Nanoparticle-Based Aptasensors for Food Contaminant Detection

CHAPTER 6

Nanoparticle-Based Aptasensors for Food Contaminant Detection Richa Sharma1, 2, 3, K.S.M.S. Raghavarao1, 2 1

Academy of Scientific and Innovative Research, CSIR-CFTRI, Mysore, India; 2Department of Food Engineering, CSIRCentral Food Technological Research Institute (CFTRI), Mysore, India; 3Department of Biotechnology, Sharda University, Greater Noida, India

Contents 6.1 Introduction 6.1.1 Food SafetydAn Area of Paramount Importance 6.1.2 AptasensingdAn Emerging Technology 6.1.3 NanomaterialsdNumerous Applications in Biosensing 6.1.3.1 6.1.3.2 6.1.3.3 6.1.3.4

Elemental Metal Nanoparticles and Nanoclusters Binary Metallic Nanoparticles (Oxides and Semiconductors) Carbon Nanoparticles Hybrid NanoparticlesdUpconversion Nanoparticles

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6.2 Transduction Approaches for Nanoparticle-Based Aptasensing 6.2.1 Optical Aptasensors

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6.2.1.1 Surface Plasmon ResonanceeBased Sensors 6.2.1.2 Fluorescence-Based Sensors 6.2.1.3 LuminescenceeBased Sensors

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6.2.2 Electrochemical Biosensors 6.2.3 Other Detection Formats 6.2.3.1 Colorimetric Assays Without Involving Nanoparticle Aggregation 6.2.3.2 DNA AmplificationeBased Assays

6.3 Conclusions and Future Perspective Abbreviations Acknowledgments References Further Reading

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6.1 INTRODUCTION 6.1.1 Food SafetydAn Area of Paramount Importance Access to adequate amounts of nutritious and safe food is imperative for the sustenance and healthy maintenance of life. However, increasing world population and urbanization have led to paradigm shifts in consumer habits as well as agricultural and food processing practices. Nowadays, consumers demand for wider varieties of food and resort to eating processed food because of lack of time and advantage of convenience. Agriculture and Nanomaterials for Food Applications ISBN 978-0-12-814130-4, https://doi.org/10.1016/B978-0-12-814130-4.00006-3

© 2019 Elsevier Inc. All rights reserved.

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animal production have been intensified and industrialized. Other upcoming challenges, such as increased risk of contamination due to growth in travel and trade, emergent pathogens, and changes in procedures for food production and distribution are threatening food safety, as well. Contaminated food is a looming problem affecting health and economy worldwide. According to the World Health Organization (WHO): • Unsafe food alone causes more than 200 diseases. • An estimated 600 million people (which accounts for approximately 1 in 10 of the world population) suffer from some or the other illness on consumption of contaminated food. • 4.2 million people die every year from food contamination (which accounts for 3.3 million healthy life years). • Children under the age of 5 years suffer from 40% of foodborne diseases, with a death toll of 1.25 million per year • The highest incidence of foodborne illnesses and associated death rates have been found in WHO African and Southeastern Asia Regions Because safe food is inseparably linked to nutrition and food security, contaminated food creates malnutrition affecting the weak components of the population. Unsafe food goes on to create socioeconomic strain, harming health care, national economies, trade, and tourism. Therefore, steps to ensure food safety should be implemented by food producers, handlers, and regulatory bodies, in all stages of food preparationdharvest, transport, processing, storage, and preparation (World Health Organization, 2015).

6.1.2 AptasensingdAn Emerging Technology Since, ensuring food safety to the global public is a thrust area for both regulatory bodies and the scientific community, methods to enable convenient, rapid, and sensitive analysis of food contaminants are currently required. Such advanced techniques, known collectively as biosensing, rely on highly specific bioreceptors coupled with efficient transducing systems. The bioreceptor acts as a probe to identify a target compound, the identification produces a chemical or biological signal that is converted to a measurable form by the transducer. Aptamers are single stranded nucleic acid or peptide molecules that have high affinity to only their target ligands, similar to antibodies, but much simpler to synthesize and modify. Aptamers serve as bioreceptors that fold into three-dimensional conformation and can differentiate between chiral molecules. They are highly specific (dissociation constants in the nanomolar to picomolar range) toward a plethora of target compounds, which include proteins, ions, viruses, toxins, and microbes and undergo conformational change on target binding. The possibility of using single-stranded nucleic acids to recognize biomolecules other than complementary strands was conceptualized when it was found that viruses can produce RNA molecules that strongly bind to viral proteins (O’Malley et al., 1986;

Nanoparticle-Based Aptasensors for Food Contaminant Detection

Sullenger et al., 1990). Soon after, a method was discovered to select and generate such nucleic acid strandsdan in vitro combinatorial technique called SELEX (Systematic Evolution of Ligands by EXponential enrichment), wherein, a nucleotide sequence with strong affinity for a target is selected from a large pool of around 1015 sequences (Tuerk and Gold, 1990; Klug and Famulok, 1994) (cf. Fig. 6.1). Aptamers present several advantages such as higher stability even at elevated temperatures, easy in vitro synthesis procedure, specificity against several nonimmunogenic target molecules, and major alteration in structure on binding when compared to other biospecific molecules such as antibodies (Jayasena, 1999; Mascini, 2008). The property of structural change has been extensively used for biorecognition, especially since aptamers are easily modifiable to suit end purposes (Campas et al., 2012; Rhouati et al., 2013; Dong et al., 2014). These advantages have enabled conception of a variety of labeled and unlabeled signal transduction modalities such as optical, electrochemical, and piezoelectric aptasensing methods (Hong et al., 2012).

