconversion material (NaYF4/ Yb3+,Er3+) combined with a visible light active semiconductor photocatalyst (AgInS2) to overcome the restricted visible light active degradation of toxic chemicals as well as the in-depth issue of photocatalysis PDT. The hybrid nanomaterial has

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EXPERIMENTAL SECTION

Chemicals. Yttrium(III) chloride (YCl3, 99.9%), ytterbium(III) chloride (YbCl3, 99.9%), erbium(III) chloride (ErCl3, 99.9%), ammonium fluoride (NH4F, ≥99.9%), oleic acid (OA, >99%), 1octadecene (ODE, 90%), sodium hydroxide (NaOH), sodium citrate, methylene blue (MB, ≥82%), 2,7-dichlorofuorescin diacetate (DCFH-DA), terephthalic acid (TA, 98%), 9,10-anthracenediylbis(methylene) dimalonic acid (ABDA, ≥90%), Calcein-AM (≥96.0%), propidium iodide (PI, ≥94.0%), and ammonium oxalate monohydrate (≥99.9%) were bought from Sigma-Aldrich. The used solvents are of analytical grade and were used as is. Synthesis of UCN (NaYF4/Yb3+,Er3+). UC NPs [NaYF4/ Yb3+,Er3+ (80:18:2)] were synthesized by the modification of a previous report.45 Briefly, in a 50 mL three-neck flask, 240 mg of YCl3 (0.8 mmol), 70 mg of YbCl3 (0.18 mmol), and 7.6 mg of ErCl3 (0.02 mmol) were mixed with 6 mL of OA and 12 mL of ODE. The mixture solution was heated at 160 °C for 30 min and then cooled to room temperature. After that, 10 mL of methanolic solution containing 2.5 mmol NaOH and 4 mmol NH4F was slowly added into the flask under stirring for another 30 min. Then, the mixture solution was slowly heated at 100 °C for 30 min. Finally, the mixture solution was heated at 300 °C for another 1.5 h under a N2 atmosphere and then cooled naturally down to room temperature. Finally, the UC NPs were precipitated out from the suspension with the addition of 20 mL of ethanol and then collected after washing with ethanol/hexane (1:1 v/v) three times. Synthesis of UCN@AIS NPs. Five mg of UC NPs was mixed with 5 mL of OA and 10 mL of ODE under magnetic stirring. Then, 1 mmol of Ag(acda)46 and 1 mmol of In(acda)347 were added to the above suspension, and the solution was stirred for 30 min. The suspension mixture was moved to a 20 mL Teflon-lined autoclave, then heated at 180 °C for 12 h, and then cooled to room temperature. The prepared product was collected by centrifugation and washing with acetone and ethanol up to several times. To obtain water-soluble UCN@AIS NPs, first, 2 mmol of sodium citrate was mixed with 15 mL of diethylene glycol. Then, 10 mg of UCN@AIS in 5 mL of cyclohexane and 2 mL of chloroform was mixed with the above sodium citrate solution, and then the mixture was heated at 160 °C for 2 h. The reaction mixture was cooled and then mixed with 0.1 M HCl solution. The UCN@AIS NPs were collected by washing with acetone and then water three times. Finally, the UCN@AIS NPs were suspended in water. Photocatalytic Degradation of MB. To a quartz cuvette with 2 mL of aqueous solution of MB (1.04 × 10−5 M) was added 2.5 mg of UCN@AIS NPs. The suspension mixture was agitated for 30 min in the dark to reach the adsorption−desorption equilibrium. Then, the suspension mixture was irradiated with a 980 nm contentious laser (2 B

DOI: 10.1021/acsabm.8b00467 ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX

