Ultrasensitive detection of uric acid in serum of patients with gout by a new assay based on Pt&at;Ag nanoflowers

Article abstract of DOI:10.1039/c9ra06481h

A ultrasensitive assay for the determination of uric acid (UA) based on Pt&at;Ag nanoflowers (Pt&at;Ag NFs) was constructed. H₂O₂ was formed by the reaction of uricase and UA and produced the hydroxyl radical (OH). The system was catalyzed by Pt&at;Ag NFs to change the color of 3,3′,5,5′-tetramethylbenzidine (TMB) from colorless to blue, and the morphology and chemical properties of Pt&at;Ag NFs were characterized by transmission electron microscopy and X-ray photoelectron spectroscopy. Under the optimized conditions, a linear relationship between the absorbance and UA concentration was in the range of 0.5-150 μM (R² = 0.995) with a limit of detection of 0.3 μM (S/N = 3). The method can be applied to detection of UA in actual samples with satisfactory results. The proposed assay was successfully applied to the detection of UA in human serum with recoveries over 96.8percent. Thus, these results imply that the UA assay provides an effective tool in fast clinical analysis of gout.

Full text of DOI:10.1039/c9ra06481h

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Ultrasensitive detection of uric acid in serum of
patients with gout by a new assay based on Pt@Ag
Cite this: RSC Adv., 2019, 9, 36578
nanoflowers
a
Xue Wang,a Shujun Chen,a Xiaomin Tang,b Daiqin Linc and Ping Qiu
*
A ultrasensitive assay for the determination of uric acid (UA) based on Pt@Ag nanoflowers (Pt@Ag NFs) was
constructed. H2O2 was formed by the reaction of uricase and UA and produced the hydroxyl radical (cOH).
The system was catalyzed by Pt@Ag NFs to change the color of 3,30,5,50-tetramethylbenzidine (TMB) from
colorless to blue, and the morphology and chemical properties of Pt@Ag NFs were characterized by
transmission electron microscopy and X-ray photoelectron spectroscopy. Under the optimized
conditions, a linear relationship between the absorbance and UA concentration was in the range of 0.5–
150 mM (R2 ¼ 0.995) with a limit of detection of 0.3 mM (S/N ¼ 3). The method can be applied to
detection of UA in actual samples with satisfactory results. The proposed assay was successfully applied
to the detection of UA in human serum with recoveries over 96.8%. Thus, these results imply that the UA
assay provides an effective tool in fast clinical analysis of gout.
Received 19th August 2019
Accepted 29th October 2019
DOI: 10.1039/c9ra06481h
rsc.li/rsc-advances
colorimetric methods for the detection of UA. One is a colori-
metric assay based on precious metal (e.g., Au and Ag) nano-
Introduction
materials, in which uric acid can induce nanoparticle
aggregation,17 etching and anti-etching18,19 to cause color
changes. However, the dispersion of the nanomaterial is
unstable and precipitates easily, which causes the color of the
solution to change or even disappear. Many external factors also
may cause undesirable changes in the state of nanomaterials,20
resulting in unsatisfactory results. The other one is the catalytic
oxidation strategy, which bases on the peroxidase-like proper-
ties of nanomaterials, such as porous metal–organic framework
MIL-53 (Fe),21 graphite carbonitride nanosheets22 and cobalt
selenide nanosheets.23 They can change color by H2O2 catalytic
peroxidase substrate. The peroxidase mimic enzymes have the
advantages of low cost, good stability, simple preparation,
controllable structure and composition, and adjustable cata-
lytic activity. Therefore, this kind of nanomaterials have become
an ideal and important colorimetric detection tool.
Precious metal nanomaterials have a wide range of applica-
tions in catalysis and assays due to their unique physical and
chemical properties.24,25 More importantly, the bimetallic
nanostructures have synergistic and controllable catalytic
properties compared with their mono-metallic nano-
structures.26 So far, nanomaterials of various shapes have been
synthesized by chemical methods, such as nanowires,27 nano-
tubes,28 nanorods29 and nanowires.30 Platinum nanomaterials
have attracted much attention due to their excellent catalytic
ability and high utilization rate, and have been applied to many
elds such as catalysis, battery, sensing and medical treat-
ment.31–34 Silver nanoowers have large specic surface area
and good electrical conductivity, especially peroxidase-like
Uric acid (UA) is the nal product of human sputum metabo-
lism,1 its concentration in serum is 120–480 mM;2 many diseases
of the human body are related to abnormal uric acid content,
such as gout, Lesch-Nyhan syndrome, diabetes, hyperuricemia,
heart disease.3–6 Monitoring the concentration of UA in human
serum is essential and can be used as an early warning for these
diseases. Many diseases are caused by diet and lifestyle, so as
a remedy, all asymptomatic gout patients should be encouraged
to change their lifestyle. This requires the development of
a suitable cost-effective monitoring system to provide adequate
feedback and treatment guidelines for gout patients.