6.1.3 NanomaterialsdNumerous Applications in Biosensing The incorporation of nanomaterials into the analysis protocols, adds on to their applicability and convenience. Nanomaterials are composed of nanosized (1e100 nm) particles. Novel nanomaterials are being designed continually that serve as powerful tools for the development of new biosensing techniques as well as for the improvement of existing ones. Nanomaterials are characterized by high surface area, which increases the functional surface of the device enabling higher immobilization density for both bioreceptors and

Figure 6.1 General SELEX procedure for aptamer screening.

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labels. Additionally, many of them have catalytic and signal amplification properties. They themselves may act as labels and are able to generate signature responses depending on their composition, shape, and size. Nanoparticles have interesting size-related properties, which include surface plasmon resonance (SPR) in noble metal and metal alloy nanoparticles, quantum confinement in semiconductor nanocrystals, high electrical conductivity, magnetic property, and distinctive optical activity. Nanomaterials can now be considered almost ubiquitous in the area of biosensor research. Combined with aptasensing, they have revolutionized bioanalytical technology, especially in the food sector. In the following sections, several cases of integration of nanomaterials with aptamers for detection of food contaminants are discussed. 6.1.3.1 Elemental Metal Nanoparticles and Nanoclusters Metal nanoparticles (5e100 nm) are composed of elemental metal and thus have free electrons on their surface, which create plasmonic effect. Some examples are gold nanoparticles, silver nanoparticles (AgNPs), and platinum nanoparticles. This endows them with unique spectral and optical properties, conductivity, redox properties, luminescence, and catalytic ability (Saha et al., 2012; Burris and Stewart, 2012). Several reports describe their use in analysis of food contaminants, toxins, and pathogens (Saha et al., 2012; Sharma et al., 2017). Noble metal nanoparticles are usually synthesized via chemical reduction of metal salts (Pillai and Kamat, 2004; Sharma et al., 2015a), templatesbased methods (Nicewarner-Pena et al., 2001; Ballabh and Nara, 2015), photochemistry (Kshirsagar et al., 2014), seed-mediated growth (Jenkins et al., 2017), electrochemistry (Singaravelan and Alwar, 2015), and radiolysis (Abedini et al., 2016). Most of these methods are simple and so are the techniques to functionalize these particles. Metal nanoclusters are smaller than conventional nanoparticles (<5 nm) and thus possess additional properties such as magnetism, insulation (Roduner, 2006), and fluorescent emission over visible and near infrared region, which can be tuned by varying size, capping agent and synthesis route, better photostability and higher quantum yield. Metal nanoclusters have less toxicity and are slowly replacing conventional dyes and quantum dots (QDs) in fluorescence-based sensing (Shang et al., 2011). Nanocrystals can be synthesized using both dry and wet techniques. Dry routes include lithography and chemical vapor deposition, whereas wet routes are solution-based methods such as microemulsion, hot injection, and solegel methods (Wang et al., 2009). 6.1.3.2 Binary Metallic Nanoparticles (Oxides and Semiconductors) Semiconductor nanoparticles used in biosensing are generally compounds of metals with nonmetallic elements. An example of extensively used semiconductor nanoparticles is QDs, which are composed of Zn, Cd, Te, and Se. They are fluorescent in nature, having better quantum yields and stability than fluorescent dyes and size-controlled emission (Gill et al., 2008). QDs can be conjugated with aptamers, keeping intact aptamer

