Bi3+-Doped BaYF5:Yb,Er Upconversion Nanoparticles with Enhanced Luminescence and Application Case for X-ray Computed Tomography Imaging

Article abstract of DOI:10.1021/acs.inorgchem.0c01818

In this work, BaYF5:20%Yb3+/2%Er3+/x%Bi3+ (abbreviated as BaYF5:Yb,Er,Bix, where x = 0-3.0) upconversion nanoparticles (UCNPs) with various doping concentrations of Bi3+ were synthesized through a simple hydrothermal method. The influence of the doping amount of Bi3+ on the microstructures and upconversion luminescence (UCL) properties of the BaYF5:Yb,Er,Bix UCNPs was studied in detail. The doping concentration of Bi3+ has little influence on the microstructures of the UCNPs but significantly impacts their UCL intensities. Under excitation of a 980 nm near-IR laser, the observed UCL intensities for the BaYF5:Yb,Er,Bix UCNPs display first an increasing trend and then a decreasing trend with an increase in the ratio x, giving a maximum at x = 2.5. A possible energy-transfer process and simplified energy levels of the BaYF5:Yb,Er,Bix UCNPs were proposed. The potential of the BaYF5:Yb,Er,Bix UCNPs as contrast agents for computerized tomography (CT) imaging was successfully demonstrated. An obvious accumulation of BaYF5:Yb,Er,Bix in tumor sites was achieved because of high passive targeting by the enhanced permeability and retention effect and relatively low uptake by a reticuloendothelial system such as liver and spleen. This work paves a new route for the design of luminescence-enhanced UNCPs as promising bioimaging agents for cancer theranostics.

Full text of DOI:10.1021/acs.inorgchem.0c01818

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Article
Bi3+-Doped BaYF5:Yb,Er Upconversion Nanoparticles with Enhanced
Luminescence and Application Case for X‑ray Computed
Tomography Imaging
Ran Luo, Lei Chen, Qinyu Li, Jie Zhou, Linqiang Mei, Zhanglei Ning, Yan Zhao,* Mengjiao Liu, Xin Lai,
Jian Bi, Wenyan Yin,* and Daojiang Gao*
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ABSTRACT: In this work, BaYF5:20%Yb3+/2%Er3+/x%Bi3+ (abbreviated as BaY-
F5:Yb,Er,Bix, where x = 0−3.0) upconversion nanoparticles (UCNPs) with various
doping concentrations of Bi3+ were synthesized through a simple hydrothermal method.
The influence of the doping amount of Bi3+ on the microstructures and upconversion
luminescence (UCL) properties of the BaYF5:Yb,Er,Bix UCNPs was studied in detail.
The doping concentration of Bi3+ has little influence on the microstructures of the
UCNPs but significantly impacts their UCL intensities. Under excitation of a 980 nm
near-IR laser, the observed UCL intensities for the BaYF5:Yb,Er,Bix UCNPs display first
an increasing trend and then a decreasing trend with an increase in the ratio x, giving a
maximum at x = 2.5. A possible energy-transfer process and simplified energy levels of
the BaYF5:Yb,Er,Bix UCNPs were proposed. The potential of the BaYF5:Yb,Er,Bix
UCNPs as contrast agents for computerized tomography (CT) imaging was successfully
demonstrated. An obvious accumulation of BaYF5:Yb,Er,Bix in tumor sites was achieved
because of high passive targeting by the enhanced permeability and retention effect and
relatively low uptake by a reticuloendothelial system such as liver and spleen. This work paves a new route for the design of
luminescence-enhanced UNCPs as promising bioimaging agents for cancer theranostics.
However, the relatively low quantum efficiency is a common
disadvantage of rare-earth fluoride UCNPs and greatly restricts
their extensive and practical applications.
INTRODUCTION
■
Lanthanide ion (Ln3+)-doped upconversion nanoparticles
(UCNPs) can absorb long-wavelength excitation and convert
to short-wavelength emission via anti-Stokes processes, which
have attracted extensive attention because their unique optical
properties.1−13 As a new generation of optical nanoprobes,
UCNPs have been widely used in various fields such as clinical
diagnosis and treatment as well as medical imaging
research.14−17 Among the various types of UCNPs, rare-earth
fluoride compounds are considered to be the optimal host
matrix for UCNPs because of their low phonon energy, superb
light stability, and large anti-Stokes efficiency,18−20 especially
for the alkali-metal rare-earth fluorides and alkaline-earth-metal
rare-earth fluorides.8 As an important member of the rare-earth
fluoride family, Ba2+-containing rare-earth fluorides have been
proven to be suitable matrixes for UCNPs.3,8,18,19 Recently,
Capobianco and his coauthors confirmed that Yb/Tm-
codoped BaYF5 has a brighter upconversion luminescence
(UCL).21 Lu and Liu’s group also reported that the BaYbF5
matrix not only owns excellent luminescence properties but
also possesses strong X-ray computed tomography (CT)
effects because of the large K-edge values and high X-ray mass
absorption coefficients of the Ba and Yb elements.22,23
Therefore, exploring Ba2+-containing rare-earth fluoride
UCNPs is of great significance for biomedical applications.