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Figure 1. Synthesis and characterizations of UCN@AIS NPs. (a) Graphical illustration for the preparation of UCN and UCN@AIS NPs. TEM images of (b) UCN and (c) UCN@AIS NPs (inset HRTEM image). (d) UV−vis−NIR absorbance spectra and (e) photoluminescence spectra with the corresponding digital photographs of (i) UCN and (ii) UCN@AIS NPs. W/cm2), and the absorption spectra were taken at particular time gaps by a spectrophotometer. In a TA photoluminescence probing technique, 2.5 mg of UCN@ AIS NPs was added to 2 mL of TA (5 × 10−3 M) solution, and then the mixture was irradiated with a 980 nm laser light. The PL spectra of the reaction mixture at every 10 min were recorded by a fluorescence spectrophotometer under an excitation wavelength of 315 nm. For detection of 1O2, 2 mL of ABDA solution was taken in a glass vial and mixed with 2.5 mg of UCN@AIS NPs, and the mixture was stirred for 30 min in the dark. Then, the suspension was irradiated with a 980 nm laser light, and the absorbance spectra were recorded by a spectrophotometer at a specific time interval. For the hole (h+) scavenging reaction, to a glass vial with 2 mL of aqueous MB solution (1.04 × 10−5 M) were added ammonium oxalate solution (0.1 mmol) and 2.5 mg of UCN@AIS NPs, and the mixture was stirred for 30 min in the dark. The suspension solution was irradiated with a 980 nm laser light, and the absorbance spectra were recorded by a spectrophotometer at a specific time interval. Cell Culture, Cell Viability, and PDT. HeLa cells (human cervical cancer cells) were cultured in Dulbecco’s modified Eagle medium (DMEM) at 37 °C with 5% CO2, which also contains fetal bovine serum (10%), streptomycin (100 mg mL−1), and penicillin (100 U mL−1). The cell survival assessments were carried out by adopting the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay technique. HeLa cells (1 × 104 cells/well) were

planted into a 96-well plate in DMEM medium. The DMEM medium was substituted after 12 h with fresh DMEM medium (100 μL/well) and incubated with varied concentrations of UCN@AIS NPs for an additional 12 h. However, in the case of the PDT study, wells were irradiated with a 980 laser (2 W/cm2) for 30 min (10 min of irradiation and then 5 min break) and again incubated for 12 h. Then, by using PBS, the cells were washed, and DMEM (100 μL/well) solution containing MTT (0.5 mg mL−1) was added to each well followed by another 4 h incubation. After that, the medium was replaced with 100 μL of DMSO solution to dissolve the violet frozen crystals. A micro plate reader was used to collect the absorbance intensity at 565 nm of each well. The relative cell viability (%) was obtained by using the following equation: [A]test/[A]control, in which [A]control is the average absorbance of the control sample and [A]test is the one for the test samples. In the case of cellular imaging studies, HeLa cells were planted in plastic-bottom μ-dishes (35 mm) (1 × 105 cells per dish) and cultured with DMEM for 1 day. After that, the cells were further incubated for 6 h with UCN@AIS NPs (200 μg mL−1). After removing the old medium, cells were washed by PBS and then fixed with formaldehyde solution (4.0%) for 10 min at room temperature. The formaldehyde solution was changed with PBS for washing, and then the slides were prepared. For detecting the intracellular ROS, the grown HeLa cancer cells in plastic bottom μ-dishes (35 mm) (1 × 105 cells per dish) were incubated for 6 h with/without UCN@AIS NPs C

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Figure 2. Structural characterizations. XPS spectra of UCN and UCN@AIS NPs: (a) survey, (b) Na 1s, (c) Y 3d, (d) F 1s, (e) Yb 4d, (f) Er 4d, (g) Ag 3d, (h) In 3d, and (i) S 2p.

