Metallic Nanoparticle-Enabled Sensing of a Drug-of-Abuse: An Attempt at Forensic Application

Article abstract of DOI:10.1002/cbic.202000157

γ-Hydroxybutyric acid (GHB) functions as a depressant on the central nerve system and serves as a pharmaceutical agent in the treatment of narcolepsy and alcohol withdraw. In recent years, GHB has been misused as a recreational drug due to its ability to induce euphoric feelings. Moreover, it has gained increasing attention as a popular drug of abuse that is frequently related to drug-facilitated sexual assaults. At the moment, detection methods based on chromatography exhibit extraordinary sensitivity for GHB sensing. However, such techniques require complicated sample treatment prior to analysis. Optical sensors provide an alternative approach for rapid and simple analysis of GHB samples. Unfortunately, currently reported probes are mostly based on hydrogen bonding to recognize GHB, and this raises concerns about, for example, the lack of specificity. In this work, we report a bioinspired strategy for selective sensing of GHB. The method is based on specific enzyme recognition to allow highly selective detection of GHB with minimum interference, even in a complex sample matrix (e. g., simulated urine). In addition, the result can be obtained by either quantitative spectroscopy analysis or colorimetric change observed by the naked-eye, thus demonstrating its potential application in drug screening and forensic analysis.

Full text of DOI:10.1002/cbic.202000157

Combining Chemistry and Biology
Accepted Article
Title: Metallic nanoparticles enabled sensing of drug-of-abuse, an
attempt to forensic application
Authors: Ming HU, Qinyu HAN, and Bengang Xing
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: ChemBioChem 10.1002/cbic.202000157
Link to VoR: https://doi.org/10.1002/cbic.202000157
01/2020

10.1002/cbic.202000157
ChemBioChem
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Metallic nanoparticles enabled sensing of drug-of-abuse, an
attempt to forensic application
Ming HU, Qinyu HAN and Bengang XING*[a]
Dedicated to special collection: Metals In Medicine
[a]
M. HU, Q. HAN, Prof. Dr. BG XING
School of Physical & Mathematical Sciences
Nanyang Technological University
21 Nanyang link, 637371 (Singapore)
E-mail: Bengang@ntu.edu.sg
Supporting information for this article is given via a link at the end of the document.
Abstract: Gamma-hydroxybutyric acid (GHB) functions as
depressant on the central nerve systems and serves as
pharmaceutical agent in the treatment of narcolepsy and alcohol
withdraw. In recent year, GHB has been misused as recreational
drug due to its ability to induce euphoric feelings. Moreover, it has
gained increasing attentions as a popular drug of abuse which is
frequently related to drug-facilitated sexual assaults. By now,
detection methods based on chromatography exhibit
extraordinary sensitivity for GHB sensing. However, such
clearance from body make it one of the most commonly used
drugs of abuse in drug-facilitated sexual assaults (DFSA)8.
Considering the potential physiological damage to human
body and social impacts associated with GHB drug abuse,
scientific researchers were greatly motivated to develop effective
methods for sensing and detection of GHB. By right, methods
based on Gas Chromatography-Mass Spectroscopy (GC/MS) or
Liquid Chromatography-Mass Spectroscopy (LC/MS) have been
well-established9-11. Although these procedures can be used for
techniques require complicated sample treatment prior to analysis. sensitive GHB detection, such methods require considerable
Optical sensors provide an alternative approach for rapid and
simple analysis of GHB samples. Unfortunately, currently
reported probes are mostly based on hydrogen bonding to
recognize GHB, which may raise concern such as lack of
specificity. In this work, we reported a bioinspired strategy for
selective sensing of GHB. Such method is based on specific
enzyme recognition to allow highly selective detection of GHB
with minimum interference even in complex sample matrix (e.g.
simulated urine). In addition, the result can be obtained by either
quantitative spectroscopy analysis as well as colormetric change
observed by naked-eye demonstrating the potential application in
drug screening and forensic analysis.