To date, many attempts have been made to enhance the
UCL of the UCNPs for their biological applications such as
bioimaging. Comparatively speaking, doping is a simple and
effective strategy to modify the lattice and electronic structures
of the phosphor host, thus significantly boosting their
luminescence properties.24−26 Two typical examples are that
the UCL of the NaLiYLuF4:Er,Yb microcrystals could be
enhanced by doping Li+ ions24 and enhancement of the UCL
in Zn2SiO4:Yb3+,Er3+ could be achieved by codoping Li+ or
Bi3+.26 As a unique alternative, Bi3+ is regarded as a viable non-
rare-earth-element dopant for fluoride phosphors because of its
special advantages, such as low toxicity, broad drug
applications, and low cost.27−30 What is more, a relatively
broad emission and absorption band associated with the typical
Received: June 19, 2020
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6s2 → 6s6p transition make Bi3+ an excellent sensitizer to
harvest the excitation light.31−33 The previous researches have
confirmed that Bi3+ can greatly sensitize the emission of
lanthanides, especially for the UCL of Er3+ and Tm3+, owing to
an efficient energy transfer from Bi3+ to Ln3+.33 Actually, the
doping of Bi3+ not only remarkably boosts the UCL intensity
of the phosphor but also broadens its excitation band.33
Predictably, the UCL intensity of the Ba2+-containing rare-
earth fluoride UCNPs also can be effectively enhanced via the
introduction of Bi3+.
[Re(NO3)3 + Bi(NO3)3] to BaCl2 of 1:1, the corresponding
Re(NO3)3 and Bi(NO3)3 solutions were added into the beaker with
continuous stirring for 0.5 h, and then 25 mmol of a NH4F dilute
solution was added dropwise into the above solution with vigorous
stirring. Finally, the formed mixture was transferred into a 100 mL
Teflon-lined autoclave and heated at 160 °C for 24 h. After that, the
supernatant was discarded, and white precipitates were centrifuged
three times in ethyl alcohol and three times in water. The collected
precipitates were dried in air at 80 °C for 12 h.
Preparation of Citrate-Coated BaYF5:20%Yb3+/2%Er3+/x%
Bi3+(x = 2.5) UCNPs. First, 100 mg of BaYF5:Yb,Er,Bix (x = 2.5)
UCNPs was added into 10 mL of a solution containing 300 mg of
trisodium citrate under vigorous stirring for 4 h. Finally, the citrate-
coated BaYF5:Yb,Er,Bix (x = 2.5) UCNPs were washed with water
and then separated by centrifugation.
CT imaging is widely used in medical diagnosis because of
its ability to visualize the structure for living objects and
provide exceptional three-dimensional (3D) anatomical
information with different spatial resolutions according to the
situation of the different organs and tissues.34−37 Currently, the
commonly used CT contrast agents with good X-ray
absorption are mainly small iodinated molecules. However,
these iodinated molecules suffer from short cycle life and
potential renal toxicity. Therefore, the development of new CT
contrast agents with low toxicity is very important and urgent.
As is well-known, Ln3+-doped UCNPs have low toxicity and
good X-ray absorption, ensuring their use in CT imaging.38−41
It is worth noting that Bi3+-doped UCNPs may both possess
excellent UCL and exhibit superior CT imaging ability.
Especially, Yb3+,Er3+-codoped BaYF5 UCNPs possess large K-
edge values and high X-ray mass absorption coefficients.41−44
More importantly, the Bi element possesses a good X-ray
attenuation property.29 In general, the brighter the nanoprobe,
the higher the signal-to-noise ratio that may be achieved in a
biological imaging system. Because the above-mentioned
characteristics of the Ba, Yb, and Bi elements can also
synergistically integrate the merits of fluorescence and CT
imaging while averting their individual demerits, making the
Bi3+-doped BaYF5 UCNPs potential dual-modal fluorescence/
CT imaging probes in single-phase materials. Unfortunately,
there has not been any relevant research on the Bi3+-doped
BaYF5 UCNPs and their biomedical applications until now.
