Article

Cite This: J. Am. Chem. Soc. 2018, 140, 12890−12899 pubs.acs.org/JACS

Small and Bright Lithium-Based Upconverting Nanoparticles

Ting Cheng,† Riccardo Marin,† Artiom Skripka,† and Fiorenzo Vetrone*
Centre É nergie, Matériaux et Télécommunications, Institut National de la Recherche Scientifique, Université du Québec, Varennes,
Quebec J3X 1S2, Canada
*
S Supporting Information

ABSTRACT: In the context of light-mediated tumor treatment,

the application of ultraviolet (UV) radiation can initiate drug
release and photodynamic therapy. However, its limited
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penetration depth in tissues impedes the subcutaneous

applicability of such radiation. On the contrary, near-infrared
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(NIR) light is not energetic enough to initiate secondary

photochemical processes, but can pierce tissues at a significantly
greater depth. Upconverting nanoparticles (UCNPs) unify the
advantages of both extremes of the optical spectrum, they can be
excited by NIR irradiation and emit UV light through the process
of upconversion, effective NIR-to-UV generation being attained
with UCNPs as large as 100 nm. However, in anticipation of
biomedical applications, the size of UCNPs must be greatly
minimized to favor their cellular internalization; yet straightforward size reduction negatively affects the NIR-to-UV
upconversion efficiency. Herein, we propose a two-step strategy to obtain small yet bright lithium-based UCNPs. First, we
synthesized UCNPs as small as 5 nm by controlling the relative amount of coordinating ligands, namely oleylamine (OM) and
oleic acid (OA). Although these UCNPs were chemically unstable, particle coarsening via an annealing process in the presence
of fresh OA yielded structurally stable and highly monodisperse sub-10 nm crystals. Second, we grew a shell with controlled
thickness on these stabilized cores of UCNPs, improving the NIR-to-UV upconversion by orders of magnitude. Particularly in
the case of LiYbF4:Tm3+/LiYF4 UCNPs, their NIR-to-UV upconversion surpassed the gold standard 90 nm-sized LiYF4:Tm3+,
Yb3+ UCNPs. All in all, these UCNPs show great potential within the biomedical framework as they successfully combine the
requirements of small size, deep tissue NIR penetration and bright UV emission.

■ INTRODUCTION
Rare earth (RE) based upconverting nanoparticles (UCNPs)
have attracted tremendous interest in the fields of nano-
medicine,1−5 bioimaging,6−11 photovoltaics12−15 and sens-
ing16−20 as they can absorb low-energy photons and emit
higher-energy ones (an anti-Stokes process),21,22 thus convert-
ing longer wavelength near-infrared (NIR) light to shorter
wavelength ultraviolet (UV), visible and NIR light. This wide
spectral range can be covered by Yb3+/Tm3+-doped UCNPs,
all under single 980 nm irradiation.23 Emission from Yb3+/
Tm3+-doped UCNPs renders UV light, which is energetic
enough to initiate multiple photochemical processes, including
photocleavage,24−26 photoisomerization,27 and photocataly-
sis28 that are of great interest for applications like wastewater
remediation,29 in vivo controlled drug delivery2,30 and
photodynamic therapy.31−33 In biomedicine, direct UV
irradiation is restricted to superficial application by its limited
penetration depth in biological tissues. Whereas exploitation of
UCNPs as transducers takes advantage of greater penetration
depth exhibited by NIR excitation, which is less attenuated by
tissue absorption and scattering.34 Furthermore, NIR light
avoids the excitation of endogenous tissue constituents
allowing for autofluorescence-free imaging either through
NIR-to-NIR upconversion or Stokes-based photolumines-
cence,35−37 decisively supporting the development of these
multifunctional agents38−40
The use of sodium-based host matrices has been regarded as
an efficient approach to attain upconversion emission and has
been widely explored for most RE3+-doped UCNPs.41−47
However, RE3+-doped LiYF4-based UCNPs are on-par in light
upconversion efficiency and in certain cases are more
preferable than their NaYF4-based counterparts, especially for
UV-blue upconversion generation.48,49 Recently, development
of lithium-based host matrices (LiREF4, RE = Y, Yb) has
focused on the core/shell engineering of these interesting
nanoarchitectures.23,50,51 However, to our knowledge, only
limited studies have been carried out focusing on the synthesis
of lithium-based host matrices spanning a wide size range, or
exploiting precise control of the core/shell architectures for
particularly small UCNPs.52,53 Most commonly, LiYF4:Tm3+,
Yb3+ UCNPs have sizes larger than 80 nm, which somewhat
restricts their potential in vivo application, where size
minimization is often a stringent requirement, especially in
favor of the particles’ internalization by cells.54 Miniaturization
is particularly pertinent when core/shell architectures of
Received: July 5, 2018
Published: September 14, 2018

© 2018 American Chemical Society 12890 DOI: 10.1021/jacs.8b07086

J. Am. Chem. Soc. 2018, 140, 12890−12899
Journal of the American Chemical Society
UCNPs are sought after, as each additional shell layer increases
the UCNPs’ size. Also, the upconversion emission of these
structures, although well regarded for the UV component, is
still majorly comprised of NIR light. This is particularly true
for reported sub-10 nm systems,50 thereby curbing their
application as photochemical initiators. Thus, the knowledge
on how to create small but efficient NIR-to-UV UCNPs is still
lacking and here we aim to shed light on the method to
overcome this trade-off.
