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Sensors/nanosensors based on upconversion materials for the determination of


pharmaceuticals and biomolecules: An overview

Abolghasem Jouyban, Elaheh Rahimpour

PII: S0039-9140(20)30674-3
DOI: https://doi.org/10.1016/j.talanta.2020.121383
Reference: TAL 121383

To appear in: Talanta

Received Date: 25 June 2020


Revised Date: 2 July 2020
Accepted Date: 4 July 2020

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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Graphical Abstract
A representation of different analyte detection mechanism by upconversion material-based
sensor/nanosensors for determination of pharmaceuticals and biomolecules
Sensors/nanosensors based on upconversion materials for the determination
of pharmaceuticals and biomolecules: An overview

Abolghasem Jouyban a,b, Elaheh Rahimpour a,c*

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

used upconversion materials as sensors for the determination of pharmaceuticals and

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

pharmaceutical compounds”, and “upconversion nanoparticles for determination of

biomolecules”. Details of each developed upconversion nanoparticles based sensor along with

their relevant analytical parameters are reported and carefully explained.

Keywords: Upconversion nanoparticles; Sensor; Pharmaceuticals, Biomolecules

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

conventional fluorescent materials. Upconversion mainly occurs with doped transition-metal

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

intensified signal-to-noise ratio is expected in sensing and luminescence measurements. This

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

pharmaceutical compounds”, and “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

analytical parameters are provided in the following sections.

2. Developed sensors based on UC materials for the determination of pharmaceuticals

and biomolecules

The reported UC material-based sensors for the determination of pharmaceuticals and

biomolecules are classified into four analyte detection mechanisms namely Förster/

fluorescence resonance energy transfer (FRET)-based sensor, radiative energy transfer-based

5
sensors, electron transfer-based sensors, and non-energy transfer-based sensors, which are

reviewed in details in the following sections.

2.1. FRET-based sensors

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

homogeneous assay for the determination of 17β-estradiol in serum samples. An upconversion

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

carboxytetramethyl-rhodamine was used as the fluorophore in a sandwich assay format. This

sensor was employed for quantitatively determining perfectly matched target DNA (5′-

GTAGCGACGATCCTTCCTGGGCATGG-3′) with a limit of detection (LOD) of 1.3 nmol.L-1.

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

chain (HBB) gene 5′- GGTGCACCTGACTCCTGTGGAGAAG -3′, with an LOD of 20 fmol.

Kumar and Zhang [16] used the same sandwich-type hybridization format (Fig. 2) with

NaYF4:Yb3+,Er3+ as the donor and N,N,N’,N’-tetramethyl-6-carboxyrhodamine as the acceptor

for determination of 5′TCCTGTGGAGAAGTCTGCCGTTACTG-3′ as the target DNA with an

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

presence of a dye as an acceptor are detailed in Table 1.

***Figs. 1 and 2***

***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

is advantageous in FRET-based experiments as both the emission and excitation wavelengths of

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

emission of Na(Y1.5Na0.5)F6:Yb3+,Er3+. In order to increase the selectivity of the nanosensor,

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

donor for determination of matrix metalloproteinase-2 in blood. The luminescence recovery is

proportional to the concentration of matrix metalloproteinase-2 in the concentration range of

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

pharmaceuticals based on FRET are listed in Table 1.

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

NaYF4:Yb/Er/Nd@NaYF4:Nd UCNPs for the quantification of epirubicin in the range of 0.09 –

189.66 µmol.L-1.

Gao et al. [101] reported an electrochemiluminescence (ECL) resonance energy transfer

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

UCNPs after functionalizing with poly(acrylic acid) (PAA). Cetyltrimethylammonium bromide

(CTAB)-capped Au NRs were treated with 11-mercaptoundecanoic acid and then bonded with

anti- prostate-specific antigen and used as an acceptor. In the presence of prostate-specific

antigen, the donors and acceptors come close to each other as a result of the antigen and antibody

interaction, causing luminescence quenching in the prostate-specific antigen concentration range

of 3.75-938 pg.mL-1.