sample treatment prior to analysis, which is laborious and may
raise concerns of unwanted loss of significant information of the
original sample12. To this end, alternative approaches (e.g. optical
sensors) have been developed to facilitate sensitive detection of
GHB with minimum sample manipulation13, 14. Although worked in
principle, most of these probes recognize GHB based on
hydrogen bonding which may hamper the detection specificity
due to the interference from complex sample matrix. In addition,
by far, most of these probes have not been reported to distinguish
GHB from its lactone precursor γ-butyrolactone (GBL) which is
the point of interest in forensic applications15. Therefore, the
development of alternative method for selective GHB analysis
with minimal sample preparation would be highly desirable. In
human body, GHB can be selectively oxidized through reactions
catalyzed by specific enzymes (e.g. GHB dehydrogenase) and
yield the oxidized form succinate semialdehyde and side reduced
nicotinamide adenine dinucleotide (NADH)16.
Introduction
Gamma-hydroxybutyric acid (GHB) is a short chain acid,
which can function as depressant on the central nerve systems.
GHB was used as anesthetic in 1960s1, 2. In addition, it has been
utilized as pharmaceutical agent in the treatment of narcolepsy
and alcohol withdraw3, 4. However, its use as therapeutic agent
has been reduced mainly for the side effects such as amnesia and
seizure5. In recent year, apart from the application as therapeutic
agents, GHB has earned popularity as recreational drug due to its
ability to induce euphoric feelings. It has been demonstrated that,
the misuse of GHB may result in neurotoxic damage especially to
maturing youths. In addition to the use as party drug, GHB has
gained increasing attentions as a popular drug of abuse which is
frequently related to drug-facilitated sexual assaults6. Considering
the fact that GHB is colorless and odorless, it is barely noticeable
when spiked in drinks7. This makes it desirable to sexual
offenders. In addition, its easy availability, low cost and rapid
Inspired by this naturally occurring process, we introduce a
simple yet effective approach based on highly specific enzymatic
reaction for selective sensing of GHB (Scheme 1). Typically, GHB
molecules in either biosamples or spiked drinks can be
recognized through specific enzyme-substrate interaction with
GHB degydrogenase (GHB-DH) and undergo oxidation reaction
generating NADH. As an ubiquitous reducing agent, the resulting
NADH molecule can promote the reduction of gold(III) complex
and form gold nanoparticles (AuNPs)17-19
. Owing to the
fascinating optical properties of metallic probes which are
dependent on the morphological and physiological states20-30 (e.g.
size, shape, aggregation state etc.) the distinct transformation
from molecular metal complex into nanoscaled particles which is
assisted by NADH reduction can be easily observed through the
generation of Surface Plasmon Resonance (SPR) peak of
AuNPs31-43. In addition, the obvious colormetric changes44-47
1
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Scheme 1. Scheme illustration of a bioinspired strategy for selective sensing of illicit date rape drug GHB.
accompanied by the formation of AuNPs allows simple GHB Results and Discussion
48, 49
detection through naked-eye observation.
In addition, such
selective analysis of drug-of abuse can be achieved even under
complex biological sample matrix, which exhibit the great
potential in future forensic application and drug screening.
Enzymatic oxidation of GHB
To achieve selective GHB detection, we started investigating
enzymatic treatment of GHB with GHB-DH. Typically, to a solution
containing 1mM NAD+ and 0.24mg/mL GHB-DH in 50mM Tris-
HCl buffer (pH 8.5), GHB substrate was added to trigger the
reaction. In order to achieve optimum activity of GHB-DH, the
reaction mixture was kept at 37℃ based on the manufacturer’s
protocol. The formation of NADH through the oxidation GHB can
be monitored by the absorbance peak of NADH at 334nm. As
shown in Figure 1a, in the absence of GHB-DH, minimum change
in absorbance spectra can be observed from the reaction mixture
of GHB and NAD+. Similarly, no obvious absorbance peak
Figure 1. a) Absorbance spectra of enzyme (0.24 mg/mL) catalyzed production
of NADH upon reduction of GHB (5 mM GHB in 50 mM Tris-HCl buffer pH 8.5,
containing 1mM NAD+); b) Time-dependent NADH produced by enzyme
reaction under different pH conditions.
Figure 2. Selectivity of NADH formation catalyzed by GHB-DH. (5 mM GHB or
GBL in 50 mM Tris-HCl buffer pH 8.5, containing 1mM NAD+).