Nanoparticle-Based Aptasensors for Food Contaminant Detection

specificity and quantum dot emission properties. The prominent methods of synthesis are physical techniques (e.g., molecular beam epitaxy) and chemical approaches such as hydrothermal synthesis, micellar synthesis, high-temperature colloidal synthesis, and refluxing (Brichkin and Razumov, 2016). Metal oxide nanoparticles composed of maghemite (g-Fe2O3) and magnetite (Fe2O3) are popular in biosensing because of their supraparamagnetic property. These magnetic nanoparticles (MNPs) present the unique ability to separate target molecules from other compounds, thereby eliminating significant matrix effects. They have also been found to improve electron conductivity, because they are chemically metal oxides (Cao et al., 2012). Coprecipitation and thermal decomposition are the most commonly used methods for synthesis (Stanicki et al., 2015). 6.1.3.3 Carbon Nanoparticles Among inorganic nanoparticles, carbon-based nanomaterials are most commonly used for biosensing. They mainly include carbon nanotubes (CNTs) and graphene (Kochmann et al., 2012; Wang et al., 2012; Jariwala et al., 2013; Najafi et al., 2014). Graphene is a two-dimensional (one atom thick) nanosheet, and CNTs are cylindrical hollow nanomaterials. They are known to have large surface area, good electron conductivity, energy acceptance ability, flexibility, and mechanical strength (Guo and Dong, 2011). These properties make them popular in electrochemical and fluorescence-quenching based biosensors (Guo et al., 2011). Approaches for the synthesis of graphene are based on epitaxial growth, mechanical cleavage, methods of exfoliation of graphite, and reduction of graphene oxide (D. Sharma et al., 2016a), whereas chemical vapor deposition is the most popular method for synthesizing single and multiwalled CNTs (Ganesh, 2013). 6.1.3.4 Hybrid NanoparticlesdUpconversion Nanoparticles Upconversion nanoparticles (UCNPs) have emerged recently as alternatives to fluorescent dyes and quantum dots. They have lattice structures that are composed of rare earth and/or alkali metal cations with halide anions. They are often doped with rare earth metals for activation. UCNPs are luminescent materials that can transform near infrared radiation into visible radiation. They are being used as fluorescent tags in biosensors due to low background noise, sharp emission bands, stable emission, and good penetration in tissues. Hydrothermal and solvothermal synthesis routes are generally used for UCNPs (Wang et al., 2011). A comprehensive review of nanoparticle-based aptasensing of different food contaminants had earlier been published by our group (Sharma et al., 2015b). It is a holistic report on all relevant biosensing formats developed in the last few years prior to the publication year. Here, we describe nanomaterial-based aptasensors for food and water contaminants, toxins, and pathogens citing outstanding reports published in the last 5 years.

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6.2 TRANSDUCTION APPROACHES FOR NANOPARTICLE-BASED APTASENSING Several principles have been used for transduction of signals generated on binding of aptamer with target, depending on the fundamental properties of the nanoparticles used in the method. Majority of the detection formats can be classified into optical and electrochemical-based transduction. Nanoparticles, however, have also been used for purposes other than signal generation, such as target separation (in the case of MNPs) and catalysis.

6.2.1 Optical Aptasensors Optical transducers are able to transform light (ultraviolet, visible, and infrared radiation) from a biochemical event into readable signals. Based on the light source and phenomenon, they are classified as SPRebased (effect on plasmon on metal nanoparticles surface), which include colorimetric and surface enhanced Raman spectra-based sensors, fluorimetric (fluorescence emission, quenching, and transfer), bioluminescence, and chemiluminescence (CL)-based (emission of luminescence due to a biological or chemical reaction) sensors. 6.2.1.1 Surface Plasmon ResonanceeBased Sensors Noble metals are characterized by the presence of free electrons near the surface (known as plasmon), which oscillate with intrinsic energy. In presence of external electromagnetic stimuli, these electrons absorb maximum amount of energy at resonance. This phenomenon is known as the SPR. They can be localized on the surface of individual particles in colloidal systems, or propagating on a planar surface coated with nanoparticle film that can be measured only through SPR instrument. The resonance wavelength is dependent on the size and shape of the particle and the film thickness. Also, change in SPR cause change in scattering properties of NPs. Such sensors are discussed in the following subsections. 6.2.1.1.1 Nanoparticle Aggregation-Based Colorimetric Aptasensors

Colorimetric nanosensors rely on the change in SPR due to size and shape of nanoparticles, especially gold nanocolloids (AuNPs) that can rapidly change color on varying particle size. The size of colloidal NPs increases due to aggregation of many NPs, which leads to change in their SPR absorption wavelength. The aggregation may occur with or without cross-linking. In cross-linking mechanism the biomolecules on surface of individual NPs bond with each other creating a cross-linked structure of hundreds of particles. In nonecross-linking strategy the AuNP solution is subjected to extreme conditions that affect the stabilizing forces on NP surface. Thus NPs fail to remain dispersed and aggregate. The signal can be observed visually and spectrally, making the system simple and often avoiding the requirement of instruments.

