j.talanta.2020.121383
j.talanta.2020.121383
j.talanta.2020.121383
PII: S0039-9140(20)30674-3
DOI: https://doi.org/10.1016/j.talanta.2020.121383
Reference: TAL 121383
Please cite this article as: A. Jouyban, E. Rahimpour, Sensors/nanosensors based on upconversion
materials for the determination of pharmaceuticals and biomolecules: An overview, Talanta, https://
doi.org/10.1016/j.talanta.2020.121383.
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a
Pharmaceutical Analysis Research Center and Faculty of Pharmacy, Tabriz University of Medical
Sciences, Tabriz, 5165665811, Iran
b
Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, 1411713135,
Iran.
c
Food and Drug Safety Research Center, Tabriz University of Medical Sciences, Tabriz, 5165665811,
Iran
*
Corresponding author. E-mail: rahimpour_e@yahoo.com
1
ABSTRACT
Upconversion materials have been the focus of a large body of research in analytical and
clinical fields in the last two decades owing to their ability to convert light between various
spectral regions and their particular photophysical features. They emit efficient and sharp
ultraviolet (UV) or visible luminescence after excitation with near-infrared (NIR) light. These
features overcome some of the disadvantages reported for conventional fluorescent materials and
provide opportunities for high sensitivity chemo-and bio- sensing. Here, we review studies that
biomolecules in the last two decades. The articles included in this review were retrieved from the
SCOPUS database using the search phrases: “upconversion nanoparticles for determination of
biomolecules”. Details of each developed upconversion nanoparticles based sensor along with
2
Contents
1. Introduction………………………………………………………………………………….. 4
2. Developed sensors based on UC materials for the determination of pharmaceuticals and 5
biomolecules
2.1. FRET-based sensors 6
2.2. Radiative energy transfer-based sensors 11
2.3. Electron transfer-based sensors 13
2.4. Non-energy transfer-based sensors 15
3. Conclusion 23
4. Future perspective 24
3
1. Introduction
Conventional fluorescent materials usually exhibit the well-known Stokes shift whereby
they emit light with a longer wavelength upon excitation by light with a shorter wavelength; this
process is called downconversion. The opposite effect is known as upconversion (UC), in which
an UC material is excited by red or infrared light and emits lights with a shorter wavelength [1].
In other words, the energy of the output photon is stronger than that of the input photon. This
concept was first reported independently by Ovsyankin, Feofilov, and Auzel in the mid-1960s
[2]. UC materials usually have narrow absorption and emission spectra, compared with those of
systems, but is also seen with rare-earth doped solids and their combinations [3, 4], and is
dependent on the sequential absorption of two or more near infrared (NIR) photons by the
dopants. In the late 1990s, following the advance in nanocrystal research, UC became more
applicable in the fields of biological assays and medical imaging [5]. The selection of the
material is important in terms of the intensity and color of the emission. Upconversion
nanoparticles (UCNPs) doped with Er3+ emit green light in the 510–570 nm wavelength range
and red light in the 630–680 nm wavelength range, but their maximum wavelengths and
intensities depended on the host lattice. Red emission is dominant in oxide-based lattices while
in fluoride-based lattices, it is green emission. Dopants such as Tm3+ mainly give blue
upconversion light (450–500 nm) along with a weak red fluorescence in certain host crystals.
Ho3+ doped lattices also emit a red and green luminescence that is comparable to that of Er3+
while lattices doped with Tb3+ show green light, Eu3+-doping shows red light, Tm3+ shows blue
light and Sm3+ shows orange light, [6]. Three ions namely Nd3+, Er3+, and Yb3+ are commonly
4
used owing to technical developments that facilitated the sensing of weak NIR emissions [7].
Most lanthanide -based UC materials depend on a solid inorganic matrix such as a crystalline or
glass host, like a metal fluoride (e.g., NaYF4, CaF2), vanadate (GdVO4), oxide (Y2O3), or
phosphate (YPO4) [8]. NaYF4 host lattice is a popular one both for nanocrystals and bulk
materials [3]. In the last two decades, UCNPs have been introduced as a new class of
nanocrystalline luminescent sensors for analytical and clinical applications [9]. As most
nontarget materials in complicated matrices do not have such photon UC features, a significantly
makes photon UC materials ideal for the detection and determination of trace concentrations of
the analytes. This review focuses on sensors based on UC materials for the determination of
pharmaceuticals and biomolecules. The studies gathered here were obtained by searching the
SCOPUS database with the search phrase of: “upconversion nanoparticles for determination of
biomolecules”. A total of 121 articles exactly related to the topic of interest were found for the
given search phrases. For each of these articles, brief explanations along with the relevant
and biomolecules
biomolecules are classified into four analyte detection mechanisms namely Förster/
5
sensors, electron transfer-based sensors, and non-energy transfer-based sensors, which are
Based on FRET theory (Fig. 1) in a FRET sensor, when the absorption of the energy
acceptor is close to the emission of the fluorophore and they are closer than 10 nm apart after
conjugation in the presence of the analyte, the emission of the energy donor is transferred to the
energy acceptor [10]. Crosby and Whan first reported the mechanism of energy transfer from
organic ligands to lanthanide ions [11]. UC materials are usually employed as donors in FRET-
based systems, typically coupled with a conventional acceptor molecule. UC materials with
excitation in the NIR range are good donor candidates because the NIR excitation wavelength is
far away from the excitation wavelength of most acceptor molecules [12]. Some FRET-based
sensors utilizing UC materials are summarized here. Kuningas et al. [13] used a UC-FRET-based
phosphor (UCP) (La2O2S:Yb3+, Er3+) coated with a 17β-estradiol -specific recombinant antibody
Fab fragment was used as the donor and an E2-conjugated dye, oyster-556, as the acceptor. The
UCP conjugated to the donor can bind 17β-estradiol and the acceptor. After excitation at 980 nm,
the UCP donor shows an anti-Stokes emission and can excite the acceptor by FRET. The
intensity of the acceptor emission (λmax= 600 nm) is inversely proportional to the analyte
concentration. An IC50 value of 3 nmol.L-1 was reported for this assay in serum samples. The
measurable concentration range extended up to 9 nmol.L-1 with a lower limit of detection of 0.9
nmol.L-1. Another similar method was developed by Zhang et al. [14] for detecting the presence
6
of specific nucleic acids. Er3+-doped NaYF4 nanoparticles were used as an energy donor and
sensor was employed for quantitatively determining perfectly matched target DNA (5′-
The authors claim that this system is effective for DNA/RNA detection and protein-DNA/RNA
interaction investigations. UCPs have also been used for studying DNA hybridization [15] based
on the FRET mechanism. NaYF4:Yb3+,Tm3+ NPs were used as the donor with SYBR Green I as
the acceptor. This UCP-based optical probe can be used for quantitative determination of the
DNA that perfectly matches, i.e. the target sequence of Homo sapiens mutant hemoglobin beta
Kumar and Zhang [16] used the same sandwich-type hybridization format (Fig. 2) with
LOD of 0.65 nmol.L-1. The increase in the acceptor’s emission shows the presence of the target
DNA. They reported that this DNA probe can distinguish completely matched target DNA from
the single nucleotide variant at four times higher concentrations as compared to matched targets.