Most of the established thermal decomposition synthesis
methods of UCNPs require the use of oleic acid (OA) as a
coordinating ligand and octadecene (ODE) as a non-
coordinating solvent.41,49,51,55 Another coordinating species,
namely oleylamine (OM), has been widely used to adjust,
usually to reduce, the size of various structures.56−58 Among
the proposed methods, Yan’s group applied this approach to
change phase, morphology and size of undoped sodium rare
earth fluorides.41
Following this seminal study, we have systematically
investigated the possibility of controlling the size of lithium-
based UCNPs from 5 to 90 nm, by exploitation of OA and OM
coordinating ligands. Examining the optical properties of
various UCNPs, decreasing trends of upconversion emission
with size reduction were observed. In an attempt to restore the
upconversion emission, shell growth strategies were employed,
yet due to the chemical instability of 5 nm-sized UCNPs the
shell growth over these structures proved to be uncontrollable.
Thus, we further reported a unique strategy to synthesize sub-
10 nm lithium-based cores, chemically stable and suitable for
further shell growth. In this way, UCNPs with controlled size
and shell thickness through the initial core-stabilization
technique can be realized. Most importantly, the synergistic
use of core-stabilization and shelling strategies allows for the
prominent UV emission generation even with sub-20 nm
UCNPs.
■
MATERIALS AND METHODS
Materials. Y2O3 (REacton, 99.999%), Yb2O3 (REacton, 99.998%),
Tm2O3 (REacton, 99.997%), trifluoroacetic acid (99%), 1-octadecene
(ODE, 90%), and oleic acid (OA, 90%) were purchased from Alfa
Aesar (USA). Lithium trifluoroacetate (98%) and oleylamine (OM,
70%) were obtained from Sigma-Aldrich (USA). All chemicals were
used as received.
Precursor Preparation. For various syntheses, 2.5 mmol of RE
trifluoroacetate precursors were prepared by mixing stoichiometric
quantities of RE2O3 (RE = Y, Tm, Yb) with 5 mL trifluoroacetic acid
and 5 mL distilled water in a 100 mL three-neck round-bottom flask.
In a typical synthesis of LiYF4:Tm3+ (0.5%), Yb3+ (25%): 0.93125
mmol (210.3 mg) Y2O3, 0.3125 mmol (123.2 mg) Yb2O3, and
0.00625 mmol (2.4 mg) Tm2O3 were used. The slurry was refluxed
under vigorous stirring at 80 °C until clear. The temperature was then
lowered to 60 °C to evaporate the solvent overnight. The obtained
solid dried materials were used as precursors for the UCNP synthesis.
Size-Controlled Synthesis of LiYF4:Tm3+, Yb3+ UCNPs.
LiYF4:Tm3+ (0.5%), Yb3+ (25%) UCNPs were synthesized via a
previously reported thermal decomposition method with minor
modifications.49 To control the size of the obtained UCNPs, an
oleic acid/oleylamine (OA/OM) mixture with different volume ratios
was used. In addition, two different synthesis approaches, namely one-
pot49 and hot-injection,59 were compared and are described below.
Synthesis of LiYF4:Tm3+, Yb3+ via One-Pot Method. Dried RE
trifluoroacetate precursors were mixed with 2.5 mmol of lithium
trifluoroacetate, 20 mL of desired OA/OM mixture and 20 mL of
ODE. Explored OA/OM volume ratios used to control the UCNP
size are listed in Table S1. The solution was stirred and degassed
under vacuum at 110 °C for 30 min. After backfilling the flask with Ar,
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the temperature of the solution was raised to 330 °C gradually and
was kept at this value for 1 h. Afterward, the solution was allowed to
cool down to room temperature, maintaining the magnetic stirring
and Ar atmosphere. Then, the oleate-capped UCNPs were
precipitated with ethanol and recollected via centrifugation at 5400
RCF for 15 min. Subsequently, the UCNPs were washed twice with a
mixture of hexane/ethanol (or toluene/acetone) (1/4 v/v) and
precipitated via centrifugation. Finally, the oleate-capped UCNPs
were redispersed in hexane for storage and characterization.
Synthesis of LiYF4:Tm3+, Yb3+ UCNPs via Hot-Injection
Method. For the hot-injection approach, two separate solutions
were prepared. Solution A was prepared by mixing 14 mL of desired
OA/OM mixture and 14 mL of ODE in a 100 mL three neck round-
bottom flask. Solution B was prepared by mixing 2.5 mmol of lithium
trifluoroacetate, dried RE precursors, 6 mL of OA/OM mixture and 6
mL of ODE. OM was added in solution B after the precursors were
dissolved under vacuum in pure OA/ODE mixture. In both A and B
solutions, the OA/OM/ODE composition was the same. The
investigated OA/OM compositions are summarized in Table S1.
Both solution A and B, were stirred and degassed under vacuum at
125 °C for 30 min. Under Ar atmosphere, the temperature of solution
A was raised to 330 °C. Once solution A reached the stable desired
temperature, solution B was injected into solution A using a pump-
syringe system at a 1.5 mL/min injection rate. Following the injection,
the subsequent synthesis steps were identical as described in the one-
pot approach: 1 h reaction time, cooling under stirring and Ar flow,
washing and storage.
Synthesis of Sub-10 nm LiREF4:RE3+ Core. Sub-10 nm
LiREF4:RE3+ cores were synthesized as described via the hot-injection
approach at a specific OA/OM mixture (50% OM). After the final
cooling step of the synthesis, the majority of the synthesized product
was stored under Ar atmosphere without washing for the subsequent
core stabilization step. A small portion (1 mL) of the product was
washed for structural characterization.
