Highly uniform α-NaYF4:Yb/Er hollow microspheres and their application as drug carrier

Article abstract of DOI:10.1021/ic4001818

Highly uniform α-NaYF₄:Yb/Er hollow microspheres have been successfully prepared via a simple two-step route. First, the core-shell structured MF@Y(OH)CO₃:Yb/Er precursor was fabricated by a urea-based homogeneous precipitation method using colloidal melamine formaldehyde (MF) microspheres as template. Then the Y(OH)CO₃:Yb/Er precursor was transformed into hollow NaYF₄:Yb/Er (α and β mixed phase) by a subsequent solvothermal method, and MF microspheres were dissolved in the solvent simultaneously. The mixed phase of NaYF₄:Yb/Er was transferred into pure α-NaYF₄:Yb/Er by calcination. The as-prepared hollow microspheres were well characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray spectrum (EDS), Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), and upconversion (UC) luminescence spectroscopy. It is found that the template can be removed without additional calcination or etching process. α-NaYF₄:Yb/Er hollow microspheres exhibit bright upconversion (UC) luminescence under 980 nm laser diode (LD) excitation. Furthermore, the hollow microspheres show sustained and pH-dependent doxorubicin hydrochloride (DOX) release properties; in particular, the emission intensity increases with the release amount of drug, making the release process able to be tracked or monitored by the change of the emission intensity, which demonstrates the high potential of this kind of hollow fluorescent material in drug delivery fields.

Full text of DOI:10.1021/ic4001818

Article
pubs.acs.org/IC
Highly Uniform α‑NaYF4:Yb/Er Hollow Microspheres and Their
Application as Drug Carrier
Yunhua Han,†,‡ Shili Gai,*,† Ping’an Ma,§ Liuzhen Wang,† Milin Zhang,† Shaohua Huang,†
and Piaoping Yang*,†
†Key Laboratory of Superlight Materials and Surface Technology, Ministry of Education, Harbin Engineering University, Harbin
150001, P. R. China
‡Jilin Institute of Chemical Engineering, Jilin 132022, P. R. China
§State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences,
Changchun 130023, P. R. China
S
* Supporting Information
ABSTRACT: Highly uniform α-NaYF4:Yb/Er hollow microspheres have
been successfully prepared via a simple two-step route. First, the core−shell
structured MF@Y(OH)CO3:Yb/Er precursor was fabricated by a urea-based
homogeneous precipitation method using colloidal melamine formaldehyde
(MF) microspheres as template. Then the Y(OH)CO3:Yb/Er precursor was
transformed into hollow NaYF4:Yb/Er (α and β mixed phase) by a subsequent
solvothermal method, and MF microspheres were dissolved in the solvent
simultaneously. The mixed phase of NaYF4:Yb/Er was transferred into pure α-
NaYF4:Yb/Er by calcination. The as-prepared hollow microspheres were well
characterized by X-ray diffraction (XRD), scanning electron microscopy
(SEM), transmission electron microscopy (TEM), energy-dispersive X-ray
spectrum (EDS), Fourier transform infrared spectroscopy (FT-IR),
thermogravimetric analysis (TGA), and upconversion (UC) luminescence
spectroscopy. It is found that the template can be removed without additional calcination or etching process. α-NaYF4:Yb/Er
hollow microspheres exhibit bright upconversion (UC) luminescence under 980 nm laser diode (LD) excitation. Furthermore,
the hollow microspheres show sustained and pH-dependent doxorubicin hydrochloride (DOX) release properties; in particular,
the emission intensity increases with the release amount of drug, making the release process able to be tracked or monitored by
the change of the emission intensity, which demonstrates the high potential of this kind of hollow fluorescent material in drug
delivery fields.
categorized into template and template-free approaches. In
addition, the template method is the most common method for
synthesizing hollow micro- and nanostructures. Generally, the
template can be divided into soft template and hard template.
