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

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Controlled Release and Delivery Systems

Novel NIR Light-Triggered Hydrophobic-to-Hydrophilic Switch Nanovalve for on-Demand Cancer Therapy Renlu Han, Junhui Shi, Zongjun Liu, Ya-Fei Hou, and You Wang ACS Biomater. Sci. Eng., Just Accepted Manuscript • DOI: 10.1021/acsbiomaterials.8b00437 • Publication Date (Web): 05 Sep 2018 Downloaded from http://pubs.acs.org on September 8, 2018

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ACS Biomaterials Science & Engineering

Novel

NIR

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 150001, People’s Republic of China.

Mailing Addresses: School of Materials Science and Engineering, Harbin Institute of Technology, No.92, Xidazhi Street, Nangang District, Harbin 150001, Heilongjiang, People’s Republic of China. Email: [email protected]

ACS Paragon Plus Environment

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ABSTRACT: An on-demand drug delivery nanoplatform based on mesoporous silica (mSiO2) coated upconversion nanoparticles (UCNP@mSiO2) with a novel near infrared (NIR) lighttriggered 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 of OFF state of nanovalve to prevent drug from releasing. Upon 980 nm light irradiation, a NIR light-triggered hydrophobic-to-hydrophilic switch, that is, transforming hydrophobic guest DNQ into hydrophilic guest 3-indenecarboxylic acid (ICA) took place so that the capped β-CD gatekeepers dissociate due to repulsion between β-CD host (hydrophobic) and ICA guest (hydrophilic) activating ON state of 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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INTRODUCTION Hydrophobic-to-hydrophilic switch exists widely in nature, and it has received considerable attentions 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-tohydrophilic switch of amphiphilic block copolymers to dissemble micelles upon an external stimulus.11-14 Inspired by this, it can be expected that the external stimulus induced hydrophobic-to-hydrophilic switch may have a potential of serving as nanovalves for on-demand drug release applications. Nowadays, on-demand drug release triggered by external stimuli such as pH,15 temperature,16-17 and enzyme etc.,18-19 become more and more popularer due to its ability in reducing side effects and improving efficiency of chemotherapy.20-23 Among various stimuli,15-19 near-infrared (NIR) light with deep tissue penetration ability and few irradiation risk provides great advantages to regulate vavles both spatially and temporally.24-28 Since the pioneering studies of Zin et al.,29-30 Shi et al.,31-32 and Lin et al.,33-34 various photochemical mechanisms for NIR-triggered drug release such as photoisomerization31 photocleavage,26,35 photolysis36 and so on have been reported based on core-shell structure engineering of mesoporous silica (mSiO2) and upconversion nanoparticles (UCNPs) denoted as [email protected] 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


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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, taking advantage of NIR light-triggered hydrophobicto-hydrophilic switch for developing smart release system is highly desired and 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-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 a) with NaYF4 (scheme b). The as-prepared UCNP cores were further capped with a mSiO2 shell noted as UCNP@mSiO2(CTAB), in which CTAB act as removable template for later mesoporous structure creation (scheme c). Scheme d exhibits a surface-functional program for the as-prepard UCNP@mSiO2(CTAB). First, 2Diazo-1,2-naphthoquinones (DNQ), which has been widely reported for phototriggered hydrophobic-to-hydrophilic switch applications,14,40-43 was chosen as the guest stalk molecules for the fabrication of nanovalves. The surface of UCNP@mSiO2 was subsequently immobilized with hydrophobic DNQ as guest stalk molecules. 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 host gatekeepers to cap DNQ host molecules via hydrophobic affinity, which plays a role of OFF state of nanovalves to prevent drug from releasing (scheme e). Upon 980 nm light irradiation, a NIR light-triggered hydrophobic-to-hydrophilic switch due to


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transforming hydrophobic DNQ into 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 ON state of nanovalves to release drug triggering on-demand cancer therapy (scheme f).

Scheme 1. Scheme for the fabrication of on-demand drug delivery nanoplatform with a NIR lighttriggered hydrophobic-to-hydrophilic switch nanovalve.

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. βCD was obtained from Chengdu Xiya Chemical Co., Ltd. CCK-8 was bought from Sangon


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Biotech (Shanghai, China). Penicillin/streptomycin, Calcein-AM, and PI were bought from Beyotime Institute of Biotechnology (Beyotime, China). Characterization. TEM images were characterized by a JEOL-1400 operated at 100 KV. XRD pattern was recorded on an X’pert diffractometer with Cu Kα radiation. UC luminescence and UC fluorescence were tested by 980 nm diode laser (Hi-Tech Optoelectronics Co. Ltd.) and lens-coupled monochromator (Zolix Instruments Co. Ltd.) respectively. Surface area and pore diameter measurement were performed by 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 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 thermo gravimetric analyzer TG 209 F1 (Netzsch) at a rate of 10 K/min from 20 to 700 oC 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 base-catalyzed sol-gel method resulting in UCNP@mSiO2(CTAB).35,

