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Recommended Citation Recommended Citation Chen, Chun-Hsien; Wang, Chun-Chi; Ko, Po-Yun; and Chen, Yen-Ling (2020) "Nanomaterial-based adsorbents and optical sensors for illicit drug analysis," Journal of Food and Drug Analysis: Vol. 28 : Iss. 4 , Article 11. Available at: https://doi.org/10.38212/2224-6614.1137

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Nanomaterial-based adsorbents and optical sensors for illicit drug analysis Nanomaterial-based adsorbents and optical sensors for illicit drug analysis

Cover Page Footnote Cover Page Footnote We gratefully acknowledge the support of the Ministry of Science and Technology of Taiwan (MOST 109-2113-M-194-011) for funding this work.

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Nanomaterial-based adsorbents and optical sensorsfor illicit drug analysis

Chun-Hsien Chen a, Chun-Chi Wang a,e, Po-Yun Ko b, Yen-Ling Chen c,d,e,*

a School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwanb Post Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwanc Department of Chemistry and Biochemistry, National Chung Cheng University, Chia-Yi, Taiwand Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwane Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan

Abstract

The abuse of illicit drugs has been prevalent in recent years and is associated with crime and public health issues. Tostrengthen public security and fortify public health services with respect to the increasing severity of drug abuse, ac-ademic and government institutes have been devoted to constructing relative analytical methods for illicit drugs. Todate, the development of sensors has been greatly emphasized due to their features of high sensitivity, prompt detectionand flexible manipulation; thus, sensors can serve as alternatives to conventional sophisticated instruments. Recently,the use of nanomaterials has inspired the development of a series of innovative sample pretreatment and detectionstrategies in the field of analytical chemistry. Herein, this review elaborated the application of nanomaterials inanalytical methods, including sample pretreatments, colorimetric sensors and fluorescent sensors. The utilization ofnanomaterials in the analytical field provides novel perspectives for the development of detection platforms and fa-cilitates the monitoring of illicit drugs in diverse complex matrices.

Keywords: Nanomaterial, Adsorbents, Colorimetric sensors, Fluorescent sensors, Illicit drugs

1. Introduction

T he prevalence of drug abuse has become asevere public health issue and a serious

criminal issue worldwide in recent years. Illicitdrugs accompanied by addiction, organ dysfunc-tion and fatality at high doses are categorized onthe basis of their traits as depressants, stimulants,narcotics or hallucinogens [1]. The abuse of thesedrugs can gradually deteriorate the mental orphysical condition of users. The United NationsOffice on Drugs and Crime reported that anenormous number of individuals, up to 188million, have used cannabis as a hallucinogen atleast once. Stimulants, such as cocaine, amphet-amine and methamphetamine, are the secondmost abused drugs, with 68 million users. Among

them, cocaine accounted for 18 million users in2017. Furthermore, 50 million individuals world-wide had taken up opioids in 2017 [2]. In Taiwan,the data according to the Analytic LaboratoryDrug Abuse Report System from 1999-2011 alsoshowed that methamphetamine was the mostwidely abused drugs [3]. According to the annualstatistic of abusing drugs in 2018 in Taiwan, 36,746individuals who were influenced by illicit drugswere reported, which presented an increasingtrend from 2016 to 2018. Moreover, the cases ofpolypharmacy were also determined to be up to73%. Among these cases, the dual combination ofillicit drugs accounts for 81.2% of multiple drugabuse. Methamphetamine and 3, 4-methyl-enedioxy-methamphetamine (MDMA) were themost prevalent drugs used in dual combination.

Received 24 May 2020; Received in revised form 23 August 2020; accepted 18 September 2020.Available online 1 December 2020

* Corresponding author at: Department of Chemistry and Biochemistry, National Chung Cheng University, Chia-Yi, Taiwan. Fax: 886 5 2721040.E-mail address: [email protected] (Y.-L. Chen).

https://doi.org/10.38212/2224-6614.11372224-6614/© 2020 Taiwan Food and Drug Administration. This is an open access article under the CC-BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

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Other illicit drugs can be also found in multipledrug abuse, such as ketamine, norketamine,morphine and codeine [4]. To efficiently controlthe extending prevalence of drug abuse, thegovernment in Taiwan also legislated cut-offlevels of illicit drugs in human urine which pre-sented in Table 1 [5,6]. Regulations in EU andUSA corresponding to that in Taiwan are alsolisted in the table [7e9].The main test methods for determining the pres-

ence of illicit drugs in medical and government in-stitutions include liquid chromatography coupledwith (tandem) mass spectrometry (LC-MS or LC-MS/MS) [10,11], gas chromatography coupled withmass spectrometry (GC-MS) [12] and immunoassays[13], which are commercially available and widelyutilized for monitoring the levels of illicit drugs. Inrecent decades, the nanomaterial-based analyticaltechniques have become a novel trend in illicit druganalysis. Nanomaterials possess unique character-istics such as high surface area, ease of modification,which can perform diverse application, such assample pretreatment and biosensor establishment,so as to facilitate the monitoring illicit drugs.To monitor the levels of illicit drugs efficiently, the

sample pretreatment procedure is a crucial factor toobtain ideal performance on detection. Neverthe-less, the elimination of interferences from complexmatrices may be challenged for the detection ofillicit drugs because the detection usually imple-mented in human body fluids (blood, urine, hairand saliva …), foods and beverages which composeof varied compounds.Samplepretreatment coupledwithnanometer-sized

magnetic nanoparticles (MNPs), can provide fasterphase separation by applying an external magneticfield and be easy to reuse.MNPs also can be utilized to

generate a high selectivity, facile extraction procedure,less reagent consumption compared to conventionalsample pretreatment methods.In addition to sample pretreatment methods,

nanomaterials can also be applied as signal re-porters that provide rapid and sensitive detection.Nanomaterial-based optical sensor systems can becategorized into colorimetric and fluorescent sensorsystems. In colorimetric methods, noble metalnanoparticles, namely gold and silver, were uni-versally utilized nanomaterials attributed to theirunique optical property of surface plasmon reso-nance (SPR) [14,15]. The phenomenon of SPR facil-itates the visual observation of the color change ofnanomaterials when the analyte is added into thedetection system. Regarding fluorescent methods,nanomaterials were utilized to develop a versatiledetection strategy. These kinds of nanomaterials,such as nanoclusters (NCs), quantum dots (QDs),carbon dots (CDs) and upconversion nanoparticles(UCNPs), possess the trait of tunable luminescentemission, which can be substituted for conventionalfluorescent indicators such as fluorescein (FAM),cyanine 3 (Cy3), carboxytetramethylrhodamine(TAMRA), carboxy-X-rhodamine (ROX), etc[16e19].Attributed to the development of novel sensors,

further evolution has also implemented a series ofrapid diagnostic strategies for illicit drugs in com-bination with nanomaterials. This review mainlyemphasizes the analytical techniques among nano-material-based adsorbents, nanomaterial-basedcolorimetric sensor systems and fluorescent sensorsfor the detection of illicit drugs.

2. Surface functionalized MNPs

Magnetic solid-phase extraction (MSPE) was firstestablished in 1999 by �Safa�rõkov�a et al. using

Table 1. Regulations of cut-off levels of illicit drugs in Taiwan, EU and USA.

Taiwan (TFDA 1) EU (EMCDDA 2) USA (HHS 3)

Urine (ng/mL) Whole blood (ng/mL) Oral fluid (ng/mL) Urine (ng/mL) Oral fluid (ng/mL)

Benzodiazepines 100 140 (Diazepam) 5 (Diazepam) - -Amphetamine 500 20 360 250 25Methamphetamine 500 20 410 250 25MDMA 500 20 270 250 25Morphine 300 10 95 2000 15Codeine 300 10 94 2000 15Cocaine - 10 170 - 8Benzoylecgonine 150 50 95 100 8Ketamine 100 - - - -Norketamine 100 - - - -THC 15 1.0 27 15 2

Abbreviation: 1 TFDA: Food and Drug Administration (Taiwan), 2 EMCDDA: European Monitoring Centre for Drugs and DrugAddiction, 3 HHS: United States Department of Health and Human Services.