Emulsion drops, polymer vesicles, surfactant micelle, polymer
aggregates, and gas bubbles have been utilized as soft
templates.11−15 However, it is usually hard to control the
dispersity and morphology of the hollow structures in soft
template-based strategy due to the deformability of the soft
templates. Compared with the soft template-based strategy, the
hard template strategy is an effective approach to prepare
hollow spheres with well-defined shape and good dispersity. In
the hard template strategy, many compounds, such as
polymeric (polystyrene,16 poly(methyl methacrylate),17−19
MF20), inorganic nonmetallic (SiO2,21−25 carbon spheres,26
CaCO327), and metallic particles (Au28), have been extensively
used as templates. In addition, the desired materials can be
INTRODUCTION
■
In modern chemistry and materials science, controlled synthesis
of uniform hollow nano- or microspheres has been a focus of
worldwide research work, since hollow structure materials hold
higher specific surface area, lower effective density, low
refractive index, and better permeation. Thereby, hollow
structured materials possess widespread potential applications
in many fields, including drug-delivery carriers, efficient
catalysts, adsorbents, sensors, photonic crystals, biomedical
diagnosis agents, waste removal, and chemical reactors.1−7
Hollow structures have gained special attention in the field of
drug storage and release, because they simultaneously possess
large voids inside the shells and mesopores at the shells.8−10
The large voids can store more drug molecules than
conventional mesoporous materials,10 and mesopores at the
shells can provide accessible channels for drug molecules
diffusion and mass transfer without blocking. Meanwhile, they
can also control the permeability of the shells for matter
exchange between voids and the outer environment. The
synthetic strategies for hollow structures can be broadly
Received: January 24, 2013
© XXXX American Chemical Society
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coated on the templates to form core−shell structured spheres.
Subsequently, the templates are removed by calcination at
elevated temperature in air or by selective etching with a
solvent to generate hollow structured spheres.
MF@Y(OH)CO3:Yb/Er was transformed into NaYF4:Yb/Er
hollow microspheres by a subsequent solvothermal process, and
MF cores were dissolved in the solvothermal process. After
calcination, α-NaYF4:Yb/Er hollow microspheres were ob-
tained. Although the UC efficiency of the hexagonal form is
about an order of magnitude higher than that of the cubic one,
β-NaYF4 can only be formed under drastic experimental
conditions, such as high temperatures, high pressure, and high
Na/Y ratio unfortunately, which are not beneficial to formation
of hollow structures. The structure, formation process, UC
luminescence properties, and drug release properties using
doxorubicin hydrochloride (DOX) as a model drug of the
hollow microspheres have been investigated in detail.
Currently, lanthanide-doped UC luminescent materials have
gained considerable attention due to their superior chemical
and optical properties, such as large Stokes shifts, multicolor
emission, high resistance to photobleaching, and photochemical
degradation.29−37 Among various lanthanide-doped com-
pounds, rare-earth fluoride with various morphologies are of
special interest because they normally possess a high refractive
index and low phonon energy.38−40 Furthermore, they exhibit
adequate thermal and environmental stability and therefore are
regarded as excellent host lattices for UC luminescence of
lanthanide ions.41−44 In particular, cubic (α-) or hexagonal (β-)
NaYF4 has been reported as one of the most efficient infrared-
to-visible UC fluorescent host materials.45 To date, many
methods have been developed to synthesize NaYF4 crystals
with various sizes and shapes. For instance, NaYF4 nanocrystals
have been made through hydrothermal or solvothermal
processes,46−52 solid treatment,53 coprecipitation in aqueous
phase,54,55 and thermal decomposition of trifluoroacetate
precursors.56,57 However, to the best of our knowledge, only
a few researchers have reported the synthesis of NaYF4 hollow
spheres. Zhang et al. prepared cubic NaYF4 hollow spheres
through a controlled ion-exchange process from solid Y2O3
spheres using HF acid as fluoride source.58 Yang et al.
employed a similar route to prepare NaYF4 hollow spheres
using lanthanide-doped Y(OH)CO3 spheres as precursor.59
However, the used corrosive acid often brings environmental
concern, and the spheres prepared from the ion-exchange route
lack high uniformity. As mentioned above, although some kinds
of well-defined hollow spheres can be prepared using the hard
template strategy, the template particles usually need to be
removed by calcination or an etching process, resulting in a
complicated process and enhanced energy consumption.