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(200 μg mL−1). After the old DMEM was removed and washed with PBS, fresh DMEM solution containing DCFH-DA (20 μm) was placed and further protected for 20 min in the dark and then illuminated with a 980 nm laser source (2 W/cm2, 30 min). In the case of Calcein-AM and PI costaining assay experiments, HeLa cells were incubated with/without UCN@AIS NPs for 6 h and followed by 980 nm laser light illumination (2 W/cm2, 30 min) and further incubated for 4 h. After that, the cells were costained with CalceinAM and PI for 30 min. Instruments and Measurements. Transmission electron microscopy (TEM) images were collected from FEG-TEM (JEM2100F, JEOL, Japan, 200 kV). X-ray photoelectron spectroscopy (XPS) measurement was conducted by a SPECS HSA3500 plus spectrometer. Nitrogen adsorption/desorption measurement was done by a Quantachrome Instruments Autosorb-iQ (Boynton Beach, Florida, USA). Liquid chromatography mass spectrometry (LCMS) measurements were done by a Waters Q-tof Premier MS spectrometer. UV−vis absorption spectra were collected by a Varian Cary5000 UV−vis−NIR spectrophotometer. Room-temperature photoluminescence (PL) spectra measurements were conducted on a Shimadzu RF-5301PC spectrofluorimeter. PL spectra measurements for UC and UC@AIS NPs were carried out by a homemade PL spectrometer equipped with a 980 nm continuous-wave laser source (Dragon lasers) and a detector (USB 4000, Ocean Optics). The Infinite 200 PRO micro plate reader was used to obtain the cell viability results. The cell images for UC@AIS NPs imaging were captured using a Leica TCS SP5X multiphoton microscope. Fluorescence microscopy images were collected from a Nikon DEclipse C1 fluorescence microscope.

RESULTS AND DISCUSSION Synthesis and Characterization of UCN@AIS NPs. At first, an oleic acid-capped UCN (NaYF4/Yb3+,Er3+) core material was produced by a commonly used solvothermal procedure from analogous rare earth ions and ammonium fluoride (Figure 1a).26 The as-synthesized UCN NP core was characterized by the TEM image as shown in Figure 1b and found to be spherical in shape with a uniform size distribution of about 20−25 nm. The UCN NP core was further coated with a cadmium-free ternary I−II−VI group semiconductor material (AgInS2, AIS), by another step of the solvothermal technique (Figure 1a). Two different precursor complexes, Ag(acda)46 and In(acda)3,47 were utilized to form the AIS layer on UCN as a core−shell material. The hydrophobic UCN@AIS NPs were then further transferred to a water medium by a ligand exchange method to form citrate-capped UCN@AIS NPs,37 which are also dispersible in phosphate buffer and cell culture medium; however, citrate-capped hydrophobic nanoparticles sometimes suffer from a weak stability in physiological environments in the case of a longterm activity compared to that of PEGylated ligands.48,49 The formation of core−shell UCN@AIS NPs was clearly verified by the TEM image in Figure 1c, and the width of the AIS shell was around 20−30 nm. The hydrodynamic diameter of the UCN@AIS NPs was about 90 nm. The optical property of UCN and UCN@AIS NPs was recorded, and the corresponding absorbance spectra and digital photographs are shown in Figure 1d. The UCNs showed its D

DOI: 10.1021/acsabm.8b00467 ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX

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Figure 3. NIR active photocatalysis. (a) Time-dependent absorption spectral changes and corresponding digital photograph for photocatalytic MB dye degradation by UCN@AIS NPs followed by 980 nm NIR light irradiation (2 W/cm2). (b) Plot of relative concentration (Ct/C0) (665 nm) versus time (t) for the MB degradation in the absence/presence of UCN, AIS, and UCN@AIS NPs in the dark or under 980 nm light irradiation. (c) The kinetic plots for photocatalytic MB degradation catalyzed by UCN@AIS NPs under 980 nm light irradiation. Comparison of (d) •OH production in the absence/presence of different catalysts under 980 nm NIR light irradiation obtained by the enhancement of the TAOH fluorescence intensity at 425 nm; (e) 1O2 production in the absence/presence of altered catalysts under 980 nm NIR light irradiation obtained by the decrease of the ABDA fluorescence intensity at 377 nm; and (f) photocatalytic degradation of MB by UC@AIS NPs under 980 nm NIR light irradiation in the absence/presence of AO as a hole scavenger.