2
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10.1002/cbic.202000157
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investigated. While NADH was efficiently produced upon
enzymatic reduction of GHB, no significant amount of NADH was
detected through enzyme catalyzed reaction in the presence of
GBL (Figure 2), which suggest the generated NADH is largely
based on the specific interaction between GHB and GHB-DH.
Such specific enzyme-substrate recognition allows us to minimize
interference from GHB-derivative GBL, which is of special interest
in some forensic analysis.
Optimization of GHB-DH enzyme reaction
To facilitate the future application in GHB sensing, the parameters
such as reaction time, substrate concentration were optimized.
Kinetic studies were performed to get the optimum reaction time
of GHB with NAD+ under the treatment of GHB dehydrogenase.
As shown in Figure 3a, upon the addition of GHB, the absorbance
of NADH increased gradually suggesting the generation of NADH
is dependent on GHB concentration. Rapid accumulation of
NADH was observed within 80mins (Figure 3a) upon addition of
GHB. As reaction time prolonged, the rate of NADH production
gradually decrease and finally reached a plateau. To facilitate
sufficient amount of NADH for subsequent detection step as well
Figure 3. a) Kinetics of NADH produced through enzymatic oxidation of GHB of
various concentration (50 mM Tris-HCl buffer pH 8.5, containing 1mM NAD+);
b) Absorbance spectra of NADH produced through GHB (1-16 mM) triggered
enzymatic reaction under optimized conditions (75min, 50 mM Tris-HCl buffer
pH 8.5) inset: linear correlation of NADH absorbance (334nm) versus GHB
concentration.
appeared in the mixture of NAD+ and GHB-DH, even with
prolonged incubation, suggesting the minimal production of
NADH. In comparison, obvious increase in the absorbance at
334nm was observed upon enzymatic treatment GHB with NAD+.
The absorbance of NADH increase as incubation prolonged,
exhibiting time-dependent spectra change, demonstrating the
enzyme promoted generation of NADH. In addition, to further
facilitate the enzymatic oxidation of GHB, the enzyme activity was
evaluated under different buffer conditions. In this case, GHB-DH,
NAD+ and GHB was added to various buffer solutions (acetate
buffer, 100mM pH 5.0, PBS buffer 1X, pH 7.2, and Tris-HCl buffer,
50mM, pH 8.5). Kinetic studies (Figure 1b) revealed that, under
acidic conditions, no obvious absorbance of NADH was observed
suggesting the minimum activity of GHB-DH under such condition.
At neutral condition, the presence of NADH signal can be
observed at a moderate rate. However, under slightly alkaline
environment, NADH can be produced rapidly in comparison to
that under acidic or neutral environment. This suggests slightly
alkaline condition can facilitate the GHB reduction as well as
promoting NADH production. Under such enzyme favorable
condition, the specificity of enzyme reaction was further
Figure 4. Absorbance spectra of growth solution containing CTAB (37mM),
HAuCl4 (0.09mM) and Au seeds (1.4 x 10-7mM) a) with NADH generated from
enzyme catalyzed reaction (GHB 1.26 mg/mL 12.6 mM, NAD+ 1mM, GHB-DH
0.24 mg/mL), b) without NADH generated from enzyme catalyzed reaction
(NAD+ 1mM, GHB-DH 0.24 mg/mL). Inset TEM micrograph representing the
gold nanocrystal formation triggered in the presence of GHB, scale bar 50nm.
3
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as to ensure time efficiency, 75mins reaction time was chosen as
the optimized reaction period of enzymatic oxidation of GHB.
Under this optimized condition, the absorbance of NADH
produced in the presence of GHB exhibited a linear increase with
respect to the concentration of GHB within 1 to 16mM (Figure 3b).
condition, the absorbance of AuNPs formed in the presence of
GHB exhibited a linear increase with respect to the concentration
of GHB within 4 to 16 mM (Figure 5a). In addition, the sensitivity
was calculated to be 3.51mM which is comparable to previously
reported methods13, 14
.