2.2. Radiative energy transfer-based sensors

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

(NaYF4: Yb3+, Tm3+ @NaYF4) and a fluorescein-based luminescence probe (5(6)-carboxy

fluorescein-O,O′-diacrylate) loaded in pores for the determination of cysteine in serum samples.

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

within the range of 20 – 200 µmol.L-1.

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

fluorescence emission of the fluorophore. Therefore, monitoring of the fluorophore fluorescence

at various concentrations of analyte leads to the development of an inner filter effect-based

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

diethylstilbestrol in urine at 0.1 – 1000 ng.mL-1 in the presence of black phosphorus/

polydopamine as a quencher, and by Fang et al. [108] for the quantification of uric acid at 0.01 –

1 mmol.L-1 with an LOD of 5.79 µmol.L-1,

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.

According to complementary base-pairing conjugation, the aptamer of sulfamethazine and its

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

structure and the fluorescence signal recovered proportionally to the sulfamethazine

concentration in the range of 0.1 -100 ng.mL-1.

2.3. Electron transfer-based sensors

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

samples. Here, MnO2 -nanosheet-modified NaYF4:Yb,Tm@NaYF4 nanoparticles was used as a

probe for quantification of H2O2 in the range of 0 – 350 µmol.L-1 H2O2 and 0-400 µmol.L-1

glucose.

Liu et al. [112] proposed a UCNPs-polydopamine nanosystem for the quantification of

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

glucose concentrations in the range of 0- 300 µmol.L-1.

***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

quantification of L-cysteine, L-ascorbic acid and glutathione. The luminescence of PAA-

functionalized Mn2+-doped NaYF4:Yb,Tm NPs is quenched by coordination of the carboxyl

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.

Wu et al. [116] used an enzymatic-induced upconversion photoinduced electron transfer

(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

range of 0.8 – 100 µmol.L-1.

2.4. Non-energy transfer-based sensors

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]

developed a multianalyte immunoassay utilizing a single-crystal NaYF4:Yb3+,Er3+ nanostructure

for the quantification of thyroid-stimulating hormone, luteinizing hormone, and prostate-specific

antigen. Biotinylated antibodies specific to each analyte were printed on streptavidin-coated

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]

used NaGdF4:Yb/ Tm@NaGdF4:Eu@NaEuF UCNCs for quantification of α-fetoprotein (AFP)

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

DNA with the sequence, 5′-CAGCATCAGTTTCTGAAACCCT- 3′ via a sandwich

hybridization on a paper-based platform. The obtained UC luminescence increased

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

sequence, 5′-UAGCUUAUCAGACUGAUGUUGA-3′, was transferred to a microplate modified

with biotin-GGCCGTCAACATCAGTCTGATAAGCTAAACATGATGACGGCC-3′ and

incubated at room temperature for 120 min after adding the hybrid buffer. Then, auxiliary probe

1: 5′-GCACCTGGGGGAGTAAGTGGCCGTCATCAT-3′ and auxiliary probe 2: 5′-

TACTCCCCCAGGTGCATGATGACGGC CACT-NH 2 -3′ modified with NaYF4 :Yb3+ /Er3+ -

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

range of 0 – 50000 ng.L-1 with an LOD of 3.14 ng.L-1.

Liu et al. [126] synthesized NaGdF4:Yb,Er@NaGdF4 core–shell NPs by a seed-mediated

method and couple the NPs with anti-cephalexin monoclonal antibody. The UCNP-based probe

is employed in a lateral flow immunochromatographic assay (LFIA) to determine cephalexin.

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

samples with a detection limit of 8µg.kg-1.

Wu et al. [129] developed an aptamer-based luminescence biosensor for the

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

chloramphenicol. In the absence of chloramphenicol, MNP-aptamer hybridizes to its

complementary DNA (cDNA) which was functionalized with UCNPs and gives a maximum

luminescence signal. On addition of chloramphenicol, the aptamer is specifically conjugated

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

determination of sulfadimethoxine in spiked samples of perch and catfish within the

concentration range of 1 – 9 ng.mL-1, by Huang et al. [135] for the quantification of

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

concentration of 0.01 – 40 ng.mL-1 with LOD of 3.6 pg.mL-1.