Stabilization of LiREF4:RE3+ Core. In order to stabilize the sub-
10 nm cores, a modified hot-injection approach was used. Solution A
was prepared by mixing 0.5 mmol of the synthesized core material
with 15 mL of OA/OM (1/1 v/v) (to distinguish from the core
synthesis step, where we use vol % OM to display the OA/OM
composition, we use v/v ratio for OA/OM in the core stabilization
step) and 15 mL ODE. Solution B contained a 20 mL mixture of OA/
ODE or OM/ODE (1/1 v/v in either case). Both solutions were
stirred and degassed under vacuum at 110 °C for 30 min. Under Ar
atmosphere, the temperature of solution A was raised and maintained
at 315 °C for 30 min. Solution B was injected into solution A in two
steps: for each step, 10 mL of solution B was injected at an injection
rate of 1.5 mL/min at time intervals of 40 min. After the annealing,
the majority of stabilized core UCNPs was stored under Ar
atmosphere without washing for further shell growth. A small portion
(1 mL) of stabilized cores was washed for structural characterization.
Synthesis of Core/Shell LiREF4:RE3+/LiREF4 UCNPs. Core/
shell UCNPs were prepared by epitaxially growing the shell, injecting
appropriate precursors via a pump-syringe system into the already
formed core batch. In a 100 mL flask, solution A was prepared by
mixing 0.1 mmol of core material in OA/ODE solution, together with
equal parts of OA and ODE up to 20 mL of total volume. Solution B
was a mixture of 0.2 mmol shell precursors, 10 mL of OA and 10 mL
of ODE. Both solutions were stirred and degassed under vacuum at
110 °C for 30 min. Under Ar atmosphere, the temperature of solution
A was raised to 315 °C. Solution B was injected into solution A at a
1.5 mL/min injection rate. After completing the injection, the mixture
was kept at 315 °C for 30 min. Subsequent steps included cooling,
washing and storage, as already described.
Transfer of LiYbF4:Tm3+/LiYF4 UCNPs to Water. Oleate-
capped UCNPs were transferred to an aqueous environment via
phospholipid or poly(acrylic acid) (PAA; MW = 1800 g/mol; Sigma-
Aldrich) coating.3,60 For the phospholipid coating, 50 mg of UCNPs
were dispersed in 8 mL of chloroform (99.9%, Sigma-Aldrich)
together with 2.8 mg (1 μmol) of 1,2-dioleoyl-sn-glycero-3-
phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]
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Figure 1. (A) Size distribution, (B) TEM images, (C) XRPD, and (D) upconversion emission spectra (λex = 980 nm) of LiYF4:Tm3+ (0.5%), Yb3+
(25%) synthesized with different OM vol %. The size of the UCNPs decreases with increasing OM vol %, which directly translates to reduced
upconversion emission that is almost completely quenched for UCNPs around 5 nm (D inset). Upconversion spectra of the smallest UCNPs is
multiplied by a factor of 200 000 for clarity. Scale bar in the TEM images is 100 nm.

(PEG-DOPE) phospholipids (Avanti Polar Lipids, Inc., USA). The
content was continuously mixed, following chloroform evaporation at
45 °C under inert Ar atmosphere and the resulting dry film was
hydrated with 5 mL of distilled water. The mixture was sonicated at
65 °C for 60 min, and then successively passed through 0.45 and 0.2
μm filters to remove larger phospholipid and UCNP-phospholipid
structures. For the PAA coating, oleate molecules were first stripped
away from the surface of 50 mg of UCNPs according to a reported
ligand removal procedure.61 Then, a water dispersion of ligand-free
UCNPs (10 mL total) was mixed with 20 μL of PAA (200 mg/mL)
and 45 μL of NH4OH (2 M), and finally sonicated at room
temperature for 30 min. Subsequently, 40 mL of isopropanol was
added into the mixture and placed under magnetic stirring. PAA-
coated UCNPs were precipitated via centrifugation (5400 RCF for 20
min), and the obtained pellet was redispersed in 5 mL of distilled
water.
Structural and Morphological Characterization of UCNPs.
The crystal phase of the UCNPs was determined via X-ray powder
diode excitation (BTW, China). Laser power and power density were
435 mW and 346 W/cm2, respectively. The upconversion emission
was collected using a lens at a 90° angle from the excitation beam and
recorded with an Avaspec-ULS2048L spectrometer (Avantes, The
Netherlands). Stray light from the excitation source was removed with
a short-pass 825 nm filter (Newport Corp., USA). Upconversion
emission was corrected to the number of UCNPs per unit volume,
which varies for different sized UCNPs in the same m/v
concentration. The number of UCNPs was estimated considering
their crystalline phase, physical dimensions and material density
properties. Absorption measurements were performed with a Lambda
750 UV/Vis/NIR spectrometer (PerkinElmer, USA). Upconversion
photoluminescence lifetime measurements were performed on a
FLS980 (Edinburgh Instruments, UK) spectrometer equipped with a
double emission monochromator, single-photon counting photo-
multiplier (Hamamatsu R928, Japan), and a 1 W 980 nm pulsed laser
diode MDL-III-980 (CNI, China) with 70 μs pulse width and 100 Hz
repetition rate.

diffraction (XRPD) analysis on a Bruker D8 Advance Diffractometer
(Germany) using Cu Kα radiation. Rietveld refinements were
performed on the XRPD patterns of selected samples using Maud
software. The morphology and size distribution of the UCNPs were
further investigated by transmission electron microscopy (TEM) on a
Philips Tecnai 12 microscope (The Netherlands). The UCNPs’ size
was determined from TEM images using ImageJ software with sample
set size of at least 200 particles per sample.