Herein, BaYF5:20%Yb3+/2%Er3+/x%Bi3+ (abbreviated as
BaYF5:Yb,Er,Bix, where x = 0−3.0) UCNPs were synthesized
by a simple hydrothermal method. The influence of Bi3+ ions
on the crystal phase, size, and upconversion (UC) emission of
the obtained BaYF5:Yb,Er,Bix UCNPs was investigated in
detail. The green emission intensity for BaYF5:Yb,Er,Bix (x =
2.5) UCNPs was 4 times greater than that of the Bi3+ free
sample, and a longer decay time could be achieved through
Bi3+ doping. Moreover, the citrate-functionalized BaY-
F5:Yb,Er,Bix (x = 2.5) UCNPs for UCL and in vivo CT
imaging were used out to investigate their biological
applications. This work offers a new strategy for the design
of luminescence-enhanced UCNPs and their biological
applications.
Characterizations. X-ray diffraction (XRD) measurement
(SmartLab, Cu Kα radiation) was used to confirm the crystal
structures of the products. Fourier transform infrared (FT-IR)
spectroscopy was recorded on an IR spectrophotometer (PerkinElmer
580B) using the KBr pellet technique. The elemental composition for
the samples was determined by inductively coupled plasma mass
spectrometry (ICP-MS; Aglient 8900). The morphology, size, and
selected-area electron diffraction (SAED) pattern of the products
were measured by transmission electron microscopy (TEM; FEI
Tecani G2 F20). The size distribution of the samples was analyzed by
ζ-potential measurements (Malvern Zetasizer NanoZS90). The
absorption spectrum was measured using a PE Lambda 750 UV−
vis−near-IR (NIR) spectrometer. The fluorescence spectrum was
recorded using a fluorescence spectrophotometer (Hitachi F-7000)
with a continuous 980 nm diode laser. The fluorescence decay curves
were recorded on a fluorescence spectrophotometer (Edinburgh
Instruments FLS1000).
Cytotoxicity Assay. The in vitro cytotoxicity experiment was
done by the standard CCK-8 analysis method. Briefly, A549 cells were
seeded into a 96-well cell culture plate at densities of 5 × 103 cells/
well in Dulbecco’s modified Eagle’s medium (DMEM) containing
10% fetal bovine serum and a 1% penicillin−streptomycin solution at
37 °C in a humid atmosphere of 95% air and 5% CO2 for 24 h. Then,
different concentrations of citrate-coated BaYF5:Yb,Er,Bix (x = 2.5)
UCNPs (0, 15.63, 31.25, 62.50, 125, 250, and 500 μg/mL) were
incubated with adherent A549 cells in 96-well plates for 24 h.
Afterward, the culture medium was removed and then added with a
serum-free DMEM-configured CCK-8 solution for 2 h. After
centrifugation for 10 min, 80 μL of supernatant was sucked into
another 96-well plate, and the absorbance at 452 nm was measured
using the standard method.
In Vitro and in Vivo X-ray CT Imaging. To investigate whether
the CT signal value was linear with the concentration of the
BaYF5:Yb,Er,Bix UCNPs, the in vitro CT imaging experiments were
performed on a Quantum GX micro computed tomograph
(PerkinElmer). The relevant detailed procedures and details are
presented in the Supporting Information (SI). According to the
standard protocol approved by the Key Laboratory for Biomedical
Effects of Nanomaterials and Nanosafety (Institute of High Energy
Physics, CAS), the mice were disposed of after the experiments were
finished.45
RESULTS AND DISCUSSION
EXPERIMENTAL SECTION
■
■
The phase structures of the obtained BaYF5:20%Yb3+/2%Er3+/
x%Bi3+ (x = 0−3.0) samples were determined by XRD. As
disclosed in Figure 1a, all of the peaks can be well matched
with the standard cubic BaYF5 (ICSD 169849), implying that
the as-prepared samples are pure cubic phases. Interestingly,
compared with the standard cubic BaYF5, the diffraction peaks
of all of the BaYF5:Yb,Er,Bix (x = 0−3.0) UCNPs slightly shift
to the higher 2θ side because of the replacement of Y3+ (r =
1.159 Å) by a smaller Yb3+ (r = 1.125 Å).29,46 Whereas the
corresponding diffraction peaks of the BaYF5:Yb,Er,Bix samples
Materials. All chemicals including Bi(NO3)3·5H2O (99%), BaCl2
(98%), ethyl alcohol (95%), NH4F (98%), trisodium citrate, Y2O3
(99.99%), Yb2O3 (99.9%), and Er2O3 (99.99%) were of analytical
grade and were used as received without any further purification.
