Light-Triggered Specific Cancer Cell Release from Cyclodextrin

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Light-Triggered Specific Cancer Cell Release from Cyclodextrin/Azobenzene and Aptamer Modified Substrate Qing Bian, Wenshuo Wang, Shutao Wang, and Guojie Wang ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.6b09734 • Publication Date (Web): 20 Sep 2016 Downloaded from http://pubs.acs.org on September 21, 2016

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ACS Applied Materials & Interfaces

Light-Triggered Specific Cancer Cell Release from Cyclodextrin/Azobenzene and Aptamer Modified Substrate Qing Bian,† Wenshuo Wang‡ Shutao Wang,*,‡ and Guojie Wang*,† †

School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing 100083, China

‡

Laboratory of Bio-inspired Smart Interface Science, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China.

ABSTRACT: Cell adhesion behaviors of stimuli-responsive surfaces have attracted much attention for their potential biomedical applications. Distinct from temperature- and pH stimuli, the photoswitching avoids the extra input of thermal energy or chemicals. Herein, we designed a novel reusable cyclodextrin (CD) modified surface to realize photoswitched specific cell release utilizing host-guest interactions between CD and azobenzene. The azobenzene-grafted specific cell capture agent was assembled onto CD modified surface to form smart surface controlling cell adhesion by light radiation. After UV light irradiation, the azobenzene switched from transto cis- isomers and the cis-azobenzene would not be recognized by CD due to the unmatched host-guest pairs, thus the captured MCF-7 cells could be released. Light-triggered specific cancer cell release with high efficiency may afford the smart surface with great potential applications for the isolation and analysis of circulating tumor cells.

KEYWORDS: Azobenzene, Aptamer, Cell adhesion, Host-guest, Photoswitch

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INTRODUCTION Cell adhesion on surfaces is significant to numerous biomedical and biotechnological applications because it is not only a fundamental principle of biology, but also can be widely used to guidance establishing a next generation of intelligent materials and functional biointerfaces.1-3 As research activity in the field of controlled cell adhesion continues to unfold, dynamic control of cancer cell capture/release on stimuli-responsive surfaces has become prevalent.4-17 Many stimuli-responsive materials rooted in the use of modified substrates have been utilized, where cell capture and release can be regulated in response to external stimuli, such as temperature,4,5 voltage,6,7 enzyme,8 light,9-12 or pH13,14. It is noted that the stimulus of light possesses the advantages of precise spatiotemporal control and convenient operation. Azobenzene is considered as an ideal photoswitch candidate for regulating cell adhesion properties, which can be reversibly photoisomerized between the trans and the cis by alternating irradiation with UV and visible light.15-17 In addition, azobenzene is also an excellent guest molecular for inclusion complexation with cyclodextrin (CD) driven by van der Waals and hydrophobic interactions.18-20 The trans azobenzene and CD can form host-guest complexes spontaneously, while the cis azobenzene cannot form an inclusion complex with CD because of the size mismatch between the host and guest. In other words, UV irradiation can disassemble the complex of azobenzene and CD due to photoisomerization of azobenzene. Very recently, azobenzene-containing materials have been widely utilized to fabricate the photoswitched biointerfaces via the host-guest interactions,21-25 while most of them are focused on the reversible immobilization of bacterial22, protein23, and cyochrome24. Until now, only a few strategies on constructing light-responsive surfaces to control cell capture and release via host-guest interaction have been reported. Zhang et al. designed a smart template consisting of photo responsive self-assembled monolayers (SAMs) containing α-CD and azobenzene-peptides with arginine-glycine-aspartate (RGD) sequence, which could control the cell adhesion upon UV/visible light irradiation.25 RGD has been used to capture cells as it has demonstrated high


