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Combining Holographic Optical Tweezers with Upconversion Luminescence Encoding: Imaging-based Stable Suspension Array for Sensitive Responding of Dual Cancer Biomarkers Chengyu Li, Di Cao, Chu-Bo Qi, Ya-Feng Kang, Chong-Yang Song, Dang-Dang Xu, Bei Zheng, Dai-Wen Pang, and Hong-Wu Tang Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.7b04299 • Publication Date (Web): 24 Jan 2018 Downloaded from http://pubs.acs.org on January 24, 2018

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Analytical Chemistry

Combining Holographic Optical Tweezers with Upconversion Luminescence Encoding: Imaging-based Stable Suspension Array for Sensitive Responding of Dual Cancer Biomarkers Cheng-Yu Lia, Di Caoa, Chu-Bo Qia,b, Ya-Feng Kanga, Chong-Yang Songa, Dang-Dang Xua, Bei Zhenga, Dai-Wen Panga, Hong-Wu Tanga* a

Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, People’s Republic of China b Hubei Cancer Hospital, Wuhan, 430079, People’s Republic of China

ABSTRACT: Establishment of a stable analytical methodology with high-quality results is an urgent need for screening cancer biomarkers in early diagnosis of cancer. In this study, we incorporate holographic optical tweezers with upconversion luminescence encoding to design an imageable suspension array, and apply it to conduct the detection of two liver cancer related biomarkers, carcinoembryonic antigen and alpha fetal protein. This bead-based assay is actualized by forming a bead array with holographic optical tweezers and synchronously exciting the upconversion luminescence of corresponding trapped complex beads fabricated with a simple one-step sandwich immunological recognition. Owing to the fact that these flowing beads are stably trapped in the focal plane of the objective lens which tightly converges the array of the laser beams by splitting a 980 nm beam using a diffraction optical element, a fairly stable excitation condition is achieved to provide reliable assay results. By further taking advantages of the eminent encoding capability of upconversion nanoparticles and the extremely low background signals of anti-Stokes luminescence, the two targets are well identified and simultaneously detected with quite sound sensitivity and specificity. Moreover, the potential on-demand clinical application is presented by employing this approach to respond the targets towards complex matrices such as serum and tissue samples, offering a new alternative for cancer diagnosis technology.

Cancer biomarkers are a kind of characteristic proteins which are produced and metabolized directly by tumor cells. 1,2 Ascribing to their wide existence and high abundance in tumor tissue, body fluid and serum for cancer patients, these proteins are commonly referred as critical indicators for reflecting and monitoring the evolution of tumors.3,4 In the past decades, the test of cancer biomarkers has been one of the most preferential procedures for cancer screening in early stage and some conventional methods such as enzyme-linked immune sorbent assay (ELISA) and chemiluminescence immunoassay (CLIA) have been established to fulfill this goal.5,6 However, these options still remain some challenges in accurate and efficient diagnosis of cancers. For one thing, they are typically employed to measure only single targets at a time and likely to cause false positive or negative cases.7 For another thing, the limited sensitivities and unfavorable stabilities may severely impede their applicability in low-abundance complicated samples.8 Thus, collecting collaborative information from multiple biomarkers with commendable assay performance to break through the current technical bottleneck is of great importance. With the rapid development of multiplexing technology, many progressive multiplexed assays including planar microarray and suspension array have been constructed to provide new opportunities. For planar microarray, a sufficient number of high affinity capture ligands (e.g. antibodies, nucleic acids and drug candidates) are immobilized on a planar surface to

position targets and form array spots, enabling one to perform ultrahigh-throughput analysis in parallel with an economical platform.9,10 Although this way has attracted much attention for its potential applications in disease diagnosis and drug discovery, it suffers from drawbacks on the quality of results, overall flexibility, binding rate and efficiency, which ultimately leads to poor reproducibility and low sensitivity. 11,12 To improve these issues, the concept of suspension array is proposed by replacing the planar surface with beads as the solidsupports. Because of the tiny difference between these supports and the feasibility of concurrently counting batch data, more convincing results can be offered in this case.13 Moreover, the ability of target selection and the binding kinetics are strongly enhanced by the facile surface modification and the high surface-to-volume ratio of beads.14 Recently, numerous advanced researches have introduced this novel multiplexed detection approach in clinical diagnosis and demonstrated its significant advantages.15-17 Up to now, various chemical and physical encoding means have been established to create a library of barcodes in suspension array. Among these available choices, optical encoding is the most efficient and convenient owing to its highspeed decoding and well-resolved capability.18 This burden is primarily being undertaken by integrating organic dyes with silica or polymer beads via embedding or assembling strategy, but these small molecules have some inherent limitations such

