Near-Infrared Light-Triggered Hydrophobic-to-Hydrophilic Switch

Article Cite This: ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX

pubs.acs.org/journal/abseba

Near-Infrared Light-Triggered Hydrophobic-to-Hydrophilic Switch Nanovalve for On-Demand Cancer Therapy Ren-Lu Han,† Jun-Hui Shi,† Zong-Jun Liu,‡ Ya-Fei Hou,† and You Wang*,† †

School of Materials Science and Engineering and ‡School of Chemical Engineering and Technology, Harbin Institute of Technology, Harbin, Heilongjiang 150001, People’s Republic of China

ACS Biomater. Sci. Eng. Downloaded from pubs.acs.org by UNIV OF SUNDERLAND on 09/23/18. For personal use only.

S Supporting Information *

ABSTRACT: An on-demand drug delivery nanoplatform based on mesoporous silica (mSiO2) coated upconversion nanoparticles (UCNP@mSiO2) with a novel near-infrared (NIR) light-triggered hydrophobic-to-hydrophilic switch nanovalve was fabricated. The surface of UCNP@mSiO2 was first immobilized with hydrophobic 2-diazo-1,2-naphthoquinones (DNQ) guest molecules. After doxorubicin hydrochloride (DOX, a universal anticancer drug) was loaded into channels of mSiO2 shell, β-cyclodextrin (β-CD) host molecules with a hydrophobic cavity were added as gatekeepers to cap DNQ stalk molecules via hydrophobic affinity, which may play a role in the OFF state of the nanovalve to prevent the drug from being released. Upon 980 nm light irradiation, a NIR light-triggered hydrophobic-to-hydrophilic switch, that transformed the hydrophobic guest DNQ into hydrophilic guest 3-indenecarboxylic acid (ICA), took place so that the capped β-CD gatekeepers dissociated due to repulsion between β-CD host (hydrophobic) and ICA guest (hydrophilic), activating the ON state of the nanovalves to release drug. The in vitro studies prove that the nanoplatform enables on-demand drug release to efficiently kill HeLa cell upon NIR light regulation. The in vivo experiment results further confirm that the nanoplatform with such fabricated nanovalves is able to inhibit tumor growth in mice. The designed nanovalves based on the novel NIR light-triggered hydrophobic-to-hydrophilic switch strategy therefore may shed new light on future development of on-demand cancer therapy. KEYWORDS: NIR light, hydrophobic-to-hydrophilic nanovalve, on-demand drug release

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cleavage,26,35 photolysis,36 and so on have been reported on the basis of core−shell structure engineering of mesoporous silica (mSiO2) and upconversion nanoparticles (UCNPs) denoted as [email protected],38 Recently, a superhydrophobic polymer has been reported for drug release, where the hydrophobic-to-hydrophilic switch was used to activate valves via host−guest dissociation.39 Unfortunately, the drug release is hardly controllable because of the disability in stimulus response, and the drug premature disclosure is therefore unavoidable. Later, a mSiO2-based nanoplatform was reported for on-demand drug release, where hydrophobic-to-hydrophilic conversion of spiropyran was triggered by UV light to release drug.4 Although much improvement has been made by using UV light as stimulus, it is detrimental to the tissues and cells and can only penetrate shallow tissues. As an alternative, it is highly desired to take advantage of the NIR light-triggered hydrophobic-to-hydrophilic switch for developing a smart release system; it has not been reported so far to the best of our knowledge. Herein, an on-demand drug delivery nanoplatform based on UCNP@mSiO2 with a novel NIR light-triggered hydrophobic-

INTRODUCTION Hydrophobic-to-hydrophilic switches exist widely in nature, and they have received considerable attention due to the various applications in liquid transportation,1,2 oil−water separation,3−5 switchable valves,6−8 and so on.9,10 In nanomedicine, functional micelles assembled from amphiphilic block copolymers can encapsulate hydrophobic drug in their interior, and the encapsulated drug can be released by regulating the hydrophobic-to-hydrophilic switch of amphiphilic block copolymers to dissemble micelles upon an external stimulus.11−14 When this is taken into account, it can be expected that the external stimulus induced hydrophobic-tohydrophilic switch may have a potential of serving as a nanovalve for on-demand drug release applications. Nowadays, on-demand drug release triggered by external stimuli, such as pH,15 temperature,16,17 enzyme, etc.,18,19 becomes more and more popular due to its ability to reduce side effects and improve the efficiency of chemotherapy.20−23 Among various stimuli,15−19 near-infrared (NIR) light with deep tissue penetration ability and little irradiation risk provides great advantages to regulate valves both spatially and temporally.24−28 Since the pioneering studies of Zink and co-workers,29,30 Shi and co-workers,31,32 and Lin and coworkers,33,34 various photochemical mechanisms for NIRtriggered drug release such as photoisomerization,31 photo© XXXX American Chemical Society