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magnetic charcoal as an adsorbent [20]. MSPE is anovel technique that accomplishes extraction by theinteraction between the functional group on thesurface-modified magnetic material as the adsor-bent and the analytes. Compared to conventionalmagnetic beads, nanometer-sized magnetic parti-cles possess the properties of superparamagnetism,better dispersibility and higher surface area, whichenhance the extraction efficiency [21]. In order toovercome the problems, such as complex matricesand time-consuming sample preparation, tech-niques on the basis of surface functionalized MNPswere developed to extract illicit drugs. Previousstudies are summarized in Table 2 which presentedextraction condition corresponding to each adsor-bent in illicit drugs analysis.

2.1. Small organic molecules

The magnetic core of magnetic nanoparticles(MNPs) is mainly composed of iron, nickel, cobaltand their oxides. In conventional MNPs, smallorganic molecules were used to modify iron oxideMNPs, including carbon [22,23], methacrylic acid-3-(trimethoxysilyl) propyl ester (MPS) [24,25], whichinfluences the ability of the adsorbent to capture illicitdrugs such asmethamphetamine [13,23], cocaine [24]and morphine [25] in urine or hair samples. Theinteraction between analytes and surface-modifiedmagnetic nanoparticles was implemented by van derWaals forces, p-p stacking interactions, and hydro-phobic or electrostatic interactions.Boojaria et al. synthesizedMPS-modifiedMNPs for

extracting morphine from human hair. The pre-treated 50 mg of hair sample was rinsed with ethanoland the solution was subsequently diluted withdeionizedwater. After that,morphinewas spiked intothe treated hair solution. The recovery ofmorphine inhair solution by using MPS-modified MNPs was ob-tained to be 87.62%. Moreover, an enrichment factorof 208 was acquired by this method, which enhancedthe detection sensitivity up to 0.1 ng/mL as the limit ofdetection (LOD) by HPLC-UV [25].

2.2. Polymer

The surface of fabricated MNPs from polymer arebetter than small molecules. It is found to havesignificant advantages, such as high stability insuspension. Haeri et al. established a biodispersiveliquid-liquid microextraction (bio-DLLME) basedon polypyrrole-coated iron oxide nanoparticles formethamphetamine extraction in urine [26]. Theurine sample was first treated with polypyrrole-coated iron oxide nanoparticles, and the desorption

solution containing methamphetamine was furtherextracted by a rhamnolipid biosurfactant. The LODwas measured to be 0.33 ng/mL by HPLC-UV andan enrichment factor of 310 within 2 min of extrac-tion time. In addition, carbon nanotubes (CNTs)[27,28] and graphene oxide (GO) [29,30] were alsoutilized as composites with iron oxide MNPs. CNTsand GO provide p-p stacking interactions andchelation sites for hydrogen bonds, respectively, toaromatic compounds such as methamphetamine,cocaine, ketamine, codeine and morphine [27e30].The MSPE method, based on a magnetite/rGO/sil-ver nanocomposite, was utilized for the extraction ofcodeine and morphine. The nanomaterials withhigh surface areas, suitable chemical surfaces andfunctional groups as adsorbed sites provided supe-rior enrichment factors for analytes up to 1000 witha 15 min extraction time. The enrichment factor ofthe novel MSPE method is much higher than thatobtained by conventional DLLME in the range of63-85 [29].

2.3. Aptamer and antibody

The utilization of specific ligand, namely aptamerand antibody, as the extraction agent for illicit drugsprovide specificity on sample pretreatment proced-ure. This kind of ligand can capture certain targetfrom complex matrix and avoid interferences duringdetection. Aptamers, short single-strand DNA orRNA, can recognize analytes and increase thespecificity of the extraction procedure. They are easyto obtain and more stable with respect to biodeg-radation. Du et al. developed a colorimetric sensorsystem for detecting cocaine [31]. Cocaine aptamerswere modified on amine-functionalized MNPs andanother cocaine aptamer with hemin-G-quad-ruplexes hydrides with cocaine aptamer-modifiedMNPs when cocaine was present simultaneously.The aptasensor can capture the cocaine within acomplex matrix by aptamer-modified MNPs in anexternal magnetic field. Hemin-G-quadruplex cancatalyze the 3,3,5,5-tetramethylbenzidine sulfate(TMB)-hydrogen peroxide system to trigger thecolor change of TMB from colorless to yellow. Usingthe aptasensor mechanism, cocaine can be quanti-fied according to the TMB color change. In additionto aptamers, antibodies also have a high affinity forselective targets. When antibody-modified MNPsare prepared, amphetamine and methamphetaminecan be purified from urine samples and analyzed bymatrix-assisted laser desorption ionization time-of-flight mass spectrometer (MALDI-TOF MS) analysis[32]. Compared with other methods using surfacefunctionalized MNPs, only 20-25 mL sample and

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Table 2. Various magnetic nanomaterial-based adsorbents for analysis of illicit drugs.

Surface functionalizedMNPs

Samplevolume

Adsorbentamount

Extractiontime

Desorptiontime

AnalyticalInstrument

Enrichmentfactor

Sample Limit of detection Ref.

Small organic moleculesCarbon 5 mL 40 mg 2 min 5 min HPLC-UV - Urine 20 ng/mL for methamphetamine [22]Carbon 6 mL 15-mm

iron wire10 min 5 min HPLC-UV - Urine 5 ng/mL for amphetamine [23]

6 ng/mL for methamphetamineSMPS@PLS 1 1 mL 10 mg 21 min 10 min HPLC-MS - Urine 0.09 ng/mL for benzoylecgonine [24]

0.26 ng/mL forbenzoylnorecgonine1.15 ng/mL for cocaethylene0.92 ng/mL for cocaine1.1 ng/mL for ecgonine0.13 ng/mL for m-hydroxybenzoylecgonine0.65 ng/mL for norcocaethylene0.20 ng/mL for norcocaine

MPS 2 50 mg 15 mg 20 min 10 min HPLC-UV 208.69 Hair 0.1 ng/mL for morphine [25]

Polymerpolypyrrole 30 mg 2 min 1 min HPLC-UV 310 Urine 0.33 ng/mL for

methamphetamine[26]

o-MWNTs 3 4 mL 15 mg 10 min 10 min GC-MS - Blood 44 pg/mL for methamphetamine [27]Urine 24 pg/mL for ketamine

CNTs 500 mL 9 mg 2 min 2 min GC-MS - Breast milk 1.5 ng/mL for benzoylecgonine [28]1.6 ng/mL for cocaine

rGO/AgNC 4 2 mL 100 mg 15 min - HPLC-UV 1000 Blood 2.1 pg/mL for codeine [29]Urine 1.8 pg/mL for morphine

MNGO 5 10 mL 40 mg 25 min 15 min HPLC-UV 168 Urine 30 ng/mL for methamphetamine [30]

Aptamer5ˊ-HS(CH2)6-TTTTTGGGAGTCAAGAACGAA-3ˊ

25 mL 0.05 mg 40 min - UV - Plasma 15 ng/mL for cocaine [31]

SerumUrine

Antibodyamphetamine antibody 20 mL 0.01 mg 10 min 10 min MALDI-TOF Urine 1.87 ng/mL for amphetaminemethamphetamineantibody

MS 3.75 ng/mL formethamphetamine

[32]

Abbreviation: 1 SMPS@PLS: SiO2 and methacrylic acid-3-(trimethoxysilyl) propyl ester-divinyl benzene and vinyl pyrrolidone core-shell, 2 MPS: methacrylic acid-3-(trimethoxysilyl)propyl ester, 3 o-MWNTs: acid-oxidized multi-walled carbon-nanotubes, 4 rGO/AgNC: reduced graphene oxide/silver nanocomposite, 5 MNGO: magnetic nano graphene oxide.