Some other pharmaceuticals and biomolecules detected using FRET of UC materials in the
***Table 1***
7
Morgan and Mitchell [85] used FRET for the detection of binding interactions. They
used the UC waveguide ‘Yaglass’ as a lanthanide-based energy donor for the identification of a
fluorescent label by employing a bound monolayer of the protein R-phycoerythrin. Fig. 3a and b
demonstrate emission from the coated waveguide before and after the attachment of the
fluorescent label.
Besides the probes mentioned above, some FRET systems use two covalently conjugated
dye molecules as the acceptor instead of one. The first dye (the absorber) and the second dye (the
emitter) are close to each other such that energy can be transferred from the absorber to the
emitter. For this energy transfer, the excitation of the emitter must overlap with the emission of
the absorber and the distance should be less than 10 nm. The utilization of two dyes components
the dyes can be set to a specific wavelength region. Rantanen et al. [86] used a tandem dyes
acceptor to enhance UC-FRET in a homogeneous biotin assays. They used PTIR550/F UCP
particles with a diameter of 2.3-6.0 µm as the donor and B-phycoerythrin as the absorber with
multiple Alexa Fluor 680 dyes as the emitter. The UCP particles coated with streptavidin (the
donor) produces emission light at 540 nm and 653 nm upon excitation at 980 nm. The sensitized
emission of the acceptor dyes is observed at 575 nm and 704 nm, but only the emission in the red
region is measured. IC50 value for this tandem dye system was reported to be 9.6 nmol.L-1.
Organic quenchers are normally employed as dye acceptors but they cannot always
adequately quench the fluorescence of the UC material [87]. This could be related to the
structure of UC materials whereby only the emitters at or near the surface of the nanocrystals can
be quenched. Nanosized materials have attracted a lot of attention in various fields owing to their
8
special structure and electronic features, which also make them excellent FRET quencher. Wang
et al. [88] synthesized Na(Y1.5Na0.5)F6:Yb3+,Er3+ UCNPs with three emission bands at 655 nm,
540 nm, and 525 nm. The green light emitted from these UCNPs in water upon excitation with a
980‐nm laser can easily be seen with the naked eye. In this study, 7‐nm gold nanoparticles (Au
NPs) with a strong absorption band at λ≈520 nm were used which matches well with the UC
UCNPs and Au NPs were conjugated with biotin. Biotinylated UCNPs that emit UC
fluorescence have been combined with biotinylated Au NPs (as the energy acceptor), and utilized
for the quantification of trace levels of avidin based on FRET. Wang et al. [89] reported a new
aptamer biosensor for thrombin which was based on FRET from UCPs to carbon nanoparticles
(CNPs). Poly-(acrylic acid) (PAA) modified UCPs were covalently attached to a thrombin
aptamer (5’-NH2 - GGTTGGTGTGGTTGG-3’), which can interact with the surface of CNPs
through π - π stacking. When the energy donors and acceptors were placed next to each other,
UCP luminescence quenching occurred. Adding thrombin induced the aptamer to form a
quadruplex structure, weakening the π - π interaction, leading to the acceptor and donor
becoming separated from each other. The luminescence of UCPs was therefore regenerated
proportionally to the thrombin concentration. This method can be used for thrombin
determination in serum samples in the range of 0.5 to 20 nmol.L-1 with an LOD of 0.25 nmol.L-1.
Wang et al. [90] applied a similar method with poly(ethylenimine) modified NaYF4:Yb,Er as the
10−500 pg.mL-1. Saleh et al. [91] used FRET between NaYF4:Yb,Er UCNPs labeled with avidin
and Au NPs labeled with biotin for identification of biotin–avidin affinity binding. In the
9
presence of avidin-functionalized UCNPs, the biotinylated Au NPs could be determined in the
range from 12 to 250 µg mL-1 by using the ration of the emission intensities at 523 and 665 nm.