Received: April 9, 2018 Accepted: September 5, 2018 Published: September 5, 2018 A

DOI: 10.1021/acsbiomaterials.8b00437 ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX

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ACS Biomaterials Science & Engineering

Scheme 1. Scheme for the Fabrication of On-Demand Drug Delivery Nanoplatform with a NIR Light-Triggered Hydrophobicto-Hydrophilic Switch Nanovalve

Calcein-AM, and PI were bought from Beyotime Institute of Biotechnology (Beyotime, China). Characterization. TEM images were characterized by a JEOL1400 operated at 100 kV. The XRD pattern was recorded on an X’pert diffractometer with Cu Kα radiation. UC luminescence and UC fluorescence were tested with a 980 nm diode laser (Hi-Tech Optoelectronics Co. Ltd.) and lens-coupled monochromator (Zolix Instruments Co. Ltd.), respectively. Surface area and pore diameter measurements were performed on a TriStar 3000. Fluorescence microscopy images were recorded using a fluorescence microscope (Olympus, Japan). FTIR and UV−vis spectra were measured using Nicolet 380 and Varian Cary 50. Zeta-potential measurement was performed by Malvern Zetasizer Nano-ZS90 after nanoparticles were dispersed in distilled water. DLS properties of the nanoparticles were tested by a Malvern Zetasizer Nano ZS90 after the nanoparticles were dispersed in suspensions (0.2 mg·mL−1) with ultrasonic treatment for 10 min. TGA measurement was taken by a thermo gravimetric analyzer TG 209 F1 (Netzsch) at a rate of 10 K/min from 20 to 700 °C under air. Preparation of DOX-UCNP@mSiO2-DNQ-CD. Monodispersed hexagonal UCNP cores (NaYF4:TmYb@NaYF4) were synthesized on the basis of literature protocols with slight modifications.32,47,48 The UCNP cores were coated with mSiO2 shell with template CTAB via the base-catalyzed sol−gel method resulting in UCNP@ mSiO 2 (CTAB). 35,45,49 The surface of as-prepared UCNP@ mSiO2(CTAB) was first modified with NH2 groups by APTES for DNQ-SO2Cl association, and CTAB was then removed (UCNP@ mSiO2-DNQ) to prepare the mSiO2 mesoporous structure.41,50,51 For uploading DOX into the resulting mesoporous mSiO2 channels via physical diffusion, the UCNP@mSiO2-DNQ nanoparticles were soaked in the concentrated DOX solution and continuously stirred for 24 h. After DOX uploading, β-CD molecules were added to cap DNQ guest molecules via hydrophobic affinity to block the access to nanopores resulting in DOX-UCNP@mSiO2-DNQ-CD. Finally, DOX-UCNP@mSiO2-DNQ-CD was isolated by centrifugation and washed to remove excessive DOX and β-CD molecules. The detailed preparation procedure of DOX-UCNP@mSiO2-DNQ-CD is given in the Supporting Information. Drug Release. DOX-UCNP@mSiO2-DNQ-CD nanoparticles (2 mg) were added in a cuvette containing PBS buffer solution (2 mL) before NIR light irradiation. Subsequently, the mixture was periodically exposed to NIR illumination for 5 min with a 10 min interval.