Optical Characterization of UCNPs. Upconversion emission
spectra of 1 mg/mL hexane dispersions of oleate-capped UCNPs were
obtained at room temperature under 980 nm continuous-wave laser
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■
RESULTS AND DISCUSSION
Tuning UCNPs’ Size by OA/OM Ratio. The size and
shape of the UCNPs can be finely controlled by mixing two
coordinating ligands in the reaction mixture, namely OA and
OM.56,57 As can be inferred from Figure 1A and 1B, the size of
LiYF4:Tm3+, Yb3+ UCNPs can be tuned from 90 to 5 nm
substituting the volume of OA in the reaction solution by OM
from 0 to 50 vol %, respectively.
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Exclusively using OA as the ligand, the largest UCNPs were
formed with size of 91 × 55 nm along their respective major
and minor axes. Increasing the OM fraction from 0% to 30%,
the UCNP size can be decreased gradually down to 69 × 44
nm (12.5% OM) and 49 × 37 nm (30% OM), respectively,
still retaining the bipyramidal morphology. Instead, replacing
more than 40% of OA by OM, almost spherical UCNPs as
small as 5 nm are obtained. It is evident that greater volumes of
OM lead to the preparation of smaller UCNPs. A similar trend
of size change was obtained when UCNPs were synthesized via
the hot-injection approach (Figure S1A). Changes in the size
of the UCNPs correlated with the XRPD analysis in the case of
one-pot and hot-injection approaches (Figure 1C and Figure
S1B, respectively). The UCNPs have a tetragonal I41/a crystal
phase (PDF # 01−077−0816), as displayed in Figure 1C. The
crystallite size estimated from the Rietveld refinements of the
XRPD patterns follows the same trend observed for the
particle size from TEM micrographs (Table S2); however, the
smaller UCNPs (synthesized in the presence of 40% and 50%
of OM) display rather weak and broad reflections as expected
for UCNPs of this size, where the disorder/defects in the
crystal lattice are large. This made it impossible to reliably fit
the experimental data using the Rietveld approach.
Stemming from these observations, we propose the
following interpretation of the OA and OM role in the growth
of the UCNPs. The carboxylic group of OA can be
deprotonated, thus yielding metal-oleates upon interaction
with the RE3+ ions. This interaction is both electrostatic and
via the lone electron pairs featured by the oxygens of the
carboxylic group. In the case of OM, the ligand molecules can
interact with RE3+ only via the lone electron pair on the
nitrogen of the primary amine group. However, the amine
group of OM can be protonated, making the interaction with
the metal ions even less likely because of the electrostatic
repulsion. Clearly that implies that the interaction of OM with
RE3+ is weaker than the one of OA. Hence, the OM-RE adduct
is less stable than OA-RE and the decomposition rate of the
former adducts is expected to be higher than that of the latter.
Here, it is understood that OA and OM adducts with RE3+ are
indeed more complex species where the ligand molecules
dynamically enter the coordination sphere of the metal ions
along with trifluoroacetate anions. For the sake of the
discussion, we simply refer to OM- and OA-containing
adducts as OM-RE and OA-RE, respectively, but it is implied
that also trifluoroacetate molecules compose these UCNP
precursors. Overall, OM-RE are the nucleation-favoring species
that can quickly provide RE-F building blocks, while OA-RE
are growth-favoring species and act as a reservoir of precursors
that are more slowly consumed. Altogether, the unstable OM
coordination with metal-trifluoroacetates leads to an increased
nucleation rate and a faster depletion of the monomer
reservoir. Indeed, as observed from the thermal decomposition
results, continuous growth of the UCNPs and thus larger sizes
are obtained when OA constitutes the major part of the
reaction mixture. Instead, a higher number of nuclei are
formed in the case of 40 and 50% of OM, preventing further
growth of the UCNPs. Additionally, we have synthesized
UCNPs in the presence of 35% of OM, once again obtaining
well-shaped and relatively large UCNPs (42 × 34 nm; Figure
S2), supporting the fact that 40% of OM in the reaction
mixture is the critical point in balancing the nucleation and
growth process of UCNPs fostered by OM and OA,
respectively. Hence, more than 35% OM in the reaction
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mixture quickly induce the depletion of the metal adducts
reservoir, thus the formation of small nuclei. In these
conditions, the ripening and size increase for the first nuclei
formed is hindered due to the restrained availability of the OA
and corresponding OA-RE species. Indeed, observed tenden-
cies are analogous to those reported for sodium-based UCNPs,
when the alpha to beta phase transition is restricted by high
content of OM in the reaction.41
Upon 980 nm excitation of these UCNPs, multiple emission
peaks span the optical spectrum from UV to NIR (Figure 1D),
each corresponding to a specific energy transition process,
which requires absorption of several excitation photons to be
achieved.49 For example, 5 or 4 photons are necessary to excite
Tm3+ ions to then emit at 340 (1I6 → 3F4) and 360 nm (1D2 →
3
H6), respectively. While as few as 2 photons are required for
the 790 nm (3H4 → 3H6) NIR emission. The different sizes of
the UCNPs synthesized varying the volume fraction of OM
also correlate with their upconversion spectrum. Specifically,
the intensity of the upconversion photoluminescence under
980 nm excitation decreases with the reduction of the UCNPs’
size from 90 to 50 nm (along the major axis; Table S3).
Meanwhile sub-10 nm UCNPs, barely feature any upconver-
sion photoluminescence due to the high surface-to-volume
ratio that leads to a prominent surface defect, capping ligand
and solvent quenching. Moreover, for extremely small UCNPs,
higher order upconversion processes entailing more photons
are unlikely, thus NIR emission dominates with respect to the
UV one. However, intense UV emission is of great appeal for
various biomedicine related applications, e.g., for tumor
treatment.62,63 Therefore, the obtained sub-10 nm UCNPs
require further modification to improve their optical perform-
ance to be truly applicable in the biomedical sciences.