Further studies involving the use of UCNPs for the determination of biomolecules and
In addition to dye and nanoparticles, graphene oxide (GO) sheet can be also used as an
acceptor in FRET systems. Zhang et al. [92] used a glucose sensor based on FRET between
concanavalin A labeled UCP nanocrystals (NaYF4: Yb,Er) and chitosan-labeled GO. The
binding of concanavalin A to chitosan quenched the fluorescence of the UCP, which is restored
in the presence of glucose, owing to competition between glucose and chitosan for binding with
concanavalin A (Fig. 4). This method can measure glucose concentration in the range of 0.56 to
2.0 µmol.L-1 with an LOD of 0.025 µmol.L-1. Other methods using the same mechanism were
applied for the determination of adenosine triphosphate in the range of 0.5 – 100 µmol.L-1 with
an LOD of 80 nmol.L-1 [93], anti-HIV-1 gp120 antibody in serum samples in the range of 5 -150
nmol.L-1 [94], kanamycin in serum samples in the range of 0.03 – 3 nmol.L-1 with a detection
limit of 18 pmol.L-1 [95], mRNAs present in Alzheimer’s disease in the femtomolar range [96],
and determination of type I topoisomerases in the concentration range of 1.5 – 18.6 nmol.L-1
[97].
***Fig. 4***
In all of the above-mentioned studies, a donor-acceptor FRET system was used for
determination and the analytes were quantitated indirectly via an effect on the energy transfer.
However, in some reports the analyte acts as an acceptor and quantitatively quenches the UC
material’s luminescence. Xu et al. [98] used a NaYF4:Yb,Tm NPs with blue UC emission for the
10
determination of doxorubicin by quenching of the UCNP emission at 466 nm. The reported
linearity for this method is 0 – 66.23 µmol.L-1 with LOD of 0.69 µmol.L-1. Similarly, Hu et al.
[99] used a NaGdF4 :48% Yb3+ ,2% Er3+ UC array for the determination of glycated hemoglobin
based on the FRET from the UCNPs to glycated hemoglobin and Mo et al. [100] used
189.66 µmol.L-1.
system for the quantification of prostate-specific antigen in serum samples. Near-infrared (NIR)-
emitting Mn2+ doped NaYF4 :Yb,Tm UCNPs were used as the donor, and gold nanorods (Au
NRs) were used as the acceptor. Anti- prostate-specific antigen was attached to the surface of
(CTAB)-capped Au NRs were treated with 11-mercaptoundecanoic acid and then bonded with
antigen, the donors and acceptors come close to each other as a result of the antigen and antibody
of 3.75-938 pg.mL-1.
The radiative energy transfer mechanism involves photon emission by the donor after
absorbing light followed by the reabsorption of the emitted photon by the acceptor molecule.
There are no specific interactions between the acceptor and donor molecules in this mechanism
and thus, radiative energy transfer can even occur with the large distances between donor and
11
acceptor [102]. Guan et al. [103] used a sensor based on mesoporous silica-coated UCNPs
Emission–reabsorption from the UCNPs to the fluorescent probe was reported as a possible
detection mechanism for this sensor. Under laser exposure at 980 nm, the UCNPs emit blue light
(λmax= 475 nm) which excites the fluorescent probe enabling the identification of cysteine. The
fluorescent probe reacts with cysteine to form 5(6)-carboxy fluorescein, with green luminescence
at around 518 nm. The peak at 518 nm increased proportionally to the cysteine concentration
When the sample contains a chromophore that can absorb wavelengths in the range of
either the excitation or emission of a fluorophore, it acts as a modulator and/or filter for the
method for analyte determination [104]. On this basis, Long et al. [105] used a UCNP-based
method for the quantification of uric acid in human serum. In this study, uricase was used to
oxidize uric acid to allantoin and hydrogen peroxide, which then oxidized to o-phenylenediamine
(OPD). NaYF4:Yb3+, Tm3+ luminescence can be specifically quenched by oxidized OPD based
on its inner filtering effect. Thus, the quenching of UCNPs is indirectly proportional to the uric
acid concentration in the range of 20 – 850 µmol.L-1 with LOD of 6.7 µmol.L-1. Chen et al. [106]
used the inner filter effect between NaYF4:12% Yb3+, 0.2% Tm3+ UCNPs and squaric acid –iron
(III) for the determination of glucose in serum samples. Glucose oxidase oxidizes glucose to
gluconic acid and hydrogen peroxide, the produced hydrogen peroxide then catalytically oxidize
Fe2+ to Fe3+ which coordinates with the squaric acid to form a squaric acid-Fe3+ complex. The
12
absorption spectrum of squaric acid-Fe3+ completely overlap with the emission spectrum of the
UCNPs; as a result, UCNPs luminescence emission from the UCNPs was effectively quenched
proportionally to the amount of glucose in the range of 7 – 340 µmol.L-1 with LOD of 2.3
µmol.L-1. Other similar works were reported by Ren et al. [107] for the quantification of
polydopamine as a quencher, and by Fang et al. [108] for the quantification of uric acid at 0.01 –
Wu and Cui [109] used an aptamer-based assay for the determination of sulfamethazine
in milk samples. NaGdF4 :Yb3+, Er3+ was modified with an aptamer sensitive to sulfamethazine and
the complementary DNA for the sulfamethazine aptamer was fixed on Au@Ag@AuNPs.
complementary DNA sequence was bonded together to produce a duplex structure. An inner
filter effect also occurred between the UCNPs and Au@Ag@AuNPs. On adding sulfamethazine,
the aptamer for sulfamethazine coupled with the sulfamethazine to produce a stable complex
Unlike energy transfer, in the case of electron transfer, the acceptor is not fluorescent and
the fluorescence of the donor is quenched after this electron exchange. Here, we summarize
some reports based on electron transfer quenching for upconversion materials. Deng et al. [110]
prepared NaYF4:Yb/Tm@NaYF4 core−shell NPs and coated them with MnO2 nanosheets by
13
adding KMnO4 in the presence of 2-(N-morpholino)ethanesulfonic acid buffer at pH 6. The
UCNP/MnO2 nanosheet assembly was used as a selective probe for the determination of
glutathione in living cells and aqueous solutions. They reported that MnO2 nanosheets coated on
the surface of the nanoparticles serve as a strong quencher for UC fluorescence. The
fluorescence can be recovered by the addition of glutathione which reduces MnO2 to Mn2+ (Fig.