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0.01-0.05 mg adsorbent were needed when usingaptamers or antibodys modified MNPs in illicit druganalysis. The ligand as the adsorbent with magneticmaterials can be flexibly selected according to thetarget analytes by different synthesis protocols.Moreover, the cooperation of the aptamer andantibody provide the specificity of extraction, lesssample and adsorbent consuming which also pos-sesses a greater tendency to eliminate interferencefrom the complex matrix.In summary, magnetic nanomaterials-based ad-

sorbents provide facile and flexible modificationwhich can utilize to capture diverse illicit drugs.According to the efficiency of eliminating sampleinterferences integrated in Table 2, a large samplevolume in the range of milliliter can be extractedand eluted with a small amount of solvent in fewmicroliter. External magnetic field play an impor-tant role on capturing magnetic adsorbent bindingwith analyte so as to eliminate the sample matrix.The sample pretreatment by nanomaterials achievesnot only effective separation of analyte from com-plex matrices but also pre-concentration of samplesolution for signal amplification. In addition, thereusability of nanomaterials-based adsorbents waspotentially available which was indicated in severalliteratures, such as five times-reused divinyl ben-zene and vinyl pyrrolidone functionalized silanizedMNPs with acceptable recovery above 76.9% [24]and eighty continuous adsorption-desorption cyclesfor magnetite/rGO/silver nanocomposite withoutlosing substantial extraction efficiency [29]. In thepart of detection sensitivity, several analyticalmethods coupled with magnetic nanomaterials-based adsorbents can obtained LODs from 0.0018 to20 ng/mL by HPLC-UV. Those obtained detectionlimits were close to LODs measured by MS systemfrom 0.001 to 6 ng/mL with conventional LLE or SPE[22,26,29]. It means the sample pretreatment caneffectively improve not only the efficiency of elimi-nating interferences from complex matrices but alsoenhance the sensitivity.

3. Nanomaterial-based colorimetric sensors

Colorimetric sensors are typically used inconjunction with nanoparticles due to their uniqueoptical properties, surface dielectric environmentand catalytic activity. AuNPs are one of the mosticonic nanomaterials and have been widely appliedin the establishment of colorimetric sensors due totheir air stability and visible spectrum owing to d-d band transitions [14]. The color change of differentsizes of AuNPs can be observed via the influence onthe plasmon oscillation while irradiating by light,

namely, surface plasmon resonance (SPR) [33]. Thecolorimetric sensing systems developed to analyzeillicit drugs were mainly small organic molecules-based AuNP sensors and aptamer-based AuNPsensors.

3.1. Small organic molecules-based AuNP sensors

Many sensors functioning on the basis of ligandinteraction or ligand exchange have been estab-lished for the detection of illicit drugs that possessfunctional groups that are prone to interact with theligand on the surface of AuNPs. The mechanism ofcitrate-capped AuNPs for the detection of abuseddrugs can be divided into ligand exchange on thesurface of AuNPs [34] or ligand interaction betweencitrate and the analyte [35,36]. The ligand exchangeprocess can be performed due to the weak surface-bound citrate as the ionic stabilization agent for theAuNPs [37]. Consequently, the molecules withstronger affinity to AuNPs can competitivelydisplace the binding sites of citrate to AuNPs. Inligand exchange, Lodha et al. developed a biosensorfor the detection of codeine sulfate in bone, bonemarrow and soil [34]. Codeine sulfate can displacethe weakly bound citrate on the surface of AuNPsvia ligand exchange and further coordinate with thesurface of AuNPs by multiple binding sites, such assulfate groups and oxygen hybrid rings. The ag-gregation of AuNPs can be observed in the presenceof codeine sulfate as the bridge between the AuNPs.The LOD for codeine sulfate was 0.6 mg/mL by adigital camera of a mobile phone [34]. The othermechanism for the citrate-capped AuNPs relies onthe direct interaction between citrate and the ana-lyte by the cross-linking process. A colorimetricsensor array was established for the detection ofopioid analogs (codeine, methadone, morphine,noroxycodone, oxycodone, thebaine and tramadol)in urine [35]. The opioids possess many hydrogenbond donor/acceptor sites, including hydroxyl,methoxy and furan-like oxygen hybrid rings, whichprovide the link between citrate and opioids toinduce the aggregation of AuNPs. Consequently,the LOD of noroxycodeine was 6.7 mg/mL, andothers were as low as 0.29 mg/mL [35]. A similarbiosensor was established by Bahram et al. for thedetection of morphine, and the LOD was 0.15 mg/mLin serum and urine samples [36].Previous studies have demonstrated that electron-

rich nitrogen-containing ligands possess high af-finity for the surface of AuNPs [38], and melamine,as a nitrogen-containing ligand, has been widelyapplied in versatile detection strategies [39]. Lodhaet al. fabricated a sensor for the detection of


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clonazepam in blood, bone and bone marrow sam-ples based on the aggregation of AuNPs by theinteraction between melamine and clonazepam,which brings AuNPs closer to each other. An LODof 0.28 ng/mL can be obtained by evaluating theabsorption ratio (A636 nm/A552 nm) [40]. A similarmechanism of melamine-modified AuNPs was alsoapplied to quantify the content of codeine andmorphine in human serum and urine samples, andthe LODs of morphine and codeine were 4.9 ng/mLand 2.7 ng/mL, respectively [41]. The incubationtime of these colorimetric sensors were less than10 min.

3.2. Aptamer-based AuNP sensors

The mechanism of colorimetric biosensors on thebasis of aptamers (or oligonucleotides) for thedetection of targets with high selectivity mainlydepends on the unique property of the bindinginteraction between aptamers and analytes. Oncethe analyte is present in the detection system, theaptamer can form a complex with the analyte, andthis phenomenon produces a conformationalchange on an aptamer that fails to perform hybrid-ization or electrostatic interactions with other sub-stances, such as complementary DNA or AuNPs[42].In the case of oligonucleotide-assisted aggrega-

tion, the color change attributed to the aggregationof AuNPs depends on the distance between theAuNPs [43]. Liu et al. designed 30-thio-modifiedDNA and 50-thio-modified DNA immobilized onAuNPs (13 nm), respectively. In the absence ofcocaine, 30-thio-modified DNA and 30-thio-modifiedDNA were assembled with linker DNA and acocaine aptamer. A passive aggregation of AuNPswas observed by the color change of AuNPs fromred to purple due to the redshift of the SPR wave-length. Once cocaine is present, the aptamer in-teracts with the cocaine, and the 50-thio-modifiedDNA cannot complement the linker DNA. A redcolor was still observed because the distance be-tween the AuNPs did not shorten [44]. In addition,the mechanism of oligonucleotide-assisted aggre-gation was also applied to detect cocaine in latentfingerprints (LFPs) by nanoplasmonic imaging [45].Cocaine aptamers with two single-strand DNAmolecules modified on AuNPs form a stem-bulge-stem structure when cocaine exists. The aggregationof AuNPs and color changes of the scattered light inthe dark-field image of an LFP were observed.Consequently, the minimal detectable content ofcocaine on LFPs was measured down to 90 ng [45].

In addition to the aptasensor based on the passiveoligonucleotide-assisted aggregation of AuNPs, theactive aggregation of AuNPs, namely, salt-inducedself-assembly, was also utilized to establish analyt-ical methods for quantifying cocaine [46e49] andmethamphetamine [50]. The strategy is based on thevan der Waals attraction between the AuNPsthemselves, which induces AuNP self-assembly,and assembly between aptamers and AuNPs, whichcan prevent the aggregation of AuNPs. In general,the surface of AuNPs was adsorbed with negativeions such as citrate, and they can inhibit the ag-gregation of AuNPs themselves. However, theaddition of salt into the colloid can induce the self-aggregation of AuNPs due to the neutralization ofcitrate ions on the surface of AuNPs, which reducesthe repulsion between AuNPs. This reaction pro-duces the redshift of the absorption wavelengthupon SPR, and the color change of the colloid canalso be visually observed to change from red topurple. On the other hand, the oligonucleotide canattach to the surface of AuNPs, which createsrepulsion between the nanoparticles. Consequently,the absorption wavelength would not transformeven in a high salt concentration [42]. According tothe theory, Zhang et al. established a colorimetricaptasensor for the detection of cocaine [46]. In thepresence of cocaine, the complex, specific secondarystructure formed due to the binding of cocaine tothe aptamer [51] can resist the attachment of anaptamer onto the surface of AuNPs due to the outerphosphate backbone that can be described asdsDNA, resulting in self-aggregated AuNPs afterthe addition of salt. In contrast, the aptamer caninteract with the surface of AuNPs by van der Waalsattraction in the absence of cocaine. Consequently,the self-assembly of AuNPs can be inhibited afterthe addition of salt into the colloid. Finally, the LODwas 0.6 mg/mL [46]. Attributed to the visual changein the color of the AuNPs, prompt measurements ofcocaine relying on RGB color codes by snappingphotographs were also developed by Smith et al.and Wang et al. [48,49]. A similar mechanism of theaptasensor can also be fabricated for the detection ofmethamphetamine in urine samples, and an LOD of0.12 mg/mL was achieved [50].