Gout is an inammatory reaction that occurs primarily in the
joints and forms UA crystals that cause pain.7 There is a direct
positive correlation between UA levels and the future risk of
gout. Specically, as the concentration of UA increases, the risk
of crystal formation increases, thereby increasing the patient's
susceptibility to gout.8
There are many approaches to detect uric acid, such as,
capillary electrophoresis,9 uorometry,10,11 chromatography,12
electrochemical methods,13,14 chemiluminescence15 and color-
imetry.16 Furthermore, the colorimetric method is widely used
because of its simple operation, fast analysis speed, high
sensitivity in these methods. Currently, there are two main
aDepartment of Chemistry, Nanchang University, Nanchang, 330031, China. E-mail:
pingqiu@ncu.edu.cn
bThe Fourth Affiliated Hospital of Nanchang University, Nanchang, 330003, China
cJiangxi Province Product Quality Supervision Testing Institute, Nanchang, 330047,
China
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properties, which provides an excellent substrate for the
construction of the assay.35–37 A new type of Pt@Ag nanoower
(Pt@Ag NFs) was prepared by adhesion of platinum nano-
particles with high catalytic activity on the surface of silver
nanoowers to further improve the ability of reducing H2O2.
This paper presents a method for preparing Pt@Ag NFs
using bovine serum albumin as raw material. A colorimetric
assay using the peroxidase-like activity based on Pt@Ag NFs was
developed to detect UA with sensitivity and high selectivity.
Pt@Ag NFs catalyze the colorimetric system of TMB and H2O2
(which is produced by uricase-specic catalysis of UA), resulting
in a solution color changing from colorless to blue. The color
change of the solution depends indirectly on the amount of uric
acid and can be judged by an ultraviolet-visible spectropho-
tometer and the naked eye.
Colorimetric measurement
150 mL of Britton–Robinson buffer (B–R buffer, pH 8.5) was
mixed with 50 mL, 100 mg mLꢀ1 uricase and 50 mL different
concentrations of UA in a 35 ꢁC water bath for 15 min. Then 200
mL, 16 mM TMB, 30 mL Pt@Ag NFs and 1520 mL, 50 mM HAc–
NaAc buffer of pH 4.0 were added to the above solution. Shake
well to bring the mixed soluꢁtion into full contact, and incubate
for another 40 min in a 55 C water bath, and collect the data
using an UV-vis spectrometer.
Analysis of UA in human serum
The serum samples of gout patients were collected from the
Nanchang University Fourth Affiliated Hospital (Nanchang city,
China). The samples treatment was relatively simple. The
samples were treated with 4000 rpm centrifugation for 15 min,
and the supernatant diluted with phosphate buffer saline (PBS,
pH 7.4). The analysis of each serum sample was repeated three
times.
Experimental
Chemical medicines and instrumentations
Silver nitrate (AgNO3), chloroplatinic acid (H2PtCl6$6H2O),
bovine serum albumin (BSA), ascorbic acid (AA), 3,30,5,50-tetra-
methylbenzidine (TMB), cysteine (Cys) and glucose (Glu) were
purchased in Sinopharm Chemical Reagent Co., Ltd. (Shanghai,
China).
Uric acid (UA), uricase, dopamine (DA), and glutathione
(GSH) were obtained from Sigma-Aldrich (Shanghai, China).
Urea, hydrogen peroxide (30 wt% H2O2), KNO3, Mg (NO3)2,
NaCl, CaCl2 were obtained from Beijing Chemical Industry Co.,
Ltd. (Beijing, China). All reagents are analytical grade and do
not require further treatment. Experimental water was ultrapure
water (18.25 MU, Millipore, USA).