GHB-mediated formation of AuNPs
Visual analysis of GHB containing samples
Moreover, to explore the possibility of selective detection of GHB
through the formation of AuNPs, we exploited the catalytic growth
of AuNPs by NADH directly generated from enzymatic recognition
of GHB. Generally, reaction mixture containing NADH was
introduced into a solution containing CTAB (37mM), HAuCl4
(0.09mM) and Au seeds (1.4 x 10-7mM, 10nm). The reaction was
allow to proceed at 30℃. As shown in Figure 4a, without NADH,
the solution exhibited a distinct absorbance peak at 392nm which
In addition, the platform was investigated for the application of
detection of GHB spiked in different types of drinks. Typically,
GHB-free and GHB-spiked beverage was incubated with GHB
dehydrogenase and NAD+ for 75min. The reaction mixture was
subsequently used to promote the reduction of HAuCl4 and the
different types of beverages including mineral water, soda as well
as alcoholic drink (e.g. white wine and rice wine Figure 5b growth
of AuNPs. As shown in Figure 5b, pink color of AuNPs formed in
-
is attributed to the presence of AuCl4 species. However, upon
treatment of NADH containing solution, the absorbance peak at
392nm gradually disappeared. In the meantime, the absorbance
of NADH at 334nm decreased (Figure 4a) simultaneously
suggesting the rapid reduction of HAuCl4 (Figure S2) which is
similar to previously reported studies17. Furthermore, as the
concentration of NADH further increase, a distinct absorbance
peak at ~539nm gradually appeared (Figure 4a). Upon prolonged
incubation, the intensity of absorbance peak at 539nm gradually
increased. Meanwhile, the colorless reaction solution gradually
developed pinkish color (Figure S3), suggesting the growth of
AuNPs (Figure S2), which matches well with reported studies17.
Moreover, the growth of AuNPs in the presence of GHB induced
NADH was further confirmed by TEM analysis (Figure S3a and
Figure S3b). The presence of spherical particles revealed the
growth of AuNPs in the presence of NADH produced from enzyme
catalyzed GHB reduction. Similarly, increased hydrodynamic
diameter of Au seeds also suggest the growth of AuNPs (Figure
S3c). In comparison, no obvious formation of AuNPs was
observed as revealed by absorbance spectra and TEM, when
there is a lack of GHB (Figure 4b) or enzyme activity (Figure S4)
during NADH production.
Optimization of AuNPs based GHB sensing
We have proved the concept of selective sensing illicit drug
GHB through the growth of AuNPs. To better apply this strategy
for the application of drug sensing in spiked drink, reaction of the
sensing step (the formation of AuNPs) has been optimized.
Kinetic investigations on the growth of AuNPs upon interaction
with NADH were carried out. It can be observed that upon the
addition of NADH, the absorbance of reaction mixture at 539 nm
gradually increased (Figure S5a), suggesting the formation of
AuNPs is dependent on the concentration of NADH. Within the
first 2 hours, no obvious increase in the absorbance was detected.
As reaction time prolonged, the absorbance at 539 nm gradually
increase over 24 hours (Figure S5a). However, the slow reaction
rate and limited sensitivity (relatively low absorbance) are the
major concerns in future application. To address these issue, the
growth of AuNPs in the presence of different concentration of
catalyst (Au seeds) was evaluated. As shown in Figure S5b,
higher concentration (7.0 x 10-7mM, 1.4 x 10-6mM) of catalyst (Au
seeds) can dramatically increase the absorbance of AuNPs within
a shorter period of time suggesting the great improvement in the
rate of AuNPs formation which is desirable for enhanced
sensitivity and detection efficiency. Therefore, the amount of
catalyst (Au seeds) was optimized as 1.4 x 10-7mM. Under this
Figure 5. a) Absorbance spectra of AuNPs produced upon addition of GHB (4-
16 mM) under optimized conditions (CTAB 37mM, HAuCl4 0.09mM, Au seed
1.4 x 10-6mM and GHB black:4mM, red 8mM, green 12mM, blue 16mM,
incubation 1h) inset: linear correlation of AuNPs absorbance (539nm) versus
GHB concentration. b) Photograph of drinks spiked with (R+, S+, C+) or without
(R, S, C) GHB (10 mM) R: rice wine, S: soda, C: chardonnay. c) Illustration of
GHB analysis in simulated urine sample by simply mix and observe. (Bottom
photo: simulated urine sample containing GHB exhibits obvious pinkish
colormetric change compare to sample without GHB.)