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Scheme 1. Schematic principle (all drawn objects are not in real scale) of the imaging-based stable suspension array by integrating holographic OT with upconversion luminescence encoding for the detection of CEA and AFP, where CEA and AFP are indentified with green emission and blue emission, respectively. as spectral overlap, photobleaching, and even autofluoreslaser beam is able to actualize the trapping of individual micence.19,20 In addition, the significant differences in their excicroscopic object, an optical manipulation technology named optical tweezers (OT) has been emerged.32,33 Considering OT tation wavelengths force the urgent demand of a cost-effective 7,11 offers an adequate gradient force originated from photon moand compact device with multiple excitation sources. mentum exchange to overcome the viscous force in fluid cirThanks to the tremendous progress of nanoscience, a fantastic cumstance, it can be served as a powerful handle to stably semiconductor nanoparticle represented by quantum dots immobilize the detected beads in suspension array to perform (QDs) gives an additional possibility for addressing these imaging assay as well. problems. With the assistance of their excellent optical properties such as photobleaching resistance, broad absorption, and Although the combination of OT with upconversion luminarrow emission, suspension array using QDs to encode is nescence is a possible way to improve the traditional suspenfrequently developed and applied to conduct bioanalysis.21-23 sion array, multiplexed detection still remains a challenge Although this sound alternative is considered to pave a way because of the restricted trapping manner that only one bead is for optical encoding assay, the use of visible light can generate trapped at a time by applying the common single-beam based strong background luminescence in complicated biological OT. Herein, for the first time we design a multiple optical samples (e.g. serum and tissue).24 Fortunately, another promitrapping strategy by introducing holographic OT and upconnent candidate, upconversion nanoparticles (UCNPs), is proversion luminescence encoding to accomplish dual-component mising to meet this expectation. Unlike traditional luminesdetection. Scheme 1 presents the detection principle of this cence principle, UCNPs are capable of absorbing the low ennewly proposed suspension array, where two vital liver cancer ergy photons from near-infrared (NIR) light region and conbiomarkers, carcinoembryonic antigen (CEA) and alpha fetal verting them into an emission in visible domain, resulting in a protein (AFP), are selected for the proof-of-principle study. unique anti-Stokes luminescence. By making use of a NIR The different target binding events are commendably distinlaser source to induce this process, background luminescence guished by employing two kinds of UCNPs with different is negligible for the assay in complex matrix.25-27 Additionally, emission colors (G-UCNPs and B-UCNPs) as the luminescent the photostability and spectral properties of UCNPs are supelabels and a simple sandwich complex bead is fabricated by rior to QDs, further laying their foundation in optical encodusing carboxyl functionalized polystyrene beads (CPBs) as the ing.26,27 carrier. When a 33 bead array, imaging assay is severally Generally, flow cytometry instrument is a platform being performed into two individual channels (green channel and frequently utilized to acquire the optical information for the blue channel) with a sensitive electron-multiplying CCD bead-based assay by taking the advantage of fast signal re(EMCCD). sponse.28 However, the drastic fluid effect makes it difficult to EXPERIMENTAL SECTION record the images of beads in real-time with photoelectronic imaging equipments, compelling one cannot observe and inMaterials. 3 μm carboxyl polystyrene beads (50 mg/mL) vestigate a single object of interest in long-term.29 For this with a coefficient variation less than 2% were received from reason, many bead-based arrays are created by exploiting miShanghai Huge Biotechnol. Co. Ltd. (China). Diethylene glycroscopic imaging technology, in which a tiny chamber is col (DEG, 99%), erbium chloride hexahydrate (ErCl3·6H2O, formed to confine the beads into a limited space and also de99.5%), thulium chloride hexahydrate (TmCl3·6H2O, 99.5%), crease the flowing speed.30 Nevertheless, owing to the disturbyttrium chloride hexahydrate (YCl3·6H2O, 99.9%), and ytterance from the viscous force generated by fluids, this manner bium chloride hexahydrate (YbCl3·6H2O, 99.9%) were oblacks stable excitation conditions and high quality results. 31 In tained from Aladdin Industrial Inc. (China). 1-octadecene actual operation, the measured beads are easy to move away (ODE, 95%), oleic acid (OA, 90%), polyacrylic acid (PAA, from the imaging plane, rendering the assistance of user interaverage MW 1.8 kDa), 1-ethyl-3-(3-dimethyllaminovention to implement loading, focusing and detecting processpropyl)carbodiimide hydrochloride (EDC·HCl, 99.9%), Nes. Since an interesting optical discovery that a highly focused hydroxysulfosuccinimide sodium salt