Results and discussion
Principle of colorimetric assay
Scheme 1 simply describes the mechanism of the detection of
UA by Pt@Ag NFs, which also involves the synthesis of Pt@Ag
NFs and the oxidation of uricase. Under weak alkaline condi-
tions, uricase specically catalyzes UA, producing allantoin,
carbon dioxide and H2O2. Pt@Ag NFs have peroxidase-like
activity, which further catalyzes the decomposition of H2O2 to
form hydroxyl radicals (cOH). cOH oxidizes the peroxidase
substrate TMB (colorless) to oxidized TMB (oxTMB, blue). These
two steps can be expressed by eqn (1) and (2):
UV-vis spectral measurements were recorded on Agilent 8453
UV-vis spectrophotometer (Agilent Technologies, Santa Clara,
CA, USA). The morphology of the Pt@Ag NFs were characterized
by transmission electron microscopy (TEM, JEM-2100, JEOL
Co., Japan). X-ray photoelectron spectroscopy (XPS) was carried
out on EscaLab 250Xi with Al K a X-ray radiation as the source
for excitation. Biochemical analysis was measured using
biochemical analyzer (AU2007, Beckman, Olympus, USA).
uricase
ƒƒ!
Uric acid þ O þ H O
allantoin þ H O þ CO
(1)
2
2
2
2
2
pH 8:5
H O þ TMB Pt@Ag NFs H O þ oxidized TMB
ƒƒƒƒƒ!
(2)
2
2
2
pH
4
In order to verify the principle of the colorimetric assay, the
UV-vis spectra of TMB and the mixture of UA, uricase, Pt@Ag
NFs and H2O2 were compared. As shown in Fig. 1, when TMB
Preparation of Pt@Ag NFs
The innovative synthesis of Pt@Ag NFs is the key step to this
experiment.37 Briey, BSA (5 mg mLꢀ1, 20 mL) and AgNO3
(10 mM, 10 mL) aqueous solution were mixed and stirred at
room temperature for 10 min, then AA (50 mg mLꢀ1, 1 mL) was
added into the above solution drop by drop. The color of the
solution turned light grey, indicating that Ag NFs had been
successfully formed. H2PtCl6$6H2O (5.6 mM, 10 mL) was then
mixed with the Ag NFs solution and the mixture was stirred at
room temperature for a further 10 min until the color turned
dark grey. This indicates that Pt@Ag NFs was successfully
synthesized, and the obtained product was repeatedly washed
three times with water and ethanol, respectively. Finally, the
precipitate was re-dissolved in 20 mL of ultrapure water for later
use.
Scheme 1 Schematic diagram of the colorimetric detection of UA
using H2O2 and Pt@Ag NFs catalytic oxidation of TMB.
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Structure and properties of Pt@Ag NFs nanoower
Pt@Ag NFs play a crucial role in the detection of colorimetric
uric acid assays. The structure and morphology of Pt@Ag NFs
were studied by transmission electron microscopy. Fig. 2a
shows the overall morphology of Pt@Ag NFs. The product
consists of a large number of ower-like structures with an
average diameter of 50 nm, which are well dispersed in water.
The magnied TEM image in Fig. 2b shows that the ower-like
Pt@Ag nanoparticles are surrounded by a thin layer of BSA.
Energy dispersive spectroscopy (EDS) is a method for charac-
terizing elemental composition and X-ray photoelectron spec-
troscopy (XPS) was performed to conrm the elemental
composition and oxidation state of the prepared nano-
composite.38–40 Fig. 2c shows the EDS spectrum of Pt@Ag NFs,
conrming the presence of Pt and Ag in Pt@Ag NFs. The
oxidation states and formations of Pt@Ag NFs were determined
using XPS measurements. A survey XPS spectrum conrm the
coexistence of Pt and Ag elements in Pt@Ag NFs (Fig. 2d). The
oxidation states of Pt and Ag are obtained by tting the peaks in
high resolution Pt 4f and Ag 3d XPS spectra (Fig. 2e and f),
where the peaks at 70.0, 73.2, 366.9, and 372.9 eV correspond to
Pt 4f7/2, Pt 4f5/2, Ag 3d5/2, and Ag 3d3/2, respectively, verifying the
formation of Pt and Ag.