to-hydrophilic switch nanovalve was fabricated. As shown in Scheme 1, UCNP core (NaYF4:Yb,Tm@NaYF4) was first prepared by coating NaYF4:Yb,Tm ( Scheme 1a) with NaYF4 (Scheme 1b). The as-prepared UCNP cores were further capped with a mSiO2 shell noted as UCNP@mSiO2(CTAB), in which hexadecyltrimethylammonium bromide (CTAB) acts as a removable template for later mesoporous structure creation (Scheme 1c). Scheme 1d exhibits a surface-functional program for the as-prepared UCNP@mSiO2(CTAB). First, 2diazo-1,2-naphthoquinone (DNQ), which has been widely reported for phototriggered hydrophobic-to-hydrophilic switch applications,14,40−43 was chosen as the guest stalk molecule for the fabrication of the nanovalves. The surface of UCNP@ mSiO2 was subsequently immobilized with hydrophobic DNQ as the guest stalk molecule. After doxorubicin hydrochloride (DOX, a universal anticancer drug) was loaded into the channels of mSiO2 shell, β-cyclodextrin (β-CD)44−46 with a hydrophobic cavity was added as a host gatekeeper to cap DNQ host molecules via hydrophobic affinity, which play a role in the OFF state of the nanovalves to prevent the drug from being released (Scheme 1e). Upon 980 nm light irradiation, a NIR light-triggered hydrophobic-to-hydrophilic switch due to the transformation of hydrophobic DNQ to hydrophilic 3-indenecarboxylic acid (ICA)14,41 took place so that the capped β-CD gatekeepers dissociate as the result of repulsion between hydrophobic β-CD and hydrophilic ICA, activating the ON state of the nanovalves to release drug triggering on-demand cancer therapy (Scheme 1f).

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EXPERIMENTAL SECTION

Materials. Rare earth chlorides X (X = Yb, Tm, Y) were bought from the JianFeng Rare Earth Company. TEOS, triethylamine (TEA), CTAB, and oleic acid were obtained from Sinopharm Chemical Reagent Co., Ltd. DNQ-SO2Cl was purchased from Tci Development Co., Ltd. Ammonium fluoride (NH4F), 3-aminopropyltriethoxysilane (APTES), and 1-octadecene were obtained from Alfa Aesar. DOX was offered by Dalian MeiLun Biology Technology Co., Ltd. β-CD was obtained from Chengdu Xiya Chemical Co., Ltd. CCK-8 was bought from Sangon Biotech (Shanghai, China). Penicillin/streptomycin, B


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Figure 1. (a−c) TEM images and (d) XRD patterns of NaYF4:TmYb, NaYF4:TmYb@NaYF4 (UCNP), and UCNP@mSiO2(CTAB). (e) Upconversion fluorescent spectra and (f) surface area and pore size distribution of UCNP@mSiO2.

Figure 2. (a) FTIR spectra, (b) UV−vis absorption spectra, (c) TGA curves, and (d) zeta potentials of the corresponding nanoparticles. and cultured for another 4 h. Residual nanoparticles were later removed, and the nuclei were stained by Hoechst 33258 solution. Cell imaging was performed using a fluorescence microscope. In Vitro Antitumor Efficiency of DOX-UCNP@mSiO2-DNQCD. HeLa cells were planted in 96 well plates with 7 × 103 cells in each well and cultured for 24 h. To determine the cytotoxicity of different nanoparticles (UCNP@mSiO2, UCNP@mSiO2-DNQ-CD, or DOX-UCNP@mSiO2-DNQ-CD) without NIR illumination, the viabilities of HeLa cells were examined after 24 h of incubation in the presence of these nanoparticles. The influence of pure NIR light

Before and after each illumination, absorbance spectra of DOXUCNP@mSiO2-DNQ-CD were taken at 480 nm to monitor the released DOX. An experiment in the dark was also performed for comparison. Cell Culture and Imaging. HeLa cells were cultured in DMEM including 10% FBS and 1% penicillin/streptomycin at 37 °C and 5% CO2 (Thermo Fisher Scientific, USA). 5 × 104 HeLa cells were planted in a culture dish and cultured for 24 h, and then, the medium was substituted by DMEM including FITC-labeled nanoparticles denoted as FITC-UCNP@mSiO2-DNQ-CD (100 μg mL−1, 2 mL) C