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affinity to αvβ3 and αvβ5 integrins that up-regulated by not only several tumor cells but also endothelial cells.26-29 However, highly specific recognition of target cancer cells is extremely essential in both fundamental cell biology research and clinical diagnostics. Thus, the biomolecules such as DNA aptamers with high affinity and specificity should be explored to control cell adhesion. Aptamers are short DNA or RNA sequences that could form unique three-dimensional (3D) structures that specifically bind to target molecules and cells with high affinity.30,31 The DNA aptamers have some inherent advantages for cell research, such as easy to synthesize, less vulnerable to denaturation, and more stable to biodegradation. Among various kinds of aptamers, S2.2 (GCA GTT GAT CCT TTG GAT ACC CTG G), a 25-mer DNA aptamer, shows high specific affinity for breast cancer cells (MCF-7).32 Herein, we designed a novel reusable CD modified surface to realize photoswitched specific cell release utilizing host-guest interactions between azobenzene and β-CD. The substrate was first modified with the host molecule cyclodextrin to form a CD-terminated surface (Si-CD); subsequently, the thiol-azobenzene were attached to the host molecule β-CD to prepare thiols terminated azobenzene modified substrates (Si-CD/Azo). Finally, the aptamer S2.2, a specific cell capture agent, was connected to the thiol-azobenzene to construct aptamer modified Si-CD/Azo surface (Si-CD/Azo-apt) which could capture the specific cells (MCF-7) via supramolecular azobenzene/β-CD interaction. This Si-CD/Azo-apt substrate can control cell adhesion by light radiation. After UV light irradiation, the azobenzene switched from trans- to cis- isomers, and the cis-azobenzene cannot be recognized by β-CD due to the unmatched host-guest pairs, thus releasing the captured MCF-7 cells. Significantly, the topographic interactions between geometrical structured substrates and cancer cells could promote the cell capture/release

efficiency.

Moreover,

the

specific

adhesion

of

MCF-7

cells

on

aptamer-functionalized surface was demonstrated when incubating a mixture of specific and nonspecific cells. The light-triggered cell release with high efficiency may afford the smart surface with great potential applications for the isolation and analysis of cancer cells. EXPERIMENTAL SECTION



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Materials. β-Cyclodextrin (β-CD, >98%), p-toluenesulfonyl chloride (TsCl, 99%), ethidene diamine (EDA), (3-Glycidyloxypropyl)trimethoxysilane (GPS, 97%), phenylamine, phenol, sodium nitrite, hexamethylene dibromide, N-hydroxysuccinimide ester (GMBS) and thiourea were purchased from Sigma-Aldrich. The silicon substrates with patterned square pillars with 20 µm high, 10 µm long and spacing of 5 µm were fabricated from Microelectronics R&D Center, Peking University. Cervical cancer cell line (Hela), breast cancer cell line (MCF-7), and lymphoma cell line (Daudi) were purchased from Beijing Xiehe Cell Resource Center. DiD and AO were purchased from BioDev-Tech Co. China. DMEM and RPMI-1640 growth medium were obtained from Invitrogen. The DNA aptamer 5’-NH2-C6-GCA GTT GAT CCT TTG GAT ACC CTG G-3’ were synthesized by Shanghai Sangon Biological Engineering Technology & Services Co. Ltd (Shanghai, China). Methods. 1HNMR spectra were recorded with a Bruker DMX-400 spectrometer in deuterated solvent at 298 K. X-ray photoelectron spectra (XPS) was measured with a Thermo Escalab250 XI spectrophotometer. UV-visible absorption spectra were recorded with a Shimadzu UV-3100 UV-Vis spectrophotometer. Contact angles (CA) were measured with an OCA20 contact angle system (Data Physics, Germany). Water drop volumes were 2 µL. Scanning electron microscopy images were obtained on a LEICA DM4000. The images of cells adsorbed on the azobenzene films were monitored by using a fluorescence microscope (Nikon, TE2000). LED irradiators (5.2 mW/cm2 at 365 nm; 7.5 mW/cm2 at 450 nm) were used for the photoisomerization of azobenzene. Synthesis of mono-6-dexoy-6-(p-tolysulfonyl)-β-CD (β-CD-OTs) and mono-6-dexoy-6ethylenediamine-β-CD (NH2-β-CD). The synthesis procedures for the preparation of β-CD-OTs and NH2-β-CD were similar to the previous report.23 Briefly, β-CD (6 g, 5.28 mmol) was dissolved in 50 mL H2O, and then NaOH (0.657 g, 16.41 mmol) in 2 mL H2O was added. The mixture was stirred for 30 min in an ice-water bath. Then TsCl (1.512 g, 7.92 mmol) in 3 mL acetonitrile was added slowly over 30 min and the process was kept in ice-water bath. After further stirring at room temperature for 2 hours, the mixture was refrigerated for 12 hours. Then,