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

cytochrome C within the concentration range of 1 – 24 µmol.L-1 owing to preferentially

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

excitation at 980 nm was quenched by NiSx-L nanoparticles. Whereas the luminescence

intensity was turned-on after addition of H2O2. They reported that NiSx-L nanoparticles is

degraded in the presence of H2O2 and NaYF4:Yb/Er @ZIF-NiSx-L nanoparticles changed to

NaYF4:Yb/Er @ZIF. This method can be detected H2O2 in the range of 0.18 – 10.2 µmol.L-1

with LOD of 0.13 µmol.L-1. Zhang et al. [145] used a Fe2+/ Tm 3+


-doped NaYF4 system for

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

concentration of miRNA-21 is proportional to the number of UCNPs; thus, the determination of


89
Y by ICP-MS provided a good method for miRNA-21 determination in the concentration range

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

quantification of dopamine in the urine. The addition of dopamine to a solution containing

NaYF4: Yb3+, Er3+ UCNPs decreases their size and the intensity of their resonance light

scattering signals proportionally to dopamine concentration. The UCNPs bind to dopamine –

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

range of 0 -300 µmol.L-1 with an LOD of 1.62 µmol.L-1.

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

of carcinoembryonic antigen by antigen- antibody affinity. This immunosensor detected

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

oligoaniline-crosslinked Au NPs imprinted with identification sites for the quantification of

dopamine in serum samples. This method presented a wide detection range (10–14–10−6 mol.L-1),

with LOD of 2 ×10–15 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)

will be enhanced. The fluorescence of the UCNPs is diminished proportionally to increasing

vitamin B12 concentrations in the range of 3-634 nmol.L-1.

3. Conclusion

It is well known that determination of pharmaceuticals and biomolecules in the biological

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

biomedical fields, such as single-molecule sensing, high-throughput multiplexed detection and

super-resolution nanoscopy. It is noteworthy that small-sized and bright UC materials are

indispensable to those applications. So, introducing UC NPs made possible a broad range of

applications, such as fluorescent microscopy, deep-tissue bioimaging, nanomedicine,

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

a new level and imparting multifaceted photonic applications.

24
Acknowledgements

This work was supported by Research Affairs of Tabriz University of Medical Sciences,

under grant number 65435.

25
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46
Fig. 1. Schematic representation of FRET between two molecules.

47
Fig. 2. Sandwich format for detecting DNA targets. Reproduced with permission of the publisher [16].

48
Fig. 3. (a) A titanium dioxide-coated ‘Yaglass’ waveguide treated with biotinylated-bovine serum

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49
Fig. 4. Schematic illustration of the UCP–GO biosensing platform and the mechanism of glucose

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50
Fig. 5. Schematic mechanism of glutathione detection using MnO2 -nanosheet-modified UCNPs.

Reproduced with permission of the publisher [110].

51
Fig. 6. (A) Schematic of the formation of Ag NCs on various DNA templates and (B) the sequences of ss-

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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

upconversion nanoparticles. Reproduced with permission of the publisher [129].