Preparation of BaYF5:20%Yb3+/2%Er3+/x%Bi3+ (x = 0−3.0)
UCNPs. In a typical synthesis procedure, Y2O3, Yb2O3, and Er2O3
were dissolved in 65% HNO3 at 60 °C and stirred for 30 min to form
pellucid solutions. The demand quantities of Re(NO3)3 (Re3+ = Y3+,
Yb3+, and Er3+), Bi(NO3)3, BaCl2, and NH4F solutions were obtained
separately. Subsequently, 25 mL of a BaCl2 solution was added into a
100 mL beaker and stirred for 30 min. According to the molar ratio of
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initial model with a reliability factor of χ2 = 1.295, affirming
that the obtained samples are in the cubic phase. To determine
the suitable doping concentration of Bi3+ in the BaYF5 host, we
have synthesized the BaYF5:Bix crystals (x = 1−7.0) and
obtained their XRD patterns (Figure S2). It was found that the
crucial doping concentration of Bi3+ for the BaYF5 host was
between 3 and 4%. It also can be seen that the obvious impure
phase will appear as long as the doping concentration of Bi3+
exceeds 4%. Actually, 3% is the largest doping concentration of
Bi3+ in the BaYF5:Yb,Er,Bix UCNPs in our experimental
conditions. What is more, the content of Bi3+ in the
BaYF5:Yb,Er,Bix (x = 0−3.0) samples was determined by
ICP-MS, and the results are shown in Table S1. As shown in
Table S1, the actual content of Bi3+ in the obtained
BaYF5:Yb,Er,Bix (x = 0−3.0) samples gradually ascends with
the ascending concentration of Bi3+ in the starting solution.
Nonetheless, the actual doping content of Bi3+ in the
BaYF5:Yb,Er,Bix (x = 0−3.0) samples is lower than the
predetermined value, implying that some of the Bi3+ ions were
left in the solution. Figure 2 shows the TEM images of the
BaYF5:Yb,Er,Bix (x = 0−3.0) UCNPs. It can be seen that all of
the as-synthesized BaYF5:Yb,Er,Bix samples are irregular
nanoparticles with good dispersions, and the mean grain size
is ∼20 nm. The high-resolution TEM (HR-TEM) image and
SAED pattern of the representative BaYF5:Yb,Er,Bix (x =
2.5%) UCNPs are also disclosed in Figure 2i,j, which clearly
confirm the high crystalline nature of the as-prepared
BaYF5:Yb,Er,Bix (x = 2.5%) UCNPs. The measured distance
between the adjacent lattice planes is 0.345 nm, which is well
accordant with the d111 spacing of the cubic BaYF5 (ICSD
169849). In addition, the SAED pattern in Figure 2j shows
spotty polycrystalline diffraction rings corresponding to the
(200), (220), and (311) planes of the cubic BaYF5 lattice,
Figure 1. (a) XRD patterns of the BaYF5:Yb,Er,Bix (x = 0−3.0)
UCNPs. (b) Enlarged XRD patterns of the BaYF5:Yb,Er,Bix (x = 0−
3.0) UCNPs in the 2θ range from 25° to 28°.
shift to the lower 2θ side (Figure 1b), contrasting with the
Bi3+-free sample, this should be ascribed to replacement of the
smaller Y3+ ions by the larger Bi3+ ions (r = 1.31 Å).29,46
Moreover, the deviation degree in these diffraction peaks
gradually increases with an ascending doping concentration of
Bi3+, suggesting that the Bi3+ ions were successfully
incorporated into the BaYF5 host lattice. Nevertheless, these
results can also verify that the doping of a small amount of Bi3+
ions will not lead to variation of the phase structure for
BYF5:Yb,Er. To further verify these results, Rietveld refine-
ments were also carried out. As shown in Figure S1, the
refinement result of the representative BaYF5:Yb,Er,Bix (x =
2.5%) sample is well consistent with that of the corresponding
Figure 2. (a−h) TEM images of the BaYF5:Yb,Er,Bix (x = 0−3.0) and citrate-coated BaYF5:Yb,Er,Bix (x = 2.5) UCNPs, respectively. (i) HR-TEM
image and (j) SAED pattern of the obtained BaYF5:Yb,Er,Bix (x = 2.5) UCNPs.
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Figure 3. Size distribution of the BaYF5:Yb,Er,Bix (x = 0−3.0) UCNPs: (a) x = 0; (b) x = 0.5; (c) x = 1.0; (d) x = 1.5; (e) x = 2.0; (f) x = 2.5; (g)
x = 3.0.