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the mixture was filtered and recrystallized three times from deionized water. The product was dried under vacuum at 45 oC for 24 hours. Afterwards, β-CD-OTs (1.5 g) was dissolved in 15 mL EDA, and refluxed at 80 oC for 4 hours. Then, the unreacted solution was removed by rotary evaporation. For further purification, NH2-β-CD was dissolved in water-methanol (1:1, v/v) and precipitated in acetone three times. The product was dried under vacuum at 50 °C for 24 hours. The 1H NMR spectra of β-CD-OTs and NH2-β-CD are shown in Figure S1. Synthesis of β-CD grafted silicon wafer (Si-CD): The substrates grafted with CD were fabricated according to the reference.25 The silicon substrates were first modified by the silanization

reaction

between

the

silanol

groups

of

silicon

surface

and

(3-glycidyloxypropyl)trimethoxysilane (GPS). Then the substrates were immersed in N,N-dimethylformamide (DMF) solution of NH2-β-CD (10 mM) at 60 oC for 24 h, and washed with DMF for three times. The substrates were dried with a flow of ultrapure N2. Synthesis of 6-[4-(Phenylazo)phenoxy]hexane-1-thiol. The procedures for the preparation of 6-[4-(Phenylazo)phenoxy]hexane-1-thiol

was

according

to

the

reference.33

First

the

4-(phenylazo)phenol was synthesized. Then, the alkyl chain was reacted onto the 4-(phenylazo)phenol via the formation of an ether and finally the remaining function was converted and hydrolyzed to thiol. The synthesis route is represented in Figure S2a. Synthesis of 4-(phenylazo)phenol. Phenylamine (3.72 g, 40 mmol) was dissolved in a solution of sodium nitrite (2.78 g, in 14 mL H2O) and then cooled to 0-5 oC. Hydrochloric acid (10%, 36 mL) was added into the above solution with stirring for 30 min. After diazotization, a mixture of phenol (3.76 g, 40 mmol), sodium hydroxide (2.4 g, 60 mmol) and H2O (20 mL at 0-5 oC) were added into the solution and vigorously stirred for 30 min, adjusting the pH of the solution to 5-7. The yellow-orange colored precipitate was filtered off, dried and recrystallized from petroleum ether. The 1H NMR spectrum of 4-(phenylazo)phenol is shown in Figure S2b. Synthesis of [4-[(6-Bromohexy)oxy]phenyl]phenyldiazene. 4-(phenylazo)phenol (0.693 g, 3.5 mmol) was dissolved in 100 mL acetone, hexamethylenedi bromide (1.44 g, 5.9 mmol), potassium carbonate (4.83 g, 35 mmol), potassium iodide (0.5 g) was added and the mixture was



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refluxed for 6 hours at 68 oC. After cooling to room temperature, the mixture was poured into 1000 mL water. The precipitate was collected by filtration. For further purification, the crude was recrystallization from n-hexane and then afforded orange crystals. The 1H NMR spectrum of [4-[(6-Bromohexy)oxy]phenyl]phenyldiazene is shown in Figure S2c. Synthesis

of

6-[4-(Phenylazo)phenoxy]hexane-1-thiol.

[4-[(6-Bromohexy)oxy]phenyl]phenyldiazene (0.43 g, 1.19 mmol) and thiourea (0.125 g, 1.5 mmol) were dissolved in 20 mL deoxygenated ethanol. The obtained solution was refluxed for 6 hours at 78 oC. Then NaOH (0.03 g) in 2.5 mL deionized water was added slowly with stirring for 1 hour. After cooling to room temperature, the mixture was neutralized with H2SO4. The solvent was removed and chloroform was added. The organic layer was washed with water and dried with MgSO4. The chloroform was evaporated and crystallized from hexane/acetone to get orange crystals. The 1H NMR spectrum of 6-[4-(Phenylazo)phenoxy]hexane-1-thiol is shown in Figure S2d. Synthesis of DNA Aptamer Modified Si-CD Substrates (Si-CD/Azo-apt). The Si-CD was treated with 6-[4-(Phenylazo)phenoxy]hexane-1-thiol in dimethyl sulfoxide (DMSO) at room temperature overnight to obtained azobenzene modified substrate (Si-CD/Azo). Then the substrate was rinsed with DMSO and treated with a coupling agent GMBS (0.25 × 10-3 M in DMSO) for 30 min. Next, the substrate was treated with PBS solution of DNA aptamer (2 × 10-5 M) for 2 hours and then washed with PBS to remove excess aptamers.8 The substrates were finally dried with a flow of ultrapure N2 and stored at 4 oC. Cell staining. The cell suspension was prepared in growth medium (DMEM or RPMI-1640). Then the cell-labeling solution (AO or DiD, 2 µg mL-1 in PBS) was added and mixed well by gentle pipeting. After incubating for 20 min at 37 oC and 5% CO2, the cell suspension was centrifuged at 1000 rpm for 3 min, and wash the cells two times with growth medium. The final cell density was tuned to 106 cells mL-1 in growth medium. Cell capture and release assay. The substrates were placed into a 6-well plate with 3 mL of cell suspension (106 cells mL-1). After incubating at 37 oC and 5% CO2 for 1 h, the substrates