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

NaYF4 :Yb3+ ,Tm3+


Au NPs Thrombin Blood 980/ 804 - 0.129 nmol.L-1 [58]
NPs

NaYF4: 0.5% Tm3+,


CdSxSe1-x/ZnS
30% Yb3+ /β-NaYF4 Thrombin Serum 980/ 614 - 230 fmol [59]
core/shell QDs
core/shell NPs
8-oxo-8H-
acenaphtho[1,2- Cysteine
NaLuF4 :Yb,Er,Tm - 980/ 540,800 - - [60]
b]pyrrole-9- Homocysteine
carbonitrile
5'-
NaYF4: 0.5% Tm3+,
CdSxSe1-x /ZnS GATGATGAACCAG
30% Yb3+ /NaYF4 Serum 980/ 570 0.005 – 2 µmol.L-1 13.31 fmol [61]
core/shell QDs GTTATGACCTTGAT
core/shell NPs
TTATTTTG-3'
Protamine 0.02 – 1.2 µg.mL-1 6.7 ng.mL-1
NaYF4 :Yb3+, Er3+ Au NPs Serum 980/ 526 [62]
Heparin 0.002-2 µg.mL-1 0.7 ng.mL-1
NaYF4 :Yb3+, Er3+ CdSe/ZnS Vitamin H - 980/ 600 8 – 250 nmol.L-1 5 nmol.L-1 [63]
5’-AATGTGCTCCCC -1 -1
NaYF4: 18% Yb, 2% Er Au NPs - 980/543 0 – 50 nmol.L 250 pmol.L [64]
CAACTCCTC -3’
58
NaYF4: 30%Yb,
CoOOH nanoflakes Ascorbic acid Plasma 980/360 0 – 60 µmol.L-1 0.2 µmol.L-1 [65]
0.5%Tm@NaYF4 NPs
0.073 – 43.65 0.12 fmol/
NaGdF4 :Yb3+, Er3+ Au NPs miRNA-21 - 980/ 520 [66]
fmol/ 10µgRNA 10µgRNA
NaYF4: Yb, Er Au NPs Cocaine Blood 980/540 0.05 – 50 µmol.L-1 10 nmol.L-1 [67]
5´-
Graphene quantum
NaYF4 :Yb,Er@SiO2 CAGAAGUCAGGUC - 980/ 400 - 10 fmol.L-1 [68]
dots.
GGAUUAAGCC-3´
50 – 2000 µmol.L-
NaYF4: Yb, Tm Ag nanodisks Cysteine - 980/ 478 1 - [69]
NaYF4
Ag NPs Glucose Serum 980/450 2.5 – 100 µmol.L-1 1.41 µmol.L-1 [70]
:Yb/Tm@NaYF4
Oleic acid -modified Palladium Carcinoembryonic
Serum 980/480 4 – 100 pg.mL-1 1.7 pg.mL-1 [71]
NaYF4 :Yb, Tm nanoparticles antigen
NaYF4: 18 % Yb, 2 % Cobalt oxyhydroxide
Ascorbic acid - 980/541 7.5 – 100 µmol.L-1 3.32 µmol.L-1 [72]
Er nanoflasks
CTAB-stabilized
Silver triangular Protamine 10 – 500 ng.mL-1 3.1 ng.mL-1
NaYF4 : 12% Yb3+, Serum 980/490 [73]
nanoplates Trypsin 5 – 80 ng.mL-1 1.8 ng.mL-1
0.2% Tm3+
β-NaYF4:
Au NPs Trypsin Serum 980/542 12 – 208 ng.mL-1 4.15 ng.mL-1 [74]
20%Yb,2%Er
NaYF4: Yb, Er Carbon NPs Immunoglobulin E Serum 980/546 0.5- 80 ng.mL-1 - [75]
NaYF4 :Yb3+, Er3+ Au NPs L-Lactate Serum 980/550 1 – 100 µmol.L-1 0.39 µmol.L-1 [76]
3’ -
TCAGAATGAAGGT
ACTAAAGAAATTG
ATAC – 5’
Alkyl Trilite™ QDs
3+ with emission 0.01 – 1.5 pmol
NaYF4: 0.5% Tm , 3’ - 980/525 980/575
maxima at 525 nm, Serum 0.05-1.5pmol - [77]
30% Yb3+/NaYF4 CAGTGGTCTGTTAC 980/620
575 nm 0.065-1.5 pmol
ATTGGCGACAACAT
and 620 nm
GG – 5’
3’ -
CTTCTTCTGGCGGT
AGTCCCGCCGCTGC

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:

 This review focuses on sensors/nanosensors based on upconversion materials.

 This review demonstrates the application of upconversion materials for determination of

the pharmaceuticals and biomolecules.

 This review discussed on the different analyte detection mechanisms by upconversion

materials.
Declaration of competing interest
The authors declare no conflict of interest.

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