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Figure 3. (a) UV−vis absorption spectra of UCNP@mSiO2-DNQ nanoparticles in solution (0.5 mg mL−1) before and after NIR illumination with intensity of 1.0 W cm−2 for 20 min. (b) pH variation of the solution containing UCNP@mSiO2-DNQ nanoparticles upon continuous NIR illumination at intensities of 0, 1.0, and 1.5 W cm−2 for 20 min. illumination on cell viabilities was checked 24 h later after NIR illumination. In contrast, 240 μg mL−1 DOX-UCNP@mSiO2-DNQCD was cocultured with HeLa cells for 4 h and treated with NIR illumination. The effects of drug release on cell viabilities were evaluated 24 h later after NIR treatment. Animals and Tumor Model. Five week old BALB/c mice were obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd. All experiments related to animals were conducted in accordance with the Guide for the Care and Use of Laboratory Animals and approved by Harbin Institute of Technology. To obtain tumorbearing mice, the shoulder of every mouse was subcutaneously injected with 1 × 107 HeLa cells. In Vivo Antitumor Efficiency of DOX-UCNP@mSiO2-DNQCD. The tumor-bearing mice were divided into 4 groups with five mice in each group: (1) control (PBS), (2) materials (DOX-UCNP@ mSiO2-DNQ-CD), (3) laser illumination only, and (4) materials (DOX-UCNP@mSiO2-DNQ-CD) with laser illumination. Intratumoral injection of 25 μL of PBS was done for the mice in group (1) and group (3) while 25 μL of DOX-UCNP@mSiO2-DNQ-CD was injected for mice in group (2) and group (4) for comparison. After 24 h, 980 nm laser illumination at an intensity of 0.5 W cm−2 was employed for mice in group (3) and group (4) for 10 min. Tumor size and body weight of mice were recorded every 2 days.

tion−desorption isotherms of UCNP@mSiO2 after removal of CTAB (Figure 1f) show surface area and pore diameters of outer mSiO2 shells are 346 m2 g−1 and 3.1 nm, respectively, indicating the inner channels can be utilized as drug carrier. The subsequent surface functionalizations of the as-prepared UCNP@mSiO2(CTAB) nanoparticles were carried out according to Scheme 1d,e as follows: (1) The outer surface of UCNP@mSiO2(CTAB) was first functionalized with amino groups using APTES, and the mesoporous structured UCNP@ mSiO2−NH2 was obtained by subsequently removing CTAB. (2) To associate β-CD gatekeepers, DNQ guest molecules were anchored on the nanoparticle surface via Hinsberg reactions between sulfonyl groups of DNQ-SO2Cl and amine groups previously decorated. The functionalization processes of the UCNP@mSiO2 surface were monitored by FTIR measurement as shown in Figure 2a. First, after mSiO2 shell is coated, a strong absorption signal for the resulting UCNP@ mSiO2 appeared at 1084 cm−1 and is attributed to asymmetric stretching of Si−O−Si,50 indicating the successful silica coating. Second, the observed new peaks at 1484 cm−1 of the UCNP@mSiO2−NH2 sample can be assigned to C−N stretching vibrations,50 indicating a successful mortification of the NH2 group. Third, the appearance of azide peak at 2150 cm −1 for UCNP@mSiO 2 -DNQ samples confirms the successful immobilization of DNQ.52 Moreover, the observed new absorption band in UV−vis absorption spectra of UCNP@mSiO2-DNQ (Figure 2b), the stepwise weight loss in TGA curves (Figure 2c), and the zeta potential change (Figure 2d) of corresponding nanoparticles all demonstrate that DNQ was anchored onto the surface of UCNP@mSiO2 nanoparticles. To load drug, the as-prepared UCNP@mSiO2-DNQ nanoparticles were soaked in a concentrated DOX solution. After that, a sufficient amount of β-CD molecules as gatekeepers was added into the mixture to associate the preanchored DNQ molecules playing a role in the OFF state of the nanovalve, preventing the uploaded drug from being released (see schematic illustration of DOX loading and β-CD capping procedure in Figure S2a). The change of weight loss in TGA curves before and after being capped with β-CD indicates the successful capping of DNQ with β-CD due to hydrophobic affinity (Figure 2c). By comparing UV−vis absorption spectra before and after DOX loading (Figure S2b), DOX loading capacity and efficiency are determined to be 4.75 wt % and

