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A Multiscale TiO2 Nanorod Array for Ultrasensitive Capture of Circulating Tumor Cells Na Sun,§,† Xinpan Li,§,†,‡ Zhili Wang,† Ruihua Zhang,†,‡ Jine Wang,† Kewei Wang,† and Renjun Pei*,† †
Key Laboratory for Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Suzhou 215123, China ‡ State Key Laboratory for Mechanical Behavior of Materials, School of Materials Science and Engineering, School of Pharmacy, Xi’an Jiaotong University, Xi’an 710049, China ABSTRACT: In this work, a uniform multiscale TiO2 nanorod array is fabricated to provide a “multi-scale interacting platform” for cell capture, which exhibits excellent capture specificity and sensitivity of the target cells after modification with bovine serum albumin (BSA) and DNA aptamer. After studying the capture performance of the BSA-aptamer TiO2 nanorod substrates and other nanostructured substrates, we can conclude that the multisacle TiO2 nanorod substrates could indeed effectively enhance the capture yields of target cancer cells. The capture yield of artificial blood samples on the BSA-aptamer TiO2 nanorod substrates is up to 85%−95%, revealing the potential application of the TiO2 nanorods on efficient and sensitive capture of rare circulating tumor cells. KEYWORDS: multiscale, TiO2 nanorod array, circulating tumor cells, high efficient capture
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INTRODUCTION Circulating tumor cells (CTCs) are rare number cells disseminating into blood from primary cancer site of cancer patients.1 CTC detection is hopeful to provide crucial clinical information for personalized therapy and early cancer diagnosis.2 Unfortunately, the rareness of CTCs in cancer patient blood leads to a difficulty in detection. Numbers of techniques for CTC detection have been developed during the past decades, including cell size-based isolation,3−5 immunomagnetic beads6,7 and microfluidic chips,8,9 which can successfully detect the presence of CTCs in metastatic cancer patients. Nevertheless, there are still some intrinsic limitations in these techniques.10,11 To date, only the Veridex CellSearch platform has been licensed by the FDA for clinical indication in prostate, colon, and breast cancers.12−16 With the development of nanotechnology, it is well-known that cells can sense and interact with the nanotopography of materials.17−19 The importance of nanomaterials has been constantly tested with the exploration of the interaction between cells and the nanotopography of materials. In the past decade, nanostructured materials have been incorporated with CTC detecting devices, and the design of nanomaterials becomes the key to solve these challenges now.20,21 Nanomaterials of different scales have been employed to capture CTCs including silicon nanopillars/nanowires,22−28 carbon nanotubes,29 graphene oxide,30−32 nanoparticles,33−36 nanofibers,37−39 and nanorough-featured surfaces.40 It was reported that nanostructures with a dimension of 150−500 nm (roughness of a rough surface, size of nanoparticles, or diameter of nanopillars and nanofibers, etc.) were effective to © XXXX American Chemical Society
highly improve capture yield of CTCs, and smaller structures of sub-100 nm apparently prefer to induce cells to make more intense response.40−43 Recently, fractal structures have attracted extensive interest due to their multiscale property.44−48 Nevertheless, most fractal structures were fabricated based on separate micro/nanoparticles, which were structural unstable and inhomogeneous when used as biointerface for CTC capture. In this work, a uniform multiscale TiO2 nanorod array49 is prepared by a simple hydrothermal synthesis method to provide a “multi-scale interacting platform” for cell capture. The overall concept is illustrated in Figure 1, panel a. The TiO2 nanorods are densely packed on F-doped SnO2 (FTO) substrates with diameter of 160−300 nm, providing a 3D interface for cell contact, and the nanorods are composed of nanoparticles of 30−50 nm, which might further enhance the topographic interaction between nanoscale structures on cell surface and TiO2 nanorod array. Bovine serum albumin (BSA) is introduced into the nanointerface, as an antifouling molecule, to inhibit nonspecific cell adhesion, which could help to reduce the capture of blood cells to improve detection accuracy of CTCs.23 A DNA aptamer is then employed to modify the multisacle interface for the specific capture of the target cells, as shown in Figure 1, panel b. The cell capture yield on the TiO2 nanorod array substrates was up to 93%. More importantly, Received: February 22, 2016 Accepted: April 22, 2016
A
DOI: 10.1021/acsami.6b02178 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX
Research Article
ACS Applied Materials & Interfaces
(about 30−50 nm in diameter). The diameter of TiO2 nanorods varies from 160−300 nm, and when the heating time is over 18 h, the nanorods have a trend to stick together, which leads to a surface without clear nanorods but a roughness of 30−50 nm. In addition, the height of TiO2 nanorods increases with the time of hydrothermal reaction turning from 4−18 h. The diameters as well as the ratios of height to diameter of various TiO2 nanorods are summarized in Figure 3, panel a.