Figure 4. (a) UCL spectra of the BaYF5:Yb,Er,Bix (x = 0−3.0) UCNPs under a 980 nm laser excitation. (b) Normalized UCL intensities of the
green and red emissions for the BaYF5:Yb,Er,Bix (x = 0−3.0) UCNPs. (c) Emission spectra of the BaYF5:Yb,Er,Bix (x = 2.5) UCNPs pumped by a
980 nm laser with different powers (67.84, 84.55, 101.26, 117.97, and 134.68 mW). (d) Double logarithm of the upconversion emission intensity
versus the pump power of the BaYF5:Yb,Er,Bix (x = 2.5) UCNPs.
respectively, further confirming that the as-synthesized UCNPs
possess a face-centered-cubic structure.
Figure 3 shows the size distribution of the prepared
BaYF5:Yb,Er,Bix (x = 0−3.0) UCNPs. With an increase of x,
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4
4
Figure 5. Decay curves for the S3/2 → I15/2 transition of Er3+ in the synthesized BaYF5:Yb,Er,Bix (x = 0−3.0) UCNPs.
the particle size of the samples exhibits a slight increasing trend
except for x = 3.0, and the average particle size for these
samples is in the range of 15−21 nm. Similar results have been
reported on the Bi3+-doped NaGdF4:Yb3+,Tm3+ UCNPs.29
The comprehensive results of XRD, TEM, and ICP-MS
indicate that Bi3+ was successfully incorporated into the BaYF5
matrix, and the doping of Bi3+ has no significant effect on the
microstructure of the samples. What deserves to be mentioned
most is that all of the as-prepared BaYF5:Yb,Er,Bix (x = 0−3.0)
UCNPs possess smaller size and better uniformity, making
them potential fluorescent probes for the biomedical
applications.
influences the UC intensities of the obtained BaYF5:Yb,Er,Bix
UCNPs. Figure 4b shows the normalized intensity of the two
green emissions and one red emission as a function of the
doping concentration of Bi3+ (i.e., x). With increasing
concentration of Bi3+ from 0 to 3.0%, the UCL intensity
initially increases and then decreases, showing the maximum at
x = 2.5%. Especially, the emission intensities of the peaks
located at 522, 546, and 656 nm for the BaYF5:Yb,Er,Bix (x =
2.5) UCNPs are about 3, 4.3, and 4 times greater than those of
the BaYF5:Yb3+,Er3+ UCNPs, respectively. Indubitably, the
doping moderate amount of Bi3+ ions can remarkably boost the
green and red emissions of BaYF5:Yb3+,Er3+ UCNPs.
Variation of the emission intensity for the obtained
BaYF5:Yb,Er,Bix (x = 0−3.0) UCNPs should be ascribed to
the following aspects in our experiment. On the one hand,
when the smaller Y3+ (r = 1.159 Å) is replaced by Bi3+ (r =
1.31 Å), the unit cell volume of the obtained nanocrystals will
increase and the crystal-field symmetry around the Er3+ ion
also will be changed, leading to a break of the forbidden
transition around the Er3+ ion,47 thus enhancing the UCL of
the BaYF5:Yb,Er,Bix UCNPs. On the other hand, the grain size
of the samples also influences the UCL intensity because the
relative intensity of the upconversion emission varies with the
surface concentration quenching effect.49,50 When 0 < x ≤
2.5%, the distortion degree of the crystal symmetry for the
obtained BaYF5:Yb,Er,Bix UCNPs gradually increases with the
The UV−vis−NIR absorption spectrum measured in the
range of 200−900 nm for the BaYF5:Yb,Er,Bix (x = 2.5)
UCNPs is given in Figure S3. The observed absorption peaks
of Er3+ and Bi3+ can well match with the corresponding
excitation absorption peaks of Er3+ and Bi3+, respectively.
Detailed information is provided in the SI. The UCL spectra of
the BaYF5:Yb,Er,Bix (x = 0−3.0) UCNPs under 980 nm
excitation are shown in Figure 4a. All of the samples present
the main green emission peaks centered at 522 and 546 nm,
2
4
4
4
respectively, derived from H11/2 → I15/2 and S3/2 → I15/2
transitions of Er3+ and a red emission centered at 656 nm
28,47,48
originating from the F9/2 → I15/2 transition of Er3+.
It
4
4
should be noted that the concentration of Bi3+ has no obvious
effect on the features of the emission peaks but significantly
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ascending doping concentration of Bi3+, leading to the
continuous increase of the UCL intensity accordingly.