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RESULTS AND DISCUSSION Th e as-prepared NaYF 4 :TmYb (Figure 1a) and NaYF4:TmYb@NaYF4 nanoparticles (Figure 1b) are monodisperse with a size of 30 ± 2 and 40 ± 2 nm, respectively. Additionally, the intensity of fluorescence spectra of NaYF4:TmYb@NaYF4 shows a significant improvement compared with NaYF4:TmYb (Figure S1). The as-synthesized NaYF4:TmYb@NaYF4 (UCNP) was then coated with a mSiO2 shell denoted as UCNP@mSiO2(CTAB). It can be observed from Figure 1c that the resulting UCNP@mSiO2(CTAB) remains monodispersed with an increased diameter of 64 ± 2 nm. XRD analyses (Figure 1d) show that all nanoparticles are well-crystallized, and all peaks match well with pure hexagonal NaYF4. Moreover, both the gradual increase of particle size (Figure 1a−c) and the emergence of amorphous peak at 2θ = 22° (Figure 1d) demonstrate that UCNP@mSiO2(CTAB) nanoparticles have been successfully synthesized as expected. Figure 1e shows UCNP@mSiO2(CTAB) nanoparticles also have great upconversion luminescence performance, indicating the coated mSiO2 thin shell has little shield effect on the upconversion luminescence of UCNPs. Further, N2 adsorpD


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Of particular interest, a “ladder” drug release behavior induced by the periodic NIR light illumination was observed as shown in Figure 4. It can be seen that the drug release profiles quickly reach a plane after NIR light illumination was turned off at the selected time, indicating the release kinetics is mainly controlled by NIR light-triggered hydrophobic-to-hydrophilic switch and the effectiveness of the OFF state of the nanovalve because little DOX could be released without NIR light irradiation. It was worth mentioning the cumulative DOX release dependence of NIR intensity (increasing from 30 to 40 wt % with increasing intensity from 1.0 to 1.5 W cm−2) and the “ladder” drug release dependence of periodic NIR illumination both indicate the released DOX dosage would be precisely controlled for our platform by tuning either illumination intensity or time of NIR light. Additional pH-varying (Figure S5) and temperature-varying (Figure S6) control experiments were also carried out for eliminating possible pH and laser thermal influences on DOX release behaviors. In vitro experiments require evaluation of the toxicity of the blank delivery system. For this purpose, we used HeLa cells to study toxicity of UCNP@mSiO2 and UCNP@mSiO2-DNQCD nanoparticles via the CCK-8 assay. As observed in Figure S7, UCNP@mSiO2 and UCNP@mSiO2-DNQ-CD showed negligible cell death after coincubation with HeLa cells even at high concentration (240 μg mL−1), demonstrating their low toxicity. Since cellular uptake of nanoparticles was a prerequisite for DOX release in cells, it was pre-examined by imaging HeLa cells incubated with fluorescence-labeled UCNP@mSiO2-DNQ-CD nanoparticles (FITC-UCNP@ mSiO2-DNQ-CD) under a fluorescence microscope, where nucleus and nanoparticles were pseudocolored in blue and green, respectively.55 As shown in Figures 5a and S8, green FITC-UCNP@mSiO2-DNQ-CD was observed mainly surrounding blue nuclei, indicating the successful cellular uptake of nanoparticles. Moreover, Figure 5b shows cell viability almost remains the same after HeLa cells cocultured with DOX-UCNP@mSiO2DNQ-CD in the dark, indicating little leakage of DOX. It can be seen that 980 nm light illumination of 15 min without nanoparticle treatment has minimal effect on the viability of HeLa cells (Figure 5c) and HUVEC cells (normal cell; see Figures S9 and S10), so it is used as a safe threshold value for performing drug delivery in cancer cells. In vitro result of our platform can be seen from Figure 5c showing that NIR illumination of DOX-UCNP@mSiO2-DNQ-CD inhibited cancer cell growth, and cell viabilities were significantly reduced from 80% to 44% upon increasing illumination time from 5 to 15 min, which is due to tunable DOX release and abundant DOX accumulation in cells. Additionally, control experiments with UCNP@mSiO2 or UCNP@mSiO2-DNQCD were extensively performed under the same circumstances (Figure S11). No observable changes of HeLa cell viabilities were found (Figure S11), indicating the death of cancer cells (Figure 5c) is mainly attributed to DOX release. Furthermore, fluorescence experiments of stained live/dead cells exhibited an analogous result to that of the CCK-8 experiment. It is well-known that a red florescence is emitted when PI is combined with dead cell and/or apoptosis cells,56 while a green florescence is emitted when calcein AM is hydrolyzed in living cells.56 It can be found from Figure 5d that not many HeLa cells were dead after treatment with DOXUCNP@mSiO2-DNQ-CD nanoparticles alone or 980 nm light alone. In contrast, DOX-UCNP@mSiO2-DNQ-CD with 980