3.3. Others

A colorimetric sensor can be developed from thesynthesis process of nanoparticles. Amjadi et al.fabricated a biosensor by enhancing the reduction ofsilver nanoparticles (AgNPs) with the addition ofcannabinoids that possess a phenolic group so thatthey can provide mild reducing properties and


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coordinate the reducing agent of AgNO3 in theprocess of synthesis of AgNPs. As a result, theincreasing SPR absorption peak of AgNPs can beobserved, and this phenomenon can be furtherapplied to quantify the species of cannabinoid [52].Another colorimetric sensor, Au@Ag core-shellnanoparticles, was immobilized with partially cor-responding complementary strands of aptamers (asa reporter probe) for the duplexed detection ofmethamphetamine. The capture probe, with apartially corresponding complementary strand ofaptamers, conjugated with MNPs. In the absence ofanalytes, the reporter probe and capture probebound to the aptamer and Au@Ag-DNA-MNPcomplex structures were formed. The intensity ofthe SPR absorption peak was lower than that in thepresence of analytes [53]. A similar mechanism wasused to simultaneously duplex the detection ofmethamphetamine and cocaine by observing mul-tiple dominant wavelengths [54]. The Au@Ag core-shell nanoparticles were synthesized by the shellcoating of silver onto the surface of AuNPs, whichproduced a blueshift of nanoparticles from 520 nmto 400 nm. Moreover, the enhancement of absorp-tion after the synthesis of Au@Ag core-shell nano-particles was mainly due to surface plasmondamping. Finally, the LODs for methamphetamineand cocaine were measured to be 75 pg/mL and1 ng/mL, respectively [54]. In addition to the

application of AgNPs and Au@Ag core-shell nano-particles for colorimetric sensors, MNPs were alsoutilized to construct a rapid detection sensor basedon a lateral flow strip for cocaine [55]. The principleof the sensor was dependent on the interaction be-tween anti-cocaine antibody-modified MNPs andcocaine, which can influence the further reaction ofMNPs to cocaine-BSA and goat anti-mouse IgGantibody immobilized on the surface of the lateralflow strip. After the reaction, two discriminablebrown bands can be observed, and the color den-sities of the bands depend on the cocaine content.Consequently, the quantification of cocaine can beachieved by calculating the ratio of RGB color codesof two bands through a smart phone camera, withan LOD of 5 ng/mL [55]. Similar mechanism oflateral flow assay for cocaine was also conducted bybenzoylecgonine mAb conjugated AuNPs and aLOQ at 10 ng/mL can be measured in syntheticsaliva [56].The following sensing mechanisms of nano-

material-based colorimetric sensors are summa-rized and shown in Fig. 1: (1) ligated-analyteinteraction, (2) oligonucleotide-assisted aggregation,(3) salt-induced self-assembly, and (4) others. Incolorimetric biosensors, AuNPs are the most widelyapplied nanomaterials used to perform versatiledetection strategies based on surface interactionsand optical properties. With the ability to visually

Fig. 1. Colorimetric strategies for illicit drugs based on nanomaterials which combine with versatile analytical platforms.


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observe the color change of AuNPs or chromo-phores, colorimetric methods possess the potentialto quickly monitor analytes without dependence onadvanced detection instruments. The colorimetricbiosensors developed in previous studies are sum-marized in Table 3 which presents analyte-bindingmedium, added volume of sample, incubation time,sample matrix and LOD of respective analyticalmethods. Most colorimetric biosensors can obtainsensitivity values on a scale of mg/mL or ng/mL foranalyzing illicit drugs. In addition, a less sampleconsumption is feasible with the added volume ofsample in the range of 1 mL - 1.2 mL (mostly below100 mL). The recognition of analyte to sensors can bealso thoroughly accomplished within 30 min. Someof methods even finished incubation of analyte lessthan 5 min. For the investigation of prolonged lifetime of a sensor, a proper storage treatmentextended the shelf-life up to 2 months withoutapparent signal decay [48].

4. Nanomaterial-based fluorescent sensors

Fluorescent detection is regarded as a more sen-sitive optical sensing technique than the use of acolorimetric sensing system. Conventional fluores-cent organic dyes exhibit high sensitivity; however,the disadvantages of fluorescent organic dyes aretheir high cost and complicated synthesis proced-ure. In recent years, nanomaterials with fluorescentcharacteristics, such as NCs, QDs, CDs and UCNPs,have become new alternatives as fluorescent sen-sors. Several fluorescent sensing mechanisms havealso been developed, including specific recognition,fluorescence resonance energy transfer (FRET) andmolecular gating. The schematic diagram is shownin Fig. 2. The fluorescent sensors developed inprevious studies are summarized in Table 4 whichpresents analyte-binding medium, added volume ofsample, incubation time, sample matrix and LOD ofrespective analytical methods.

4.1. Noble metal nanomaterial-based sensors

Noble metal nanomaterials with size-dependentoptical properties are an alternative to conventionalfluorophores or are used as quenchers due to theirhigh quenching ability. There were three applica-tions of noble metal nanomaterials, including sta-bilizing ligand-induced fluorescent sensors, FRET-based fluorescent sensors and controlled-releasefluorescent sensors.

4.1.1. Stabilizing ligand-induced fluorescent sensorsMetal nanoclusters (NCs) were defined as

comprising several to a few hundred atoms less thanapproximately 1 nm in size. As the metal is on thesame scale as the NCs, discrete energy levels can beproduced. When the external energy is focusedupon the NCs, fluorescence can be induced due toquantum confinement by electronic transitions be-tween discrete energy levels. Compared to conven-tional organic dyes and semiconductor quantumdots, NCs possess the properties of photostabilityand low toxicity [16]. In addition, to stabilize theNCs that are prone to self-aggregate, several tem-plates were used to achieve the desired outcome,including molecular ligands [57], dendrimers [58],polymers [59] and DNA [60]. Given the stability andoptical properties of NCs, they are suitable for theestablishment of biosensors. Furthermore, the NCtechnique was used to determine the presence ofillegal drugs such as cocaine [61e64] and ketamine[65].In the detection of cocaine, Zhou et al. developed

two sensors based on copper nanoclusters (CuNCs)[61] and silver nanoclusters (AgNCs) [62] throughthe interaction between the NCs and DNA as thetemplate. The nanocluster diameter of Cu can besupported only by double-strand DNA (dsDNA)with an emission wavelength of 596 nm and anexcitation wavelength of 340 nm. According to thespecific stabilization of CuNCs by dsDNA, theaptamer can be used as a blocker against the hy-bridization of DNA by the addition of aptamer-corresponding substances, namely, cocaine, toinhibit the formation of CuNCs. Consequently, theestablished aptasensor exhibited a detection limit of30 ng/mL for cocaine. The DNA sequence withcytosine and guanine provides an ideal scaffold forthe synthesis of AgNCs due to the strong affinity forsilver ions. Moreover, the emitted fluorescence ofAgNCs can be enhanced through close proximity toa guanine-rich DNA sequence because guaninepossesses the lowest oxidation potential amongnucleotides and can play the role of an electrondonor to reduce the oxidized NCs to emit unoxi-dized NCs [66]. According to the theory of fluores-cence-enhanced NCs, Zhou et al. also established anaptasensor based on AgNCs for the detection ofcocaine [62]. The two oligonucleotides weredesigned for the synthesis of AgNCs with guanine-rich sequences, and they can hybridize together toform a specific secondary structure only in the


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Table 3. Various nanomaterial-based colorimetric sensors for analysis of illicit drugs.