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(Sulfo-NHS, 99.9%), and bovine serum albumin (BSA, 99.5%) were purchased from Sigma-Aldrich Co. (USA). All protein molecules purified by affinity chromatography (purities > 95%), including CEA, AFP, prostate specific antigen (PSA), pairing anti-CEA monoclonal mouse antibodies, and pairing anti-AFP monoclonal mouse antibodies were supplied by Zhengzhou Biocell Biotechol. Co. Ltd. (China). Nucleic acids (DNA and RNA) with random sequences were synthesized by Shanghai Sangon Biotech. (China). Other reagents provided by Sinopharm Chemical Reagent Co. (China) were of analytical grades. Ultrapure water (Resistivity ≥ 18.25 MΩ·cm-1, Millipore) was used throughout to prepare buffer solutions. Real samples including six individual whole blood samples and liver tissues from two individual patients were obtained from Hubei Cancer Hospital (China). The experiments using the human blood and tissue samples were approved by the ethical committee of Wuhan University. Preparation of hydrophobic NaYF4: Yb, Er/Tm nanoparticles coated with OA. 1 mmol of rare earth chloride mixtures with a specified proportion (Y: Yb: Er = 0.78, 0.2, 0.02 or Y: Yb: Tm = 0.798, 0.2, 0.002) and a solution containing 6 mL of OA and 15 mL of ODE were first mixed together in a 100 mL three-necked flask. Then, the temperature was increased to 160 ºC and kept vigorous stirring for 40 min to form a pale yellow transparent solution under argon atmosphere. After cooling to room temperature, 10 mL of methanol solution dissolving with 100 mg of NaOH and 148 mg of NH4F was injected dropwise into the system to obtain rare earth oleates. Thereafter, the as-obtained white turbid liquid were degassed at 110 ºC for 40 min to remove methanol and residual water, followed by heating to 305 °C at a rate of 20 °C/min under argon protection. By maintaining this reaction condition for 1 h under vigorous stirring, the resulting products were mediated and precipitated by adding 20 mL of ethanol at room temperature. Finally, the nanoparticles were washed four times with ethanol/water (v/v = 1:2) to remove the residual precursors and purified three times with hexane/ethanol (v/v = 1:6). The as-prepared hydrophobic pellets were sonicated and dispersed in 4 mL of non-polar solvents such as chloroform to regulate the concentration at 20 mg/mL for further use. Preparation of hydrophilic NaYF4: Yb, Er/Tm nanoparticles modified with PAA. 650 mg of PAA was first dissolved with 15 mL of DEG in a 50 mL three-necked flask to form a transparent solution under argon atmosphere. Subsequently, the system was heated to 110 °C and 2 mL of the as-prepared hydrophobic nanopartilces (NaYF4: Yb, Er or NaYF4: Yb, Tm) were slowly injected into the mixture. After removing the chloroform by maintaining for 1 h, it was heated to 240 °C and kept at this temperature for about 2 h until the solution became pale yellow under vigorous stirring. The resulting products were precipitated with the addition of excessive amount of ethanol, followed by purifying with ethanol for three times. The final hydrophilic pellets were sonicated and dispersed in 4 mL of ultrapure water to regulate the concentration at 10 mg/mL, and stored at 4 °C for long-term use. Preparation of immunobeads. 300 μg of CPBs were first washed three times with ultrapure water and then resuspended into 150 μL of MES buffer solution (50 mM, pH 5.5) dissolving with 250 μg of EDC and 250 μg of Sulfo-NHS. After reacting for 1 h at room temperature, the beads were recovered and washed three times, followed by transferring into 200 μL

of PBS buffer solution (100 mM, pH 7.5). Subsequently, 10 μg of capture antibodies (Anti-CEA Ab1 or Anti-AFP Ab1) were incubated with the as-activated beads for 4 h under gentle shaking. The final immunobeads was obtained by washing three times with PBST buffer solution (100 mM, pH 7.5, 0.5% Tween-20) to remove the unbound antibodies and processed with 0.3% BSA to block other binding sites, and stored at 4 °C for later use. Preparation of UCNP probes. Initially, 60 μL of the asprepared water-soluble nanoparticles were sonicated and dispersed into 100 μL of MES buffer solution (10 mM, pH 6.0). Then, 2.5 μg of EDC and 2.5 μg of Sulfo-NHS were added into the mixture to act as the activator, and the reaction was gentle shaken for 1 h to active the surface PAA. Subsequently, the as-obtained nanoparticles were centrifuged and washed three times, followed by redispersing into 100 μL of HEPES buffer solution (10 mM, pH 8.2). After incubating with 1 μg of detection antibodies (Anti-CEA Ab2 or Anti-AFP Ab2) for 4 h at room temperature, the unbound antibodies were removed by washing three times with HEPEST buffer solution (10 mM, pH 8.2, 0.5% Tween-20). Finally, the UCNP probes were recovered and stored at 4 °C for later use. RESULTS AND DISCUSSION