69.14%, respectively, according to a reported method.53 The particle size distributions of UCNP, UCNP@mSiO2, UCNP@ mSiO2-DNQ, and DOX-UCNP@mSiO2-DNQ-CD measured by DLS were 45, 69, 193, and 76 nm, respectively (Figure S3). The stepwise changes in particle size indicate DOX-UCNP@ mSiO2-DNQ-CD nanoparticles were successfully prepared. According to previous literature,42,54 DNQ upon UV light illumination will be transformed into ICA, which is a carboxylic acid with strong hydrophilicity in aqueous solution. Thus, the transformation of hydrophobic DNQ into the strongly hydrophilic ICA upon 980 nm NIR illumination of UCNP@ mSiO2-DNQ was proved by the following two different approaches. (1) Upon NIR illumination of UCNP@mSiO2DNQ, Figure 3a shows two UV−vis absorption peaks at 330 and 399 nm significantly decrease, indicating the transformation from DNQ to ICA did take place.40 By the way, the broad peak appearing around 255 nm can be attributed to deprotonated carboxylate generation, which is in agreement with the ICA formula.41 For the control experiment as shown in Figure S4, it should be noted that no detectable change in UV−vis spectra of DNQ-modified pure mSiO2 nanoparticles was observed upon NIR illumination. (2) Upon NIR illumination, the pH value of solution containing UCNP@ mSiO2-DNQ nanoparticles (5 mg mL−1) decreases greatly in contrast with negligible pH change without NIR illumination (Figure 3b), which further confirms the NIR illumination induced transformation.14 Overall, both approaches conformably confirm that a NIR light triggered hydrophobic-tohydrophilic switch did take place as proposed in Scheme 1, which in principle can be used to activate nanovalve by dissociating β-CD gatekeepers and releasing drug. On-demand DOX release behavior from DOX-UCNP@ mSiO2-DNQ-CD was monitored by exposing its solution to a 980 nm NIR light periodic irradiation at different intensities of 0, 1.0, and 1.5 W cm−2, respectively. It can be seen from Figure 4 that significantly cumulative released DOX (above 25 wt %)

Figure 4. DOX release profile from DOX-UCNP @mSiO2-DNQ-CD upon periodic 980 nm NIR ON/OFF illumination at different intensities of 0, 1.0, and 1.5 W cm−2.

was detected upon intermittent NIR light irradiation in contrast to less than 6.0 wt % of cumulative DOX release without NIR illumination, the latter of which demonstrates DOX can be efficiently capped inside pore channels at the OFF state of the nanovalve and could only be released at the ON state of the nanovalve when activated by NIR illumination. E


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Figure 5. (a) Fluorescence microscopy images of nanoparticles. The left, middle, and right image correspond to Hoechst 33258 stained nuclei (blue), FITC-UCNP@mSiO2-DNQ-CD (green), and a merged one, respectively (Scale bar = 50 μm). (b) Effects of DOX-UCNP@mSiO2-DNQCD concentrations on cell viabilities in the dark. (c) Viabilities of cells incubated without or with DOX-UCNP@mSiO2-DNQ-CD upon 980 nm NIR illumination (1.0 W cm−2) as a function of illumination time. (d) Fluorescence microscopy images of stained live/dead cells after different treatments (Scale bar = 0.5 mm).

significant change could be found in the normalized tumor volume for either group 2 or group 3 compared with the control group (treated with PBS), suggesting neither DOXUCNP@mSiO2-DNQ-CD nanoparticles nor 980 nm NIR light illumination alone could affect tumor growth. As expected, the tumor growth could be partially inhibited in group 4, with the relative tumor volume reaching 5.1-fold. These results demonstrate that the hydrophobic-to-hydrophilic switch nanovalve can be successfully regulated in living organisms in agreement with the above in vitro results. Toxicities of both nanoparticles and 980 nm illumination could be neglected because there is almost no change in body weight of all mice involved as shown in Figure 6b. When relative tumor volumes of the control group were big enough (14 d), all mice were sacrificed and their tumors were excised. It can be found from Figure 6c that the tumor size in group 4 was the smallest among all groups, indicating the regulation of NIR illumination could switch the hydrophobic-to-hydrophilic nanovalve for on demand in vivo drug release. Figure 6d shows the histological sections of tumor. No detectable necrosis of tumor cells could be observed in groups 1−3, while a moderate change with some cell apoptosis could be found in group 4, which proves the promising tumor ablating activity. Histopathological slices of major organs including heart, liver, spleen, lung, and kidney for all mice have been analyzed in Figure 7 to systematically evaluate the biosafety of DOX-