Nanoparticle-Based Aptasensors for Food Contaminant Detection

Such colorimetric aptasensors have been designed using almost exclusively AuNPs. AuNPs display bright cherry red color in its dispersed state and dull purple color in aggregated state. In nonecross-linking aggregation, aptamers adsorbed on AuNPs surface protect them from aggregating agents. In presence of analyte, the aptamer desorbs from nanoparticle surface, leaving them unprotected and leading to aggregation. The advantages of such a format are that the signal is a rapid visual color transformation, the NPs need not be surface-modified, and the aptamers need not be labeled. Various food analytes and contaminants such as bisphenol-A (BPA) (Mei et al., 2013), acetamiprid (Shi et al., 2013), melamine (Yun et al., 2014), and chloramphenicol (R. Sharma et al., 2016b) were detected using the same principle of “nonecross-linking aggregation” mechanism of AuNPs. A recent report by Ma et al. (2017) describes detection of Salmonella typhimurium using this principle. The detection limit achieved was 56 colony forming units (cfu)/mL. In an attempt to devise a low-cost, disposable, and convenient chip-based sensor for chlorpyrifos insecticide, Chaumpluk and Janduang (2017) used a plastic acrylic chip with preadded aptamer and AuNP solutions and a sample socket to add sample. In a few simple steps and within 10 min, the chip showed visual color change with a detection limit of 10 ppb. Salt-induced aggregation of AgNPs served the basis for kanamycin detection by Xu et al. (2015). A second molecule is often used as a mediator for aptamer binding and nanoparticle protecting. This method was used by He et al. (2013) for detection tetracycline (TET) in milk. The aptamer formed a duplex with a cationic polymer (instead of AuNPs) in the absence of analyte. The cationic polymer was the aggregating agent. On addition of analyte, the aptamer releases the polymer that aggregates the nanoparticles. Tetracycline could be detected till 1 mM visually and up to 45.8 nM using a colorimetric detector. Similar techniques were devised for lysozyme assay in egg white by Yao et al. (2016) and for identifying malathion in presence of other interfering substances by Bala et al. (2016) (cf. Fig. 6.2). There are fewer reports on cross-linked aggregation-based food contaminant detection. An aptamerecross-linked hydrogel was designed as quantitative detection of Ochratoxin A (OTA). The hydrogel network was formed by hybridization between a single strand of OTA aptamer and two complementary DNA strands linked to linear polyacrylamide chains. This hydrogel was preloaded with AuNPs. In presence of OTA, the aptamer binds with OTA, disrupting and dissociating hydrogel structure and releasing AuNPs, which can be observed visually. In the same work, encapsulated Au@Pt coreeshell nanoparticles were incorporated in the hydrogel instead of AuNPs. These particles catalyzed the oxidation of H2O2 generating O2 that gave a visual quantitative readout on a chip. This provided a portable detection format and OTA was detected in beer followed by immunoaffinity-based enrichment at a limit of 0.51 ppb (Liu et al., 2015).

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Figure 6.2 Schematic illustration of a colorimetric aptasensor based on gold nanoparticles for the detection of malathion. In the absence of malathion, the aptamer interacts only with the polymer and hence, the gold nanoparticles are well dispersed due to lack of sufficient amount of poly(diallyldimethylammonium) PDDA. However, in the presence of malathion, the aptamer interacts with the malathion and free PDDA aggregate the AuNPs, thereby leading to the color change of the solution from red to blue. (Reprinted from Bala, R., Kumar, M., Bansal, K., Sharma, R.K., Wangoo, N. , 2016. Ultrasensitive aptamer biosensor for malathion detection based on cationic polymer and gold nanoparticles. Biosensors and Bioelectronics 85, 445e449 with permission from Elsevier.)

Aggregation-based colorimetric detection, though widely used, needs some additional measures for successful detection in real samples, such as, separation of unmodified AuNPs or surplus aptamers from the reaction mixture and requirement of small aptamers for small molecular targets. 6.2.1.1.2 Propagating Surface Plasmon Resonance and Rayleigh ScatteringeBased Sensors

In a dedicated SPR sensing instrument, the propagating SPR on a noble metal-coated surface is transduced. On the event of a biorecognition on the surface, the SPR property changes leading to a change in the refractive index that is registered by the instrument. Under resonance condition, Rayleigh scattering (reemission or scattering of photons carrying same quantum of energy as absorbed incident photons) is also found to be maximum. The phenomenon is called resonance Rayleigh scattering (RRS). The assay mechanism for RRS is based on aggregation of NPs as in colorimetric detection. The measurement of RRS signal, however, is carried out using a regular spectrofluorometer. An aptamer selected for peanut allergen Ara h1 was used for its capture from food matrix and subsequent sandwich assay using fiber optic SPR biosensor. The probe tip

Nanoparticle-Based Aptasensors for Food Contaminant Detection

containing the aptamer-captured Ara h1 was dipped in solution containing specific polyclonal antibodies followed by protein AeAuNPs conjugate to increase sensitivity (Tran et al., 2013). Another allergen protein lysozyme was detected up to 2.4 nM in spiked red and white wines using biotinylated aptamer attached to thiolated-gold layer capped with neutravidin (Mihai et al., 2015). Chang et al. (2013) developed an AuNP-aptamer probe based RRS detection technique for single cells of Staphylococcus aureus. Both methods that were described, involved attachment of the probes, followed by their elution and RRS measurement. Aggregated AuNPs have been shown to have catalytic effect, a property that was used for RRS-based detection. In one report, it catalyzed the formation of cuprous oxide cubic (that generated RRS signals) in the absence of analyte tetracycline in milk (Luo et al., 2014). In another report, preformed aggregated AuNPs catalyzed synthesis of a second type of AuNPs, and the latter generated the signals. The aggregation of the catalytic AuNPs was dependent on protection by aptamers against analyte lead ions in natural water samples (Ye et al., 2016), explained in Fig. 6.3. Antimony ions were detected using RRS energy transfer from graphene oxide nanoparticles (GO NPs) to iodide ion. Reduced

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Figure 6.3 Principle of aptamer nanogold catalytic detection of Pb2þ with resonance Rayleigh scattering effects. (Reprinted from Ye, L., Wen, G., Ouyang, H., Liu, Q., Liang, A., Jiang, Z., 2016. A novel and highly sensitive nanocatalytic surface plasmon resonance-scattering analytical platform for detection of trace Pb ions. Scientific Reports 6, 24150 with permission from Nature Publishing Group.)