Therefore, it is highly desirable to develop a cheap and
environmentally friendly strategy to prepare well-defined and
uniform NaYF4 hollow spheres without an additional template
removal process. In addition, hollow structures generally
possess large voids inside the shells and small pores or broken
holes at the shells and have great potential in the field of drug
delivery. First, the large voids can store more drug molecules
than that of the conventional porous materials. Second, the
small pores or broken holes at the shells, on the one hand, can
provide accessible channels for drug molecules diffusion and
mass transfer without blocking and, on the other hand, could
control the permeability of the shells for matter exchange
between voids and the outer environment. In particular, the
excellent UC luminescent properties of Yb3+/Er3+-codoped
NaYF4 make them a real-time, a simple, and an effective way to
monitor the route of drug-transport carriers in a living system.
In addition, the near-infrared excitation light offers high
excitation-penetration depth and negligible photodamage.
Therefore, NaYF4 hollow structures as drug delivery systems
can be easily identified, tracked, and monitored to evaluate the
efficiency of drug release and disease therapy.
EXPERIMENTAL SECTION
■
Materials. All materials including Y2O3, Yb2O3, Er2O3, urea,
formaldehyde, melamine, and formic acid were purchased from
Sinopharm Chemical Reagent Co., Ltd. Y(NO3)3, Yb(NO3)3, and
Er(NO3)3 were prepared by dissolving Y2O3, Yb2O3, and Er2O3 in
dilute HNO3 solution under heating and agitation. The superfluous
HNO3 was driven off by heating until the pH value of the solution
reached between 3 and 4. All other chemicals were analytical-grade
reagents and used directly without further purification.
Synthesis of Monodisperse MF Microspheres. Monodisperse
MF colloidal microspheres were prepared according to the literature
with a slight modification.60 In a typical procedure, a solution
containing 4.25 mL of formaldehyde (37%) and 80 mL of deionized
water was heated to 80 °C. Subsequently, 1.0 g of melamine was added
into the solution with stirring. When melamine was dissolved
completely, formic acid was then introduced into the solution with
vigorous stirring until reaching pH = 5. The transparent solution was
further stirred for several minutes and then became turbid. After
additional agitation for another 40 min, the obtained white colloidal
particles were washed with deionized water and ethanol several times
and dried in air at 60 °C for 12 h.
Preparation of MF@Y(OH)CO3:Yb/Er Microspheres. Typically,
1.6 mmol of Y(NO3)3, 0.36 mmol of Yb(NO3)3, and 0.04 mmol of
Er(NO3)3 were added to 30 mL of distilled water. Then 3.0 g of urea
was dissolved in the solution with vigorous stirring to form a clear
solution. Subsequently, 0.2 g of as-prepared MF microspheres was
added and well dispersed into the above solution with the assistance of
ultrasonication for 30 min. Finally, the mixture was transferred to a
round-bottomed flask and heated to 85 °C for 3 h with vigorous
stirring before the product was collected by centrifugation. Then as-
obtained MF@Y0.8Yb0.18Er0.02(OH)CO3, also denoted as MF@
Y(OH)CO3:Yb/Er, microspheres was washed with deionized water
and ethanol several times. To confirm formation of
Y0.8Yb0.18Er0.02(OH)CO3 on the surface of MF, the experiment and
results without the presence of MF as template are shown in the
Supporting Information.
Synthesis of α-NaYF4:Yb/Er Hollow Microspheres. In a typical
process for the synthesis of α-NaYF4:Yb/Er hollow microspheres, the
as-obtained MF@Y(OH)CO3:Yb/Er was dispersed into 15 mL of
deionized water and then added to 50 mL of ethylene glycol (EG).
After stirring for 20 min, 10 mL of a solution containing 0.2015 g of
NaF was dripped into the suspension under stirring. After additional
agitation for 10 min, the as-obtained mixture was transferred into a
100 mL autoclave and heated at 180 °C for 12 h. After the autoclave
was naturally cooled to room temperature, the precipitate was
separated by centrifugation, washed with deionized water and ethanol
in sequence, and then dried in air at 60 °C for 12 h. Hollow
NaYF4:Yb/Er microspheres were obtained. After calcination at 550 °C
for 3 h, α-NaYF4:Yb/Er hollow microspheres were achieved.
In this study, Yb3+/Er3+-codoped α-NaYF4 (denoted as α-
NaYF4:Yb/Er) hollow microspheres with UC emission
property have been fabricated through a two-step approach.
