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Cite This: ACS Appl. Mater. Interfaces 2018, 10, 6618−6623
Conjugated Polymer-Based Photoelectrochemical Cytosensor with Turn-On Enable Signal for Sensitive Cell Detection Shanshan Liu,†,‡ Ping He,‡ Sameer Hussain,‡ Huan Lu,‡ Xin Zhou,‡ Fengting Lv,‡ Libing Liu,‡ Zhihui Dai,*,† and Shu Wang*,‡ †
School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, P. R. China Beijing National Laboratory for Molecular Science, Key Laboratory of Organic Solids, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
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‡
S Supporting Information *
ABSTRACT: In this work, a new photoelectrochemical (PEC) cytosensor was constructed by using cationic polyfluorene derivative, poly(9,9-bis(6′-(N,N,N,trimethylammonium)hexyl)fluorene-co-alt-1,4-phenylene)bromide (PFP) as the photoelectric-responsive material for sensitive cell detection. Positive-charged PFP with high photoelectric conversion efficiency can generate robust photocurrent under light illumination. In the PEC cytosensor, 3-phosphonopropionic acid was linked to the indium tin oxide electrode, followed by modification with antiepithelial-cell-adhesionmolecule (EpCAM) antibody via amide condensation reaction. Thus, target SKBR-3 cells with overexpressed EpCAM antigen could be captured onto the electrode via the specific antibody−antigen interactions. Upon adding cationic PFP, a favorable electrostatic interaction between cationic PFP and negatively charged cell membrane led to a turn-on detection signal for target SKBR-3 cells. This new cytosensor not only exhibits good sensitivity because of the good photoelectric performance of conjugated polymers, but also offers decent selectivity to target cells by taking advantage of the specific antibody−antigen recognition. KEYWORDS: photoelectrochemical cytosensor, conjugated polymers, turn-on signal, SKBR-3 cell, sensitive detection atic.30 Therefore, it is still required to explore new photoelectric-responsive materials for developing high-performance PEC biosensors. Conjugated polymers (CPs) with π-conjugated backbones and charged side chains possess robust light-harvesting ability, excellent photostability, and good semiconductive characteristic.31 These features endow them promising applications in photocatalytic water splitting,32 bioimaging,33 and disease therapy.34 CPs could generate electron−hole pairs under light illumination. The electrons migrating along the backbone could be captured by electron accepter, accompanied by the elimination of holes, resulting in the generation of stable photocurrent.35 However, the exploration of CPs as photoelectric-responsive materials in PEC biosensors is still rare. It should be noted that, in previous works, the developed cytosensors are usually dependent on turn-off signal to achieve the purpose of detecting cells, where the dielectric behavior of cells is generally utilized to block charge transfer and decrease the PEC response of photoelectric-responsive materials.5,36,37 The current detection method based on more convenient PEC is cost-effective (unlike optical techniques) and require low
1. INTRODUCTION Photoelectrochemical (PEC) measurement with light as excitation source and photocurrent as detection signal has attracted extensive attention as an emerging analytical technique in recent years.1−5 Owing to the remarkable merits including convenient operation, low background signal, and high sensitivity,6−8 a variety of PEC biosensors has been developed for the detection of biomacromolecules,9−11 metal ions,12−14 chemical molecules,15,16 and cells.17,18 Because the photoelectric conversion efficiency of photoelectric-responsive materials plays a crucial role in the performance of PEC biosensors, considerable efforts have been focused on the exploitation of good photoactive semiconductor materials, including inorganic species (such as CdTe,19 TiO2,20−22 ZnO,9,23 PbS24 nanomaterials) and organic species (such as porphyin,25 phthalocyanine,26 ruthenium complexes27). However, inorganic photoelectric-responsive materials suffer from low photovoltaic conversion efficiency, strong photocorrosion, limited spectral absorption range, or biotoxicity, whereas organic photoactive species possess inferior photostability or charge transfer performance.28,29 Although the combination of wide band-gap semiconductors with narrow band-gap ones or inorganic semiconductors with organic molecules could overcome some drawbacks, the selection for the energy-level matching materials and operation system remains problem© 2018 American Chemical Society
Received: December 1, 2017 Accepted: January 25, 2018 Published: January 25, 2018 6618
DOI: 10.1021/acsami.7b18275 ACS Appl. Mater. Interfaces 2018, 10, 6618−6623
Research Article
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Scheme 1. Schematic Illustration of Construction and Working Mechanism of PEC Cytosensor for Target Cell Detection Using Cationic PFP as Photoelectric-Responsive Material
Figure 1. Fluorescence microscopy images of ITO/BSA/anti-EpCAM/cells/PFP electrode (1 × 104 cell·mL−1).