Fig. 1 UV-vis spectra of TMB interacting with different substrates. (1)
TMB + UA; (2) TMB + uricase; (3) TMB + Pt@Ag NFs; (4) TMB + H2O2;
(5) TMB + UA + uricase + Pt@Ag NFs; (6) TMB + H2O2 + Pt@Ag NFs;
conditions: UA, 20 mM; uricase, 1.25 mg mL; Pt@Ag NFs, 30 mL; TMB,
1.6 mM; H2O2, 20 mM.
was only mixed with one of the above substances, there was no
signicant absorption peak of oxTMB at 652 nm (black, red,
blue and purple curves). In addition, when TMB was added to
the mixed solution of Pt@Ag NFs, UA and uricase, the absor-
bance increased obviously at 652 nm (green curve). At the same
time, when H2O2 was mixed with TMB and Pt@Ag NFs (dark
blue curve), a similar phenomenon can be observed, and the
absorbance increases. This indicates that Pt@Ag NFs catalyzes
H2O2 and TMB in the same way as UA, uricase and TMB. The
results of the whole experiment demonstrated that UA was rst
catalyzed by uricase to produce H2O2, and then further cata-
lyzed H2O2 by Pt@Ag NFs, and the color of reaction substrate
TMB changed. Therefore, it can be seen that there is a signi-
cant color change from colorless to blue in Scheme 1.
Optimization of sensing system
It is known from previous literature that the optimal pH,
incubation temperature and incubation time for uricase-
ꢁ
catalyzed UA reaction are 8.5, 35 C and 15 min, respectively.
Relative activity was used to judge the optimal value of reaction
parameters, which can be represented by (A ꢀ A0)/A (A is the
absorbance in the presence of UA, A0 is in the absence of UA).
Fig. 2 Characterization of the Pt@Ag NFs: (a) TEM image; (b) magnified images; (c) energy dispersive spectra; (d) the XPS spectrum of the Pt@Ag
NFs, (e) the high resolution Pt 4f; (f) the high resolution Ag 3d, respectively.
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Fig. 3 Effects the peroxidase – like activity of Pt@Ag NFs (a) pH, (b) incubation temperature, (c) incubation time (d) Pt@Ag NFs volume and (e)
TMB concentration.
Next, the catalytic activity of Pt@Ag NFs catalyst was optimized temperature was easy to control, which was convenient for
to obtain the best sensing response of UA assay. These param- practical operation. Fig. 3c shows the effect of incubation time
eters include pH, incubation temperature, incubation time, (10–100 min) on the catalytic activity of Pt@Ag NFs. It can be
Pt@Ag NFs volume and TMB concentration. As can be seen seen from the gure that when the time is 40 min, the relative
from Fig. 3a, with the increase of pH (3.0–6.5), the relative activity tends to be maximum and there is a small uctuation.
activity at 652 nm increases rstly and then decreases. At pH ¼ We choose 40 min as the optimum time. At the same time, the
4.0, the relative activity is the maximum. The catalytic activity of volume of Pt@Ag NFs and the concentration of TMB also have
nanozymes at 25–65 ꢁC was studied (Fig. 3b). With the increase a signicant effect on the response of the assay. A series of
of temperature, the intensity of absorption peak at 652 nm Pt@Ag NFs volumes for UA detection were optimized (Fig. 3d).
gradually increased to the stage of platform, and the incubation The relative activity increased gradually at the volume of 10–30
Fig. 4 (a) Pt@Ag NFs determination of UA (from low to high: 0.5, 1.5, 2.5, 10, 20, 30, 40, 50, 70, 80, 100, 120, 130, 150 mM), illustrations: linear
standard curve of UA; (b) a digital image of reaction systems with different amounts of UA (from left to right: 0, 1.5, 2.5, 10, 20, 30, 40, 50, 70, 80,
100, 120, 130, 150 mM).
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Table 1 Comparison of analytical performances of different UA assays
Assay system
Signal output
Linear range (mM)
LOD (mM)
Real sample
Ref.
TCPO–H2O2–rubrene
CNCo
PrGOa/PB
TMB/g-C3N4/uricase
Ag nanoprism/uricase
MPADs
N, Fe-CDs
Au/Ag NCs
TMB-Pt@Ag NFs/uricase
Chemiluminescence
Current
Current
Colorimetry
Colorimetry
Colorimetry
Fluorescence
Fluorescence
Colorimetry
10–1000
2–110
40–415
10–100
1–40
100–1000
0.8–133
5–50
5.0
0.83
8.0
8.9
0.7
37
0.49
5.1
0.3
Serum
Serum
Serum
NR
Serum
Serum
Urine
Serum
Serum
41
42
43
22
16
44
45
46
0.5–150
This work
mL of Pt@Ag NFs, but aer 30 mL, it decreased. Therefore, 30 mL indicate that the assay has a special response to UA regardless of
was chosen as the optimal volume of Pt@Ag NFs. Fig. 3e shows the presence or absence of interfering substances.
that the relative activity increases with the increase of TMB
concentration until saturation. It is worth noting that when the
concentration of TMB is more than 1.6 mM, the reaction begins
to recrystallize due to its low solubility in the aqueous phase.