Core−shell structured MF@Y(OH)CO3:Yb/Er microspheres
were first fabricated by a urea-based homogeneous precipitation
method using colloidal MF microspheres as template. Then
Preparation of Drug Storage/Release System. In a modified
process,61 30 mg of as-prepared α-NaYF4:Yb/Er hollow microspheres
was dispersed in 5 mL of phosphate buffer solution (PBS, pH = 7.4)
with a DOX concentration of 0.5 mg/mL. The mixture was shaken for
24 h at room temperature to reach the equilibrium state in dark
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condition. Then the solution was centrifuged to collect the DOX-
loaded NaYF4:Yb/Er sample, which is denoted as DOX-NaYF4:Yb/Er.
The supernatant solution was collected, and the content of residual
DOX was determined by UV−vis measurement at a wavelength of 480
nm, as shown in Figure S1, Supporting Information. The in vitro
delivery test was performed by immersing the DOX-NaYF4:Yb/Er
sample in 10 mL of PBS under gentle stirring in dark condition, and
the immersing temperature was kept at 37 °C. At a selected time
interval, the buffer solution was quickly taken and replaced with an
equal volume of fresh buffer solution. The amount of released DOX in
the supernatant solution was measured by a UV−vis spectropho-
tometer. To evaluate the DOX loading amount and loading efficiency,
the supernatant and washed solutions were collected and the residual
DOX content (RDOX) was obtained by UV−vis measurement at 480
nm. The loading efficiency of DOX can be calculated as follows:
[(ODOX − RDOX)/ODOX] × 100%, where ODOX is the original DOX
content.
Biocompatibility Assay. The biocompatibility of α-NaYF4:Yb/Er
hollow microspheres was assessed by the standard 3-(4,5-dimethylth-
iazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In a typical
procedure, 5000−6000 L929 fibroblast cells in 200 μL of media per
well were plated in 96-well plate and cultured in 5% CO2 at 37 °C for
24 h overnight to allow the cells to attach to the wells. α-NaYF4:Yb/Er
sample was sterilized by ultraviolet irradiation for 2 h; then serial
dilutions of the particles at concentrations of 6.25, 12.5, 25, 50, 100,
and 200 μg/mL were added to the culture wells to replace the original
culture medium and incubated for another 24 h in 5% CO2 at 37 °C. A
5 mg/mL amount of a stock solution of MTT was prepared in PBS,
and 20 μL of this stock solution was added to each well containing
different amounts of NaYF4:Yb/Er and incubated for another 4 h.
During this period, viable cells reduce MTT to formazan pigment,
which can be dissolved by dimethyl sulfoxide (DMSO). After
incubation, 100 μL of acidified isopropanol was added to each well
and placed on a shaking table (150 rpm, 5 min) to thoroughly mix the
formazan into the solvent. The absorbance of the suspension was
recorded under a microplate reader at 570 nm.
Characterization. X-ray powder diffraction (XRD) was examined
on a Rigaku D/max-TTR-III diffractometer at a scan rate of 10°/min
in the 2θ range from 10° to 80° using Cu Kα radiation (λ = 0.15405
nm). The morphology and composition of the as-prepared samples
were inspected on a scanning electron microscope (SEM, JSM-6480A,
Japan Electronics) equipped with an energy-dispersive X-ray spectrum
(EDS, INC250, Japan Electronic). Transmission electron microscopy
(TEM) and high-resolution transmission electron microscopy
(HRTEM) were performed on a FEI Tecnai G2 S-Twin transmission
electron microscope with a field emission gun operating at 200 kV to
elucidate the dimensions and structural details of the particles. N2
adsorption/desorption isotherms were measured at a liquid nitrogen
temperature (−196 °C) using a Micromeritics ASAP 2010 M
instrument. The specific surface area was determined by the
Brunauer−Emmett−Teller (BET) method. Fourier transform infrared
spectroscopy (FT-IR) spectra were recorded with a Perkin-Elmer
580B infrared spectrophotometer using the KBr pellet technique.
Thermogravimetric analysis (TGA) was carried out on a Netzsch STA
409 thermoanalyzer with a heating rate of 5 °C/min. UC emission
spectra were obtained using 980 nm LD Module (K98D08M-30W,
China) as the excitation source and detected by R955 (HAMAMAT-
SU) from 400 to 900 nm. UV−vis absorption spectra were obtained
on a UV-1601 spectrophotometer. All of the measurements were
performed at room temperature.