Figure 1. (a) Diagrammatical illustration of cell capture on TiO2 nanorod array. (b) Representation of biointerface fabrication on TiO2 nanorod array for specific capture of the target cells.
considerable capture sensitivity from blood samples with capture yield over 85% was obtained.
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RESULTS AND DISCUSSION Fabrication of TiO2 Nanorod Array on the FTO Glass. A hydrothermal synthesis method was utilized to fabricate the oriented TiO 2 nanorods on FTO substrates. As the morphology of the prepared TiO2 nanorod array was varied depending on the condition of the hydrothermal reaction, we fabricated a series of TiO2 nanorod arrays via changing the time of hydrothermal reaction from 4−24 h to systematically explore the effect on TiO2 nanorod size and density on substrates. The microtopography of the TiO2 nanorod arrays was analyzed using environmental scanning electron microscopy (ESEM), as shown in Figure 2. We can observe that the substrate is covered uniformly with perpendicular and tetragonal TiO2 nanorods, and there are allover tiny grids on the surface of nanorods
Figure 3. (a) The ratios of height to diameter of TiO2 nanorod arrays with different hydrothermal time. (b) Influence of the ratio on cell capture yield. (c) Influence of incubation time on capture performance. (d) Effect of BSA on nonspecific cell adhesion, and specific cell capture of DNA aptamer. (e) Comparison of captured cells on the bare surface, BSA coated surface, and BSA-aptamer modified surface of TiO2 nanorods, and the scale bar in the fluorescence images is 100 μm.
Highly Efficient Cell Capture on TiO2 Nanorod Array Substrates. The prepared TiO2 nanorod array substrates were modified by BSA and cell-capture DNA aptamer that was selected against EpCAM.50 MCF-7 cells (a breast cancer cell line) here were taken as EpCAM-positive cancer cell model for cell capture. The effect of nanostructures of TiO2 nanorod array on capture yield of MCF-7 cells was first investigated as shown in Figure 3, panel b. It shows that the capture yield increases with the rising of the ratio of h/d of the TiO2 nanorods. It achieved the maximum, about 465 MCF-7 cells/mm2, when the hydrothermal reaction time was 12 h with the maximum h/d value, which indicates that the ratio of height to diameter of TiO2 nanorods is a key factor for the capture efficiency of MCF-7 cells. When the nanorods stuck together in 24 h, the capture efficiency decreased sharply, demonstrating that the nanostructure only with a scale of 30−50 nm is ineffective for improvement of capture efficiency. As a result, the optimal capture condition of BSA-aptamer modified TiO2 nanorod array substrates was obtained with the maximum ratio of h/d and the average diameter of 230 nm at 12 h of hydrothermal reaction time.