Nanomaterial-based colorimetricsensors

Sample volume Incubationtime 1


Small molecular-based AuNP sensorsCitrate-capped AuNPs 1 mL - Bone 0.62 mg/mL for

codeine sulfate[34]

Bone marrowSoil

Citrate-capped AuNPs 1.2 mL 10 min Urine 0.3 mg/mL forcodeine

[35]

0.3 mg/mL formethadone0.29 mg/mL formorphine6.7 mg/mL fornoroxycodone0.31 mg/mL forthebaine

Citrate-capped AuNPs - 10 min Serum 0.15 mg/mL formorphine

[36]

UrineMelamine-modified AuNPs - 3 min Blood 0.28 ng/mL for

clonazepam[40]

BoneBone marrow

Melamine-modified AuNPs - 10 min Serum 2.7 ng/mL forcodeine

[41]

Urine 4.9 ng/mL formorphine

Aptamer-based AuNP sensors(A) Oligonucleotide-assisted aggregationComplementary strand-modified AuNPs andcocaine aptamer

- 10 s - No LOD(for cocaine)

[44]

Aptamer sequence:5ˊ-ACTCATCTGTGAATCTCGGGAGACAAGGATAAATCCTTCAATGAAGTGGGTCTCCC-3ˊCocaine aptamer fragment1-modified AuNPs andcocaine aptamer fragment2-modified AuNPs

10 mL 30 min Fingerprints 90 ng forcocaine

[45]

Aptamer sequence(fragment 1): 5ˊ-GTTCTTCAATGAAGTGGGACGACATTTTTTTTTT-SH-3ˊAptamer sequence(fragment 2): 5ˊ-GGGAGTCAAGAACTTTTTTTTTT-SH-3ˊ

(B) Salt-induced self-assemblyAuNPs and cocaine aptamerfragment 1 & 2

2 mL 2-3 min - 0.6 mg/mLfor cocaine

[46]

Aptamer sequence(fragment 1): 5ˊ-GTTCTTCAATGAAGTGGGACGACA-3ˊAptamer sequence(fragment 2): 5ˊ-GGGAGTCAAGAAC-3ˊAuNPs and cocaine aptamer 20 mL 30 min Urine 0.3 ng/mL

for cocaine[47]

(continued on next page)


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Table 3. (continued)




Aptamer sequence:5ˊ-GGGAGACAAGGAAAATCCTTCAATGAAGTGGGTCGACA-3ˊAuNPs and cocaine aptamer 18.2 mL 30 min - 0.25 mg/mL

for cocaine[48]

Aptamer sequence: 5ˊ-GGCGACAAGGAAAATCCTTCAACGAAGTGGGTCGCC-3ˊAuNPs and cocaine aptamerfragment 1 & 2

1 mL 5 min - 2.36 mg forcocaine

[49]

Aptamer sequence(fragment 1):5ˊ-ACAGCAGGGTGAAGTAACTTCTTG-3ˊAptamer sequence(fragment 2): 5ˊ-GGGAGTCAAGAAC-3ˊAuNPs andmethamphetamine aptamer

120 mL 5 min Urine 0.12 mg/mL formethamphetamine

[50]

Aptamer sequence:5ˊ-ACGGTTGCAAGTGGGACTCTGGTAGGCTGGGTTAATTTGG-3ˊ

OthersAgNPs - 30 min Hashish 52 ng/mL for

cannabidiol[52]

77 ng/mL forcannabinol

65 ng/mL fortetrahydro-cannabinol

Complementary strand-modified Au@AgNPs andmethamphetamine/cocaineaptamer

10 mL - Urine 15 pg/mL formethamph-etamine

[53]

Aptamer sequence(methamphetamine): 5ˊ-ACGGTTGCAAGTGGGACTCTGGTAGGCTGGGTAATTTGG-3ˊ

0.15 ng/mL forcocaine

Aptamer sequence (cocaine):5ˊ-GGGAGACAAGGATAAATCCTTCAATGAAGTGGGTCGATA-3ˊComplementary strand(methamphetamine)-modifiedAu@AgNPs andmethamphetamine aptamer

5 mL 30 min Waste water 75 pg/mL formethamphetamine

[54]

Complementary strand(cocaine)-modified AuNPs andcocaine aptamer

1 ng/mL forcocaine

Aptamer sequence(methamphetamine):5ˊ-ACGGTTGCAAGTGGGACTCTGGTAGGCTGGGTAATTTGG-3ˊAptamer sequence (cocaine):5ˊ-GGGAGACAAGGATAAATCCTTCAATGAAGTGGGTCGATA-3ˊ



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presence of cocaine. Finally, the LOD of cocaine was30 ng/mL.Other aptasensors based on AgNCs were also

developed. For instance, Zhang et al. established anaptasensor in combination with a nicking endonu-clease-assisted signal amplification method for thedetection of cocaine in serum samples with an LODof 0.6 ng/mL [63], Sharon et al. also fabricated anaptasensor based on FRET between AgNCs andquenchers with an LOD of 91 ng/mL [64], and Dinget al. used a DNA sequence (dC12) composed of anAgNC template and ketamine-binding DNA as thescaffold for the stabilization of AgNCs. In the pres-ence of ketamine, the DNA scaffold of the AgNCsdisintegrated and further interacted with ketamine,resulting in the transformation of the DNA complexstructure so that the fluorescence emitted from theAgNCs could be quenched. The LOD was 60 pg/mL[65]. A novel sensing system based on AgNCs andthe technique of artificial intelligence was estab-lished for the detection of illegal drugs [67]. Thesensing principle is mainly based on the change in

the fluorescence of AgNCs influenced by the inter-action between the analyte and AgNCs. After that,sensing statistics can be integrated by a deeplearning (DL) model, which is a subfield of artificialintelligence. The DL model can be utilized toconstruct three-dimensional fingerprint-likespectra. The spectra are composed of recognizablepeak distributions by a fluorescence excitationemission matrix while the analyte interacted withAgNCs. In this study, the spectra for illicit drugs,namely, 3,4-methylenedioxyamphetamine (MDA),MDMA, codeine, meperidine and methcathinone,were established. The novel detection techniquewas capable of identifying and semiquantifyingthese drugs down to 2 mg/mL and possessed thepotential to rapidly identify multiple illicit drugs[67].

4.1.2. FRET-based fluorescent sensorsThe typical principle of fluorescent sensors is

mainly based on the quenching effect of the fluo-rophore by FRET. The excited-state energy from the

Fig. 2. Fluorometric strategies for illicit drugs based on nanomaterials which were constructed as fluorophore or quencher and utilized to establishdiverse sensing mechanisms.





Cocaine antibody-modifiedMNPs

80 mL 10 min Urine 5 ng/mL for cocaine [55]

Benzoylecgonine mAbconjugated AuNPs

100 mL - Synthetic saliva 10 ng/mL for cocaine [56]

Abbreviation: AuNPs: gold nanoparticles; AgNPs: silver nanoparticles; Au@AgNPs: gold-silver core-shell nanoparticles.1 Incubation time: the time of recognition of the analyte in sensing procedure.


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Table 4. Various nanomaterial-based fluorescent sensors for analysis of illicit drugs.

Nanomaterial-basedfluorescent sensors

Sample volume Incubation time 1 Sample Limit of detection Ref

Noble metal nanomaterials-based sensors(A) Salt-induced self-assemblyDNA-CuNCs andcocaine aptamerAptamer sequence:5ˊ-GACAAGGAAAATCCTTCAATGAAGTGGGTC-3ˊ

-

15 min

-

30 ng/mL for cocaine

[61]

DNA-AgNCs andcocaine aptamerfragment 1 & 2

- 15 min - 30 ng/mL for cocaine [62]

Aptamer sequence(fragment 1): 5ˊ-TTCGTTCTTCAATGAAGTGGGACGACAATGTGGAGGGT-3ˊAptamer sequence(fragment 2): 5ˊ-AGGGACGGGAAGGGAGTCAAGAACGAA-3ˊDNA-AgNCs andcocaine aptamer

5 mL 1 h Serum 0.6 ng/mL for cocaine [63]

Aptamer sequence:5ˊ-CCACTGACCTCAGCATGTCGAGGGAGACAAGGAAAATCCTTCAATGAAGTGGGTCGACATGCTGA-3ˊDNA-AgNCs andcocaine aptamer

- 30 min - 91 ng/mL for cocaine [64]

Aptamer sequence:5ˊ-GCTGCAGAATGGGATCTTCATGACAAGGAAAATCCTTCAATGAAGTGGGTCAATTAT-3ˊDNA-AgNCs andketamine aptamer

30 mL 5 min Blood 60 pg/mL for ketamine [65]

Aptamer sequence:5ˊ-TGGGGATGGAGAACTCCCCCCCCCCCC-3ˊAgNCs - 3 min Urine No LOD for MDA,

MDMA, codeine,meperidine,methcathinone

[67]

(B) FRET-based fluorescent sensorsCocaine aptamer-modified AuNPs andcomplementary strand-modified SNPs

10 mL 40 min Serum 89 pg/mL for cocaine [72]



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Aptamer sequence:5ˊ-CCATAGGGAGACAAGGATAAATCCTTCAATGAAGTGGGTCTCCC-SH-3ˊComplementarystrand-modifiedAuNPs and cocaineaptamer

3 mL 1 h - No LOD for cocaine [73]