nm irradiation leads to the death of most HeLa cells. Compared with the other in vitro results of NIR induced drug release experiments based on the photoisomerization or photocleavage mechanism, the present study based on the hydrophobic-to-hydrophilic switch mechanism shows relatively higher sensitivity and cell killing ability. For example, regulating drug release to kill 50% of cancer cells requires a 20 min laser irradiation of 2.4 W cm−2 for photoisomerization31 and 2 h laser irradiation at an intensity of 5.0 Wcm−2 for photocleavage,36 while only 15 min of laser irradiation at an intensity of 1.0 W cm−2 is required for the hydrophobic-tohydrophilic switching nanoplatform to achieve the same effect. Since the illumination intensity and time are much lower and shorter than those of the correspondingly reported studies,57,58 it may not change the chemical state of DOX, the effectiveness of which has been solidly confirmed in this study. Inspired by the exciting in vitro results mentioned above, we subsequently performed the in vivo studies of DOX-UCNP@ mSiO2-DNQ-CD nanoparticles on tumor-bearing mice. In the in vivo studies, mice were divided into 4 groups and treated with (1) PBS, (2) materials (DOX-UCNP@mSiO2-DNQCD), (3) 980 nm NIR illumination only, and (4) materials (DOX-UCNP@mSiO2-DNQ-CD) with 980 nm NIR illumination, respectively. After 14 d, the volume of tumors was measured and normalized according to the original size (0 d). From statistical curves of tumor growth (Figure 6a), no F


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the transformation of hydrophobic DNQ into hydrophilic ICA took place so that the repulsion between hydrophobic β-CD cavity and hydrophilic ICA triggered the dissociation of β-CD caps activating the ON state of the nanovalve to release DOX. Both in vitro and in vivo studies confirmed that the nanoplatform with novel NIR light-triggered hydrophobic-tohydrophilic switch nanovalves enables an on-demand drug release in a highly controlled way to efficiently kill HeLa cells. We believe that this on-demand drug release nanoplatform may have potential applications for future cancer therapy.

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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/acsbiomaterials.8b00437. Experimental details, UV−vis absorption spectra, upconversion fluorescent spectra and fluorescence microscopy photos of corresponding nanoparticles, and effects of nanoparticles concentrations without NIR light irradiation and light exposure without nanoparticles on viabilities of HeLa cells (PDF)

Figure 6. (a) In vivo antitumor efficiency of DOX-UCNP@mSiO2DNQ-CD nanoparticles. The change of relative tumor volume (a) and body weight (b) after different treatments, which are categorized into four groups: (1) control, PBS only; (2) materials, DOX-UCNP@ mSiO2-DNQ-CD only; (3) laser, 980 nm NIR illumination only; (4) materials + laser, DOX-UCNP@mSiO2-DNQ-CD with 980 nm NIR illumination. (c) Digital images of excised tumors undergoing the above treatments for 14 d. (d) Histological sections of tumor slices (Scale bar = 100 μm).

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

UCNP@mSiO2-DNQ-CD in vivo. No detectable physiomorphology variations and side effects could be found from the slices of major organs, confirming the favorable biocompatibility of our designed nanoparticles employed.

ORCID

You Wang: 0000-0002-2278-0541 Notes

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The authors declare no competing financial interest.

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CONCLUSIONS A novel NIR light-triggered hydrophobic-to-hydrophilic switch nanovalve for on-demand drug release on the basis of mSiO2coated UCNP has been fabricated. The hydrophobic-tohydrophilic switch nanovalve consists of hydrophobic DNQ as guest stalk which can associate with host β-CD caps acting as the OFF state of the nanovalve to avoid DOX release by blocking the access to the nanopores. Upon 980 nm NIR illumination, a hydrophobic-to-hydrophilic switch induced by

ACKNOWLEDGMENTS The study was financially supported by the National Natural Science Foundation of China (NSFC 51541303). REFERENCES

(1) Ichimura, K.; Oh, S. K.; Nakagawa, M. Light-driven Motion of Liquids on A Photoresponsive Surface. Science 2000, 288, 1624− 1626.

Figure 7. Histopathological slices of major organs for the 4 groups of mice after the different treatments (Scale bar = 100 μm). G


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