Stabilization of UCNPs. In order to alleviate the
shortcomings of the low intensity UV emission of small
UCNPs under NIR irradiation, we have investigated the
LiYbF4:Tm3+/LiYF4 core/shell architecture, which should
significantly foster the UV emission while allowing to preserve
the small size of the UCNPs. As it stands, the pure LiYbF4 host
compared to Yb3+-doped LiYF4 enhances the overall 980 nm
light harvesting, as more sensitizer ions are available to collect
the excitation energy and funnel it to the activator Tm3+
ions.51,64 Moreover, it has been proven that a preponderant
role in upconversion emission quenching is played by surface
defect states and vibrational modes of ligand and solvent
molecules, while the sensitizer concentration is a less influential
parameter.65,66 So, although initial works have indicated that
more than 25% of Yb3+ doping results in severe upconversion
emission quenching,49 recent studies demonstrated that, once
passivated by an inert shell, the cation sublattice of the UCNP
core can be composed entirely of the sensitizer (Yb3+) ions.51
Actually, the use of the so-called active-core/passive-shell type
UCNPs allows exploiting pure sensitizer-type hosts like
LiYbF4, thus simultaneously minimizing the surface quenching
and maximizing excitation light absorption, ultimately leading
to brighter upconversion emission. Ideally, growing thicker
shells ensures a higher emission intensity,65 but at the same
time increases the overall size of the UCNPs. Therefore, it is
desirable to be able to precisely optimize the photo-
luminescence vs size of UCNPs, tailoring them to the specific
applications sought after (e.g., biomedical and photochemical).
In order to synthesize ultrasmall active-core/passive-shell
UCNPs, LiYbF4:Tm3+ cores of 5.1 ± 0.6 nm were first
prepared following the hot-injection approach using an OA/
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Figure 2. TEM images following the size focusing process of (A) doped/undoped LiYbF4 and (A′) doped/undoped LiYF4 via OA/ODE injection
into the respective first nuclei. In the case of (A) the size of the UCNPs is focused right after the first OA/ODE injection, while (A′) indicates
slower rate of focusing requiring double injection; also the stabilized core sizes between the Y3+ and Yb3+-hosts differ greatly. (B) The size of doped
LiYbF4 or LiYF4’s first nuclei is maintained unchanged with OM/ODE injection, corroborating the necessity of the OA for self-size focusing. (C)
XRPD of first nuclei and stabilized cores. XRPD pattern color-coding corresponds to the samples’ colored scale bars in (A) and (A′). The more
pronounced and sharper reflections of stabilized core patterns follow the trends observed by TEM. Scale bar in the TEM images is 20 nm.

OM mixture composed of 50% OM. LiYF4 shell precursors
were then injected in the preformed cores to prompt shell
formation. In fact, we found that the shell growth was hardly
controllable if directly performed on the sub-5 nm cores.
Various approaches of shell precursor injection were system-
atically investigated, obtaining dissimilar core/shell structures:
(i) injecting the shell precursors dissolved in OA/OM/ODE
into cores dispersed in OA/OM/ODE, (ii) injecting shell
precursors dissolved in OA/ODE into cores dispersed in OA/
OM/ODE, (iii) injecting shell precursors dissolved in OA/
ODE into cores dissolved in OA/ODE. Ideally, the size of the
UCNPs after the shelling procedure can be estimated with the
assumption that the influence of cation intermixing at the
core/shell interface is negligible.67 The LiYbF4:Tm3+/LiYF4
core/shell size should be stoichiometrically correlated with the
material added as shown in Table S4. TEM images in Figure
S3 summarize the results of the aforementioned approaches,
revealing in fact that each of them leads to an uncontrolled
shell growth process, indicated by increased shell thickness not
correlated to the amount of shell precursors added. Details of
the comparison between actual size obtained with different
approaches and expected size are listed in Table S4, from
which it can be noted that the unexpected size increase seemed
to correlate to the amount of the OA present in the reaction
mixture. The uncontrolled growth of the particles was
observed immediately after the injection of shell precursors
dissolved in OA/ODE into core UCNPs also dispersed in an
OA/ODE mixture, while the same effect is noticeable only
after the second shell injection in the case of OA/OM/ODE
dispersed cores. Although uncontrolled shelling can still
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enhance the upconversion photoluminescence,50 it becomes
practically impossible to carefully optimize the photolumines-
cence vs size of UCNPs through the creation of multishell
nanostructures. Following our initial observations, we were
able to draw several pivotal conclusions. First, the presence of
OM inhibits the shell growth and fosters the appearance of a
secondary UCNP population alongside the original ultrasmall
structures of substantially unchanged size (Figure S3C).