I15/2, 4S3/2 → 4I15/2, 2H11/2 → 4I15/2, and 2H9/2 → 4I15/2 transitions of Er3+, respectively.26 After coating with AgInS2, a notable change in the emission spectrum was observed as shown in Figure 1e. The peaks cantered at 659, 524, and 440 nm nearly disappeared, and the peak at 545 nm was significantly compressed compared to its original emission (∼82%). However, a less pronounced PL decrease (∼45%) was observed in the case of the physical mixture of UCN and AIS NPs. Therefore, we can conjecture that a nonradiative luminescence resonance energy transfer (LRET) or Förster resonance energy transfer (FRET) process may take place for the mechanistic PL decrease in the hybrid material, which is well-matched with previous reports.29−44 Less than a 10 nm donor−acceptor distance is typically required for the LRET mechanism, and the current configuration with the AgInS2 shell fits to this model. However, for the physical mixture, a usual emission−reabsorption energy transfer process takes place, since AgInS2 was not directly bounded to the surface of UCNs.50 4

typical absorption between 920 and 1000 nm, which represents the 2F7/2 → 2F5/2 transition of Yb3+ ions and 4I15/2 → 4I11/2 transition of Er3+ ions, respectively.45 However, in the UV−vis absorbance spectrum of UCN@AIS, a sharp rise in absorbance from ∼700 nm emerged, which corresponds to its direct band gap energy (Eg) of 2.12 eV, along with its original characteristic peak at ∼980 nm. The band gap energy of AIS was blue-shifted compared to the bulk AgInS2 band gap energy (Eg = 1.91 eV)16 due to the quantum confinement effect. From this absorbance phenomenon, we can assume that the visible photon energy produced via the upconversion process of NaYF4/Yb3+,Er3+ could be absorbed by AgInS2 around NaYF4/ Yb3+,Er3+ via an energy transfer between them.29−44 To conclude the above-mentioned phenomenon, we further investigated the characteristic emission property of neat UCNs and the identical ones after the coating with AgInS2 under NIR laser excitation (980 nm), and the emission spectra are displayed in Figure 1e. The PL spectrum of UCN showed a characteristic green visible emission (Figure 1e (i), inset photograph) at 659, 545, 524, and 440 nm due to the 4F9/2 → E

DOI: 10.1021/acsabm.8b00467 ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX

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Scheme 2. Schematic Illustration of the Development of Reactive Oxygen Species (ROS) by 980 nm NIR Light Illumination to UCN and Corresponding Energy Transfer to AIS