Figure 1. XRD patterns of (A) MF@Y(OH)CO3:Yb/Er, (B)
NaYF4:Yb/Er hollow microspheres, and (C) α-NaYF4:Yb/Er hollow
microspheres after calcination at 550 °C for 3 h. Standard data for
cubic NaYF4 (JCPDS No. 06-0342) and hexagonal NaYF4 (JCPDS
No.16-0334) are presented for comparison.
precursor before solvothermal reaction has been confirmed to
be Y0.8Yb0.18Er0.02(OH)CO3 on the basis of a previous report
and the XRD pattern and SEM image provided in the
Supporting Information (Figures S2 and S3).62 When the
precursor reacted with NaF at 180 °C for 12 h in the
solvothermal process, the diffraction peaks of as-synthesized
product can be indexed to the mixed phase of α- and β-NaYF4
(Figure 1B), and both the intensity and position of (111),
(220), and (311) diffraction peaks can be assigned to the α
phase. Thereby, α-NaYF4 is predominant. To further determine
the chemical composition of the product, the sample was
calcined at 550 °C for 3 h. It is well known that Y(OH)CO3
will be thermally decomposed into Y2O3 after annealing at 550
°C. While the XRD pattern of the calcined sample (Figure 1C)
indicates that the peaks can be well indexed to pure cubic
NaYF4 phase (JCPDS No. 06-0342), no diffraction peaks of
Y2O3 can be found, revealing Y(OH)CO3 precursor was
completely converted into mixed phase NaYF4 through the
solvothermal process and further converted into pure α-NaYF4
after calcination.
As shown in the SEM image of MF microspheres (Figure
2A), the MF template consists of uniform microspheres with an
average diameter of 2.2 μm. The magnified SEM image (Figure
2B) reveals that MF microspheres have very smooth surfaces.
In Figure 2C for MF@Y(OH)CO3:Yb/Er microspheres, the
sample inherits the spherical shape and good dispersion of the
MF cores. The surfaces are much rougher than those of bare
MF cores due to precipitation of the Y(OH)CO3:Yb/Er layer,
which can be clearly confirmed by the magnified SEM image
(Figure 2D). In the TEM image for MF@Y(OH)CO3:Yb/Er
(Figure 2E), the apparent contrast between the core and the
shell directly evidence the core−shell structure. As shown in the
magnified TEM image (Figure 2F), the average size of MF@
Y(OH)CO3:Yb/Er microspheres and the shell is about 2.4 μm
and 190 nm, respectively.
RESULTS AND DISCUSSION
From the SEM images of α-NaYF4:Yb/Er hollow micro-
spheres (Figure 3A and 3B), we can see that the as-prepared
NaYF4:Yb/Er is composed of uniform microspheres with
narrow size distribution. In addition, the average size of α-
NaYF4:Yb/Er hollow microspheres is about 2.2 μm. It should
be noted that the hollow structure can be clearly observed from
the broken particle (inset in Figure 3B). The hollow structure is
also confirmed by the TEM image, as shown in Figure 3C. In
■
Phase, Structure, and Morphology. Figure 1 shows the
XRD patterns of MF@Y(OH)CO3:Yb/Er microspheres and
NaYF4:Yb/Er hollow microspheres with or without calcination,
respectively. It is found that no obvious diffraction peak appears
in Figure 1A, which indicates that the as-formed MF@
Y(OH)CO3:Yb/Er is amorphous via a urea-based homoge-
neous precipitation method. The component of the amorphous
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elements in the hollow structure, and no oxygen element is
detected, confirming complete transformation from Y(OH)-
CO3:Yb/Er to NaYF4:Yb/Er. In the HRTEM image (Figure
3E), the distance of 0.31 nm between the adjacent lattice
fringes of NaYF4:Yb/Er hollow microspheres matches well with
the d110 spacing (0.314 nm) of cubic NaYF4 (JCPDS No. 06-
0342). This is also supported by the fast Fourier transform
(FFT) pattern (inset in Figure 3E), which shows diffraction
spots of the (110) planes of α-NaYF4 and also reveals the
single-crystalline nature of the sample.
Figure 4 gives the N2 adsorption/desorption isotherm and
pore size distribution of α-NaYF4:Yb/Er hollow microspheres.