Second, shell precursors dissolved in the presence of OA and
added to the different dispersions of ultrasmall UCNPs
promote their coarsening and coalescence, leading to drastic
size changes. It is also important to note that after an initial
sudden size increase, subsequent addition of shell precursors
results in more stoichiometrically correlated shell epitaxial
growth (Figure S3). Overall, we inferred that the sub-5 nm
cores obtained in the presence of high concentration of OM
are not thermodynamically stable and the injection of a ligand
with stronger coordinating capabilitylike OAcan induce
size focusing of the primary cores into slightly largerbut
thermodynamically stableUCNPs. Razgoniaeva et al. have
also reported a similar behavior for quantum dots, observing
that injecting pure coordinating ligands led to their size
focusing.68
In the following part of the core size stabilization study, we
refer to the synthesized ultrasmall UCNPs, formed in OA/OM
(v/v 1/1), as first nuclei, while the stabilization (annealing)
process was initiated by injection of fresh OA/ODE mixture
containing no precursor material. TEM images in Figure 2A
(from left to right) show the size focusing process of
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Figure 3. (A) Size distribution, (B) TEM images and (C) upconversion emission spectra (λex = 980 nm) of LiYbF4:Tm3+ (0.5%) core and
LiYbF4:Tm3+ (0.5%)/LiYF4 core/shell UCNPs with increasing shell thickness. As presented in (A) once the stable core of UCNPs is formed the
subsequent shell growth can be attained with high precision, as the size of the structures follows the numerical estimates. Multifold increase in the
upconversion emission (C) of UCNPs can be observed once the surface of the UCNPs is passivated with a 4−5 nm thick shell. (D) Enhancement
of the upconversion, due to the shelling of the LiYbF4:Tm3+ (0.5%) cores with LiYF4 is evident from decay time measurements of the 1I6 → 3F4
band around 347 nm. When comparing upconversion decay times of classical LiYF4:Tm3+ (0.5%), Yb3+ (25%) (∼91 × 55 nm in size) with core/
shell LiYbF4:Tm3+/LiYF4 (∼20 × 20 nm in size) UCNPs, it is apparent that both high (E, 1I6 → 3F4, 347 nm) and low (F, 3H4 → 3H6, 789 nm)
order upconversion emissions are more efficient in the latter structure. In (C), upconversion spectra of core/shell #1 UCNPs is multiplied by a
factor of 10 for clarity. Scale bar in TEM images is 50 nm.

LiYbF4:Tm3+ first nuclei by sequential injection of a pure OA/
ODE mixture in the reaction flask.
Initially, the first nuclei have an average diameter of 5.8 nm,
which is maintained even after 30 min at 315 °C in an OA/
OM/ODE reaction mixture of v/v/v 1/1/2. However, once
fresh OA/ODE v/v 1/1 mixture (10 mL in total; precursor-
free) is injected in the dispersion of first nuclei, their size
increases to 9.4 × 8.0 nm and a more noticeable bipyramidal
morphology can be observed, typical of larger LiREF4 crystals.
Consistently, the appearance of defined reflections in the
XRPD pattern of the stabilized cores (Figure 2C) confirms the
improved crystallinity and increased size compared to the first
nuclei. Most importantly, a second injection of 10 mL of OA/
ODE, which changes the OA/OM volume ratio from 2/1 to 3/
1, does not further influence the UCNPs’ size, indicating that a
stable configuration has been reached. We examined different
parameters of the OA-assisted LiYbF4:Tm3+ first nuclei
annealing, including extension of the annealing time from 1
to 3 h, reducing the first nuclei amount from 0.5 to 0.25 mmol,
dispersing the first nuclei in a fresh OA/ODE mixture as in the
case of one-pot synthesis, and varying the temperature of
annealing from 270 to 330 °C. All but one of the investigated
conditions led to the same final size (9.3−9.4 nm) of the
stabilized UCNPs (Figure S4). Conducting annealing at 270
°C, the particle size did not change and remained below 5 nm,
indicating that relatively low temperatures do not provide
enough energy to the system to overcome the energy barrier
for core annealing processes, i.e., ripening, to take place. To the
12895
best of our knowledge, these particles constitute the smallest
sub-10 nm pure-phase LiYbF4:Tm3+ UCNPs reported so far.
On the basis of these findings, we attempted to stabilize also
LiYF4:Tm3+, Yb3+ first nuclei by the same coarsening
procedure, i.e., injecting fresh OA/ODE mixture, results of
which are shown in Figure 2A′. In fact, following this approach
we obtained relatively large UCNPs (∼20 nm) along with a
fraction of smaller UCNP colony. Also, we were able to
stabilize the first nuclei only prolonging the annealing up to 3 h
and reducing the concentration of the first nuclei, which
ultimately led to a lesser residual fraction of smaller UCNPs.
(Figure S5). Additionally, as a control experiment, fresh OM/
ODE mixture was injected into LiYbF4:Tm3+ or LiYF4:Tm3+,
Yb3+ first nuclei dispersions and, as shown in Figure 2B, the
size of first nuclei in both cases remained unchanged, further
evidencing the necessity for a high affinity coordinating ligand
like OA.
In order to rationalize the discrepancies observed in the first
nuclei stabilization for the two materials, we applied the same
procedure on pure LiYF4 and LiYbF4 first nuclei. Figure 2A
and A′ shows the core stabilization process of LiYF4 and
LiYbF4 first nuclei, respectively. Similar to LiYF4:Tm3+, Yb3+,
pure LiYF4 first nuclei kept on growing prolonging the
annealing time (6, 17, 22 nm for 0, 1, 2 h of annealing,
respectively), while, as in the case of LiYbF4:Tm3+, pure
LiYbF4 reached a stable core size of 9.3 × 7.8 nm immediately,
without further size alteration. However, when LiYF4 first
nuclei were annealed using the one-pot method, no small
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Journal of the American Chemical Society
LiYF4 nanoparticles were observed; yet, unlike LiYbF4,
different sizes were obtained for different annealing conditions
(Figure S6). It can be inferred that LiYF4-based sub-10 nm
core is thermodynamically unstable. The larger size of the
LiYF4-based UCNPs can be attributed to the larger ionic
radius of Y3+ (r = 115.9 pm) compared with Yb3+ (r = 112.5
pm).45,46,69,70 Moreover, following the model proposed by
Wang et al., it is possible that the increase in the surface
electron charge density, provided here by Yb3+ ions, slows
down the diffusion of F− ions to the nanoparticle’s surface,
hence rendering the stabilized LiYbF4 UCNPs significantly
smaller in size than in the case of LiYF4. Thus, if ultrasmall and
bright UV emitting nanostructures are sought after, LiYbF4 is
intrinsically a better core host candidate in this context not
only due to increased sensitization of the upconversion
processes, but also due to the possibility to form particularly
small and stable UCNPs.