Simultaneously, the grain size of the BaYF5:Yb,Er,Bix UCNPs
slightly increases with the ascending x, also contributing to the
enhancement of UCL intensity. Hence, the comprehensive
effects of the above two aspects make the sample
BaYF5:Yb,Er,Bix with x = 2.5 exhibit the strongest UCL
emission. As for the sample BaYF5:Yb,Er,Bix with x = 3.0, the
weakest UCL emission should be mainly attributed to the
concentration quenching effect, although the reduced size also
has some influence on the UCL emission. As mentioned earlier
(see the SI), the crucial doping concentration of Bi3+ for the
BaYF5 host is between 3 and 4%, and it also can be seen that
the obvious impure phase will appear as long as the doping
concentration of Bi3+ exceeds 4%. Actually, 3% is the largest
doping concentration of Bi3+ in the BaYF5:Yb,Er,Bix UCNPs in
our experimental conditions. For such a higher content of Bi3+
ment mechanism in the luminescence lifetime is similar to their
enhancement in UCL. In other words, it should be attributed
to the synergistic effect of the symmetric distortion around the
Er3+ crystal field and grain-size-induced surface concentration
quenching effect. On the basis of the reported energy transfer
in Bi3+,Er3+-codoped phosphors33 and the existing energy
transfer in Yb3+,Er3+-codoped fluoride systems,19,34,41
a
possible energy-transfer process and simplified energy levels
of the BaYF5:Yb,Er,Bix (x = 0−3.0) UCNPs are shown in
Figure 6. Detailed explanations are shown in the SI.
3+
ions, Bin aggregates may be formed, which play the role of
trapping centers and consume the absorbed energy non-
radiatively instead of transferring it to the Er3+ activator ions.
Obviously, the probability of energy transfer from Bi3+ to Er3+
strongly relys on the doping concentration of Bi3+. Similar
results have been reported in the Er3+,Bi3+-codoped CaSnO3
nanocrystals and Eu3+,Bi3+-codoped YVO4 red phosphors.51,52
Figure 4c shows the UCL emission spectra of the
BaYF5:Yb,Er,Bix (x = 2.5) UCNPs pumped by a 980 nm
laser with different powers. Under pumping of all of the
powers, although the observed upconversion emission profiles
for the BaYF5:Yb,Er,Bix (x = 2.5) UCNPs are the same, the
emission intensity increases with increasing power because of
the boosted efficiency of UC multiple-step sensitizing energy
transfer. To deeply investigate the involved UCL mechanism
for the studied samples, the dependence of the green and red
emission intensities of the BaYF5:Yb,Er,Bix (x = 2.5) UCNPs
on the pump power was measured, as disclosed in Figure 4d.
The UCL emission intensity has a nonlinear dependence on
the excitation power, which can be described by the following
relationship:47
Figure 6. Schematic diagram of the energy-level structure of the
BaYF5:Yb,Er,Bix UCNPs.
For the subsequent biological experiment, the selected
BaYF5:Yb,Er,Bix (x = 2.5) UCNPs were modified with citrate,
and the successful surface modification of citrate was verified
by FT-IR spectroscopy (Figure S4). The cytotoxicity test was
carried out on human lungadenocarcinoma cancer cells (A549)
through the standard CCK-8 assay. After incubation with the
citrate-coated BaYF5:Yb,Er,Bix (x = 2.5) UCNPs at different
concentrations (15.63−500 μg/mL) for 24 h, the cell viability
of A549 was still maintained at a high level (Figure S5). Even
after the concentration of the UCNPs increased to 500 μg/mL,
the cell viability can still maintain about 87%, suggesting that
the BaYF5:Yb,Er,Bix (x = 2.5) UCNPs have negligible cell
toxicity and can be safely used for bioimaging.
X-ray CT imaging is widely used as a reliable clinical
diagnosis because of the high-resolution 3D structure details
and deep penetration.34−37 First, we compared the CT imaging
capability in vitro for all of the obtained BaYF5:Yb,Er,Bix (x =
0−3.0) UCNPs, and the results and corresponding explan-
ations are provided (Figure S6 and Table S2). It can be seen
that the doping concentration of Bi3+ has a very weak influence
on the CT signal of these BaYF5:Yb,Er,Bix (x = 0−3.0)
UCNPs, which could be attributed to the much lower doping
level of Bi3+. In view of the strongest UCL emission, we
therefore compared the CT imaging signal of the citrate-coated
BaYF5:Yb,Er,Bix (x = 2.5) UCNPs with that of the
I ∝ Pn
(1)
I represents the upconversion emission intensity, P represents
the laser pump power, and n refers to the number of photons
required in the UCL emission. The values of n for the UCL
emissions centered at 522, 546, and 656 nm were deduced
based on the double logarithm of the upconversion emission
intensity versus the pump power of the BaYF5:Yb,Er,Bix (x =
2.5) UCNPs. As shown in Figure 4d, the slopes of the linear
fittings for the 522, 546, and 656 nm emissions are 1.91, 1.76,
and 1.57, respectively, which indicate that a two-photon
process is involved to produce the green and red emissions.