Figure 2. Low- (A) and high-magnification (B) SEM images of pure
MF colloidal microspheres, low- (C) and high-magnification (D) SEM
images of MF@Y(OH)CO3:Yb/Er microspheres, and low- (E) and
high-magnification (F) TEM images of MF@Y(OH)CO3:Yb/Er
microspheres.
Figure 4. N2 adsorption/desorption isotherm (left) and pore size
distribution (right) of α-NaYF4:Yb/Er hollow microspheres.
We can see that the sample shows a typical IV-typed isotherm
with a H1-hysteresis loop, which are related with the typically
mesoporous structure. The BET surface area and total pore
volume are calculated to be 49 m2/g and 0.128 cm3/g,
respectively. Notably, the pore sizes are mainly due to the small
pores or broken holes in the shells formed during the
solvothermal process, which is also confirmed by the SEM
and TEM images (Figure 3).
Figure S4, Supporting Information, shows the TG curves of
the MF@Y(OH)CO3:Yb/Er microspheres and α-NaYF4:Yb/Er
hollow microspheres, respectively. As shown, weight loss can be
observed before 100 °C, which may be caused by the absorbed
water on the surface of the samples. For MF@Y(OH)CO3:Yb/
Er, the two rapid weight losses can be assigned to dehydration
and burning of MF template from 100 to 550 °C and
conversion from amorphous precursor to crystalline Y2O3
between 550 and 800 °C. In addition, the total weight loss is
about 67.1%. As for α-NaYF4:Yb/Er hollow structure, only a
weight loss of 3.7% from 100 to 550 °C indicates that MF
template has been effectively removed during the solvothermal
process. From 550 to 800 °C we can hardly find the weight
loss, indicating that no Y(OH)CO3:Yb/Er exists in NaYF4
hollow microspheres, which agrees with the XRD result.
FT-IR spectra are used to identify the functional groups of
the MF template, MF@Y(OH)CO3:Yb/Er microspheres, and
α-NaYF4:Yb/Er hollow microspheres (Figure S5, Supporting
Information). The FT-IR spectrum of the MF template (Figure
S5A, Supporting Information) shows the obvious absorption
bands of OH/NH2 (3377 cm−1), NH2 (1558, 1496, 1351
cm−1), C−N (1164 cm−1), C−O−C (1007 cm−1), and C−N−
C (811 cm−1).60 The FT-IR spectrum of MF@Y(OH)CO3:Yb/
Figure 3. Low- (A) and high-magnification (B) SEM images of α-
NaYF4:Yb/Er hollow microspheres; (inset) enlarged single hollow
microsphere with open pore. (C) TEM image of α-NaYF4:Yb/Er
hollow microspheres. (D) EDS of α-NaYF4:Yb/Er hollow micro-
spheres. (E) HRTEM image of α-NaYF4:Yb/Er hollow microspheres;
(inset) corresponding fast Fourier transform (FFT) image.
addition, the hollow structures possess large voids inside the
shells and small pores or broken holes at the shells. The average
diameter (2.2 μm) of the NaYF4 hollow microspheres with
rough surfaces is slightly decreased in comparison with that of
the MF@Y(OH)CO3:Yb/Er precursor (2.4 μm). It is believed
that the shrinkage is caused by conversion from the loosely
ranged Y(OH)CO3:Yb/Er precursor to the relatively compact
NaYF4:Yb/Er layer and dissolving of the MF templates. EDS
(Figure 3D) confirms the presence of Na, Y, F, and Yb
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Er is very similar to that of the MF template. However, the IR
band of the ether group (1007 cm−1) disappears, which may be
caused by coating the Y(OH)CO3:Yb/Er precursor onto the
surface of MF microspheres. As for α-NaYF4:Yb/Er hollow
microspheres (Figure S5C, Supporting Information), the
absorption band at 3354 cm−1 can also be assigned to the
vibration of hydroxyl (−OH). Notably, most of the functional
groups of MF template nearly disappear, revealing that the MF
template can be effectively removed during the solvothermal
process.20,62,63
Formation Process of NaYF4:Yb/Er Hollow Micro-
spheres. On the basis of above experimental results, a general
schematic illustration of the formation process of α-NaYF4:Yb/
Er hollow microspheres is proposed in Scheme 1. First,
region, which corresponds to the photograph under 980 nm
irritation (inset in Figure 5A). The excitation power-dependent
UC green and red emissions of α-NaYF4:Yb/Er hollow
microspheres are presented in Figure 5B. It is well known
that the output UC luminescent intensity (IUC) is proportional
to the infrared excitation power (IIR) as IUC ∝ IIRn, where n is
the absorbed photon numbers per emitted visible photon; its