Altogether, we foresee that the proposed process of first
nuclei annealing in the presence of coordinating species
upon careful optimization of the reaction conditionscould
be more generally extended to the synthesis of small LiREF4
host nanostructures, as can be inferred by successful tests
conducted on LiLaF4, LiGdF4 and LiLuF4 particles (Figure
S7). Notably, the size of as synthesized LiREF4 (RE = La, Gd,
Yb) first nuclei increased with RE atomic number. However,
after annealing in the presence of OA, stabilized LiLuF4
displayed similar morphology and size compared with
LiYbF4, whereas stabilized LiGdF4 showed a morphology like
that of LiYF4. Ill-shaped LiLaF4 were observed even after
stabilization.
Passive-Shell vs Active-Shell. Eventually, after obtaining
stabilized LiYbF4:Tm3+ cores, active LiYbF4 or passive LiYF4
shells were epitaxially grown (Figure S8A). Injecting 0.2 mmol
of desired shell material in a dispersion of 0.1 mmol of
stabilized core material, the size of the UCNPs increased from
9 to 13 nm in either of the shell composition cases, allowing to
obtain well-defined active-core/passive-shell or active-core/
active-shell structures. As probed by spectral measurements,
the superiority of passive shell to suppress surface quenching
and significantly enhance upconversion emission holds in our
system too, as can be seen in Figure S8B. We compared the
optical performance of 1 mg/mL dispersions of LiYbF4:Tm3+
stabilized core, LiYbF4:Tm3+/LiYbF4 and LiYbF4:Tm3+/LiYF4
UCNPs under identical 980 nm laser irradiation conditions.
When an active-shell is grown on the stabilized cores,
LiYbF4:Tm3+/LiYbF4 structures show a 2-fold increase of
upconversion emission intensity compared to parent
LiYbF4:Tm3+ cores, primarily owing to the increased UCNP
size and the larger number of available sensitizer ions
associated with it. Nonetheless, since the possibility of energy
migration events to the surface is not effectively suppressed,
the overall upconversion emission intensity is low and NIR
emission at 800 nm is dominant. A completely contrasting
effect can be seen once the passive-shell is grown:
LiYbF4:Tm3+/LiYF4 UCNPs showed a more than three-
orders-of-magnitude increase of the absolute intensity
compared to stabilized LiYbF4:Tm3+ parent cores. Prom-
inently, the UV and blue upconversion emissions become
dominant in these structures. Hence, the passive-shell acting as
a barrier to limit energy loss to the surroundings allows to
funnel most of the Yb3+-gathered excitation energy to the Tm3+
ions, promoting higher order upconversion processes that are
otherwise clearly observed only in above-50 nm UCNPs.71,72
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Article
Super Bright Core/Shell. To optimize the emission
performance vs size for ultrasmall core/shell structures, we
grew passive-shells of different thicknesses on the stabilized
LiYbF4:Tm3+ cores (Figure 3A and B). Injecting 0.2, 0.4, and
0.8 mmol of shell precursors in 0.1 mmol of stabilized core
reaction mixtures resulted in the growth of 2, 4, and 5 nm-thick
shells. Subsequently, the UCNP size increased from 9.3 × 8.2
nm to 13.8 × 13.2 nm, 17.7 × 16.7 nm and 19.6 × 19.5 nm,
respectively. Importantly, the final size of core/shell structures
was consistent, within the 10% margin, with the size pre-
estimated based on the amount of precursors injected (Figure
3A). Pre-estimation calculations were carried out neglecting
cation intermixing at the core/shell interface and thus
assuming the shell density being the same as LiYF4, as
displayed in Table S5. The possibility of estimating a priori the
shell thickness based on the amount of precursors injected
proves the high degree of control that it is possible to exert
over these structures and that an elegant and precise design of
multishell architectures is achievable. As observed from the
comparison of the upconversion emission of different UCNPs
obtained with the proposed approach (Figure 3C), inevitably
as the thickness of the shell increases so does the absolute
upconversion emission intensity. As mentioned above, a shell
of 2 nm thickness increased the emission intensity to a degree
comparable to that of dispersions of 90 × 60 nm-sized
LiYF4:Tm3+, Yb3+ UCNPs at the same mass concentration.
Further increase of the shell thickness to 4 and 5 nm
enhanced the upconversion emission even more, surpassing
that of large LiYF4:Tm3+, Yb3+ UCNPs, as shown in Figure
S9A,B. Due to the relatively small change of upconversion
emission intensity between the 4 and 5 nm thick shells, we
believe that the latter thickness can be regarded as optimal to
achieve bright upconversion emission while keeping the small
size of these UCNPs, in line with recent observations made for
other UCNPs.65,66 Steady-state upconversion photolumines-
cence measurements were corroborated by the lifetime analysis
of the LiYbF4:Tm3+/LiYF4 core/shell nanoarchitectures
(Figure 3D). The lifetime of the 1I6 excited state (monitoring
the 1I6 → 3F4 transition at approximately 347 nm, following
980 nm excitation) increased drastically for the UCNPs with 2,
4, and 5 nm thick shells, indicating the suppression of
nonradiative decay pathways (surface, ligand, and solvent
related) responsible for the upconversion emission quenching.