Figure 5 displays the decay curves for the S3/2 → I15/2
transition of Er3+ in the BaYF5:Yb,Er,Bix (x = 0−3.0) UCNPs.
These decay curves can be fitted to a single-exponential
function as I(t) = I0 + A exp(−t/τ),53 where A is constant, I(t)
and I0 refer to the emission intensities at time t and 0,
respectively, and τ represents the luminescence lifetime. As
shown in Figure 5, the decay times of these BaYF5:Yb,Er,Bix
samples were determined to be 66.52, 65.64, 65.03, 69.56,
75.26, 101.85, and 55.98 μs, respectively, and basically match
with their UCL emission intensities. Obviously, the lumines-
cence lifetimes of the BaYF5:Yb,Er UCNPs can be markedly
prolonged after doping a suitable amount of Bi3+ ions,
effectively enhancing their UCL. Accordingly, the improve-
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commercially used iohexol in vitro. With an increase of the
concentration from 0 to 50 mg/mL, the CT contrast signals of
the citrate-coated BaYF5:Yb,Er,Bix (x = 2.5) UCNPs and
iohexol obviously enhanced (Figure 7a). A good linear
Figure 8. In vivo CT images of the mice after intratumoral injection
of the citrate-coated BaYF5:Yb,Er,Bix (x = 2.5) UCNPs: (a)
preinjection; (b) 2, (c) 8, and (d) 12 h postinjection.
such as liver and spleen could be attributed to high passive
targeting by the enhanced permeability and retention effect
(EPR) and relatively low uptake by the RES. In addition, we
calculated the X-ray absorption coefficients of the BaY-
F5:Yb,Er,Bix UCNPs by the XMuDat computer program, and
the obtained X-ray absorption coefficients of the BaY-
F5:Yb,Er,Bix UCNPs as a function of the photon energy have
also been provided.54 All of the samples have very similar
relationship graphs of the X-ray absorption coefficients as a
function of the photon energy, and they almost overlapped;
hence, we just display the curve for the representative sample
of the BaYF5:Yb,Er,Bix UCNPs (x = 2.5; Figure S9). It can be
seen that the obtained attenuation coefficient of the
BaYF5:Yb,Er,Bix UCNPs (x = 2.5) is comparable to those of
other high-Z nanomaterials such as Bi2S3, Bi2Se3, and Cu3BiS3
and is rather higher than that of the soft tissues, suggesting that
these BaYF5:Yb,Er,Bix UCNPs are capable of concentrating
more X-ray dose into tumor tissues for enhanced CT imaging
and even great potential for radiotherapy in the future.54
Figure 7. (a) In vitro CT images of the citrate-coated BaYF5:Yb,Er,Bix
(x = 2.5) UCNPs and iohexol at different concentrations. (b) CT
value (HU) of the citrate-coated BaYF5:Yb,Er,Bix (x = 2.5) UCNPs
and iohexol as a function of the concentrations of the citrate-coated
BaYF5:Yb,Er,Bix (x = 2.5) UCNPs and iohexol, respectively.
relationship between the Hounsfield units (HU) value and
concentrations of both the BaYF5:Yb,Er,Bix (x = 2.5) UCNPs
and iohexol can be observed (Figure 7b). Evidently, the HU
values of the citrate-coated BaYF5:Yb,Er,Bix (x = 2.5) UCNPs
are higher than that of iohexol at equivalent concentrations,
confirming that the obtained UCNPs are efficient contrast
agents for CT imaging. The good CT imaging performance of
the BaYF5:Yb,Er,Bix (x = 2.5) UCNPs in vitro motivated us to
further use BaYF5:Yb,Er,Bix (x = 2.5) for in vivo CT imaging.
As shown in Figure 8, the tumor CT images were obtained
preinjection (0 h) and after intratumoral injection of the
citrate-coated BaYF5:Yb,Er,Bix (x = 2.5) UCNPs at different
time intervals for 2, 8, and 12 h. The bright-field image of the
mouse before intratumoral injection of the citrate-coated
BaYF5:Yb,Er,Bix (x = 2.5) UCNPs was recorded in Figure S7.