reach adsorption−desorption equilibrium for 30 min. Figure 3a is the absorption spectral change of MB solution under 980 nm light irradiation in the presence of UCN@AIS NPs. A gradual decrease in absorption intensity at 665 nm was observed with respect to the light illumination time, and after 9 h of illumination, the peak almost disappeared, which designates the comprehensive degradation of MB.18 The degradation of MB could also be monitored by the naked eye, as the blue solution of MB was changed to colorless after 9 h in the presence of UCN@AIS followed by laser illumination (Figure 3a, inset). Moreover, a comparative study was performed to reveal the superior NIR-mediated photocatalytic activity by the UCN@AIS NPs, and MB solution was treated under the following conditions: (i) MB in the dark, (ii) MB under 980 light illumination, (iii) MB with UCN in the dark, (iv) MB with UCN under 980 light illumination, (v) MB with AIS in the dark, (vi) MB with AIS under 980 light illumination, (vii) MB with UCN@AIS NPs in the dark, and (viii) MB with UCN@AIS NPs under 980 light illumination, and the results are summarized in Figure 3b. The plot of relative concentration (Ct/C0) vs time (t) showed a very weak contribution to the photocatalytic degradation of MB in the dark and under light irradiation in absence of the hybrid catalyst (UCN@AIS). The reaction rate constant (k) was calculated from the linear plot of ln(C0/Ct) vs time for the degradation of MB with a hybrid and was found to be 0.425 h−1 (Figure 3c). The obtained rate constant value or the required time for degradation of MB is quite comparable and/ or even better from the previously reported efficient upconversion-semiconductor photocatalysts (viz. NaYF4/ Yb 3+ ,Tm 3+ /Er 3+ @TiO, 2 β-NaYF 4 /Yb 3+ ,Tm 3+ ,Gd 3+ /mCTiO2).32,33,39,44 Henceforth, the result proves that the designed hybrid material has a superior photocatalytic activity for MB dye degradation under 980 nm NIR light illumination. It has been well-studied that the photocatalytic degradation of organic pollutants is mainly resulted from the generation of ROS (O2−•, •OH, and 1O2) and holes (h+) in the solution medium in the presence of a hybrid catalyst and under suitable light irradiation.11−20,29−44 Therefore, to establish the most suitable mechanism, we explored the formation of these ROS by spectroscopic measurements. As shown in Figure 3d, the conversion of nonfluorescent TA to fluorescent TAOH was monitored in the presence of UCN@AIS NPs under 980 nm laser illumination, which supports the formation of hydroxyl ̇ radicals (OH) in the solution medium.32 Several controlled

To gain further insight into the structural features of UCN and UCN@AIS NPs, we investigated the elemental composition by XPS analysis (Figure 2a−i). The existence of expected elements in both of the cases, such as Na, Y, F, Yb, and Er in UCN as well as Na, Y, F, Yb, Er, Ag, In, and S in UCN@AIS NPs, were well-distinguished in the survey spectra (Figure 2a). The characteristic peak at 1070.9 eV was observed in high-resolution XPS spectra of the Na 1s region for UCN@ AIS (Figure 2b), shifted from 1069.5 eV for UCN.39 Two deconvoluted XPS peaks in the Y 3d region for UCN@AIS appeared at 160.3 and 158.4 eV with a difference of 1.9 eV, which resembled 3d3/2 and 3d5/2, respectively (Figure 2c), again shifted to a higher binding energy (∼0.6 eV) compared to bare UCN.39 The peaks at 684.5 (Figure 2d), 186.8 (Figure 2e), and 170.9 eV (Figure 2f) were ascribed to F 1s, Yb 4d, and Er 4d, respectively, which were also shifted from the base positions in UCN.39 In the high-resolution region for Ag 3d, two deconvoluted peaks at 373.0 and 367.1 eV with a difference of 6.1 eV were obtained for 3d3/2 and 3d5/2, respectively (Figure 2g).16 As shown in Figure 2h, two deconvoluted peaks for In 3d3/2 and 3d5/2 appeared at 451.5 and 443.9 eV, respectively, with a difference of 7.6 eV.16 In Figure 2i, two deconvoluted XPS peaks located at 162.7 and 160.9 eV can be assigned to S 2p3/2 and S 2p1/2, respectively.39 The binding energies were slightly altered from their original values in each case, which further suggests the strong binding interaction between UCN and AIS and the formation of a hybrid as [email protected] The N2 adsorption/desorption isotherm measurement was also carried out to investigate the porous nature and surface area of UCN@AIS NPs. As shown in Figure S1a, the type-IV isotherms were detected, which specify the mesoporous structure of the material. The typical pore size was found to be ∼2.8 nm as per the observation from the BJH pore size distribution curve, shown in Figure S1b. The BET surface area was also calculated to be about 82.45 m2 g−1. Photocatalytic Degradation of Methylene Blue. The NIR light active photocatalytic activity of the UCN@AIS hybrid material was then investigated by considering the degradation of MB dye as a typical example in the perspective of organic pollutant decomposition.18 Typically, the experiments were carried out in a quartz cuvette containing an aqueous MB solution (2 mL, 1.04 × 10−5 M) with and without the presence of UCN@AIS NPs (2.5 mg) under irradiation of a 980 nm NIR laser source (2 W/cm2). Prior to laser illumination, all samples were kept under dark conditions to F