5). This sensor was able to determine glutathione with a detection limit of 0.9 µmol.L-1. A
similar work was performed by Yuan et al. [111] for determination of H2O2 and glucose in blood
probe for quantification of H2O2 in the range of 0 – 350 µmol.L-1 H2O2 and 0-400 µmol.L-1
glucose.
glucose in whole blood and human serum. Dopamine monomers spontaneously bind to the
NaYF4:Yb/Er UCNPs and further polymerize to produce a polydopamine shell that quenches the
UC fluorescence of the UCNPs. This quenching is effectively inhibited by H2O2 generated from
glucose in the presence of glucose oxidize, which can be applied for the indirect determination of
***Fig. 5***
Kannan et al. [113] synthesized a coated gold nanorods on NaYF4 :Yb/Tm upconversion
nanocrystals (UCNCs), modified with 2-thiouracil and used it for non-enzymatic determination
of uric acid. Upon the addition of uric acid to the modified UCNCs, a red-shift was observed in
the LSPR spectrum accompanied by a gradual decrease in the absorbance. At the same time, the
luminescence emission peak appearing at ~805 nm also present a steady decrease. This decrease
14
in absorbance and fluorescence is attributed to the aggregation of gold nanorods on the UCNCs.
This method shows a linear response for uric acid concentrations from 1 pmol.L-1 to 10 µmol.L-1
with LOD of 1 pmol.L-1. Zhang et al. [114] used a redox reaction system based on UCNPs for
groups in the PAA to Fe3+ to produce a UCNPs/Fe3+ complex. L –Cysteine, L -ascorbic acid, and
glutathione reduced Fe3+ to Fe2+, with fluorescence regeneration proportional to the analyte
concentration. This system presents a linear response to glutathione concentrations from 0.25-
300 µmol.L-1, L –cysteine within the range of 0.5–875 µmol.L-1 and L -ascorbic acid within the
range of 0.5–350 µmol.L-1, and the LODs were 0.2 µmol.L-1, 0.5 µmol.L-1 and 0.2 µmol.L-1.
Zhou et al. [115] prepared Mn2+ -doped NaYF4:Yb,Er UCNPs and used them for quantification
of uric acid in human serum. The procedure was based on the fact that hydroxyl radicals
produced in the presence of uricase effectively quench the UCNP luminescence. This method can
detect uric acid in the concentration range of 4-10000 nmol.L-1 with LOD of 1.90 nmol.L-1.
(PET) method for the determination of tyrosine in serum sample. Tyrosinase catalyzes tyrosine
to melanin-like polymers which are adsorbed on the surface of NaYF4:Yb, Tm UCNP capped
with polyethyleneimine and effectively quench its fluorescence through PET under excitation at
980 nm. This quenching showed a linear fluorescent response to the tyrosine concentration in the
15
Cui et al. [117] reported Ag NCs templated by single- and double-stranded DNAs (Fig. 6)
as nanoprobes for in situ selective DNA biosensing. DNA nucleobase identification with the in
situ synthesized Ag NCs is realized via the Ag NCs’ UC emission. The UC emission of these Ag
NCs can easily be tuned by using DNA templates with different lengths, sequences, and
structures based on their emission of the corresponding Stokes mode. Päkkilä et al. [118]
microtiter wells. The control spots and captured analytes were identified using antibody-coated
UCNPs. The array was imaged using a microwell imager and standard plots for each analyte
were constructed from the images by quantifying the mean intensities of the spots using ImageJ
software. The reported LODs in this multianalyte assay for thyroid-stimulating hormone,
luteinizing hormone, and prostate-specific antigen were 0.64 mU.L-1, 0.45 U.L-1 and 0.17 ng.mL-
1
, respectively, which are close to the values obtained for the single analyte assay. Liu et al. [119]
in human serum. For this purpose, the capture anti-AFP antibody was first immobilized on a 96-
well microplate after incubation and then conjugated with the analyte solution of the AFP
antigen because of high binding affinity and specific recognition. Subsequently, the solution of
biotinylated anti- AFP antibody that was bound to the biotinylated nanoprobe using the avidin
linker was added to label the analyte. Thus, the AFP concentration can be quantified by
recording the UC luminescence of the Eu3+ in the nanoprobes attached to a 96-well microplate
under excitation at 980 nm within the range of 0.01 – 60 ng.mL-1. Huang et al. [120] reported a
LiLuF4:Ln3+ core/shell NPs for determination of the β subunit of human chorionic gonadotropin
16
(β-hCG). The UCNPs were modified with the avidin and biotinylated β-hCG antibody and
specific antibody–antigen bonding was used for analyte recognition. The UCNP luminescence
signal gradually increased proportionally to the amount of β-hCG antigen within the range of 0 -
310 ng.mL-1. Ju et al. [121] developed a paper-based method for DNA identification using Ln3+-
doped LiYF4 UCNCs as the bioprobe. The UCNCs are bonded to single-stranded DNA
oligonucleotides to provide a bioprobe that can selectively identify trace concentrations of target
proportionally with increasing concentration of the target DNA (2- 80 nmol.L-1) added to the
paper and the LOD for the method was reported to be 1.8 nmol.L-1.