value is obtained from the slope of the fitted line of the plot of
log (IUC) versus log (IIR). As shown in Figure 5B, the respective
slope of the linear fits of log (IUC) versus log (IIR) for the green
and red emissions in α-NaYF4:Yb/Er sample is 1.91 and 1.72,
indicating that two photons are involved to produce the green
and red UC emissions. The result is in good agreement with
previous reports for other Yb3+/Er3+-doped fluorides. The UC
energy transfer process upon 980 nm LD excitation based on
above result is proposed in Figure 5C. It can be seen that the
green and red emissions all need a two-photon process to
Scheme 1. Schematic Illustration of the Formation Process
for α-NaYF4:Yb/Er Hollow Microspheres
2
4
populate the H11/2/4S3/2 or F9/2 level. First, the ground state
4
electrons are excited to the I11/2 intermediate state of the Er3+
ion and then to the 4F7/2 state via a successive transfer of energy
from Yb3+ (2F5/2 excited state). Subsequently, those electrons
2
nonradiatively decay to the lower H11/2 and 4S3/2 excited state
energy levels, respectively. After these electrons return to the
ground state again, it gives the green emission. Alternatively,
4
the electron can further relax and populate the F9/2 level.
4
Subsequent radiative relaxation from the F9/2 level of the Er3+
4
ion to the ground state I15/2 level leads to the red emission.
Drug Loading, Release Properties, and Biocompati-
bility. As a typical antitumor drug, DOX was selected to
evaluate the release behavior from drug-loaded NaYF4:Yb/Er
system. In the DOX loading process, the DOX molecules are
entrapped within the hollow structure by an impregnation
process. The drug loading amount is determined to be 23.2 μg/
mg (DOX/NaYF4:Yb/Er), and the loading efficiency is 27.8 wt
% at pH = 7.4.
Figure 6 shows the in vitro release profiles of DOX from
DOX-NaYF4:Yb/Er systems in PBS buffer solutions with
different pH values at 37 °C. We find a relatively fast release
within the first 1.5 h followed by a sustained release over 12 h.
The initial fast release can be assigned to rapid diffusion of the
physically adsorbed drug molecules weakly adsorbed on the
outer surfaces or near the pore entrances. Then the drug
adsorbed in the inner surfaces or channels of the pores by
strong interaction between drug molecules and the hydrogen
bonds on the material surface will dissolve in a sustained
manner. Furthermore, to inhibit tumor cell growth in tumor
treatment, the initial burst DOX release is preferable to achieve
sufficient initial dosage of the antitumor drug. For the cancer
cells that survive the initial stage of drug release, the sustained
DOX release is necessary to prevent their further proliferation.
Thus, the drug release performance of the carrier makes it a
promising candidate for tumor therapy.
Notably, the carrier exhibits obvious pH-dependent release
properties in different pH solutions, which may be explained by
the fact that with the decrease of the pH value the potential of
the particle surface becomes more positive, thus weakening the
electrostatic adsorption force with positively charged DOX
molecules, leading to faster drug release. Considering the
various pH values at different body sites and especially that
cancer tissue is acidic extracellular, the pH-sensitive carrier can
be used to control the release of drug, which is beneficial to
targeting cancerous tissues and reducing toxic side effects for
normal tissues. Thus, this carrier with pH-dependent release
monodisperse colloid MF microspheres were prepared, which
will act as the hard template. Then, MF@Y(OH)CO3:Yb/Er
precursor was fabricated via a urea-based homogeneous
precipitation route on the surfaces of colloidal MF spheres.
Then Y(OH)CO3:Yb/Er layer was transformed into NaY-
F4:Yb/Er with the mixed phase of α and β by a subsequent
solvothermal process, and MF cores were dissolved in the
solvent simultaneously. This process can be described as
follows: the Y3+ (Yb3+, Er3+) ions ionized from the precursor
react with Na+ and F− in the solution to form NaYF4:Yb/Er
layer on the surface of MF microspheres; meanwhile, MF
microspheres are dissolved in the organic solvent under high
temperature and pressure. Finally, pure α-NaYF4:Yb/Er hollow
microspheres are obtained by a subsequent calcination process.