DOI: 10.1021/acsabm.8b00467 ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX

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Figure 4. In vitro cell imaging. CLSM images of HeLa cells as a (a−c) control (upper panel) and (d−f) treated with UCN@AIS NPs (200 μg/mL) (bottom panel).

measured to be 1.36 and −0.76 eV, respectively. The generated electrons and holes were then transferred to the interface of nanocrystals and water solution for further redox reaction to generate ROS. The CB of AIS is situated above the MB redox potential (E0 MB•+/MB = 1.08 eV vs NHE), thus allowing AIS as an active center for photocatalysis.32 The excited electrons in the VB of AIS then reduced O2 to O2−• rapidly, since the ECB of AIS (−0.76 eV) is more negative than E0 of O2/O2−• (−0.33 eV vs NHE).53 The generated O2−• was further reacted with photogenerated holes to produce H2O2 and eventually • OH by further steps.54 However, in this case, the holes were not responsible for the direct formation of •OH from H2O, since the VB potential (EVB) of AIS (1.36 eV) is more negative than E0 of •OH/OH− (2.38 eV vs NHE).16,39 Therefore, these holes could also be available for the direct oxidation of MB, since the EVB is more positive than E0 of MB•+/MB (1.08 V vs NHE).16,39 Again, in our spectroscopic studies, we observed the significant generation of 1O2 during the photocatalysis process, which can be attributed to the conversion of dissolved O2 to 1O2 in the presence of holes, since the reduction potential of 1O2/O2−• (0.95 eV) is less positive than EVB of AIS.52,55 Therefore, it was observed that these photogenerated O2−•, •OH, 1O2, and h+ generated in the system are the active species for MB degradation under 980 nm NIR light illumination. In order to expose the mechanistic property of the photocatalysis process by UCN@AIS NPs, we further investigated the fate of MB molecules before and after the photocatalysis by LCMS analyses (Figure S2). Only the MB molecule was detected in the LCMS spectrum (Figure S2a) in the solution before the photocatalysis process (m/z = 284).56 However, after 4 h illumination of NIR light in the presence of UCN@AIS NPs, the number of the m/z peak was increased in the spectrum and m/z 284 peak related to the MB molecule was decreased significantly (Figure S2b).56 At the end point of the reaction, the LCMS spectrum showed the disappearance of m/z 284 peak (Figure S2c), which suggests the complete degradation of MB.56

experiments in the presence/absence of UCN@AIS NPs or presence of individual NPs (UCN and AIS) were also conducted to compare the reactivity toward the production ̇ of OH (Figure 3d), and the main contribution was noticed for the hybrid material compared to that of other conditions. On the other hand, compared to that of the control experiments (Figure 3e), a substantial decrease in the absorbance intensity of ABDA solution was detected in the presence of UCN@AIS NPs under laser illumination (Figure 3d), which further proves the formation of 1O2 in the solution medium during the reaction process by UCN@AIS NPs only.51 In addition, the role of photogenerated holes for the direct decomposition of MB was also examined by the addition of a hole scavenger (ammonium oxalate (AO)) during the photocatalysis process (Figure 3f). As shown in Figure 3f, the comparison outcomes briefly showed that the rate of degradation of MB was remarkably reduced upon the addition of AO, which further confirms the contribution of photogenerated holes for MB degradation.39 In demand to fully realize the photocatalytic degradation mechanism, we constructed a band energy diagram for the UCN@AIS system along with the standard redox potential values of O2/O2−•, 1O2/O2−•, •OH/OH−, and MB•+/MB in Scheme 2. First, upon illuminating the UCN@AIS NPs by a 980 nm laser, the lower energy NIR energy was converted to a higher visible light energy by an upconversion procedure.22−26 Due to the occurrence of AIS in a close proximity toward the UCN, the visible light was then transferred by the LRET mechanism,50 as described above, and the AIS NPs were excited, leading to the formation of electron−hole pairs.16 The edge potentials of valence band (VB) and conduction band (CB) of AIS were calculated by the following equations: EVB = X − Ee + 0.5Eg and ECB = EVB − Eg, where Eg is the band gap energy of AIS (Eg = 2.12 eV, obtained from UV−vis absorbance), EVB is the VB edge potential, ECB is the CB edge potential, X is the electronegativity of AIS (4.8 eV), and Ee is the energy for free electrons on a hydrogen scale (4.5 eV).52 From the above-mentioned equations, EVB and ECB were G