Lan et al. [122] synthesized NaYF4 :Yb3+ /Er3+ UCNPs and applied them for direct
determination of breast cancer-associated circulating miRNA. First, target miRNA with the
incubated at room temperature for 120 min after adding the hybrid buffer. Then, auxiliary probe
COOH nanocrystals were added to the microplate and kept at 25 ℃ for 120 min. The
fluorescence of the UCNPs was recorded after excitation at 980 nm. The photoluminescence
intensity arise with concentrations of target miRNA-21 from 10 fmol.L-1 to 1 pmol.L-1. Similar
work were reported by the same research group for the determination of vascular endothelial
growth factor in spiked serum samples with LOD of 6 pmol.L-1[123], and for the determination
17
of c-erbB-2 oncogene within the range of 100 amol.L-1 to 100 fmol.L-1 with LOD of 40 amol.L-
1
[124].
Sirkka et al. [125] used combination of antibodies for the determination of cardiac
troponin I (cTnI) in plasma samples. In their method, two different antibodies were utilized to
capture the analyte and a third antibody was employed to identify the captured analyte.
Biotinylated anti-cTnI monoclonal antibody (Mab) and a Fab fragment attached to streptavidin-
coated wells were employed to capture cTnI. The captured cTnI was then identified from the
surface of the dry wells after 15 min incubation with PAA-modified NaYF4: Yb3+, Er3+ UCNPs
attached to the second anti-cTnI Mab. This sensor can determine cTnI within the concentration
method and couple the NPs with anti-cephalexin monoclonal antibody. The UCNP-based probe
The LFIA strip consists of five components: conjugate pad used to load the particle-labeled
antibody, a sample pad for applying the sample solution, an absorbent pad as the liquid sink, a
nitrocellulose (NC) membrane as the chromatography matrix, and a backing card for supporting
all of the above components (Fig. 7). A band of coating antigen (cephalexin– bovine serum
albumin) and a band of goat anti-mouse IgG were drawn on the NC membrane as the test line (T
line) and the control line (C line), respectively. Competitive experiments were performed by
applying 100 µL aliquots of cephalexin solution at various concentrations to the sample pad.
After about 20 min, the fluorescence of the testing strip was seen upon excitation at 980 nm by a
CW laser. The fluorescence intensity was calculated by integrating the fluorescence signals of
both the C and T lines. The signal of the T line is inversely proportional to the cephalexin
18
concentration in the range of 0.5 – 100 ng.mL-1. Similar works were reported by Tang et al.
[127] for the determination of human procalcitonin within the concentration range of 0 – 10
ng.mL-1 in serum samples, and by Hu et al. [128] for determination of sulfaquinoxaline in food
determination of chloramphenicol. The biosensor was prepared by binding an aptamer onto the
surface of magnetic nanoparticles (MNPs), which were used to capture and concentrate
complementary DNA (cDNA) which was functionalized with UCNPs and gives a maximum
with it and resulting in the dissociation of some of the cDNA modified with UCNPs, leading to a
decreased luminescence signal on the MNPs surface (Fig. 8). This method can be applied to
quantify chloramphenicol within the concentration range of 0.01 to 1 ng mL-1with a LOD of 0.01
ng mL-1. Similar methods were applied by Fang et al. [130] for the determination of
oxytetracycline within the concentration range of 0.05 – 100 ng.mL-1 with a detection limit of
0.036 ng.mL-1, by Liu et al. [131] for the determination of kanamycin and oxytetracycline in the
range of 1 – 50 ng.mL-1 with LOD of 0.85 ng.mL-1 for oxytetracycline and 0.92 ng.mL-1 for
kanamycin, by Ouyang et al. [132] for the determination of tetracycline within the range of 0.01
– 100 ng.mL-1 with an LOD of 0.0062 ng.mL-1, by Hu et al. [133] for the determination of
sulfaquinoxaline in food samples in the range of 0.1 – 100 µg.L-1, by Liu et al. [134] for the
carcinoembryonic antigen in human serum in the range of 2.5 × 10−12 to 1 × 10−8 g.mL-1, by
19
Jiang et al. [136] for the determination of Aβ oligomer within the concentration range of 0.2 – 15
nmol.L-1, and by Qiu et al. [137] for the determination of carcinoembryonic antigen at
Guo et al. [138] combined molecular imprinting technology with the luminescence
features of UCNPs for cytochrome C determination. The nanosensor was synthesized by in situ
functionalizing cytochrome C imprinted materials onto the surface of the carboxyl modified
NaYF4:Yb,Er NPs usin a sol–gel technique. The fluorescence intensity of the UCNPs@
molecularly imprinted polymer (MIP) (λex/ λem 980/660 nm) reduced gradually with increasing
interaction between the template protein and the UCNPs when the imprinted sites close to the
template protein in rebinding process. The selectivity of the method was studied in the presence
of bovine serum albumin and lysozyme and the results showed that the identification sites were
not complementary to the investigated proteins. The LOD of the method was 0.73 µmol.L-1.
Similar works were reported by Tian et al. [139] for sulfamethazine within the concentration
range of 50 – 700 ng.mL-1 (with LOD of 34 ng.mL-1), by Tang et al. [140] for the determination
of enrofloxacin within the range of 0.063 – 60 µg.L-1 (with LOD of 8 ng.L-1), by Guo et al. [141]
for the determination of bovine hemoglobin concentration in the range of 0.1 – 0.6 mg.mL-1
(with a detection limit of 0.062 mg.mL-1), by Liu et al. [142] for determination of enrofloxacin in
perch and catfish (with LOD of 0.04 ng.mL-1), and by Tang et al. [143] for determination of
some quinolones in fish tissue, namely enroflaxacin within the concentration range of 0.001-0.28
µmol.L-1, enoxacin in the range of 0.004 – 0.25 µmol.L-1, levofloxacin in the range of 0.007-0.28
µmol.L-1, fleroxacin in the range of 0.002-0.22 µmol.L-1, and ciprofloxacin in the range of 0.008-
0.3 µmol.L-1.