Figure 2. Morphology of TiO2 nanorods with different hydrothermal time: (a) 4 h, (b) 8 h, (c) 10 h, (d) 12 h, (e) 18 h, and (f) 24 h. The scale bar in image is 500 nm, and in the inset is 2.5 μm. B
DOI: 10.1021/acsami.6b02178 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX
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Figure 4. (a) Capture performance of MCF-7 cells on bare, antifouling molecule coated and aptamer coated flat substrate and four nano/ microstructures including chitosan microparticles (1 μm), chitosan nanoparticles (∼200 nm), chitosan nanofibers (150−250 nm), and TiO2 nanorods. Cell morphology captured on (b) flat substrates, (c) chitosan nanofibers, and (d) TiO2 nanorods.
the results on aptamer coated substrates show that the TiO2 nanorod substrate is of better cell performance with higher capture efficiency, probably owing to van der Waals force from TiO2 nanorods, which helps cells loading onto the surface for the following specific capture. Great difference of cell behavior was observed on aptamer coated flat substrates, chitosan nanofibers, and TiO2 nanorods. Compared to that on antifouling interfaces, cells captured on aptamer coated surfaces tended to spread more filopodia or lamellipodia, which demonstrates that the specific capture would also induce cell adhesion. Thus, the synergistic effect of interface molecules (BSA and DNA aptamer) and topographic interaction cooperatively contribute to the specific recognition and highly efficient capture capability of BSA-aptamer TiO2 nanorod array substrates. Cell Capture Sensitivity of Rare CTCs on TiO2 Nanorod Array Substrates. To evaluate the capture purity of target cells on the BSA-aptamer coated TiO2 nanorod array substrates, EpCAM-positive cells (MCF-7, prestained with DiI) and human white blood cells (WBCs) were mixed at a ratio of 1:1 for a specific cell capture. In the cell-mixture experiment, a considerable capture efficiency of 81.6% as well as a high purity of 96.2% of target cells was achieved on the TiO2 nanorod array substrates (Figure 5). The results demonstrate that high capture efficiency and purity of target cancer cells can be obtained on TiO2 nanorod array substrates with the cooperation of BSA and DNA aptamer. We then performed a cell capture experiment to further access the capture sensitivity of the optimal TiO2 nanorod array
To confirm the optimal incubation time for cell capture, we examined the cell capture performance of the optimal TiO2 nanorod array substrate coated with BSA and DNA aptamer at incubation time from 10−60 min. As shown in Figure 3, panel c, along with the increase of the incubation time, the capture yield of MCF-7 cells increases obviously at the beginning 40 min, and the captured cell density could be achieved 465 MCF7 cells/mm2 with a capture yield of ∼93% after 40 min of cell incubation. To better understand the influence of surface modification on the cell capture efficiency, we investigated the capture performance on three kinds of substrates: bare, BSA immobilized, and BSA-aptamer functionalized substrates. As summarized in Figure 3, panels d and e, the density of captured MCF-7 cells on the bare substrates is 356 ± 27 cells/mm2 (71.2 ± 5.4%), while on BSA-immobilized substrates, it is apparently reduced to 60 ± 9 cells/mm2 (12.0 ± 1.8%), indicating that BSA can effectively decrease the nonspecific cell adhesion. Simultaneously, the capture density of MCF-7 cells on the TiO2 nanorod array substrates immobilized by BSA-aptamer reaches 465 ± 20 cells/mm2 (93 ± 4%), which is approximately eighttimes more than that on the BSA-modified substrates, suggesting that the introduction of DNA aptamer can effectively capture the targeted cells. To deeply understand the effect of interface molecular design (DNA aptamer and antifouling molecule) as well as topographic interaction, and to better prove the capture performance of TiO2 nanorod array substrates, more nano/microstructured substrates, including chitosan microparticles (1 μm), chitosan nanoparticles (∼200 nm), and chitosan nanofibers (150−250 nm), of different interfaces were tested. The results under the same cell capture condition are summarized in Figure 4. From the comparison of the capture efficiency on bare substrates without any modification, we can see that there is more cell adhesion on TiO2 nanorods indicating very strong topographic interaction between the TiO2 nanorod substrate and the adhered MCF-7 cells, which may result from more van der Waals force created by nanorod array than flat surface, micro/nanoparticles, or nanofibers. As shown in Figure 4, panels b−d, cells captured on bare TiO2 nanorod substrate exhibit more lamellipodia than that on bare flat surface and nanofibers, indicating that the adhesion force between TiO2 nanorods and cells is relatively large. As the antifouling molecules were employed into these interfaces, the nonspecific cell adhesion was controlled perfectly, which was confirmed by the morphology of cells captured on these interfaces. Moreover,