45, 49

The surface of as-

prepared UCNP@mSiO2(CTAB) was first modified with NH2 groups by APTES for DNQSO2Cl association and CTAB was then removed (UCNP@mSiO2-DNQ) to prepare 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


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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 were 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. Before and after each illumination, absorbance spectra of DOX-UCNP@mSiO2-DNQ-CD were taken at 480 nm to monitor the released DOX. 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-labelled nanoparticles denoted as FITC-UCNP@mSiO2-DNQ-CD (100 µg mL-1, 2 mL) 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 fluorescence microscope. In vitro antitumor efficiency of DOX-UCNP@mSiO2-DNQ-CD. 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@mSiO2DNQ-CD) without NIR illumination, the viabilities of HeLa cells were examined after 24 h incubation in the presence of these nanoparticles. The influence of pure NIR light illumination on cell viabilities were checked 24 h later after NIR illumination. In contrast, 240 µg mL-1 DOX-


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UCNP@mSiO2-DNQ-CD were co-cultured with HeLa cells for 4 h and treated with NIR illumination. The effect of drug release on cell viabilities were evaluated 24 h later after NIR treatment. Animals and tumor Model. 5 weeks 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 tumor-bearing mice, the shoulder of every mouse was subcutaneously injected with 1 ×107 HeLa cells. In vivo antitumor efficiency of DOX-UCNP@mSiO2-DNQ-CD. The tumor-bearing mice were divided into 4 groups with five mice in each group: (1) control (PBS), (2) materials (DOXUCNP@mSiO2-DNQ-CD), (3) laser illumination only, and 4) materials (DOX-UCNP@mSiO2DNQ-CD) with laser illumination. Intratumoral injection of 25 µL PBS was done for the mice in group (1) and group (3) while 25 µL 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 two days.

RESULTS AND DISCUSSION The as-prepared NaYF4:TmYb (Figure 1a) and NaYF4:TmYb@NaYF4 nanoparticles (Figure 1b) are monodisperse with a size of 30 ± 2 nm 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


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UCNP@mSiO2(CTAB). It can be observed from Figure 1c that the resulting UCNP@mSiO2(CTAB) remains monodisperse with an increased diameter of 64 ± 2 nm.

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..

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 (Figures 1a-c) and the emergence of amorphous peak at 2θ = 22o (Figure 1d) demonstrate

that

UCNP@mSiO2(CTAB)

nanoparticles

have

been

successfully

synthesised 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 adsorptiondesorption isotherms of UCNP@mSiO2 after removal of CTAB (Figure 1f) shows surface


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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 d and 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 nanoparticle surface via hinsberg reactions between sulfonyl groups of DNQ-SO2Cl and amine groups previously decorated. The functionalization processes of 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-OSi,50 indicating the successful silica coating. Second, the observed new peaks at 1484 cm-1 of UCNP@mSiO2-NH2 sample can be assigned to C-N stretching vibrations,50 indicating a successful mortification of NH2 group. Thirdly, the appearance of azide peak at 2150 cm-1 for UCNP@mSiO2-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 into a concentrated DOX solution. After that, a sufficient amount of β-CD molecules as gatekeepers were added into the mixture to associate the pre-anchored DNQ molecules


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playing a role of OFF state of nanovalve preventing the uploaded drug from releasing (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 β-CD capped 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 loaded (Figure S2b), DOX loading capacity and efficiency are determined to be 4.75 wt% and 69.14% respectively according to a reported method.53 The particle size distribution of UCNP, UCNP@mSiO2, UCNP@mSiO2-DNQ and DOX-UCNP@mSiO2-DNQ-CD measured by DLS were 45 nm, 69 nm, 193 nm and 76 nm respectively (Figure S3). The stepwise changes in particle size indicate DOX-UCNP@mSiO2-DNQ-CD nanoparticles were successfully prepared.

Figure 2. (a) FTIR spectra, (b) UV-vis absorption spectra, (c) TGA curves, and (d) zeta potentials of the corresponding nanoparticles.


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According to previous literature,42,

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DNQ upon UV light illumination will be

transformed into ICA, which is a carboxylic acid with strong hydrophily 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@mSiO2-DNQ, Figure 3a shows two UV-vis absorption peaks at 330 and 399 nm significantly decrease, indiating the transformation from DNQ to ICA did take place.40 By the way, the appeared broad peak around 255 nm can be contributed to deprotonated carboxylate generation, which is in agreement with 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-to-hydrophilic switch did take place as proposed in Scheme 1, whicn in principle can be used to activate nanovalve by dissociating β-CD gatekeepers and release drug. On-demand DOX release behaviour 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%) were 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


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pore channels at the OFF state of nanovalve and could only be released at the ON state of nanovalve activated by NIR illumination.

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.

Of particular interest, a “ladder” drug release behaviour 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 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


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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 behaviours.