DOI: 10.1021/acsabm.8b00467 ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX

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Figure 5. In vitro PDT. (a) Relative cell viability of HeLa cells treated with UCN, AIS, and UCN@AIS NPs in the dark and/or under the exposure of a 980 nm laser (2 W/cm2) for 30 min (5 min break after 10 min of irradiation) by the MTT assay. (b) Cell viability of HeLa cells after irradiation with 980 nm laser light under different irradiation times up to 30 min (5 min break after 10 min of irradiation). CLSM images of HeLa cells incubated with UCN@AIS and DCFH-DA as a (c) control, (d) in the dark, and (e) under irradiated with a 980 nm laser for detection of intracellular ROS. CLSM image of HeLa cells costained with Calcein AM (living cell, green fluorescence) and PI (dead cell, red fluorescence) as a (f) control, (g) incubated with UCN@AIS NPs in the dark, and (h) incubated with UCN@AIS NPs and under 980 nm laser irradiation (2 W/cm2, 30 min).

In Vitro Cellular Imaging and PDT. UCNs are one of the outstanding and promising classes of nanomaterials for indepth NIR bioimaging and therapy of tumor cells.22−26 The less auto fluorescein of background, in-depth penetration of 980 nm NIR light in tissue with an excellent stability and low inherent cytotoxicity makes them a suitable candidate for practical biomedical applications.22−26 Thus, in this study, in vitro cellular imaging property of the UCN@AIS NPs was further demonstrated by incubating with the human cervical cancer cells (HeLa cells) for 6 h, and the images are shown in Figure 4. A clear internal localization of UCN@AIS NPs in the cell cytoplasm by green fluorescence was observed from the CLSM images (Figure 4d−f) compared to less activity of the untreated cells (Figure 4a−c), which confirms the bioimaging capability of the hybrid material with less background. Meanwhile, no signal was detected at the outside of the cells, whereas the intracellular region showed that the hybrid material was adopted into the cells rather than merely stained on the surface of the membrane.

As speculated by the generation of ROS during the photocatalysis process, we then checked the antitumor activity, so-called PDT, of the hybrid material in HeLa cancer cells under 980 nm NIR light illumination (2 W/cm2).30,31 Before light irradiation, the inherent cell cytotoxicity profile of the hybrid material (UCN@AIS NPs) was measured by a standard MTT assay method with a dose-dependent manner along with several controlled experiments with UCN and AIS similarly. As shown in Figure 5a, no significant dark cytotoxicity of HeLa cells was observed with material concentration ranging from 0.39 to 400 μg/mL for UCN@AIS, UCN, and AIS for 12 h of incubation. The cell viability test suggests that the UCN@AIS NPs are not harmful to cancer cells up to a high concentration range of 400 μg/mL (Figure 5a, wine red).29,35 The phototoxicity of the 980 nm NIR laser light was also examined, and we found that the effect of both the irradiation time and power density toward HeLa cells was negligible (Figure 5b).30 However, as compared to the above conditions, when the HeLa cells incubated with UCN@AIS NPs were irradiated H

DOI: 10.1021/acsabm.8b00467 ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX

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ACS Applied Bio Materials with a 980 nm laser for 30 min (10 min of irradiation and then 5 min break), a substantial reduction in cell viability up to ∼27% was obtained (Figure 5a, royal blue), which supports the higher cancer cells inhibition efficacy by PDT.29,30,35 The obvious cancer cell killing efficiency by UCN@AIS NPs under the exposure of 980 nm laser irradiation was also confirmed by conducting the controlled experiments with the incubation of UCN or AIS followed by laser irradiation. The displayed results of MTT assay tests in Figure 5a depicted that the decent cancer killing phenomenon could only be achieved by the use of UCN@AIS NPs as a photocatalyst under NIR laser illumination. It has been well-known that the cell function could easily be hampered just by unbalancing the proper level of required ingredients for cell functioning (ROS is one of the major factors) by oxidative stress ensues.57 Therefore, in our case, the superior antitumor activity could be explain by the generation of a higher level of ROS inside the cells under 980 nm laser irradiation, which are the key species for disruption of mitochondrial function and activation of caspases followed by further cell death.31 The intracellular ROS generation inside the cells was detected by monitoring the CLSM image of HeLa cells incubated with UCN@AIS NPs and DCFH-DA irradiated with a 980 nm laser. The nonfluorescent DCFH-DA was converted to fluorescent dichlorofluorescein (DCF) by reacting with ROS, and a bright green fluorescence was obtained in the CLSM image as compared to control conditions (Figure 5c−e), which proves the generation of a higher level of ROS during the PDT treatment.58 In addition, the PDT cell killing effect of UCN@AIS NPs on HeLa cells was further verified by exhausting calcein AM and PI costaining.59 The cells without incubation of UCN@AIS NPs under laser irradiation as control group displayed green fluorescence (Figure 5f), indicating the laser irradiation was not responsible for cell death. The HeLa cells incubated with UCN@AIS NPs before laser irradiation also showed green fluorescence (Figure 5g), again suggesting that the UCN@AIS NPs were nontoxic to cancer cells in the dark under the studied dose. However, HeLa cells incubated with UCN@AIS NPs, followed by 980 nm laser irradiation, were obviously killed as directed by the strong red fluorescence as shown in Figure 5h. Therefore, the tumor cells were successfully killed by the PDT effect from UCN@AIS NPs under 980 nm NIR laser exposure. The explored experimental results demonstrate that the synthesized UCN@AIS NPs could be an excellent candidate for realistic and nontoxic cancer treatment agents for substantial applications in biomedical science.

tumor therapy and biomedical science based on a single nanoplatform.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsabm.8b00467.

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BET analyses and LCMS spectra of MB solution before, during, and after photocatalysis (PDF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Swarup Kumar Maji: 0000-0003-3282-3397 Dong Ha Kim: 0000-0003-0444-0479 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Research Foundation of Korea Grant funded by the Korean Government (2017R1A2A1A05022387) and by the Creative Materials Discovery Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (2018M3D1A1058536). S.K.M. is thankful to Khatra Adibasi Mahavidyalaya, India, (KAM) for supporting the research programme for faculty quality improvement. S.K.M. is also thankful to the Department of Higher Education, Science and Technology & Biotechnology, Government of West Bengal, India, for granting special study leave from his academic position (KAM).

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REFERENCES

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CONCLUSION A unique hybrid nanostructure composed of a UCN core and AgInS2 shell (UCN@AIS) was synthesized for the first time for NIR active multifunctional photocatalysis. Upon 980 nm NIR laser irradiation, the hybrid material efficiently produced ROS for typical photocatalytic processes. The hypothesis has been first assessed by considering a model toxic dye (MB) for degradation under NIR light illumination for the application in wastewater management and degradation of hazardous chemicals for the environment issues. The multifunctional property was studied in terms of cellular bioimaging and photocatalysis-induced PDT effect for tumor cells under 980 nm laser irradiation. Such simultaneous imaging capability and cancer therapy efficiency further suggest a future application in I

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