Figure 5. Specific cell capture on BSA-aptamer modified TiO2 nanorod array. (a) Cell capture performance of MCF-7 and WBCs from the mixture sample at the ratio of 1:1. (b) Merged image of MCF-7 (red) and WBCs (circled with green), corresponding to panel a. C
DOI: 10.1021/acsami.6b02178 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX
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purchased from MP Biomedicals, LLC. Aptamer sequences were purchased from Sangon Biotech Co., Ltd. (Shanghai, China). The 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI) was purchased from Energy Chemical (Shanghai, China). Instrumentation. An electric oven (DHG-8053A) used to heat was purchased from Shanghai YiHeng Scientific Instrument Co., Ltd. The morphology and diameters of TiO2 nanorod array were analyzed by a scanning electron microscope (SEM, FEI Quanta 400F). We used an optical and electron microscope with Nikon ECLIPSE TS100 to observe cell states. A centrifuge made in Taiwan with Hitachi *CT6E was purchased from Hitachi Koki Co., Ltd. The captured cells were imaged using an inverted fluorescence microscope (Nikon ECLIPSE Ti). Preparation of TiO2 Nanorod Array. A hydrothermal synthesis approach previously reported was used to prepare the oriented singlecrystal rutile TiO2 nanorod array. The typical synthesis was performed in a sealed Teflon-lined stainless steel autoclave (100 mL) for different times at 150 °C. First, the FTO glasses (∼2.2 mm thick) were cleaned, respectively, with dishwashing liquid, water, industrial alcohol, and absolute ethyl alcohol to remove contaminations from organic grease. Prior to the reaction, the clean FTO substrates were put into Teflon liner with their conducting sides facing up. Next, a mixture of deionized water and hydrochloric acid (HCl, 36.0−38.0% by weight) was stirred for 10 min at ambient condition. After the addition of 1.2 mL of tetrabutyl titanate, the mixture was poured into the Teflon liner with FTO glasses. The autoclave was then transferred into an electric oven at 150 °C, during which the TiO2 nanorods could be fabricated on the substrates. The nanorod length could be easily controlled by altering the heating time. Surface Modification of the TiO2 Nanorod Array. First, the TiO2 nanorod array substrates were immersed in 1% (v:v) APTES ethanol solution for 1−2 h. After they were washed, respectively, with ethanol and 1 × PBS, they were transferred into 2.5% GA (v:v) in a 1 × PBS solution for 2−4 h at 4 °C. Then the substrates were immersed into 10 mg/mL of BSA solution at 4 °C overnight. After they were treated with 2.5% GA again, 50 μL of DNA solution (1 μM) was added onto the substrates at room temperature for 4−6 h, and ethanol amine (1 M) was utilized to block the unreacted aldehyde group for 10 min. Finally, the prepared samples were kept at 4 °C for storage. Cell Capture Procedure. DNA-modified TiO2 nanorod array substrates were cut into pieces 1 cm × 1 cm in dimension and placed into a 24-well plate. The cells were stained using DiI (emitting red fluorescence, 10 μg/mL) or DiO (emitting green fluorescence, 10 μg/ mL) for 20 min to permit the identification of target cells. Then 1 mL of prestained cell suspensions of 105 cells/mL was added into each well and then incubated at 37 °C (5% CO2) for predetermined time. After that, the substrates were washed carefully five times. Ultimately, the target cells captured on the substrates were imaged using a fluorescence microscope. For the capture experiment of rare cancer cells, DNA-functionalized TiO2 nanorod array substrates were cut to the dimension of approximately 0.9 cm × 1.8 cm and put into a four-well Lab-TekII Chamber Slide. MCF-7 cells prestained by DiI were separately spiked into a 1 mL suspension containing 106 CCRF-CEM cells at the concentrations of approximately 10, 20, 50, 100, and 200 cells/mL. After 40 min of incubation in a cell incubator, the modified TiO2 nanorod array substrates were then washed gently at least five times and taken for fluorescence imaging of captured target cells.