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

In vitro experiments require evaluation of the toxicity of the blank delivery system. For this purpose, we used Hela cell to study toxicity of UCNP@mSiO2 and UCNP@mSiO2DNQ-CD nanoparticles via CCK-8 assay. As observed in Figure S7, UCNP@mSiO2 and UCNP@mSiO2-DNQ-CD showed negligible cell death after co-incubation with Hela cell even at high-concentration (240 µg mL−1), demonstrating their low toxicity. Since cellular uptake of nanoparticles was prerequisite for DOX release in cells, it was pre-examined by imaging HeLa cells incubated with fluorescence-labelled UCNP@mSiO2-DNQ-CD nanoparticles (FITC-UCNP@mSiO2-DNQ-CD) under a fluorescence microscope, where nucleus and nanoparticles were pseudocoloured in blue and green, respectively.55 As shown in Figure 5a and Figure S8, green FITC-UCNP@mSiO2-DNQ-CD was observed mainly surrounding blue nuclei, indicating the successful cellular uptake of nanoparticles.


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Figure 5. (a) Fluorescence microscopy images of nanoparticles. The left, middle and right image corresponding 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-DNQ-CD concentrations on cell viabilities in the dark. (c) Viabilities of cells incubated without or with DOXUCNP@mSiO2-DNQ-CD upon 980 nm NIR illumination (1.0 W cm-2) as function of illumination time. (d) Fluorescence microscopy images of stained live/dead cells after different treatments. (Scale bar = 0.5 mm).

Moreover, Figure 5b shows cell viability almost remains the same after HeLa cells cocultured with DOX-UCNP@mSiO2-DNQ-CD in the dark, indicating little leakage of DOX. It can be seen that 980 nm light illumination of 15 min without nanoparticles treatment has minimal effect on the viability of HeLa cell (Figure 5c) and HUVEC cell


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(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 cells growth, and cell viabilities were significantly reduced from 80% to 44% upon increasing illumination time from 5 to 15 min, which is due to tuneable DOX release and abundant DOX accumulation in cells. Additionally, control experiments with UCNP@mSiO2 or UCNP@mSiO2-DNQ-CD were extensively performed under 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 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 florescent is emitted when calcein AM is hydrolyzed in living cells.56 It can be found from Figure 5d that little HeLa cells was dead after DOX-UCNP@mSiO2-DNQ-CD nanoparticles alone or 980 nm light alone treatment. In contrast, DOX-UCNP@mSiO2-DNQ-CD upon 980 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 photoisomerization or photocleavage mechanism, the present study based on hydrophobic-to-hydrophilic switch mechanism shows relative higher sensitivity and cell killing ability. For example, regulating drug release to kill 50% 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 photocleavage36, while only 15 min laser irradiation at an intensity of 1.0 W cm -2

is required for hydrophobic-to-hydrophilic switching nanoplatform to achieve the same effect.


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For 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, the in vivo studies of DOXUCNP@mSiO2-DNQ-CD nanoparticles on tumor-bearing mice were subsequently performed. In the in vivo studies, mice were divided into 4 groups and treated with 1) PBS, 2) materials (DOX-UCNP@mSiO2-DNQ-CD), 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 significant change could be found in the normalized tumor volume for either group 2 or group 3 compared

with

control

group

(treated

with

PBS),

suggesting

neither

DOX-

UCNP@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 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 little change in body weight of all mice involved as shown in Figure 6b. When relative tumor volumes of control group reached 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


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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 cells apoptosis could be found in group 4, which proves the promising tumor ablating activity.

Figure 6. (a) In vivo antitumor efficiency of DOX-UCNP@mSiO2-DNQ-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).

Histopathological slices of major organs including heart, liver, spleen, lung and kidney for all mice have been analysed in Figure 7 to systematically evaluate the biosafety of DOX-UCNP@mSiO2-DNQ-CD in vivo. No detectable physiomorphology variations and


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side effects could be found from the slices of major organs, confirming the favourable biocompatibility of our designed nanoparticles employed.

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

CONCLUSIONS A novel NIR light-triggered hydrophobic-to-hydrophilic switch nanovalve for on-demand drug release on the basis of mSiO2-coated UCNP has been fabricated. The hydrophobic-tohydrophilic switch nanovalve consist of hydrophobic DNQ as guest stalks which can associate with host β-CD caps acting as OFF state of nanovalve to avoid DOX release by blocking the access to nanopores. Upon 980 nm NIR illumination, a hydrophobic-to-hydrophilic switch induced by 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 βCD caps activating ON state of nanovalve to release DOX. Both in vitro and in vivo studies confirmed that the nanoplatform with novel NIR light-triggered hydrophobic-to-hydrophilic


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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.

ASSOCIATED CONTENT

Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Experimental details, UV-vis absorption spectra, upconversion fluorescent spectra and fluorescence microscopy photos of corresponding nanoparticles, effects of nanoparticles concentrations without NIR light irradiation and light exposure without nanoparticles on viabilities of HeLa cells

AUTHOR INFORMATION

Corresponding Author *E-mail: [email protected] Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT

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

REFERENCES


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For Table of Contents use only

Novel NIR 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*


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

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