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were rinsed with PBS for three times. For cell release, substrates were then immersed into PBS, and irradiated with LED irradiators (5.2 mW/cm2 at 365 nm) for 80 s. The cells were imaged by fluorescence microscope (Nikon, TE2000) and counted via Image-Pro Plus software (version 6.0). RESULTS AND DISCUSSION In order to construct a reusable supramolecular surface for capture and release of specific cells, a substrate modified with the host molecules which allowed to assemble with guest molecules was fabricated. As shown in Figure 1a, the β-CD terminated SAMs (Si-CD) on the silicon substrates were fabricated through ring-opening reactions between (3-Glycidyloxypropyl)trimethoxysilane (GPS) and mono-6-dexoy-6- ethylenediamine-β-CD (NH2-β-CD). NH2-β-CD was synthesized according to the previous report23 (see Supporting information). GPS was modified on the silicon substrates via a silanization reaction after the substrate was treatment with “piranha” solution (H2O2/H2SO4=3:7). The wettability of the surfaces at different modification stages was studied by measuring the water contact angle (WCA), as shown in Figure 1b. On the pristine silicon substrate, the WCA was 26.1o± 2.5o; after modified with GPS, the WCA increased to 83.8o± 1.7o. When the β-CD grafted onto the silicon substrates, the WCA decreased to 73.4o± 2.2o for the hydrophilicity of outer part of β-CD.23,34 As is known, the surface wettability is governed by both the chemical structures and surface geometrical structures.35,36 The geometrical structures used in this work are shown in Figure S3.35 For the rough substrate modified with the GPS, the WCA significantly increased to 117.6o± 4.5o, since air could exist in the microgrooves and the increase of the air/water interface could make the surface more hydrophobic.36-38 After the β-CD grafted onto the rough substrates, the WCA remarkably decreased to 21.2o± 2.6o because of the hydrophilic outer part of β-CD (Figure 1c).



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Figure 1. (a) Chemical routes for preparation of Si-CD; (b) and (c) Images of water drops on flat and rough substrates with three different kinds of surfaces, respectively: (Ⅰ) Pristine silicon substrate, (Ⅱ) the SAM containing silane terminated with GPS groups, (Ⅲ) the SAM containing β-CD (Si-CD).

The thiol-azobenzene was prepared to assemble with β-CD on Si-CD surface via host-guest interaction. Subsequently, the cell capture agent, specific aptamer (S2.2), was connected to the thiol-azobenzeneusing chemical coupling agents to achieve the azobenzene-thiol terminated aptamer (Si-CD/Azo-apt). Thus, specific capture of target cells can be achieved through host-guest interaction between azobenzene and CD (Figure 2a). The thiol-azobenzene, which could partake in such a host-guest interaction with CD in its trans form, was synthesized via alkylation of 4-hydroxyazobenzene with hexamethylenedi bromide and subsequent thiolation of the ω-bromide, shown in Figure S2. After preparation of the thiols terminated azobenzene modified substrates, GMBS was employed to introduce specific aptamer onto the surface to obtain the aptamers terminated surface. The chemical compositions assembled with various functional molecules were compared by X-ray photoelectron spectroscopy (XPS) analysis. Figure 2b shows the typical XPS spectra of the Si-CD and Si-CD/Azo-apt surfaces, respectively. The appearance of S2p and P 2p signals at binding energy of 163.4 eV and 135.6 eV indicate that the aptamer has been attached to the Si-CD surface (Figure 2c). The XPS high-resolution spectra of carbon (C) and oxygen (O) of specific aptamer bound to the Si-CD surface were also depicted in Figure 2d, and 2e respectively. Comparing Si-CD/Azo-apt with bare Si-CD surfaces, two shoulder peaks at 286.1 and 287.0 eV in C 1s spectrum appeared due to the introduction of the N-C=O and C=O groups from the nucleic bases.39-41 As for O 1s, the three peaks at 531.3, 532.1 and 532.9 eV correspond to N-C=O, C-O-C and PO4 bonding, respectively.40 The peak at 531.3 eV represents the oxygen in the bases and sugars. The one at 532.1 eV is corresponding to the cyclic ether bonds from deoxyribose in aptamer. Another peak at 532.9 eV is assigned to the backbone phosphate group. The above results indicate that the aptamers were successfully anchored onto the Si-CD surface.