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antimony was bound to acceptor iodide ions and reduced energy transfer efficiency, thus increasing the RRS intensity (Wen et al., 2017). 6.2.1.1.3 Surface-Enhanced Raman ScatteringeBased Sensors

The Raman scattering signature of biomolecules is immensely amplified by surface plasmondthe phenomena are termed as surface-enhanced Raman scattering (Craig et al., 2013). This enhancement has enabled single molecule detection. Pesticides (isocarbophos, phorate, omethoate, and profenofos) were detected till parts per million (ppm) concentrations using aptamer conjugated silver dendrites (Pang et al., 2014). Formation of self-assembled monolayers on the surface of AuNPs was used to detect BPA (Marks et al., 2014). The monolayers helped in AuNP stabilization, specific aptamer conjugation, and protection from chemical degradation. This phenomenon was used for quantification of S. typhimurium using goldesilver coreeshell nanoparticles (Duan et al., 2016) and spiny gold nanoparticles (Ma et al., 2018) and lysozyme using silver dendrites (Boushell et al., 2017). 6.2.1.2 Fluorescence-Based Sensors Fluorescence is a phenomenon due to which a molecule or a nanomaterial absorbs light at shorter wavelengths and emits at higher wavelength while returning to ground state. An exceptional case is UCNPs that emit light at a shorter wavelength than the excitation wavelength. The most common mechanism used for fluorescence-based aptasensing is competitive binding between the analyte and a complementary strand to the aptamer. A pair of molecules is used for signal generationdthe fluorophore is either paired with a quencher (that absorbs the fluorescence turning off the emission) or with a second fluorophore (that absorbs emission from first fluorophore and reemits at different wavelength). This transfer of radiation from one molecule to the next at resonance wavelength is known as fluorescence resonance energy transfer (FRET). In the assay, the aptamer and the complementary strand are labeled with fluorophore and quencher or vice versa. Because of structure switching of aptamers on analyte binding, the complementary strand is displaced from the hybridization complex and the resulting distance between the two generates a fluorescent signal. Nanoparticles can be used either as fluorophores or quenchers. Alternatively, quenching nanoparticles may be used on which fluorophoretagged aptamers directly adsorb, when analyte is not present. 6.2.1.2.1 FRET Based on Fluorophore-Tagged Aptamer and Quencher Nanoparticles or Complementary Strands

The hybridization technique has been used to detect S. typhimurium with aptamers labeled with donor UCNPs and complementary strands labeled with acceptor FAM (carboxyfluorescein) (Wang et al., 2017a), whereas AFB1 was detected by fluorescent donor polymer dots and acceptor AgNPs (Nasirian et al., 2017). The latter approach of

Nanoparticle-Based Aptasensors for Food Contaminant Detection

adsorption on nanoparticles was used for multiplexed detection of lysozyme, cytochrome c, and thrombin by fluorophore FAM-labeled aptamers and GO quencher. This method required separation of the three aptamer-protein complexes by a hybrid isoelectric focusingecapillary zone electrophoresis method (Lin et al., 2014). One research group described fluorescence quenching using FAMelabeled complementary strands to aptamers and AuNP as quenchers to detect antibiotics streptomycin (Emrani et al., 2016) and kanamycin in milk (Ramezani et al., 2016). Dual FRET is a technique that employs fluorescence emission at two wavelengths each by a different fluorophore, which recognize distinct analytes. It enables simultaneous detection of multiple targets. Dual FRET by UCNPs as fluorophores and GO as quencher was used to identify two mycotoxins (Wu et al., 2012) and by UCNPeAuNP pair to assay mercury and lead ions (Wu et al., 2014b). 6.2.1.2.2 FRET Based on Singular Molecular Beacons

The above method may suffer from quenching even if fluorophore- and quencher-tagged molecules are not adsorbed or hybridized to each other. This is due to their chance proximity in solution, in which the soluble or suspended molecules are in a dynamic state of motion. In a simpler FRET mechanism, there is no necessity of a complementary strand or colloidal nanoparticles. This also avoids the issue of nonspecific quenching. The fluorophoreequencher pair is attached to either ends of the aptamer. On structureswitching the ends might come closer to each other or move apart, turning the fluorescence signal either off or on. Aptamers tagged as such are called molecular beacons. Molecular beacons have been successfully used to detect Hg2þ employing FAMeAuNPs pair (Tan et al., 2013), Fumonisin B1 by UCNPseAuNPs pair (Wu et al., 2013), and BPA using QDeAuNPs pair (Li et al., 2016). The exclusive requirement of this mechanism is an aptamer whose structure changes considerably so that there exists substantial distance between its ends before or after binding, to give an output with acceptable resolution. The different modes of FRET that are used for biosensing are illustrated in Fig. 6.4. 6.2.1.2.3 Fluorescence-Based Detection Coupled with Magnetic Separation