The technical concept of constructing our home-built holographic OT setup is based on exploiting a diffractive optical element (DOE) to realize phase-modulated. As displayed in Figure 1A, a single Gaussian-shaped beam with a maximum output power of 950 mW derived from a single-mode fibercoupled CW laser diode operating at 980 nm (Connet, China) has the double function of producing the trapping force and exciting the upconversion luminescence at the same time. A parallel beam with 3 mm in diameter is first regulated by a collimator (F260APC-980, Thorlabs), after which its axial height is conjugated with the inverted microscope platform (Olympus IX70, Japan) by utilizing an adjusting frame composed of two reflection mirrors (Zolix, China). This adjustment beam is then expanded by a 1:2.5 expander system, resulting in a diameter of 7.5 mm to slightly overfill the entrance aperture of the oil-immersion objective (100, NA 1.30, Olympus, Japan) to obtain an optimal focus level, followed by proceeding with the DOE. It can be seen from the NIR card that the original single beam is split into a homogeneous 33 major array (detection region) and a peripheral array with inhomogeneous intensities. The former one is generated by the zeroth order (one beam centered) and the first order diffractions (eight beams around), and the latter is generated by the second order diffraction. After accurately controlling the axial position of the beam array to match the imaging plane through a 1:1 telescope system, it is then projected onto a dichroic mirror (DM, 850 nm, Edmund) and reflected upward. Finally, a 33 trapping array with about 8 μm in spacing is formed by tightly focusing the beam array onto the sample stage equipped with a self-made sample chamber, which is fabricated by binding a cover glass with a PDMS layer. Before capturing the upconversion luminescence images with a cooled EMCCD (Evolve-512Delta, Photometrics, Canada), the interference from the 980 nm laser should be further shielded via a NIR blocking filter (BF, FF01-760/SP-25, Semrock), inserted into the filter cube of the microscope. The upconversion luminescence signals are selectively collected into two channels, in which a bandpass filter (Filter 1, 540/50, Edmund)



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Figure 1. (A) Schematic illustration of the home-built holographic OT setup by introducing a DOE to split a single 980 nm Gaussian-shaped laser beam into an array of 9 beams. Optical path for this laser beam (before and after splitting) and bright-field illumination is presented in red line and yellow line, respectively. Green line and blue line show the two different upconversion emissions. Beam expander system and telescope system are composed of two lens with different focal lengths (L1: 20 mm, L2: 50 mm) and two lens with equal focal lengths (L3: 300 mm, L4: 300 mm), respectively. Inset diagram shows details of the home-made sample chamber fabricated onto a PDMS layer and blocked with 1% BSA. (B) Representative TEM images and corresponding digital images in chloroform (absence of 980 nm irradiation) of the two types of OA coated UCNPs (Er 3+ doped in top and Tm3+ doped in bottom). (C) Upconversion luminescence spectra (left) and corresponding digital images (right, presence of 980 nm irradiation) for these hydrophobic UCNPs. (D) Representative TEM images and corresponding digital images in ultrapure water (absence of 980 nm irradiation) of the two types of PAA capped UCNPs obtained via a ligand exchange process (Er3+ doped in top and Tm3+ doped in bottom). (E) Upconversion luminescence spectra (left) and corresponding digital images (right, presence of 980 nm irradiation) for these hydrophobic UCNPs. and a shortpass filter (Filter 2, 500 nm, Edmund) are coupled to the asymmetrical stretching of methylene group, and the onto a splitter to guarantee the acquisition of green emission adjacent bands at 1558 cm-1 and 1464 cm-1 are ascribed to the and blue emission, respectively. Under the bright-field illumisymmetric and the anti-symmetric stretching vibration of carnation with a converged white-light LED source, all trapping boxylate anions, respectively, leading to form a transparent events can be monitored with a digital camera (DC) in real solution in non-polar solvents such as chloroform (Figure 1B). time. Because of the power diminishment raised by the above Upon irradiating these solutions with a 980 nm CW laser optical elements, approximately 45% of the output power is source, far less spectral overlap is exhibited in the digital immaintained at the focus. ages and the upconversion luminescence spectra (Figure 1C), where one appears green emission with two peaks at 528 nm Hydrophobic UCNPs stabilized with OA molecules are synand 546 nm, resulting from the energy level transitions of Er3+ thesized via a thermal coprecipitation method reported by 34 in 4H11/2 → 4I15/2 and 4S3/2→4I15/2, and the other presents blue Zhang et al. Two types of UCNPs can be alternatively createmission (1D2 → 3F4 and 1G4 → 3H6 transitions of Tm3+), aled by varying the compositions of lanthanide ions, where 2% lowing the fine-resolution of optically encoding by employing Er3+ and 0.3% Tm3+ are selected as the activators, respectively. these two unique spectral signatures. Representative TEM images (Figure 1B) reveal that the morphologies of these monodispersed nanoparticles are sphereTo synchronously transform the hydrophobic ones into walike with mean sizes of approximately 28 nm for both cases. ter dispersible and realize surface functional modification, a Simultaneously, quite narrow size distributions (n = 300, σ ligand exchange principle is adopted in our subsequent expe 5 ng/mL, AFP > 25 ng/mL) while the relatively low levels are measured for the healthy volunteer (sample 6). To investigate the accuracy of these evaluated data, they are compared with the results obtained by CLIA accord-