which provides carboxyl groups for further antibody modification. The antiepithelial-cell-adhesion-molecule (antiEpCAM) antibody was then linked onto the ITO surface via amide condensation reaction. Subsequently, bovine serum albumin (BSA) was coated onto the ITO surface to minimize the nonspecific binding of cells. Thus, target SKBR-3 cells with overexpressed EpCAM antigen can be captured onto the electrode via specific antibody−antigen interactions. Finally, cationic PFP was added, which can successfully bind with the negatively charged cell membrane through electrostatic interactions. The loading of PFP can produce photocurrent under light irradiation to provide a turn-on response signal; hence, specific detection of SKBR-3 cells is realized using the PEC cytosensor. To confirm the successful linking of anti-EpCAM antibody onto ITO electrode, ITO/BSA/anti-EpCAM and ITO/BSA were, respectively, treated with rabbit antimouse immunoglobulin G labeled with Alexa Fluor 555 dye that could specifically recognize anti-EpCAM antibody.38 After incubating at 37 °C for 30 min, they were washed three times with phosphatebuffered saline (PBS) (pH = 7.4, 0.01 M) and then observed under a fluorescence microscope. As shown in Figure S1A, obvious green fluorescence of Alexa Fluor 555 was observed for
operating potential. It is unlike electrical or electrochemical measurements, which usually necessitate high operating voltage. Moreover, the PEC technique entirely separates the detection signal (current) from the excitation source (light), which in turn reduces the undesired background signal to deliver high sensitivity for bioanalysis compared with the classical methods such as fluorescence. In this work, for the first time we employed cationic CPs as the photoelectric-responsive material instead of traditional semiconductors to construct a PEC cytosensor with turn-on enable signal for sensitive cell detection.
2. RESULTS AND DISCUSSION The construction and working mechanism of PEC cytosensor are illustrated in Scheme 1. The positive-charged polyfluorene derivative, poly(9,9-bis(6′-(N,N,N,-trimethylammonium)hexyl)fluorene-co-alt-1,4-phenylene)bromide (PFP), is chosen here as photoelectric-responsive material due to its high light adsorption coefficient and good semiconducting property. The indium tin oxide (ITO) electrode was modified with 3phosphonopropionic acid by the esterification reaction between hydroxyl groups on the surface of ITO and phosphate groups, 6619
DOI: 10.1021/acsami.7b18275 ACS Appl. Mater. Interfaces 2018, 10, 6618−6623
Research Article
ACS Applied Materials & Interfaces the ITO/BSA/anti-EpCAM electrode, whereas negligible fluorescence was observed for the ITO/BSA electrode without anti-EpCAM antibody modification (Figure S1B). The surface density calculated for the surface-immobilized antibodies using bicinchoninic acid assay was found to be about 5.7 ng mm−2. This confirms the successful linking of anti-EpCAM antibody onto the ITO electrode. We then investigated the capture and detection abilities of ITO/BSA/anti-EpCAM for EpCAM antigen overexpressed SKBR-3 cells. The fabricated PEC cytosensor was immersed in target cell suspension at a certain concentration and incubated at 37 °C for 1 h, followed by washing with PBS (pH 7.4, 0.01 M) to remove the nonspecifically adsorbed cells. Then, the cytosensor was immersed into PFP solution (50 μM) to absorb positivecharged PFP through electrostatic interactions. The image of ITO/BSA/anti-EpCAM/BSA/cell/PFP was recorded by fluorescence microscopy (Figures 1 and S2). The bright field image showed that cells were successfully captured on the surface of ITO/BSA/anti-EpCAM. Furthermore, the ITO electrode emitted bright fluorescence upon excitation at 405 nm, which suggested that positive-charged PFP could bind to the surface ITO electrode in virtue of SKBR-3 cells. The photocurrent responses of ITO electrode with stepwise modifications were investigated in the PBS (0.1 M, pH = 7.4) containing ascorbic acid (AA) under white light irradiation at applied potentials. Before PEC response tests, the measurement conditions, including the concentration of ascorbic acid and applied potential, were optimized. The bias potential was a significant factor influencing the generation of the photocurrent (Figure S3A). The photocurrent increased slightly on changing the applied voltage from −0.4 to −0.2 V and then decreased sharply on further changing it from −0.2 to 0.2 V. Considering the low applied potential as beneficial for the elimination of interference from other species coexisting in the samples, −0.2 V was chosen