The tumor site shows an obvious enhancement with a
significantly higher CT value 8−12 h postinjection, as shown
in Figure 8c,d, which is also evidence for the high
accumulation in tumor sites. Moreover, Figure S8 also gives
the signal intensities in the tumor obtained preinjection (0 h)
and after intratumoral injection of the citrate-coated
BaYF5:Yb,Er,Bix (x = 2.5) UCNPs at different time intervals.
Apparently, the time-dependent accumulation of BaY-
F5:Yb,Er,Bix in tumor sites was observed within 12 h. The
obvious accumulation of BaYF5:Yb,Er,Bix in tumor sites along
with negligible uptake in a reticuloendothelial system (RES)
CONCLUSIONS
■
In summary, we have successfully synthesized a series of the
BaYF5:Yb,Er,Bix (x = 0−3.0) UCNPs by a facile hydrothermal
method. Although the doping concentration of Bi3+ has
negligible influence on the microstructures of the BaY-
F5:Yb,Er,Bix UCNPs, it remarkably affects their UCL
intensities. The BaYF5:Yb,Er,Bix (x = 2.5) UCNPs own the
strongest green emission intensity, exhibiting about 3−4 times
enhancement compared with that of the Bi3+ free sample. A
possible energy-transfer process and simplified energy levels of
the BaYF5:Yb,Er,Bix UCNPs were also proposed. Compared
with iohexol, the as-synthesized BaYF5:Yb,Er,Bix (x = 2.5)
UCNPs possess significant CT signals, showing potential
biomedical applications as an ideal CT imaging contrast agent.
The obvious accumulation of BaYF5:Yb,Er,Bix in tumor sites
was observed during in vivo CT imaging. It was suggested that
the citrate-coated BaYF5:Yb,Er,Bix (x = 2.5) UCNPs have a
high EPR effect and relatively low uptake by the RES. This
work provides a new strategy for the design of luminescence-
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enhanced UNCPs as a promising cancer nanotheranostic for
bioimaging and cancer treatment.
Mengjiao Liu − College of Chemistry and Materials Science,
Sichuan Normal University, Chengdu 610066, P. R. China
Xin Lai − College of Chemistry and Materials Science, Sichuan
Normal University, Chengdu 610066, P. R. China
Jian Bi − College of Chemistry and Materials Science, Sichuan
Normal University, Chengdu 610066, P. R. China
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.inorgchem.0c01818.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.inorgchem.0c01818
Rietveld XRD refinement of the BaYF5:Yb,Er,Bix (x =
2.5) UCNPs, ICP-MS of the BaYF5:Yb,Er,Bix (x = 0−
3.0) UCNPs, FT-IR spectra of the BaYF5:Yb,Er,Bix (x =
2.5) and citrate-coated BaYF5:Yb,Er,Bix (x = 2.5)
UCNPs, viability of A549 cells incubated with the
citrate-coated BaYF5:Yb,Er,Bix (x = 2.5) UCNPs
(15.63−1000 μg/mL) for 24 h by the standard CCK-8
assay and bright-field image of the mouse before
intratumoral injection of the citrate-coated BaY-
F5:Yb,Er,Bix (x = 2.5) UCNPs, in vitro and in vivo X-
ray CT imaging and a possible energy-transfer process in
the BaYF5:Yb,Er,Bix UCNPs, and X-ray absorption
coefficients of the BaYF5:Yb,Er,Bix (x = 2.5) UCNPs
as a function of the photon energy (PDF)
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Sichuan Science and
Technology Program (Grant 2019YJ0525), Scientific Research
Fund of Sichuan Provincial Education Department of Sichuan
Province (Grant 16TD0007), National Basic Research
Programs of China (Grant 2016YFA0201600), National
Natural Science Foundation of China (Grants 51772293 and
U1932112), Beijing Natural Science Foundation (Grant
2202064), and CAS Key Laboratory of Nano-Bio Interface
(Grant 20NBI01).
AUTHOR INFORMATION
■
Corresponding Authors
Yan Zhao − College of Chemistry and Materials Science,
Sichuan Normal University, Chengdu 610066, P. R. China;
orcid.org/0000-0001-6318-6082; Email: zhaoyan@
sicnu.edu.cn
Wenyan Yin − Key Laboratory for Biomedical Effects of
Nanomaterials and Nanosafety, Institute of High Energy
Physics, Chinese Academy of Sciences (CAS), Beijing 100049,
P. R. China; CAS Key Laboratory of Nano-Bio Interface,
Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese
Academy of Sciences (CAS), Suzhou 215123, P. R. China;
orcid.org/0000-0001-6726-3938; Email: yinwy@
ihep.ac.cn
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