4
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10.1002/cbic.202000157
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Hz, 2H), 2.26 (t, J = 7.4 Hz, 2H), 1.93–1.74 (m, 2H). M/Z=103.20
(negative mode)
the presence of GHB can be easily observed in and Figure S6)
suggesting the feasibility of such platform for the application of
GHB sensing in a variety type of beverages. More importantly, the
application of GHB detection in biological samples was evaluated.
In this case, GHB-DH and NAD+ was added to simulated urine
sample and allow for enzyme reaction. Subsequently the reaction
mixture was dropped into the growth solution (CTAB 37mM,
HAuCl4 0.09mM, Au seed 1.4 x 10-6mM) and stirred at 30℃. As
shown in Figure 5c, obvious pinkish color appeared in the
simulated urine sample spiked with GHB. In comparison, sample
without GHB remained clear colorless solution. Such results
suggested that our bio-inspired sensing technique based on
enzyme reaction is capable of analyzing the presence of GHB in
complex sample matrix (e.g. beverage and biological sample).
Moreover, the facile visual analysis can be achieved through
simply mix and observe which can largely reduce the laborious
and sophisticated sample pretreatments.
Scheme 2. Synthetic scheme of GHB (sodium salt)
Enzymatic reduction of GHB: Enzymatic reduction of GHB
sodium salt was monitored at 37℃ in 1mL of 1mM NAD+ in 50mM
Tris-HCl buffer (pH 8.5) containing 0.24mg/mL GHB-DH. The
reaction was triggered by the addition of GHB sodium salt to
20mM .The reaction process was monitored in a cuvette of 1cm
light path by the absorbance of NADH centered at 334nm.
GHB-mediated formation of AuNPs: The GHB-mediated
formation of AuNPs was carried out in 2 steps. Generally, a
solution of Tris-HCl buffer 50mM (pH 8.5) containing NAD+ (1mM),
GHB-DH (0.24mg/mL) and different concentration of GHB was
allow to react at 37℃. Then 100uL aliquot of the resulting mixture
was added to a growth solution (120uL) containing CTAB (37mM),
HAuCl4 (0.09mM) and AuNPs (1.4 x 10-7mM, 10nm). The reaction
was performed at 30℃, pH=4.0. The absorbance spectra of the
solution were recorded at different time duration.
Conclusion
To conclude, we have developed a simple yet effective
approach based on highly specific enzymatic reaction for
selective sensing of GHB. Typically, the drug-of abuse can be
recognized through specific enzyme-substrate interaction and
generate a side product NADH. The resulting NADH can facilitate
the reduction of gold(III) species and form AuNPs which can be
analyzed through either absorbance spectrometer or naked-eye
observation. Investigations have demonstrated the ability of such
platform to detect GHB drug in a variety type of spiked drink.
Moreover, such strategy can be utilized for analyzing GHB in
complicated biological samples suggesting the potential of our
strategy in the application of drug screening and forensic
investigation.
Acknowledgements
B.X. acknowledges the financial supports from SPMS-
M4082042.110, National Natural Science Foundation of China
(NSFC) (No. 51929201), Tier 1 RG5/18 (S), MOE 2017-T2-2-110
and A*Star SERC A1983c0028 (M4070319) in Nanyang
Technological University (NTU).
Keywords: colorimetric detection • drug sensing • Au NPs
Experimental Section
Reference
Materials: γ-butyrolactone (GBL), nicotinamide adenine
dinucleotide (NAD+) were purchased from TCI chemical (Japan).
Tris(hydroxymethyl)aminomethane (Tris), Diaphorase (from
Clostridium kluyveri), gold(III) chloride trihydrate (HAuCl4•3H2O),
cetrimonium bromide (CTAB), gold colloid (10 nm) were acquired
from Sigma-Aldrich. GHB-DH was order from prima biomed (U.S.).
Simulated urine was prepared according to reported methods50.
All theese reagents indicated above were used directly without
further purification.
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