Upconversion Photoluminescence Properties. NaYF4
has proved to be an efficient host lattice for downconversion
and upconversion processes due to the lower phonon
energies.64−66 Here, we select Yb3+- and Er3+-codoped ions to
investigate the UC emission properties of the hollow structured
product. Figure 5 shows the upconversion spectrum of α-
NaYF4:Yb/Er hollow microspheres under 980 nm laser LD
excitation. It is found that two primary bands in the green
emission region with maxima at 521 and 543 nm can be
assigned to the 2H11/2 → 4I15/2 and 4S3/2 → 4I15/2 transitions of
the Er3+ ions, and a weak band at about 651 nm is attributable
4
4
to the F9/2 → I15/2 transition of Er3+ ions. The chromaticity
coordinates are x = 0.272 and y = 0.661, locating in the green
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Figure 5. (A) Upconversion emission spectrum of α-NaYF4:Yb/Er hollow microspheres under 980 nm LD excitation, (B) pump power dependence
of the green and red upconverted emissions under 980 nm LD excitation, and (C) proposed energy transfer mechanism in Yb3+/Er3+-doped α-
NaYF4 hollow microspheres. Inset in A is the luminescent photograph of the sample under 980 nm irradiation.
Figure 7. UC emission intensity of Er3+ in DOX-loaded α-NaYF4:Yb/
Figure 6. Cumulative DOX release from DOX-NaYF4:Yb/Er system
Er as a function of release time.
in PBS buffers with different pH values.
properties should have high potential as a smart carrier for
releasing antitumor drug by changing the pH environment.
The UC emission intensity of a DOX-loaded NaYF4:Yb/Er
system as a function of release time (the cumulative released
amount of DOX) at a pH value of 7.4 is given in Figure 7 and
Figure S6A, Supporting Information. As shown, the emission
intensity (the integrated green and red emissions) of the system
strongly depends on the amount of released DOX. It is well
known that emission of rare-earth ions will be quenched to
some extent in environments which contain high phonon
frequency.67 (For example, emission of Eu3+ will be seriously
quenched by OH groups with a vibrational frequency near 3450
cm−1.) The emission intensity is greatly quenched by the
loaded DOX with high-frequency phonon vibrations (1000−
3450 cm−1) and increases with the released DOX, achieving its
maximum when the release process is completely stopped. The
gradually weakened quenching effect due to the released DOX
yields the increase of emission intensity. The result suggests the
potential of this functional carrier to be tracked or monitored
during the release process. In addition, MTT assay (Figure S7,
Supporting Information) demonstrates the satisfactory bio-
compatibility of the sample in all dosages, indicating that the
nontoxic property of the sample and therefore is promising as
drug carrier.
CONCLUSIONS
■
In summary, we reported a two-step and accurate route for
fabrication of highly uniform α-NaYF4:Yb/Er hollow micro-
spheres with an average diameter of 2.2 μm using core−shell
structured MF@Y (OH)CO3:Yb/Er microspheres as template,
followed by the solvothermal and calcination processes. It is
worthy to note that MF spheres were directly dissolved in the
organic solvent under hydrothermal environment without
additional calcination and leaching process. The as-prepared
α-NaYF4:Yb/Er hollow microspheres exhibit the characteristic
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green UC emissions of Er3+ under the 980 nm LD excitation.
Furthermore, this hollow structured material demonstrates
good biocompatibility, sustained DOX release properties, and
potential tracked/monitored properties, which are have high
potential in the biomedical field.
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ASSOCIATED CONTENT
* Supporting Information
■
S
This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: gaishili@hrbeu.edu.cn (S.G.), yangpiaoping@hrbeu.
edu.cn (P.Y.).
■
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (NSFC 21271053), Research Fund for
the Doctoral Program of Higher Education of China
(20112304110021), Program for New Century Excellent
Talents in University, Natural Science Foundation of
Heilongjiang Province (LC2012C10), Harbin Sci.-Tech.
Innovation Foundation (RC2012XK017012), and Fundamen-
tal Research Funds for the Central Universities of China is
greatly acknowledged.
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