20
Hao et al. [144] synthesized NaYF4:Yb/Er @ZIF-NiSx-L nanoparticles and used them for
determination of H2O2 in the living cell. The luminescence intensity of UC NPs at 450 nm with
intensity was turned-on after addition of H2O2. They reported that NiSx-L nanoparticles is
NaYF4:Yb/Er @ZIF. This method can be detected H2O2 in the range of 0.18 – 10.2 µmol.L-1
determination of H2O2 in the infant formula milk powder. The possible mechanism is based on
this fact that H2O2 could oxidize Fe2+ to Fe3+ and caused quenching of the upconversion
luminescence. H2O2 can be detected by this method in the range of 0.25 – 5 µmol.L-1 with LOD
of 0.1 µmol.L-1.
Liu et al. [146] used NaYF4:Yb,Er@NaYF4 NPs as an elemental tag for the quantification
of AFP in human serum samples by inductively coupled plasma mass spectrometry (ICP-MS).
Anti-human AFP antibody in the coating buffer was immobilized on the 96-well plate. After
rinsing several times, UCNP– monoclonal mouse anti-human AFP antibody conjugates were
poured into each well and incubated for 1.5 h. After removing the excess conjugates, 100 µL of
formic acid was added into each well and the eluent was then analyzed by ICP-MS for the
indirect quantification of AFP within the concentration range of 0.5 – 35 ng.mL-1. The LOD for
this method was 0.31 ng.mL-1. Another research group employed the same elemental tag for the
quantification of miRNA-21 in plasma samples [147]. Hairpin structures DNA H1 and H2 were
designed, and DNA H1 was attached to ultrasmall lanthanide UCNPs to produce UCNPs@DNA
conjugate sensors. The target miRNA triggers a chain reaction of alternating hybridization
between DNA H1 (bound on the UCNPs@DNA probe) and DNA H2. This results in UCNPs
21
accumulation and serves as an efficient signall amplification method for UCNP. The
of 0.1 – 500 fmol.L-1. The LOD of the method was reported to be 41 amol.L-1.
Hao et al. [148] fabricated aptamer based Au UCNP pyramids and used them to
simultaneously quantify prostate-specific antigen and thrombin via fluorescence and surface-
enhanced Raman scattering (SERS), respectively. The SERS intensity diminishes and the
fluorescence intensity increases when the aptamers attach to the targets. The detection ranges for
thrombin and prostate-specific antigen were 0.001 – 0.01 fmol.L-1 and 0.04 – 1 amol.L-1.
Pulgarín et al. [149] used a scattering method based on the resonance light of UCNPs for the
NaYF4: Yb3+, Er3+ UCNPs decreases their size and the intensity of their resonance light
quinone by electrostatic interactions and hydrogen bonding. The resulting strong decrease in
resonance light scattering can be used for quantification of dopamine within the concentration
Liu et al. [150] used the ECL behavior of Mn2+-doped NaYF4:Yb/Er NPs. These UCNPs
were coated on the surface of SiO2 NPs and immobilized on a glassy carbon electrode (GCE).
The electrode was then placed into a solution of anti- carcinoembryonic antigen (0.1 mg mL-1 in
0.1 mol.L-1 phosphate buffer solution, pH 7.4) to modify the electrode for selective determination
carcinoembryonic antigen in serum samples within the concentration range of 0.01 – 40 ng.mL-1
22
with a LOD of 5.2 pg.mL-1. Jin et al. [151] modified a GCE with reduced GO as a carrier for
immobilizing UCNPs, which boosted the ECL response of the UCNPs owing to the superior
electron transport rate, high conductivity, and large specific surface area. The introduction of the
MIP increased the ECL sensor selectivity toward clenbuterol. In the presence of clenbuterol, the
ECL intensity diminished, as a result of the re-combination of clenbuterol with the binding sites
on the MIP blocking electron transport channels between the fluorophor UCNPs and the
electrolyte. This sensor could detect clenbuterol at concentrations from 0.01 to 100 µmol.L-1
with a LOD of 6.3 nmol.L-1. Similar work was performed by Gu et al. [152] who used
dopamine in serum samples. This method presented a wide detection range (10–14–10−6 mol.L-1),
Wiesholler et al. [153] synthesized Tm3+ -doped NaYF4 UCNPs and the nanoengineered
interfaces are prepared by the attaching of the UCNPs to an Au nanotriangle array by self-
assembly. Applying an electromagnetic field at the hot spots of Au NPs will confine the
excitation power density and the intensity of the peak at 345 nm peak (with excitation at 980 nm)
3. Conclusion
and clinical applications is an important field of research. The present literature review
demonstrated that UC materials have valuable merits and unique properties in terms of chemo-
23
and bio- sensing. The literature was classified based on the reported analyte detection mechanism
and the analytical properties of each method were summarized. This review has been shown that
most of the UC-based methods used for pharmaceutical and biomolecule analyses are based on
the FRET mechanism. However, despite the obvious advantages of UC materials as discussed in
this review, several factors limit the wider used of UC materials in bioanalyses, such as a lack of
commercial instruments specifically designed for the measurement of the UC emissions and a
lack of standardized methods for the surface modification and characterization of UC materials.
4. Future perspective
The unique optical properties of UC materials have largely impacted biological and
indispensable to those applications. So, introducing UC NPs made possible a broad range of
optogenetics, security labelling and volumetric display. The majority of currently synthesized
UC NPs are around 20–50 nm. It has been challenging to design and fabricate <10 nm UC NPs
with emission output comparable with that of quantum dots and organic dyes. Owing to
brightness issues, UC NPs with a large number of dopants may present exceptional optical
properties in compared with bulk or homogeny nanoparticles. We believe that these sub-10 nm
and heterogeneously doped UC NPs have the potential in pushing the performance of UC NPs to
24
Acknowledgements
This work was supported by Research Affairs of Tabriz University of Medical Sciences,
25
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Fig. 1. Schematic representation of FRET between two molecules.