as the optimal applied potential in the PEC measurements. In addition, the effect of AA concentration on the PEC response was also investigated (Figure S3B). The photocurrent intensity increased gradually when the concentration of AA changed from 0 to 0.09 M and reached a plateau at 0.09 M. Therefore, 0.09 M AA and applied potential of −0.2 V were selected as the optimized parameters for the PEC measurement in all experiments. As shown in Figure 2A, the bare ITO, ITO/anti-EpCAM, ITO/BSA/anti-EpCAM, and ITO/BSA/anti-EpCAM/cells could not generate photocurrents (Figure 2A, plots a−d). When PFP was introduced onto the ITO/BSA/anti-EpCAM/cells electrode, a robust cathode photocurrent was observed since the PFP could be excited, and it generated electron−hole pairs upon light illumination (Figure 2A, plot e).39 At the negatively applied bias of −0.2 V, the protons in the PBS containing AA consumed the electrons on the lowest unoccupied molecular orbital and the electrons from the ITO electrode transferred to scavenge photoinduced holes on the highest occupied molecular orbital. AA as a nontoxic electron donor could also neutralize a portion of photogenerated holes, which inhibited the electron−hole recombination.40 The efficient charge separation and transfer guaranteed the generation of robust cathode photocurrent. Meanwhile, the cathodic photocurrent was relatively stable periodically over time (Figure 2A, plot e). It was noted that the bare ITO electrode without antibody and cells could also generate weak photocurrent upon immersing it into PFP solution (50 μM) probably due to nonspecific absorption (Figure 2B, plots b−d). However, such photocurrents were
Figure 2. (A) Photoelectrochemical responses of modified ITO electrodes: bare ITO (a), ITO/anti-EpCAM (b), ITO/BSA/antiEpCAM (c), ITO/BSA/anti-EpCAM/cell (5 × 104 cell·mL−1) (d), and ITO/BSA/anti-EpCAM/cell/PFP (e). (B) Photoelectrochemical responses of modified ITO electrodes: ITO/BSA/anti-EpCAM/cell/ PFP (5 × 104 cell·mL−1) (a), ITO/BSA/PFP (b), ITO/BSA/antiEpCAM/PFP (c), and ITO/BSA/cell/PFP (d). The measurement was performed in the PBS (0.1 M, pH = 7.4) containing 0.09 M ascorbic acid (AA) under white light irradiation at an applied potential of −0.2 V.
much weaker than those of the ITO/BSA/anti-EpCAM/cells/ PFP electrode (Figure 2B, plot a) owing to the strong adsorption capacity of the cell membrane to PFP by electrostatic interactions. The PEC cytosensor was then applied for the quantitative determination of SKBR-3 cells. To accomplish this, different ITO/BSA/anti-EpCAM electrodes were dipped into SKBR-3 cell suspensions of variable concentrations (0, 1 × 102, 5 × 102, 1 × 103, 5 × 103, 1 × 104, 5 × 104, 1 × 105, 5 × 105, 1 × 106 cell·mL−1), followed by incubation at 37 °C for 1 h and washing with PBS (pH 7.4, 0.01 M). During measurements, an increment in the intensity of photocurrent was observed on increasing the concentration of cells, which was likely due to an enhanced PFP captured by the modified electrode (Figure 3A). A good linear relationship can be obtained between the ΔI (ΔI = I − I0, where I is the photocurrent for the SKBR-3 cells at different concentrations and I0 is the background signal when SKBR-3 cell concentration was 0) and the logarithmic value of the SKBR-3 cell concentration in the range from 1.0 × 102 to 5.0 × 105 cell·mL−1 (Figure 3B). The linear regression equation was ΔI (μA) = −2.706 + 1.769 lg C (cells per mL) with a correlation coefficient of 0.996. The detection limit was estimated to be 24 cells per mL at a signal-to-noise ratio of 3. In addition, the parallel measurements of five independent electrodes incubated with cell suspension (1.0 × 104 cell·mL−1) were recorded, and the relative standard deviation was calculated to be about 8.4%, which suggested that the constructed PEC cytosensor possessed good reproducibility and reliability. These results revealed that our cytosensor possessed satisfactory analytical performance toward SKBR-3 cells. Compared with previous reports,41−43 the proposed PEC cytosensor platform exhibited better detection capability based on the excellent PEC property of conjugated polymers. Furthermore, most of the methods41,42 reported for selective capturing of target cells by specific surface-immobilized antibodies were based on the classical “turn-off” signal mechanism, which usually exhibited high background interference and limited range of linearity. It was unlike the “turn-on” 6620
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samples, suggesting the potential for application in clinical diagnoses and prognosis of cancer.