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Figure 2. (a) Schematic illustration of preparation of light-triggered specific cell capture/release Si-CD/Azo-apt surfaces. (b) XPS wide spectra of Si-CD (black line) and Si-CD/Azo-apt (red line) surfaces. (c) High-resolution XPS spectra of S 2p, P 2p. (d) and (e) XPS C 1s and O 1s core-level spectra of Si-CD and Si-CD/Azo-apt surfaces, respectively.

The UV-vis absorption spectra of the thiol-azobenzene in dimethylsulfoxide (DMSO) are shown in Figure 3a, 3b and 3c. Upon UV light irradiation, shown in Figure 3a, the absorption band centered at 348 nm declines remarkably, and concurrently the band centered at 435 nm increases a little, reaching a photostationary state in 50 s. The absorption bands at 348 nm and 435 nm are ascribed to π-π* and n-π* transitions of the azobenzene group, respectively. The change of the absorption bands induced by UV irradiation indicates the trans-to-cis photoisomerization of the azobenzene. When the polymeric solution was exposed to visible light at 450nm (Figure 3b), the π-π* absorption increases again with as light decrease in the n-π* absorption, which implied the process of back-conversion from cis to trans form.35 Furthermore, the reversible photoisomerization of azobenzene could be repeated several times by alternative UV and visible light irradiation (Figure 3c). The formation of host-guest inclusion complex



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between thiol-azobenzene and β-CD in DMSO was also determined by absorption spectra. Upon gradual addition of the β-CD, the absorption of azobenzene increased remarkably, and the absorbability increased to maximum after the ratio of β-CD/Azo increased to 1/1, shown in Figure S4. The enhanced absorption suggests that trans azobenzene forms an inclusion complex with β-CD.42,43 Moreover, the 2D NOESY study can provide detailed information about the binding geometries of azobenzene and β-CD. Once the trans azobenzene occupies the cavity of β-CD, the NOESY correlation signals between the trans azobenzene and the β-CD can be observed, shown in Figure S5a. After UV light irradiation, little NOESY correlation signals between cis azobenzene and β-CD can be noticed, indicating that UV light triggered the disassembly of the host-guest complex (Figure S5b).44,45 Figure 3d shows the UV-vis spectra of the Si-CD, Si-CD/Azo, Si-CD/Azo-apt surfaces, and then irradiated the Si-CD/Azo-apt with UV light, respectively. After modification of thiol-azobenzene on the surface, a noticeable peak at 344 nm could be observed, providing further evidence of azobenzene functionalization on the Si-CD. When the aptamer was immobilized onto the Si-CD/Azo, the peak intensity at 240 nm of DNAs enhanced significantly. When the Si-CD/Azo-apt substrates were irradiated with UV light, the absorption bands at 344 nm of the azobenzene and 240 nm of the aptamer became inconspicuous (Figure 3d). The absorption maxima relating to the azobenzene and aptamer on the various substrates are summarized in Table S1. The changes of UV-vis absorption spectra indicate that the azobenzene-aptamers (Azo-apt) were detached from the Si-CD surface after UV irradiation because of the size mismatch between the cis-azobenzene and β-CD.


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a) 3.0

b) 2.5

1.5 1.0

1.0 0.5

0.0

0.0

400 500 Wavelength (nm)

600

Vis

Vis

2.0 1.5

UV

1.0 1

UV 2

3 4 Cycles

UV 5

300

400 500 Wavelength (nm)

d) 1.0

3.0 2.5

0 min 1 min 2 min 4 min 8 min 15 min

1.5

0.5

300

c)

Absorbance

0s 10 s 20 s 30 s 40 s 50 s

2.0

Vis light

2.0

UV light

Absorbance

Absorbance

2.5

Absorbance

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


600

Si-CD/Azo-apt Si-CD/Azo Si-CD/Azo-apt-UV 80 s Si-CD

0.5

0.0

6

200

300

400 500 600 Wavelength (nm)