Another approach to isolate the fluorophore to avoid quenching by matrix or proximal quenchers is usage of MNPs. They also aid in concentrating the fluorophore to achieve higher sensitivity. Most of these assays use a sandwich format, where capture aptamer is labeled with MNPs and reporter aptamer with fluorescent labels. In one sandwich assay, UCNPs acted as dual color fluorescent labels for S. typhimurium and Staph. aureus in real water samples. In the presence of magnetic field, the MNP aptamer cellseUCNP aptamer complex could be concentrated reducing the detection limits to 5 and 8 cfu/ mL, respectively (Duan et al., 2012). The same pathogens were quantified by Wang et al. (2016) using identical assay format with lanthanide-doped fluorescent nanoparticles. Concentration of the complex enabled lowering of detection limit from 100 cfu/mL to

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Figure 6.4 Different modes of fluorescence resonance energy transfer (FRET)ebased aptasensors (A). Competitive binding between complementary strand and analyte with aptamer. Both aptamer and complementary strand are labeled (B). Competitive binding between nanoparticle and analyte with aptamer. Aptamer is labeled (C) Competitive binding between complementary strand and analyte with aptamer. Complementary strand is labeled, its fluorescence quenched by nanoparticle. (D) Molecular beacon with both ends of aptamer labeled.

15e20 cfu/mL. A slightly different multiplexed detection of three pathogens was attempted by Wu et al. (2014a). Here the format was competitive, and the complementary strand was labeled with MNPs. The UCNPs attached aptamers bound to pathogens in their presence. The excess unbound aptamers were hybridized with complementary

Nanoparticle-Based Aptasensors for Food Contaminant Detection

strand MNPs. After magnetic separation, luminescence intensity was measured, which was inversely proportional to the number of bacterial cells. This method was used using catalytic property of DNA as signal generator by Chen et al. (2014). DNA oligomers could catalyze synthesis of fluorescent silver nanoclusters. The catalytic complementary strand to aptamer against OTA was tagged to magnetic beads for separation. The amount of analyte was directly proportional to the number of displaced strands and thereby the mass of fluorescent AgNCs synthesized. Here, magnetic separation ensures the conduction of a second reaction for detection. Nanoparticles were tagged to aptamers recognizing Staph. aureus and S. typhimurium for their multiplexed detection. Strips can be used to immobilize capture or reporter molecules to avoid any background quenching by the matrix. They have been employed for direct fluorescence measurement that do not involve FRET or quenching. Aptamers recognizing pathogens in food were used for their detection using lateral flow test strips that had capture antibodies (Bruno, 2014). The reporters were aptamers labeled with either AuNPs or QDs, giving visible color or fluorescence signals. 6.2.1.3 LuminescenceeBased Sensors Luminescence is the spontaneous emission of light from a substance due to chemical reaction, electrical events, or motion at subatomic level. CL specifically involves emission of light from a chemical reaction wherein an intermediate chemical compound returns from excited to ground state while emitting photons. Luminescence gains advantage over fluorescence, due to the lack of requirement of excitation energy. Nanoparticles such as UCNPs can be synthesized to possess intrinsic luminescence. They can also aid in enhancement of luminescence due to their electronic properties (Abhijith et al., 2014). Analytical applicability of CL primarily relies on their fast reaction kinetics, wide linear range, and simple reaction chemistry. Similar to fluorescence, luminescence energy transfer can be used for foodcontaminant detection. Dai et al. (2016) demonstrated an aptamer-complementary strandebased competitive sensor for OTA in beer. UCNPs served as luminescent particles and gold nanorods as acceptors (quenchers). Recently, UCNPs and gold nanorods were used to detect S. typhimurium in milk (Cheng et al., 2017). However, in this assay the aptamer-tagged UCNPs are directly adsorbed on gold nanorods due to electrostatic attraction, and complementary strand was omitted. A very common application of nanoparticles in CL-based assays is their catalytic effect on the CL reaction. Both aggregated and unaggregated AuNPs have been used for catalyzing and thereby enhancing CL signals. In one report, MNPs-linked capture antibodies were used for chloramphenicol binding. The reporter probe (complementary strand) was labeled with N-(4-aminobutyl)-N-ethylisoluminol (ABEI)-functionalized gold nanoflowers. In presence of the target, the entire complex could be magnetically separated and nanoflowers catalyzed CL reaction between ABEI, p-iodophenol, and hydrogen

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peroxide (Hao et al., 2015). In the same year, Hosseini et al. (2015) published a report on AFB1 detection, using nonecross-linked aggregated AuNPs that catalyzed luminolhydrogen peroxide CL.