Aptamer sequence(cocaine):5ˊ-Cy5-AAGTGGGGAGACAAGGATAAATCCTTCAATGAAGTGGGTCTCCC-3ˊ

Cocaine aptamer andAuNPs

5 mL 4 h - 9.1 ng/mL for cocaine [74]

Aptamer sequence(cocaine aptamerfragment 1):5ˊ-AMCA-AGACAAGGAAAA-3ˊAptamer sequence(cocaine aptamerfragment 2):5ˊ-TCCTTCAATGAAGTGGGTCG-3ˊAuNPs - 3 min Serum 19 pg/mL (serum) for

morphine[75]

Urine 17 pg/mL (urine) formorphine

NTS@SNPs 29equivalents 5 min - No LOD formethamphetamine

[76]

Cocaine aptamerfragment 1-modifiedSNPsand cocaine aptamerfragment 2

80 mL 25 min Serum 25 pg/mL for cocaine [77]

Aptamer sequence(fragment 1): 5ˊ-biotin-GGGAGTCAAGAAC-BHQ-1-3ˊAptamer sequence(fragment 2): 5ˊ-FAM-GTTCTTCAATGAAGTGTGGGACGACA-TAMRA-3ˊ

(C) Control-released fluorescent sensorsPseudorotaxanecapped mesoporousSNPs

100 mL 2 h Water 0.94 mg/mL for MDMA [79]

complementarystrand-modified NAAandcocaine aptamer

100 mL 20 min Saliva 0.15 mg/mL for cocaine [80]



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Aptamer sequence:5ˊ-TTTTGGGGGGGGGAGACAAGGAAAATCCTTCAATGAAGTGGGTCTCCAGGGGGGTTTT-3ˊ

Quantum dots-based fluorescent sensorsmorphine antibody-labeled CdS@MAA-QDs

0.2 mL - - No LOD for morphine [82]

Morphine antibody-labeled CdSe/ZnS QDs

100 mL - Soup 0.27 ng/mL formorphine

[83]

7-aminoclonazepamantibody-modified CdTe-QDs

- 15 min Urine 21 pg/mL for 7-aminoclonazepam

[84]

Complementary strand-modified QDs andcocaine aptamer

- - - 0.15 mg/mL for cocaine [85]

Aptamer sequence:5ˊ-ACTCATCTGTGATATCTCGGGAGACAAGGAAAATCCTTCAATGAAGTGGGTCTCCC-3ˊComplementary strand-modified QDs andcocaine aptamer

80 mL 5 min - 36 mg/mL for cocaine [86]

Aptamer sequence:5ˊ-ACTCATCTGTGAATCTCGGGAGACAAGGATAAATCCTTCAATGAAGTGGGTCTCCC-3ˊAuNPs-conjugatedcocaine aptamer-modified QDs

25 mL 3 h Artificial urine 40 pg/mL for cocaine [87]

Aptamer sequence:5ˊ-C6-NH2-AGACAAGGAAAATCCTTCAATGAAGTGGGTCG-SH2-C3-3ˊ

480 ng/mL forbenzoylecgonine

L-cysteine capped CdSQDs

- - Urine 1.8 ng/mL formethamphetamine(fluorescence)

[88]

0.086 ng/mL formethamphetamine(chemiluminescence)

D-Cysteine molecules-functionalized CdSe QDs

- - - 17 ng/mL for L-morphine

[89]

Streptavidin-QDs,complementary strand-modified AuNPs andcocaine aptamer

10 mL 25 min - 0.15 pg/mL for cocaine [90]

Aptamer sequence:5ˊ-ATCTCGGGAGACAAGGATAAATCCTTCAATGAAGTGGGTCTCCCAAAAAAAAAA-Biotin-3ˊ



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Carbon nanomaterials-based fluorescent sensorsMethamphetamineaptamer-modified CDsand CoOOH nanosheets

- 20 min 0.48 ng/mL formethamphetamine

[92]

Aptamer sequence: 5ˊ-NH2-(CH2)6-ACGGTTGCAAGTGGGACTCTG GTAGGCTGGGTTAATTTGG-3ˊCDs 1.5 mL 5 min Beverage 2.0 mg/mL for

nitrazepam[93]

CDs-functionalized paper 10 mL 10 min Urine 1.3 mg/mL for 4-chloroethcathinone

[94]

GQDs - 1 min - 1.48 mg/mL formethamphetamine

[97]

0.5 mg/mL formorphine

GQDs with antimorphine(antibody)

- - - 18 ng/mL for morphine [98]

GO and cocaine aptamerfragment 1 & 2

- 10 min Plasma 30 pg/mL for cocaine [101]

Aptamer sequence(cocaine aptamerfragment 1): 5ˊ-GGGAGTCTCAAGAAC-FAM-3ˊAptamer sequence(cocaine aptamerfragment 2): 5ˊ-GTTCTTCAATGAAGTGGGACGACTAT-3ˊGO and cocaine aptamer 20 mL 20 min Urine 57 ng/mL for cocaine [102]Aptamer sequence:

5ˊ-GGGAGACAAGGAAAATCCTTCAATGAAGTGGGTCTCCCTAGTTTTCTAGGGAGAC-PO4-3ˊCocaine aptamerfragment 1-modifiedGQDs and cocaineaptamer fragment 2-modified AuNPs

1 mL 1 h Plasma 30 ng/mL for cocaine [103]

Aptamer sequence(fragment 1):5ˊ-NH2-(CH2)6-TTTTTGGGAGTCAAGAACGAA-3ˊ

Serum

Aptamer sequence(fragment 2):5ˊ-SH-(CH2)6-TTCGTTCTTCAATGAAGTGGGACGACA-3ˊ

Saliva

Urine



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fluorophore as a donor transfers to the quencher asan acceptor-based dipole-dipole interaction in thecontext of the proximity between the donor andacceptor in the range from 10 to 100 Å [68].Furthermore, alternatives to quenchers, such asmetal nanoparticles (AuNPs) and graphene oxide,are based on the properties of surface plasmonresonance (SPR) and heterogeneous electronicstructures [69]. The heterogeneous electronic struc-ture of graphene oxide is attributed to its composi-tion of sp2 and sp3 binding, which providesproperties of FRET and nonradiative dipole-dipolecoupling [69,70].Sensors coupled with aptamers, known as apta-

sensors, have been developed to enhance detectionselectivity. The first fluorescent aptasensor aimed atdetecting cocaine was established by Stojanovicet al.[71]. The strategy of detection was based onmolecular beacons that were labeled with fluores-cein as the fluorophore and dabcyl as the quencheron the double end of the cocaine-specific aptamer.The aptamer can form a secondary structure afterthe presence of cocaine. The conformational changeof the aptamer shortens the proximity between thefluorophore and the quencher, which producesfluorescent degeneration.Gold nanoparticles (AuNPs) are ideal candidates

for fluorescent quenchers with unique opticalproperties by surface plasmon resonance (SPR)[72e75]. The aptasensor coupled with AuNPs can bedivided into unmodified and oligonucleotide-modified. For instance, Zhang et al. developed anaptasensor based on complementary aptamer-modified AuNPs for the detection of cocaine [73].

The interaction between the cocaine and the fluo-rescent aptamer allows the aptamer to exhibit sterichindrance by forming a secondary structure withcocaine. As a result, the prehybridized fluorescentaptamer can be released, and the fluorescence canbe recovered. Luo et al. developed an aptasensorbased on unmodified AuNPs for the detection ofcocaine [74]. The fluorescent aptamer can attachonto the surface of AuNPs with van der Waalsforces, and the fluorescence will be quenched due tothe close distance between the aptamer and AuNPs.In the presence of cocaine, the complex of theaptamer and cocaine becomes a secondary structurethat resists the attachment to AuNPs by electrostaticrepulsion [42] and allows the recovery of fluores-cence. Consequently, the LOD for the detection ofcocaine was 9.1 ng/mL. Another fluorescentbiosensor was also developed by the direct inter-action between the analyte and AuNPs. Nebu et al.established a biosensor for the detection ofmorphine based on the competitive attachment be-tween morphine and fluorescein onto the surface ofAuNPs to influence the quenching of fluorescein byAuNPs, and this sensor had an LOD up to 17 pg/mLfor urine and 19 pg/mL for serum [75].A similar mechanism of aptasensors coupled with

silica nanoparticles (SNPs) was applied for signalamplification [72,76,77]. Sarreshtehdar et al. re-ported an aptasensor based on AuNPs as thequencher and SNPs for the enhancement of fluo-rescent intensity, and the technique possessed highsensitivity, up to 89 pg/mL, for the detection ofcocaine in serum [72]. Rouhani reported a nano-sensor based on 1,8-naphthalimide-thiophene-