3. CONCLUSIONS In this work, a new photoelectrochemical (PEC) cytosensor with turn-on signal was constructed by using cationic conjugated polymer as the photoelectric-responsive material. The positive-charged conjugated polymer could be absorbed via electrostatic interaction onto the ITO electrode modified with cells. Under white light irradiation, the conjugated polymer formed electron−hole pairs, resulting in the generation of stable photocurrent. The PEC cytosensor exhibited photocurrent variation after capturing different amounts of SKBR-3 cells and a wide linear relation between photocurrent change and cell concentration. This new cytosensor exhibited good sensitivity with a detection limit of 24 cells per mL because of the good photoelectric performance of conjugated polymers. Remarkable selectivity in the assay of SKBR-3 cells was realized by taking advantage of the specific antibody−antigen recognition. This work paved a simple method for the assay of cells, showing a promising perspective for the construction of versatile PEC platforms and application for cancer prognosis.
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ASSOCIATED CONTENT
* Supporting Information
Figure 3. (A) PEC responses of the cytosensor to SKBR-3 cells with different concentrations at 0, 1 × 102, 5 × 102, 1 × 103, 5 × 103, 1 × 104, 5 × 104, 1 × 105, 5 × 105, and 1 × 106 cell·mL−1 (a−j). (B) Linear calibration curve between photocurrent change and logarithmic value of the SKBR-3 cell concentration.
S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsami.7b18275. Experimental procedures, additional Figures S1−S4 (PDF)
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signal approach employed in our work, which showed a wide range of linearity. The selectivity of PEC cytosensor toward cells was also investigated. As shown in Figure 4, the photocurrent against
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected] (Z.D.). *E-mail:
[email protected] (S.W.). ORCID
Libing Liu: 0000-0003-4827-6009 Zhihui Dai: 0000-0001-7049-7217 Shu Wang: 0000-0001-8781-2535 Author Contributions
S.L. and X.Z. performed the photoelectrochemical experiments. P.H. and H.L. conducted the fluorescence imaging studies. S.H. performed the surface density experiment and grammatically improved the manuscript. S.L., F.L., L.L., Z.D., and S.W. designed the experiments and conceptualized the work. All authors discussed the results and wrote the manuscript.
Figure 4. Photoelectrochemical responses of the cytosensor to SKBR3, Jurkat, and HeLa cells. The measurement was performed in PBS (0.1 M, pH = 7.4) containing 0.09 M ascorbic acid (AA) under white light irradiation at an applied potential of −0.2 V. The cell concentration was 1 × 104 cell·mL−1.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors are grateful to the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA09030306) and the National Natural Science Foundation of China (Nos. 21661132006, 21625502, 21475062, 21533012, and 21473221).
Jurkat or HeLa cells with negatively expressed EpCAM was negligible compared to that of SKBR-3 cells with overexpressed EpCAM, which indicated that the PEC cytosensor had a good capability for specific detection of SKBR-3 cells. We further applied the cytosensor to detect SKBR-3 cells in the Roswell Park Memorial Institute-1640 (RPMI-1640) medium and RPMI-1640 with 10% fetal bovine serum mixed medium (Figure S4). The results showed that the PEC cytosensor worked well in the medium containing complicated component
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