6.2.2 Electrochemical Biosensors Electrochemical sensors measure change in current, potential, conductance, or impedance due to redox reactions occurring at biomolecule-modified electrodes. These immobilized molecules are mostly bioreceptors or mediators of electron transfer, and the reactions either reduce or oxidize the target. Nanomaterials play the dual role of increasing surface area on electrodes for bioreceptor immobilization and to catalyze redox reactions. A few examples of such studies are the use of AuNPs to facilitate aptamer immobilization, and thereby signal amplification to detect of acetamiprid (Fan et al., 2013), and iridium oxide nanoparticles on screen-printed carbon electrodes to detect OTA in wine samples (Rivas et al., 2015). AuNPs-coated electrodes were employed in a competitive assay format for streptomycin in serum. Both aptamer and complementary strand were immobilized on the electrode, and their mutual hybridization created an arch-like structure (cf. Fig. 6.5). Exonuclease I was subsequently added, which is capable of cleaving only the 30 end of single strand DNA. The enzyme could not affect the arch and no electrons were generated at 3-/4-

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Figure 6.5 Schematic illustration of streptomycin detection based on an electrochemical aptasensor. In the absence of streptomycin, the Arch-shape structure of Apt-CS conjugate is intact and redox probe does not have access to the surface of electrode, leading to a weak electrochemical signal (A). In the presence of streptomycin, aptamer binds to streptomycin and leaves the CS. Addition of Exo I degrades CS, leading to access of redox probe to the surface of electrode and a strong electrochemical signal (B). (Reprinted from Danesh, N.M., Ramezani, M., Emrani, A.S., Abnous, K. and Taghdisi, S.M, 2016. A novel electrochemical aptasensor based on arch-shape structure of aptamer-complimentary strand conjugate and exonuclease I for sensitive detection of streptomycin. Biosensors and Bioelectronics 75, 123e128 with permission from Elsevier.)

Nanoparticle-Based Aptasensors for Food Contaminant Detection

the electrode. In presence of the antibiotic, the aptamer was dehybridized from the complementary strand. The free single strand was digested by exonuclease I, generating amplified current at the electrode (Danesh et al., 2016). Composite nanoparticles have often been used to combine the advantages of several nanomaterials, e.g., AuNPs with polymers and carbon nanomaterials. Self-assembled gold nanoparticles/conducting polymers were used for kanamycin detection (Zhu et al., 2012) and AuNP/graphene composite for BPA detection (Zhou et al., 2014) both in milk-based samples. Multiple nanocomposite layers, i.e., grapheneeAuNPs, chitosaneAuNPs, and multiwalled CNTsecobalt phthalocyanine, were used for their synergistic enhancement in kanamycin detection (Sun et al., 2014). In a unique format, the nanoparticles were not coated on the electrode. A sandwich aptasensing technique was used to detect Staph. aureus in real water samples. One set of aptamers were tagged with MNPs and the other with AgNPs. After analyte binding the complex was magnetically separated, and AgNPs were stripped at anode generating a voltametric signal (Abbaspour et al., 2015).

6.2.3 Other Detection Formats 6.2.3.1 Colorimetric Assays Without Involving Nanoparticle Aggregation As mentioned in Section 6.2.1.1.2, AuNPs are capable of catalyzing nanoparticle synthesis. Silver reduction by AuNPs for detecting S. typhimurium was proposed by Yuan et al. (2014). In a sandwich format, specific capture aptamers were immobilized onto microtitre plates. The second set of detection aptamers were conjugated to thiolated AuNPs. A silver salt solution was added, which was reduced to AgNPs that produce a dark gray color. Cells could be visually quantified (cf. Fig. 6.6). Another visual assay for OTA was developed by Soh et al. (2015), which was based on the effect of biomolecule capping density on AuNPs growth. If aptamer coverage on AuNP surface was high, the AuNPs further grew into spherical particles. If coverage was less, branched Au nanostructures were formed. With higher OTA concentrations, more aptamers were engaged by it and lesser was available for AuNP coverage. The morphological differences were reflected in the plasmon distribution, thereby influencing the SPR absorbance and hence the color of AuNP solutions. 6.2.3.2 DNA AmplificationeBased Assays Suh and Jaykus (2013) described MNP labeled aptamer-qPCR (quantitative polymerase chain reaction) assay for sensing Listeria monocytogenes. After the bacterial cells were captured, the complex was magnetically separated, aptamers were isolated, amplified, and quantified using qPCR. The same group later published detection of Campylobacter jejuni using identical magnetic capture principle (Suh et al., 2014). Alternatively immunomagnetic separation can be coupled with aptamer PCR amplification. For capturing S. typhimurium from ground turkey magnetic-bead linked antibodies were used. The

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Figure 6.6 Schematic illustration of the detection of Salmonella typhimurium using aptamereAuNPs and silver enhancement. (Reprinted from Yuan, J., Tao, Z., Yu, Y., Ma, X., Xia, Y., Wang, L., Wang, Z., 2014. A visual detection method for Salmonella typhimurium based on aptamer recognition and nanogold labeling. Food Control 37, 188e192 with permission from Elsevier.)

aptamers are bound to the complex in sandwich fashion, after which they were isolated and amplified (L. Wang et al., 2017b).