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Fig. 2. Sandwich format for detecting DNA targets. Reproduced with permission of the publisher [16].
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Fig. 3. (a) A titanium dioxide-coated ‘Yaglass’ waveguide treated with biotinylated-bovine serum
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Fig. 4. Schematic illustration of the UCP–GO biosensing platform and the mechanism of glucose
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Fig. 5. Schematic mechanism of glutathione detection using MnO2 -nanosheet-modified UCNPs.
51
Fig. 6. (A) Schematic of the formation of Ag NCs on various DNA templates and (B) the sequences of ss-
DNA (DNA1, DNA2, and DNA3) and ds-DNA (DNA4 and DNA5) used in this work. Reproduced with
52
Fig. 7. The competitive LFIA principle based on UC nanoparticles. Reproduced with permission of the
publisher [126].
53
Fig. 8. Schematic illustration of chloramphenicol detection based on a magnetic capture probe and
54
Table 1
Analytical characteristics of reviewed studies using FRET of UC materials in the presence of a dye or nanoparticles as an acceptor for
the detection of pharmaceuticals and biomolecules.
Donor Acceptor Target molecule Matrix λex/ λem (nm) LR LOD Ref.
NaGdF4:Er3+ 2%, Yb3+
Concanavalin A
20% conjugated with
conjugated with Lectins - 980 /585 0.3 – 1.6 µmol.L-1 - [17]
poly(amidoamine)
tetramethylrhodamine
dendrimers
Silica-coated Plasmid DNA pEGFP-
POPO-3 Serum 980/514 - - [18]
NaYF4:Yb/Er N1
N,N,N’,N’-
0.1 to 0.75
NaYF4 : Yb3+, Er3+ NPs tetramethyl-6- Adenosine triphosphate - 980/ 540 20 µmol.L-1 [19]
mmol.L-1
carboxyrhodamine
DNA 5’-
NaYF4 : Yb3+, Er3+ NPs SYBR Green I TCCTGTGGAGAAGT - 980/ 530,477 - - [20]
CTGCCGTTACTG-3’
NaYF4:Yb, Er Dopamine-quinone Glutathione Serum 980/ 550 1 – 75 µmol.L-1 0.29 µmol.L-1 [21]
IS6110 sequence of the
NaYF4:Yb, Er SYTOX Orange dye Mycobacterium - 980/ 543 - - [22]
tuberculosis complex
DNA: 5′-CTCCACC
GTGCAGCTCATC
NaYF4 :Yb3+ , Tm3+
SYBR Green I ATGCAGCTCATG - 980/ 533,477 - 0.01 pmol [23]
NPs
CCCTTC
G-3′
NaYF4: 2% Er3+ , 18% Cy3 dye Survival Motor Neuron
980/ 542
Yb3+ /NaYF4 Serum - - [24]
980/ 653
Core/Shell UCNPs Cy5.5 dye glucuronidase gene
5’-G
NaYF4; Yb3+ ,Tm3+ GGACCCACTCCA
SYBR Green I - 980/ 533,477 - 1 fmol [25]
NPs TCGAGATTTCTC
TGTAGCTAGACC
55
AAAATC A-3’
β-NaYF4 :2% Er3+, 3′-TAA AAC AGA
Cy3 - 980/ 542 0- 1.2 pmol 34 fmol [26]
18% Yb3+ CTT TGG GAC A-5′
Lysozyme
2.8 nmol.L-1
5’-CTAAGTAACTCT 30 – 210 nmol.L-1
NaYF4 :Yb, Er NPs TAMRA Serum 980/ 580 2.8 nmol.L-1 [27]
GCACTCTTTAGC 40 -200 nmol.L-1
CCTGAT-3’
5′-GGTGCAGCA
β-NaYF4 :2%Er3+,
Cy3 GAAAAAGTTGTA Serum 980/540 - 146 fmol [28]
18%Yb3+
GGATTAACTGAA-3′
NaYF4: Yb, Tm SYBR Green-I Oxytetracycline - 980/ 530,477 0.1 – 10 ng.mL-1 0.054 ng.mL-1 [29]
β-NaYF4: Yb3+/Er3+ Ring-opened
Cysteine - 980/ 540,651 10 – 100 µmol.L-1 1.1 µmol.L-1 [30]
rhodamine
Coomassie Brilliant Whole
NaYF4 :Yb3+, Er3+ Glycated Hemoglobin 980/ 545 - - [31]
Blue G-250 blood
Fluorescein Carcinoembryonic
NaYF4 :Yb,Tm Serum 980/ 520, 480 0 – 100 ng.mL-1 0.89 ng.mL-1 [32]
isothiocyanate antigen
NaYF4 : Yb3+ , Er3+
Cy3 Cytochrome C Living cell 980/ 570 0.05 – 10 µmol.L-1 20 nmol.L-1 [33]
@NaCdF4 UCNPs
5’-
NaYF4 :Er3+, Yb3+ Cy3 UAGCUUAUCAGAC - 980/545 0.2-1.4 nmol.L-1 0.095 nmol.L-1 [34]