Real sample detection
In order to study the feasibility of UA assay, we used the
proposed method and biochemistry analyzer to test the serum
samples of 5 gout patients. The serum sample was centrifuged
at 4000 rpm for 3 min. Then, 5.6 mL serum mixed with uricase,
4-aminoantipyrine (4-AAP), and 3,5-diphenylamine disodium
salt (MADB). And the samples were put in the biochemical
analyzer and measure at 660/800 nm. The measurement values
of the two methods are almost identical (Table 2), and the
average relative error is 3.2%, which means that the developed
assay has good accuracy and can be used for the determination
of UA in human serum samples. As shown in Table 2, the
recoveries of this method are in the range of 96.8–103.3%, and
the relative standard deviation (RSD, n ¼ 3) of 5 samples is less
than 2.6%. These results show that colorimetric assay for the
detection of UA has great practical value in clinical application.
Therefore, the optimal concentration of TMB was 1.6 mM in the
following experiments.
Linearity and detection limit
In the analysis and detection, the sensitivity of the biological
enzyme assay is one of the most important factors. In order to
verify the sensitivity of Pt@Ag NFs assay for detecting UA,
a series of concentrations of UA standard solutions were
detected under optimal conditions. With the increase of UA
concentration (0.5–150 mM), the absorbance of the solution at
652 nm also increases (Fig. 4a). Moreover, as shown in Fig. 4b,
the color of the solution in the centrifuge tube from le to right
also showed a visible change (colorless to blue). The illustration
of Fig. 4a is a calibration curve for UA concentration and
absorbance. There is a linear relationship between DA and UA
concentration (0.5–150 mM) and the limit of detection (LOD)
was 0.3 mM (S/N ¼ 3). The corresponding linear equation is
expressed as: DA ¼ 0.0051C + 0.0453 (mM) and the correlation
coefficient (R2) is 0.995. For comparison, Table 1 summarized
the analytical parameters of some systems used to detect uric
acid. As can be seen from the table, the method used herein has
higher sensitivity and lower detection limit.
Test of selectivity
To verify the selectivity of the assay in detecting uric acid, we
tested several potential interfering substances in human serum,
including cysteine, ascorbic acid, glucose, and several inorganic
ions. Under the optimum conditions, the following experiments
have been carried out. One is the signal of only UA and inter-
fering substances mixed the detection system (Fig. 5 black
column). Compared with the absorbance of adding UA, the
interference is basically negligible, which proves the specic
catalysis of UA by uricase and the assay has a higher selectivity.
The other is the response of uric acid, uricase and various
Fig. 5 Selectivity of UA assay. In the absence of UA (black) and pres-
ence (red), the interfering substances were added to the reaction
solution, respectively. The concentration of UA, ascorbic acid, gluta-
thione and dopamine: 20 mM, and the concentration of other inter-
interfering substances coexist (Fig. 5 red column). These results fering substances: 200 mM.
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Table 2 Determination of UA in human serum of goat patients by proposed method and biochemical analysis
Proposed assay
(mM)
Biochemistry analyzer
(mM)
Average relative
error (%)
Found
(mM)
Recovery
(%)
Sample
Added (mM)
RSD (%)
Serum 1
Serum 2
Serum 3
Serum 4
Serum 5
711
616
936
522
482
751
604
967
502
490
3.2
500
500
500
500
500
1229
1122
1420
1016
969
103.3
101.2
96.8
98.8
97.4
1.6
1.8
2.3
1.9
2.6
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Conclusions
In conclusion, a new assay based on Pt@Ag NFs was con-
structed to detect UA by the simple colorimetric method. UV-vis
spectroscopy showed that Pt@Ag NFs had high sensitivity with
the limit of detection for 0.3 mM and high selectivity in the
detection of UA. The proposed assay was successfully applied to
the detection of UA in human serum with the recoveries in the
range of 96.8–103.3%, which has the potential of the simple and
fast UA detection platform for point-of-care diagnostics.
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Compliance with ethical standards
The study was approved by the ethics committee of Jiangxi
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Conflicts of interest
The authors declare that they have no competing interests.
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This work was nancially supported by the National Natural
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