ing to the t-test principle (Table S7). Approvingly, all the t values for positive cases are significant lower than tcrit (tcrit[0.05,4] = 2.77), implying the well concordance between the two methods. In addition, our method has the ability to detect much lower levels of the targets than the LODs of CLIA. Therefore, this platform brings a tremendous potential in biomedical analysis.

Figure 5. (A) Pretreatment and enrichment procedures for analysis of tissue samples. (B) Representative pseudocolor luminescence images of the measured tissue samples. Scale bars are 6 μm for all cases. (C) Corresponding luminescence intensities counted from Figure 5B and error bars indicate the SD from three independent measurements.

Since the analysis of human tissue samples is another essential operation for accurately diagnosing cancer, we finally explored the adaptability of this approach to detect the levels of CEA and AFP in liver tissues. In our design, the paraffinembedded liver tumors and their surrounding normal tissues from the same liver cancer patient are selected as the experimental group and the control group, respectively. Before enriching the targets, the original tissues are excised into small pieces and then extracted their total proteins (Figure 5A). To ensure the same amounts of total proteins for the two examined tissues in each sample, we regulate their UV-vis absorbance values at 280 nm keep consistent (Figure S17) via dilution. As can be found in Figures 5B and 5C, the experimental groups exhibit much stronger green emissions and blue emissions than those of control groups for the two individual samples, indicating that the abundances of CEA and AFP in liver tumors are significantly higher than normal tissues. In this sense, the as-proposed approach offers a new alternative for cancer diagnosis technology, by which various cancer related targets in clinical tissues can be indentified and detected. CONCLUSIONS

In conclusion, we have presented an exceptional suspension array by combining holographic optical tweezers with upconversion luminescence encoding. This system is based on the splitting of a 980 nm laser beam to realize multiple optical trapping and the using of two kinds of UCNPs with unique spectral signatures to implement optical encoding, laying the



foundation for performing dual-component detection. The described analytical platform in this work shows approving sensitivity and selectivity and is able to respond two liver cancer biomarkers by adopting a simple enrichment strategy. More importantly, it serves as a powerful tool for measuring targets in complex biological samples such as serum and human tissue with high-quality working capability. To a great extent, the developed analytical technology can lead to a new concept for clinical diagnosis and is anticipated to open up extensive applications in medical and life sciences. Its future prospective will be focused on constructing a portable device and reducing the pretreatment time to meet the requirement of point-of-care detection, and improving the detection throughput to achieve multiplex detection by generating larger trapping array and developing multicolor UCNPs.

ASSOCIATED CONTENT Supporting Information The supporting information is available free of charge on the ACS Publications website: Instruments, fabrication of sample chamber, calibration of 33 trapping array, detection of single-component cancer biomarker, simultaneous detection of dual-component cancer biomarkers, specificity investigation, total proteins extraction from human tissues (PDF) Optical trapping and manipulating of a 33 bead array (Avi)

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected].

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was supported by the National Natural Science Foundation of China (81572086, 81772256 and 21535005) and Wuhan Municipal Basic Research Project (2016060101010052).

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Scheme 1

Figure 1

9 ACS Paragon Plus Environment


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Figure 2

Figure 3 10 ACS Paragon Plus Environment

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Figure 4



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Figure 5


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Table of Content (TOC)

We constructed an imaging based stable suspension array by integrating holographic optical tweezers with upconversion luminscence encoding.


Combining Holographic Optical Tweezers with ... - ACS Publications

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