UGAUGUUGA-3’
MiRNA 122:
NaGdF4 @NaGdF4
TAMRA UGGAGUGUGACAA - 980/545,580 0-1 pmol.L-1 0.1 pmol.L-1 [35]
:Yb,Er
UGGUGUUUG
NaLuF4 :Gd3+, Yb3+,
Rhodamine B
Er3+ Glutathione Serum 980/ 540,658 0.3-40 µmol.L-1 50 nmol.L-1 [36]
derivative
NaYF4 :Er, Yb, Tm CYD1 H2O2 Living cells 980/525, 631 0 – 60 µmol.L-1 0.08 µmol.L-1 [37]
0 – 10 mmol.L-1 0.83 mmol.L-1
TCG Glutathione 980/ (540/800 or
NaYF4: Yb, Er, Tm Living cell 0 – 60 µmol.L-1 4.37 µmol.L-1 [38]
BCH H2O2 650/800)
NaYF4: 20 mol% Yb,
1.8 mol% Er, 0.5 mol% Rhodamine B Hypochlorous Acid Living cells 980/ 541,800 0 – 120 µmol.L-1 0.32 µmol.L-1 [39]
Tm
56
ROS including
• 0.03 µmol.L-1
b-NaFY4: OH 0.02 µmol.L-1
18%Yb/2%Er Rhodamine B ClO‒ Living cell 980/570, 660 -
0.06 µmol.L-1
[40]
nanocrystals ONOO‒ 0.1 µmol.L-1ench
O2‒
• 1.2 – 194.6
NaYF4:Yb, Tm NP Modified orange G OH Living cell 980/478 1.2 fmol.L-1 [41]
fmol.L-1
β-NaGdF4: 20% Yb, •
Methylene blue OH Living cell 980/ 650 - 2 nmol.L-1 [42]
2% Er@NaGdF4 NP
NaYF4: 20% Yb, 2%
Rhodamine B Nitric oxide Living cell 980/ 656, 540 7.4 – 110 µmol.L-1 73 nmol.L-1 [43]
Er, 0.2% Tm
NaYF4
:30%Yb,1%Nd,0.5%Er Cyanine dye hCy3 ClO − Living cell 808/ 540,654 0 – 80 µmol.L-1 - [44]
@NaYF4:20%Nd
Zinc-dithizone
NaYF4:Yb,Er ClO − Living cell 980/ 540,650 0 – 200 nmol.L-1 3 nmol.L-1 [45]
Complex
β-NaYF4:30%Yb
/1%Nd/0.5%Er@NaYF Cy787 dye ClO − Living cell 980, 808/540 - 3.6 nmol.L-1 [46]
4:20%Nd
NaYF4: 20% Yb, 2%
MC dye HS‒ Living cell 980/ 548 0 – 115 µmol.L-1 0.58 µmol.L-1 [47]
Er, 0.2% Tm
NaYF4: 20% Yb, 2%
Merocyanine dye H2S Living cell 980/ 530 - 1.15 µmol.L-1 [48]
Er, 0.2% Tm
β-NaYF4:Yb/Tm NPs Cy7-Cl H2S Living cell 980/800 1.0 – 90 µmol.L-1 510 nmol.L-1 [49]
Coumarin- ‒ -1 -1
β-NaYF4, Yb, Tm, Er SH Living cell 980/ 541,800 0 – 50 µmol.L 0.13 µmol.L [50]
hemicyanine
2− − -1 -1
β-NaYF4:Yb,Er,Tm HIAN SO3 /HSO3 - 980/543 10 – 250 µmol.L 0.14 µmol.L [51]
3.75 – 112.5
NaYF4 :Yb,Er NPs Au nanorod Thrombin Plasma 980/ 661 1.5 nmol.L-1 [52]
nmol.L-1
platelet-derived growth 200 – 1200
NaYF4 :Yb,Er NPs Au NPs Serum 980/ 547 10 nmol.L-1 [53]
factor nmol.L-1
0.04 – 1.0 µg.mL-1
Cysteine 0.0124 µg.mL-1
NaYF4 : Yb3+, Er3+ NPs Au NPs Tab water 980/ 550 0.06 – 1.80 [54]
Homocysteine 0.0151 µg.mL-1
µg.mL-1
NaYF4: Yb3+, Er3+ NPs Au NPs Thrombin - 980 / 801 3.75 – 112.50 - [55]
57
nmol.L-1
3+ 3+
NaYF4: Yb , Er NPs Au NPs Streptavidin - 980/ 800 0.5 – 100 µmol.L-1 80 nmol.L-1 [56]
NaYF4:Yb,Tm/NaGdF4 0.18 – 11.44
Au NPs α-Fetoprotein Serum 980/ 804 0.16 ng.mL-1 [57]
core−shell NPs ng.mL-1
59
TG – 5’
0.002 – 100
NaYF4: Yb/Er Au NPs MiRNA 21 - 980/540 - [78]
nmol.L-1
NaYF4 :Yb,Er,Gd Au NPs α-Fetoprotein Serum 980/665 0.098- 15 ng.mL-1 0.095 ng.mL -1
[79]
NaYF4 :Yb, Er CdTe QDs Procalcitonin Serum 980/540 0.1 – 10 ng.mL-1 0.25 ng.mL-1 [80]
Prostate-specific
NaYF4 :Yb3+, Er3+ Au NPs Serum 980/ 550 0 – 500 pmol.L-1 1 pmol.L-1 [81]
antigen
0.4 – 1.87 µmol.L-
NaYF4 :Yb, Er Au NPs Glucose Serum 980/545 1 0.02 µmol.L-1 [82]
Carcino-embryonic
NaYF4 : Yb3+, Er3+ Au-NPs Serum 980/540 0.05 – 2.0 ng.mL-1 0.02 ng.mL-1 [83]
antigen
Poly(acrylic acid)
NaGdF4:Yb/Tm ClO − Living cell 980/ 476 0.5 – 15 µmol.L-1 0.384 µmol.L-1 [84]
modi fi ed MoS 2
60
Highlights:
materials.
Declaration of competing interest
The authors declare no conflict of interest.