700

Figure 3. (a) and (b) UV-vis spectra of the thiol-azobenzene in DMSO under irradiation of UV light and visible light, respectively. (c) Reversible absorbance changes at 350 nm under the alternative UV light irradiation for 50 s (365 nm, 5.2 mW/cm2) and visible light irradiation for 15 min (450 nm, 7.5 mW/cm2). (d) UV-vis spectra of Si-CD (pink line), Si-CD/Azo (red line), and Si-CD/Azo-apt (black line) surfaces, then the Si-CD/Azo-apt surface irradiated with UV light for 80 s (blue line).

Photoswitched supramolecular surfaces for immobilization strategies provide substantial opportunities for smart biomedical applications. As shown in Figure 4a, MCF-7 cells could be captured on the Si-CD/Azo-apt surface, while after UV irradiation, the azobenzene modified with the aptamer would be detached from the substrate and the captured cells could be released from the surface. To test the cell adhesion performance of the Si-CD/Azo-apt upon light irradiation, the prepared substrates were dipped into a cell suspension (105 cells mL-1 of MCF-7) in Dulbecco’s modified Eagle’s medium (DMEM) and kept in an incubator (5% CO2, 37 oC) for 60 min. After washing with PBS for three times, the captured cells were imaged and counted by using a fluorescence microscope (Nikon, Ti-E). On the flat substrate, the density of captured



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cells was measured to be 4030 ± 545 cm-2 before UV light irradiation, shown in FigureS7a. Then the samples with cells were put into the phosphate buffer saline (PBS) and irradiated with UV light (365 nm, 5.4 mw/cm2) for 80 s, and the density of adhered cells decreased to 454 ± 181 cm-2 (Figure S7b). The azobenzene can reversibly switch between trans and cis forms upon light irradiation46-47 and the photoisomerization of azobenzene dominates the inclusion and exclusion between azobenzene and β-CD.18-20 After UV irradiation, the azobenzene changed from trans to cis, then the inclusion complex with CD was dissociated and thus the cells captured on the azobenzene-aptamer were released from the surface. Azobenzene modified surfaces can either capture or resist cells depending on the conformation of the azobenzene embedded in SAMs, however, the efficiency for photoswitched cell capture and release on the flat SAMs is relatively low.27,28 It is noted that the geometrical structures can affect cell adhesion greatly.36 Figure 4b shows the fluorescence images of MCF-7 cells captured on the Si-CD/Azo-apt surface with the geometrical structures with patterned square pillars, 20µm high, 10 µm long and with spacing of 5 µm between the silicon pillars. The density of captured cells on the substrate with geometrical structures was 26800 ± 1090 cm-2 (Figure 4b1), which increased remarkably compared to that on the flat substrate. The microstructures increased the contact area between the aptamer modified substrates and the cells and thus resulted in a high cell adhesion density.35 After UV light irradiation, the density of adhered cells on the surface decreased significantly to 1363 ± 454 cm-2, shown in Figure 4b2. The significant decrease upon UV irradiation could be attributed to the dissociation of the azobenzene-aptamer from the Si-CD substrate. Moreover, the substrate could be reconstructed and reusable for next cycles after immobilizing Azo-apt on the Si-CD surface. The cell-capture number on the surface after immobilizing Azo-apt on the same Si-CD surface (Figure 4b3) could be recovered to a similar level of cells initially captured (Figure 4b1). Also, the cells captured on the substrate could be released again by UV light irradiation (Figure 4b4). Figure 4c shows the statistical histogram of the captured cells on the various substrates in the cycles. On the Si-CD substrate, the density of captured cells was only 781±181 cm-2. When the aptamer was immobilized onto the substrate, the density of captured cells was significantly


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enhanced to 26800 ± 1090 cm-2. After UV irradiation, the aptamer linked with azobenzene would be detached from the substrate for the disruption of the host-guest interaction between cyclodextrin and azobenzene and the density of captured cells decreased to 1363 ± 454 cm-2. Then the density could be recovered to 29736 ± 1545 cm-2 after immobilizing Azo-apt on the substrate and the density decreased to1690±363 cm-2 after UV irradiation.