Upconversion nanoparticles-based fluorescent sensorsCocaine aptamerfragment-modifiedAuNPs and UCNPs

2 mL 40 min Rat plasma LOQ: 3 ng/mL(aqueous solution) forcocaine

[105]

Aptamer sequence:5ˊ-SH-TTTTTACAGCAGGGTGAAGTAACTTCTTG-3ˊ

Saliva LOQ: 15 ng/mL (saliva)for cocaine

Cocaine aptamer-modified UCNPs

0.1-10 mg 30 min Fingerprints 0.1 mg for cocaine [106]

Aptamer sequence:5ˊ-NH2-TTTTTTGACAAGGAAAATCCTTCAATGAAGTGGGTC-3ˊ

Abbreviation: CuNCs: copper nanoclusters; AgNCs: silver nanoclusters; MDA: 4,5-methylene-dioxy amphetamine; MDMA: 3,4-meth-ylene dioxy methamphetamine; SNPs: silica nanoparticles; NTS: 4-thiophene-N-propyl(trithoxysilane)1,8-naphthalimide; NAA: nano-porous anodic alumina; MAA: mercaptoacetic acid; CDs: carbon dots; CoOOH: cobalt oxyhydroxide; GQDs: graphene quantum dots;GO: graphene oxide; UCNPs: upconversion nanoparticles.1 Incubation time: the time of recognition of the analyte in sensing procedure.


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doped SNPs for the detection of methamphetamine.The interaction between 1,8-naphthalimide andmethamphetamine not only triggers the exhibitionof fluorescence but also enhances the sensitivity[76]; Abnous et al. also established an aptasensorbased on SNPs for the detection of cocaine in serumwith a limit of detection of 25 pg/mL [77].

4.1.3. Control-released fluorescent sensorsIn addition to nanomaterials that possess optical

properties to develop sensor systems, porousnanomaterials can also be utilized to construct adetection system on the basis of a molecule gate thatcan efficiently control the release of molecules in-side the cavities of porous nanomaterials. Meso-porous silica nanoparticles (SNPs) were used toestablish a sensing platform for the detection ofillicit drugs. Mesoporous SNPs have many cavitieson the surface, and they possess a large load ca-pacity, biocompatibility and on-command deliveryapplication [78]. The fundamental principle of fluo-rescent controlled-released SNPs is accomplishedby capping the cavities by molecules and oligonu-cleotides to prevent the release of fluorophores inthe cavities. As the analytes interact with thecapping substances, the gate can be destroyed, andthe fluorophores can be released. With this theory,pseudorotaxane capped mesoporous SNPs wereestablished by Lozano-Torres et al. to detectMDMA. Detection can be accomplished dependingon the competitive interaction between MDMA andpseudorotaxane, which induces the uncapping ofcavities and facilitates the release of fluorescein.Consequently, an LOD of 0.94 mg/mL could beachieved for MDMA [79]. In addition, alumina canalso be constructed as nanoporous anodic alumina(NAA), which is capable of loading small molecules.Ribes et al. fabricated an aptasensor based on NAAfor cocaine that possesses cavities with an averagesize of 8 nm [80]. Likewise, the assistance of thecocaine-aptamer complex provided a moleculargate that blocked the release of fluorescent re-porters, rhodamine B, keeping them in the cavities.In the presence of cocaine, the aptamer bound withcocaine and detached from the NAA. Subsequently,rhodamine B be released from of cavities. Conse-quently, the quantification of cocaine can be ach-ieved, and the LOD for cocaine was 151 ng/mL insaliva [80].

4.2. Quantum dot-based fluorescent sensors

Quantum dots (QDs) are nanocrystals composedof semiconducting material with a small size, mainlyin the range of 2-10 nm. The diameters of QDs are

intermediate between the bulk of semiconductorsand discrete molecules. Attributed to the tiny size ofQDs in close proximity to the wavelength of theelectron, the phenomenon of quantum confinementeffects is due to the energy gap between the valenceband and the conducting band. The size-dependentband gap provides the optical and electronic prop-erties of QDs, such as excitation and electron-holeinteractions, which lead to photoluminescence[17,81]. With the property of fluorescent exhibition,QDs have been used in the development of manysensors for the detection of various substances in awide variety of industries, such as the environment,biology, and medicine. Moreover, QD techniques incombination with other techniques, such as immu-noassays [82e84] and aptamers [85e87], have alsobeen used to detect illegal drugs in recent research,and these techniques are considered reliable anduseful tools for the establishment of trace analyticalmethods.In the development of sensors simply based on

the modification of QDs, Hassanzadeh et al. devel-oped a sensor based on L-cysteine capped CdS QDsfor the detection of methamphetamine. The inter-action of methamphetamine to the surface of theQDs, which can affect the efficiency of fluorescentemission and an LOD of 1.8 ng/mL, can be obtainedin a urine sample [88]. Similarly, the sensor basedon D-cysteine-functionalized CdSe possessed theselectivity of chiral analyte on the detection of L-morphine with the LOD at 17 ng/mL [89]. Further-more, the surfaces of QDs modified with an anti-morphine antibody and denatured bovine serumalbumin were also established as immunosensorsfor the detection of morphine [82,83] and 7-amino-clonazepam [84].Aptasensors coupled with QDs were also utilized

to detect cocaine. Two aptasensors, one based onQDs and Cy5 and the other based on QDs, Cy5 andIowa Black RQ, were established through themechanism of FRET for the detection of cocaine [85].In the aptasensor based on QDs and Cy5, the QDsurface was modified with a short sequence of oli-gonucleotides that can hybridize with the cocaineaptamer, and Cy5 was modified on another partlycomplementary sequence of the cocaine aptamer.The Cy5-modified complementary sequence ofcocaine aptamer can hybridize with the cocaineaptamer, and the mechanism of FRET was furtherinstigated by the energy transfer from the QDs toCy5 with an excitation wavelength at 488 nm in theabsence of cocaine. After the addition of cocaine, theaptamer can form a specific secondary structure thatresists hybridization between the cocaine aptamerand the Cy5-modified complementary aptamer.


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Therefore, FRET cannot be induced, and the emis-sion signal of QDs at 605 nm can be observed.Finally, the aptasensor had a detection limit of0.15 mg/mL. The CdSe/ZnS core-shell QDs wereused as the fluorophore and AuNPs were used asthe quencher for the detection of cocaine and ben-zoylecgonine. The analytical method successfullyquantified the analytes with an LOD of 41 pg/mL forcocaine and 0.48 mg/mL for benzoylecgonine inartificial urine [87]. In addition, the technique incombination with QDs, aptamers and AuNPs wasalso developed by Zhang et al. The aptamer-modi-fied microfluidic beads served as the main body ofthe sensing platform [90]. Complementary-aptamerDNA-AuNPs (cDNA-AuNPs) loaded with horse-radish peroxidase (HRP) were used as the mediumto trigger the interaction between tyramine-biotinand streptavidin-QDs. The linkage of biotin-strep-tavidin provided strong fluorescence to microbeadsdue to the numerous QDs bound to them. However,the interaction failed to function properly in thepresence of cocaine because cocaine can occupy thehybridized sites of the cDNA-AuNPs to microbeadsso that further reaction will be interrupted. Finally,an LOD of 0.15 pg/mL could be achieved for cocainethrough this method [90].