6.3 CONCLUSIONS AND FUTURE PERSPECTIVE Since the inception of aptamers as alternatives to antibodies in biorecognition, numerous research groups have endeavored to develop affordable and sensitive diagnostics using the same. Existing nanomaterial-aided platforms were incorporated into these biosensing systems with considerable success. Several analytes are yet to be determined, against which aptamers may or may not have been selected. In this chapter, we have sought to enlighten the readers on the existing principles of food contaminant detection that bring into synergy the advantages of both nanomaterials and aptamers. Optical- and electrochemicalbased transduction mechanisms are majorly employed in these sensors. To extend the knowledge in aptamer-based biosensing, several reports and reviews may be useful. A

Nanoparticle-Based Aptasensors for Food Contaminant Detection

few of them summarize generic aptasensors (with and without nanomaterials) (Dong et al., 2014; Acquah et al., 2015; Gaudin, 2017) and few focus on nanomaterial-based aptasensing in other fields, i.e., environment, clinical, etc. ( Jo and Ban, 2016; Singh et al., 2017). However, it is essential to acknowledge that to bring aptamers to mainstream biosensing, researchers as well as industry must overcome certain obstacles. A few technical issues with aptasensing concern their stability in real solutions, nonspecific interactions, and lack of understanding of conformational change dynamics. Use of MNPs and some novel nanomaterials may grant the assays higher specificity, as will convenient sample pretreatment methods. Advances in SELEX protocol, especially for small molecules, will be able to generate more specific aptamers. There is also a pressing need for reliable software systems that will be able to predict single strand DNA folding in solution. At the same time, the industry and government agencies should extend considerable support in ratification, development, and commercialization of portable field-applicable aptasensors. Given that aptamers are substantially advantageous bioreceptors as compared to antibodies, in terms of biosynthesis, ease of derivatization and modification, successful purification to homogeneity, and considerably lower cost, they will make excellent candidates for nanoparticle-aided detection strategies, once even a few of the abovementioned challenges are successfully combated.

ABBREVIATIONS ABEI N-(4-aminobutyl)-N-ethyl-isoluminol AgNPs Silver nanoparticles AuNPs Gold nanoparticles BPA Bisphenol A cfu Colony forming units CL Chemiluminescence CNT Carbon nanotubes FAM Carboxyfluorescein FRET Fluorescence resonance energy transfer GO Graphene oxide MNP Magnetic nanoparticles NP Nanoparticles OTA Ochratoxin A PCR Polymerase chain reaction PDDA Poly(diallyldimethylammonium) ppb Parts per billion ppm Parts per million QD Quantum dots qPCR Quantitative polymerase chain reaction RRS Resonance Rayleigh Scattering S. typhimurium Salmonella typhimurium SELEX Systematic evolution of ligands by exponential enrichment

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SERS Surface enhanced Raman scattering SPR Surface plasmon resonance Staph. aureus Staphylococcus aureus TET Tetracycline UCNP Upconversion nanoparticle

ACKNOWLEDGMENTS The authors thank the Director of the CSIR-CFTRI for support and encouragement.

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FURTHER READING Duan, N., Ding, X., He, L., Wu, S., Wei, Y., Wang, Z., 2013. Selection, identification and application of a DNA aptamer against Listeria monocytogenes. Food Control 33, 239e243. Duan, N., Wu, S., Dai, S., Miao, T., Chen, J., Wang, Z., 2015. Simultaneous detection of pathogenic bacteria using an aptamer based biosensor and dual fluorescence resonance energy transfer from quantum dots to carbon nanoparticles. Microchimica Acta 182, 917e923.

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Ferrier Jr., R.C., Lee, H.S., Hore, M.J.A., Caporizzo, M., Eckmann, D.M., Composto, R.J., 2014. Gold nanorod linking to control plasmonic properties in solution and polymer nanocomposites. Langmuir 30, 1906e1914. Liu, X., Wang, F., Aizen, R., Yehezkeli, O., Willner, I., 2013. Graphene oxide/nucleic-acid-stabilized silver nanoclusters: functional hybrid materials for optical aptamer sensing and multiplexed analysis of pathogenic DNAs. Journal of the American Chemical Society 135, 11832e11839. Nayak, P., Anbarasan, B., Ramaprabhu, S., 2013. Fabrication of organophosphorus biosensor using ZnO nanoparticle-decorated carbon nanotubeegraphene hybrid composite prepared by a novel green technique. Journal of Physical Chemistry C 117, 13202e13209. Poma, A., Brahmbhatt, H., Pendergraff, H.M., Watts, J.K., Turner, N.W., 2015. Generation of novel hybrid aptameremolecularly imprinted polymeric nanoparticles. Advanced Materials 27, 750e758. Rojas, J.V., Higgins, M.C.M., Gonzalez, M.T., Castano, C.E., 2015. Single step radiolytic synthesis of iridium nanoparticles onto graphene oxide. Applied Surface Science 357 (B), 2087e2093. Smuc, T., Ahn, I.Y., Ulrich, H., 2013. Nucleic acid aptamers as high affinity ligands in biotechnology and biosensorics. Journal of Pharmaceutical and Biomedical Analysis 81e82, 210e217. Yin, P.T., Kim, T.H., Choi, J.W., Lee, K.B., 2013. Prospects for grapheneenanoparticle-based hybrid sensors. Physical Chemistry Chemical Physics 15, 12785e12799.

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