Figure 4. (a) Schematic illustration for cell capture and release on as-prepared substrates by using host-guest assembly of β-CD and azobenzene-aptamer. (b) Fluorescence micrographs of the Si-CD/Azo-apt surface captured with MCF-7 cells (b1); release of the cells after irradiated the surface with UV light (b2); after regeneration of the surface and then captured with MCF-7 cells (b3); release again upon UV light irradiation (b4). (c) Quantitative evaluations of MCF-7 cells captured on different surfaces.

To test the specificity of Si-CD/Azo-apt surface, parallel cell-capture experiments were carried out utilizing three cancer cells: MCF-7, Hela, and Daudi cells, separately, shown in Figure 5a. The densities of captured cells of MCF-7, Hela, and Daudi were 26800 ± 1090 cm-2, 2181 ± 545 cm-2, and 1727 ± 1181 cm-2 on Si-CD/Azo-apt surfaces, respectively. After UV irradiation, the adhesion densities decreased to 1363 ± 454 cm-2, 1090 ± 363 cm-2, and 1181 ± 363 cm-2, respectively. The density of captured MCF-7 was 12-fold more than that of Hela and 15-fold



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more than that of Daudi cells on Si-CD/Azo-apt before UV irradiation. After UV irradiation, the captured number of MCF-7 decreased significantly, while, the number of non-specific cells (Hela, Daudi) changed only a little. The fluorescence micrographs are shown in Figure S8. This result demonstrates that the Si-CD/Azo-apt surface exhibits excellent specificity to capture/release specific MCF-7 cells through light irradiation. The ability of identifying and isolating targeted cells was further proved utilizing a mixture of targeted cells (green fluorescently stained MCF-7 cells) and non-targeted cells (red stained Hela cells). Accordingly, a mixed cell suspension containing MCF-7 cells and Hela cells (1:1, 105 cells mL-1, 3 mL) was prepared and the substrate was put into the above suspension and incubated for 60 min at 37 oC, then targeted cells were selectively captured onto the substrate, shown in Figure 5b1. After UV light irradiation, the density of targeted cells captured on the substrate decreased significantly (Figure 5b2). Figure 5c shows the statistical histogram of captured cells from the mixtures before and after UV light irradiation. The densities of captured cells of MCF-7 and Hela were 25272 ± 2090 cm-2 and 2195 ± 545 cm-2 on Si-CD/Azo-apt surfaces, respectively. After UV irradiation, the adhesion densities decreased to 1818 ± 727 cm-2 and 1545 ± 454 cm-2, respectively. These results confirm that the designed substrate could selectively recognize and release targeted cells from cell mixtures efficiently.


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Figure 5. (a) Quantitative evaluations of specific cell capture/release performance of Si-CD/Azo-apt surfaces before and after UV irradiation using three cancer cells (MCF-7, Hela, and Daudi). (b) Fluorescence micrographs of the Si-CD/Azo-apt surface captured with MCF-7 cells from the mixed cell suspension

containing targeted MCF-7 cells (green) and non-targeted Hela cells (red) (1:1, 105 cells mL-1) before (b1) and after (b2) UV irradiation. (c) Densities of captured MCF-7 and Hela cells on Si-CD/Azo-apt surfaces before and after UV irradiation.

CONCLUSION In conclusion, we have successfully constructed a novel photoresponsive surface with a specific aptamer to trigger cells capture/release via the host-guest interactions between azobenzene and β-CD. The reversible Si-CD/Azo supramolecular interaction can be used to realize a noninvasive photoswitch of capture or release of targeted cells. It is noted that the geometrical microstructures of the substrate could improve the cell capture and release performance. This Si-CD/Azo-apt modified surface is easily regenerated for the next cycles. This strategy offers a photoresponsive surface, on which specific cell release can be controlled by light irradiation



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based on the inter-conversion of azobenzene’s trans and cis forms. Besides, the surface could selectively recognize and capture targeted cells from the binary mixture of cell suspension. This work may promote the application of photoresponsive surfaces for specific cell capture and release.

■ASSOCIATED CONTENT Supporting Information 1

H NMR spectra, synthetic routes, UV-visible absorption spectrum, SEM images, and cell

images. This material is available free of charge via the Internet at http://pubs.acs.org. ■AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. *E-mail: [email protected]. Notes The authors declare no competingfinancial interest. ■ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (51373025) and the Program for New Century Excellent Talents in University (NCET-11-0582).

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The TOC Graphic


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Light-Triggered Specific Cancer Cell Release from Cyclodextrin

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