4.3. Carbon nanomaterial-based fluorescent sensors

The development of carbon nanomaterials hasdrawn great attention to the application of sensingsystems as they have less toxicity and environ-mental hazards than QDs. Carbon nanomaterialsthat are widely used in the establishment of bio-sensors can be divided into three parts: carbon dots(CDs), graphene quantum dots (GQDs) and gra-phene oxide (GO).Quantum-sized carbon nanoparticles, known as

CDs, possess the stable property of photo-luminescence. The principle of photoluminescencefrom CDs may be caused by the presence of surfaceenergy traps that become emissive upon stabiliza-tion because of surface passivation [18,91]. Saberiet al. developed an aptasensor using CDs as thefluorophore and cobalt oxyhydroxide nanosheets(CoOOH) as the quencher for the detection ofmethamphetamine and a schematic illustration ofthe aptasensor [92]. The CDs were synthesized fromthe grape leaves by hydrothermal treatment andwere further immobilized onto the aptamer ofmethamphetamine. The CD-modified aptamer canattach onto the surface of the CoOOH nanosheet byvan der Waals forces in the absence of metham-phetamine, and the fluorescence emitted from theCDs was quenched by CoOOH through FRET. In

contrast, the aptamer can conjugate with metham-phetamine, and the complex can resist the interac-tion between the aptamer and the CoOOHnanosheet. Consequently, fluorescence can beobserved, and the limit of detection of metham-phetamine was measured to be 0.48 ng/mL inhuman plasma. Furthermore, the fluorescenceemitted from CDs can also be quenched accordingto the absorption of the target onto the surface ofCDs. The attachment of the target to CDs triggerselectron transfer, which depends on the functionalgroups of the analyte, and further FRET occurs. Yenet al. developed a biosensor based on CDs for thedetection of nitro-containing benzodiazepines,namely, nimetazepam, which is regarded as a typeof date rape drug. This method provides an LOD fornimetazepam at 2.13 mg/mL in beverages such asbeer, juice, wine and whiskey [93]. Likewise, CDswere also modified onto paper for the detection of 4-chloroethcathinone and a LOD can be obtained tobe 1.3 mg/mL in urine sample [94].Similar to the CDs, GQDs also possess the optical

property of photoluminescence with significantquantum confinement and edge effects as the size ofGQDs is below 100 nm [95,96]. Different from thespherical nanoparticles of CDs composed of sp3

hybridized carbon, the GQDs are composed of sp2

hybridized carbon, which represents a layer ofcrystalline structure. A sensor based on GQDs wasdesigned for the detection of D-methamphetamineand L-morphine through their interaction withGQDs. The quenching effect was observed by theaddition of methamphetamine. Meanwhile, thefluorescence enhancement effect was found by theaddition of morphine. The limits of detection for D-methamphetamine and L-morphine were 1.48 mg/mL and 0.5 mg/mL, respectively [97]. Furthermore,the LOD of morphine was improved to 18 ng/mL byusing GQDs modified with antimorphine [98].Apart from quantum dot-characterized carbon

materials, another widely applied technique is gra-phene oxide (GO), which is a thin sheet of graphitefabricated by “top-down [99]” or “bottom-up [100]”methods. GO possesses the property of quenchingthe fluorescent species by FRET or nonradiativedipole-dipole coupling as the distance between theGO and fluorophore is less than approximately20 nm. Moreover, the ionic groups and aromaticgroups of GO allow charged species such as pro-teins and DNA to attach onto the GO surface byelectrostatic interactions and p-p stacking, respec-tively [69]. Consequently, GO can easily capturefluorescent substances to produce quenching ef-fects. GO was used in the development of abiosensor for the detection of cocaine in body fluids,


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namely, urine, plasma, serum and saliva [101e103].Zhang et al. established an aptasensor based on GOas the quencher and exonuclease III (Exo III) forsignal amplification [101]. Exo III was a crucial factorin the feasibility of the aptasensor, which possessedthe property of cleaving the 3-hydroxyl termini ofmononucleotides from double-stranded DNA andacted from the 30 to 50 direction [104]. In the pres-ence of cocaine, the aptamer can bind with thecocaine and form a specific secondary structure.Subsequently, the partly complementary DNAsequence corresponding to the aptamer can befurther hybridized with the folding structure to formdouble-stranded DNA. The addition of Exo III cancleave the complementary DNA modified with FAMinto mononucleotides. Therefore, FAM failed toattach to the surface of GO, and fluorescence wasobserved. On the other hand, the complementaryDNA can attach onto the surface of GO in theabsence of cocaine, and the quenching of fluores-cence was achieved. The biosensor was establishedwith an LOD of 30 pg/mL in the plasma sample.

4.4. Upconversion nanoparticle-based fluorescentsensors

In recent years, nanomaterials constructed by rareearth elements such as yttrium (Y), ytterbium (Yb)and erbium (Er), namely, upconversion nano-particles (UCNPs), have been utilized as biosensors.Attributed to the composition of rare earth ele-ments, UCNPs possess the unique trait of emittingultraviolet/visible (UV/Vis) light under near-infrared excitation, which efficiently circumventsinterference. This property is achieved throughintraconfigurational transitions by rare earth ele-ments with abundant energy levels that allowcontinuous energy transition from low level excita-tion to high level emission [19]. In addition, thesurface of UCNPs is compatible with modifyingsubstances such as oligonucleotides and polymers.He et al. constructed a portable UCNP-based paperdevice coupled with aptamer-modified AuNPs forthe prompt detection of cocaine free from the lab-oratory. The cellulose filter paper device wasimmobilized with PEI-UCNPs and NH2-anti-cocaine aptamer fragments. Another fragment ofanti-cocaine aptamers was modified onto AuNPs,which acted as a quencher to diminish the lumi-nescence of UCNPs. In the presence of cocaine, twoaptamer fragments can link together and shortenthe distance between AuNPs and UCNPs. As aresult, the luminescence can be quenched, andcocaine quantification can be accomplished withLOQs of 3 ng/mL and 15 ng/mL in aqueous solution

and saliva, respectively [105]. In addition, UCNPswere also used for LFP detection. Wang et al.developed an aptasensor based on aptamer-modeled UCNPs as signal reporters of LFP for thedetection of cocaine, and the method was able to beused to monitor the content of cocaine down to0.1 mg [106].In summary of nanomaterial-based fluorescent

sensors, the utilization of nanomaterials in ananalytical method provides superior detection effi-ciency for monitoring illicit drugs. LODs of analytescan be measured down to the range of pg/mL andng/mL. Furthermore, less sample consumption ofapproximately 100 mL can be also obtained in mostestablished methods. For incubation time of analyteto sensor, some methods can accomplish the reac-tion within 10 min which achieve the strategy ofrapid detection.

5. Conclusion

Attributed to the development of analytical stra-tegies coupled with nanomaterials, features ofprompt monitoring, high sensitivity, economicalequipment and simple manipulation can be ac-quired. These advantages provide efficient detectiontechniques for illicit drugs in bodily fluids and theenvironment. This review summarizes the applica-tion of nanomaterials with respect to the establish-ment of analytical methods divided into samplepretreatment, colorimetric and fluorescent sensors.Sample pretreatment methods using metal mag-netic nanoparticles offer high extraction efficiencywith short-term consumption and target specificity,which is more straightforward than traditionalsample preparation methods. Colorimetric methodswere mainly based on the unique optical propertiesof AuNPs and AgNPs with representative extinctionwavelengths that can change following their aggre-gation. Fluorescent sensors were also successfullydeveloped by the assistance of fluorophores,namely, NCs, QDs, CDs, UCNPs and quencherssuch as AuNPs, CNTs and GO. In addition to thesedetection strategies, nanomaterials can also be uti-lized to analytical methods based on surfaceenhanced raman scattering (SERS) for illicit drugswhich were investigated in other literature [107,108].With the application of nanomaterials for illicitdrugs, numerous innovative methods can be con-structed in combination with other techniques, suchas antibodies, aptamers, MIPs, chip (paper) devicesand artificial intelligence. Some of these methodseven provide high sensitivity up to pg/mL, similar tothe performance of conventional sophisticated in-struments. Among these detection methods for


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illicit drugs, many of them were combined withaptamers, which possess high compatibility withnanomaterials and can be utilized to improvespecificity. However, aptamers for illicit drugs havenot been sufficiently established because the ma-jority of analytical methods with the assistance ofaptamers were developed for cocaine and meth-amphetamine, while a minority were developed forcodeine and ketamine. Aptamers corresponding toother illegal drugs remain incompletely developed,especially for those that have been prevalent inrecent years, such as cannabis and morphine. Theestablishment of analytical methods coupled withaptamers is still considered a potential approach tofacilitate the monitoring of a wide variety of forensicdrugs. Although the clinical detection of forensicdrugs currently relies on immunoassays and so-phisticated instruments such as HPLC-MS and GC-MS, novel biosensors in combination with nano-technology are expected to realistically monitorforensic drugs in the future.

Conflict of interest

The authors have declared no conflict of interest.

Acknowledgements

We gratefully acknowledge the support of theMinistry of Science and Technology of Taiwan(MOST 109-2113-M-194 -011) for funding this work.

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