Furthermore, the superiority of our LiYbF4:Tm3+/LiYF4
UCNPs (∼20 × 20 nm in size) compared to the classical
LiYF4:Tm3+, Yb3+ ones (∼91 × 55 nm in size) can be directly
inferred from the change of the UV−NIR upconversion
emission ratio (comparing integrated intensities of the 340 nm
band, 1I6 → 3F4 to that of the 800 nm one, 3H4 → 3H6) as
displayed in Figure S9A′,B′. Due to the different photon-order
of these transitions, the UV−NIR ratio typically increases with
increasing the power density of the laser excitation.
Remarkably, at each power density value studied,
LiYbF4:Tm3+/LiYF4 core/shell structure showed a much
higher UV−NIR ratio compared to large LiYF4:Tm3+, Yb3+
UCNPs. Even at relatively low power density (20 W/cm2) the
UV−NIR ratio for LiYbF4:Tm3+/LiYF4 was higher than that of
LiYF4:Tm3+, Yb3+ at 100 W/cm2. In fact, this ratio for
LiYbF4:Tm3+/LiYF4 UCNPs asymptotically tends to approach
unity, indicating that the 340 nm UV emission band can be
comparable in intensity to the NIR emission at 800 nm, and
thus that the five-photon upconversion process in this system
is as efficient as the two-photon one.73,74 Although both
DOI: 10.1021/jacs.8b07086
J. Am. Chem. Soc. 2018, 140, 12890−12899
Journal of the American Chemical Society
compared UCNPs show similar dynamics in the generation of
upconversion emission, as indicated by the power study plots
(Figure S10), the smaller core/shell LiYbF4:Tm3+/LiYF4
UCNPs can harvest more of the excitation energy due to the
high Yb3+ content per particle, and reduced scattering of the
excitation light, which is non-negligible for large LiYF4:Tm3+,
Yb3+ UCNPs (Figure S11). Importantly, addition of the
passive LiYF4 shell suppresses the above-mentioned non-
radiative de-excitation processes in the small LiYbF4:Tm3+/
LiYF4 UCNPs, hence both five-photon and two-photon
upconversion generated transitions in the UV and NIR
regions, stemming from the 1I6 and 3H4 excited states,
respectively, have longer emission lifetimes than those
originating from the classical LiYF4:Tm3+, Yb3+ UCNPs
(Figure 3E,F).
In addition, we have transferred our LiYbF4:Tm3+/LiYF4
UCNPs to water using either phospholipid or PAA coatings in
order to confirm the viability of these UCNPs to operate in the
aqueous milieu. In both cases, intense upconversion emissions
from UV to NIR could be observed (Figure S12A), which have
not significantly changed from day-to-day over a one-week
period (Figure S12B,C), alluding to the importance of the
passive LiYF4 shell and surface coatings (phospholipids, PAA
and etc.) to suppress possible ion diffusion from the UCNPs,
and their subsequent degradation and cytotoxicity.75
Overall, this evidence shows great improvement in our
understanding of UCNP fabrication and design, as structures
nearly five-times smaller than the commonly employed ones
could be fabricated with matching or even surpassing
upconversion performance. These results are of particular
interest in the context of biomedical applications, where the
aim is often to reduce the size of UCNPs while retaining the
capability to initiate secondary photochemical processes
through NIR generated UV upconversion emission.
■
CONCLUSIONS
We have successfully tuned the size of LiYF4:Tm3+, Yb3+
UCNPs from 90 to 5 nm by changing the ratio between two
coordinating ligands, namely OA and OM. In the process of
core/shell UCNPs synthesis, the obtained 5 nm particles were
found to be thermodynamically unstable. In the pursuit of
small and brightly UV-emitting UCNPs, instead, 5 nm
LiYbF4:Tm3+ particles were prepared and we unprecedentedly
demonstrated that annealing in the presence of OA leads to
their stabilization. With this annealing approach, stable sub-10
nm LiYbF4:Tm3+ cores were obtained, the smallest ever
reported UCNPs of this type. We also found that LiYF4-based
UCNPs could be stabilized but possessed larger particle size,
explaining the prior difficulties in successfully miniaturizing
LiYF4 host-based UCNPs. Moreover, considering the results
obtained for different LiREF4 nanoparticles, we anticipate that
this annealing procedure could be optimized and extended to a
variety of lithium-based host materials.
Eventually, an epitaxial crystal growth strategy was
repeatedly performed to create LiYbF4:Tm3+/LiYF4 core/
shell structures. In this way, we gained access to sub-20 nm
particles with greatly enhanced UV upconversion emission and
finely controlled size, two features that make these UCNPs
incredibly promising as photoactivators for biomedical and
photocatalysis applications.
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Article
■
*
ASSOCIATED CONTENT
S Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b07086.
Additional NP characterization data, size estimation
calculus and synthesis/annealing results of other LiREF4
NPs; including Tables S1−S6 and Figures S1−S12
(PDF)
■ AUTHOR INFORMATION
Corresponding Author
*vetrone@emt.inrs.ca
ORCID
Ting Cheng: 0000-0001-6088-5312
Riccardo Marin: 0000-0003-3270-892X
Artiom Skripka: 0000-0003-4060-4290
Fiorenzo Vetrone: 0000-0002-3222-3052
Author Contributions
†
T.C., R.M., and A.S. contributed equally.
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
F.V. acknowledges funding from the Natural Sciences and
Engineering Research Council (NSERC) of Canada through
the Discovery Grants program, the Discovery Accelerator
Supplement (DAS) award, and the Strategic Partnership
Grant. A.S. is grateful to the Fonds de Recherche du Québec
− Nature et technologies (FRQNT) for financial support in
the form of a scholarship for doctoral studies (Bourses de
doctorat en recherche). The authors thank Dr. Artu̅ras
Katelnikovas (Faculty of Chemistry and Geosciences, Vilnius
University, Lithuania) for assistance with the lifetime measure-
ments.
■
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