using a series of artificial mixture samples spiked with rare number of MCF-7 cells. The experiments were performed using a four-well Lab-TekII Chamber Slide with the BSAaptamer modified substrate cutting into approximately 0.9 cm × 1.8 cm in dimensions. The mixture samples were prepared by numbering 10, 20, 50, 100, and 200 target cells, which were prestained with DiI into 1 mL of pure DMEM and 1 mL of CCRF-CEM cell suspension containing 106 CCRF-CEM cells, respectively. The mixture samples were incubated in a cell incubator (37 °C, 5% CO2) for 40 min. The results are summarized in Figure 6, panel a. More than 80% spiked MCF-7
Figure 6. (a) Capture performance of the TiO2 nanorod substrates under different spiked MCF-7 cells in DMEM and in 106CCRF-CEM cell suspension. (b) Capture yield of whole blood samples with rare cancer cells.
cells could be captured from these DMEM samples and mixture samples. When we spiked 10 MCF-7 cells into the solution, almost all of the spiked cells were captured on the TiO2 nanorod surface. The TiO2 nanorod array substrates displayed considerable capture efficiency and sensitivity of MCF-7 cells, especially in the test with rare target cell samples. To investigate the clinical application of BSA-aptamer modified TiO2 nanorod array substrates, cell capture experiment of whole blood samples was carried out. For this, 10, 20, 50, and 100 MCF-7 cells (prestained by DiI) were spiked into 1 mL of whole blood respectively to mimic patient blood samples. As shown in Figure 6, panel b, an excellent capture yield of 85%−95% was achieved from whole blood, which exhibited great potential value on clinical application of BSAaptamer modified TiO2 nanorod array substrates for rare cancer cells detection.
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CONCLUSIONS In conclusion, a mutiscale TiO2 nanorod array is fabricated using a hydrothermal synthesis method, which exhibits excellent capture specificity and sensitivity of target cells after modification with BSA and DNA aptamer. By the comparison with other nanostructured substrates, we can conclude that the multisacle TiO2 nanorod substrates could indeed effectively enhance the capture performance of target cancer cells even in a low cell density situation. The capture yield of artificial blood samples on the BSA-aptamer TiO2 nanorod substrates is up to 85%−95%, which reveals the potential application of TiO2 nanorods on highly efficient capture of rare number CTCs. This work provides a new platform for rare cancer cell capture, and the multisacle TiO2 nanorod array is promising to be applied on clinical detection and early diagnosis.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Author Contributions
EXPERIMENTAL SECTION
§
These authors contributed equally to this work.
Materials. The (3-aminopropyl) triethoxysilane (APTES), glutaraldehyde (GA), and 3−3′-dioctadecyloxacarbocyanine perchlor (DiO) were purchased from Sigma-Aldrich. ChromatoPur BSA was
Notes
The authors declare no competing financial interest. D
DOI: 10.1021/acsami.6b02178 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX
Research Article
ACS Applied Materials & Interfaces
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ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (Nos. 21305154, 21275156), the Natural Science of Foundation of Jiangsu Province (No. BK20130351), the State Key Laboratory of Electroanalytical Chemistry (No. SKLEAC201410), the CAS Hundred Talents program, and the CAS/SAFEA International Innovation Teams program.
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DOI: 10.1021/acsami.6b02178 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX
Research Article
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DOI: 10.1021/acsami.6b02178 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX
