Small and Bright Lithium-Based Upconverting Nanoparticles - Journal

Subscriber access provided by Kaohsiung Medical University

Article

Small and Bright Lithium-Based Upconverting Nanoparticles Ting Cheng, Riccardo Marin, Artiom Skripka, and Fiorenzo Vetrone J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b07086 • Publication Date (Web): 14 Sep 2018 Downloaded from http://pubs.acs.org on September 14, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

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%. The size of the UCNPs decreases with increasing OM%, 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. 150x116mm (300 x 300 DPI)

ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 2. TEM images following the size focusing process of (A) doped/undoped LiYbF4 and (A’) doped/undoped LiYF4 via OA/ODE in-jection 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+ 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 colorcoding 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 TEM images is 20 nm. 150x93mm (300 x 300 DPI)


Page 2 of 14

Page 3 of 14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 3. (A) size distribution, (B) TEM images and (C) upconversion emission spectra (λex = 980 nm) of LiYbF4:Tm3+ (0.5%) core and Li-YbF4: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 in-crease 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 measure-ments of the 1I6 → 3F4 band around 347 nm. When comparing upconversion decay times of classical LiYF4:Tm3+ (0.5%), Yb3+ (25%) (~91 x 55 nm in size) with core/shell LiYbF4:Tm3+/LiYF4 (~20 x 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. 314x187mm (300 x 300 DPI)



Page 4 of 14

Small and Bright Lithium-Based Upconverting Nanoparticles Ting Cheng‡, Riccardo Marin‡, Artiom Skripka‡ and Fiorenzo Vetrone* Centre Énergie, Matériaux et Télécommunications, Institut National de la Recherche Scientifique, Université du Québec, Varennes, QC, J3X 1S2, Canada 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 penetration depth in tissues impedes the subcutaneous applicability of such radiation. On the contrary, near-infrared (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, being excitable by NIR irradiation and emitting UV light through the process of upconversion, effective NIR-toUV 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. Firstly, 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. Secondly, 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 nanomedicine,1-5 bioimaging,6-11 photovoltaics12-15 and sensing16-20 as they can absorb low-energy photons and emit higher-energy ones (an anti-Stokes process),21-22 thus converting 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 a single 980 nm irradiation.23 Emission from Yb3+/Tm3+-doped UCNPs renders UV light, which is energetic enough to initiate multiple photo-chemical processes, including photocleavage, 24-26 photoisomerization,27 and photocatalysis28 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 exhibiting 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 photoluminescence,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, studies on lithiumbased host matrices (LiREF4, RE = Y, Yb) have 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 lithiumbased 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 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 tradeoff. 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

1 ACS Paragon Plus Environment

Page 5 of 14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Following this seminal study, we have systematically investigated the possibility of controlling the size of lithium-based UCNPs by exploitation of OA and OM coordinating ligands, from 5 to 90 nm. 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 sub10 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 ºC until clear. The temperature was then lowered to 60 ºC 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 onepot49 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 ºC for 30 min. After back-filling the flask with Ar, the temperature of the solution was raised to 330 ºC gradually and was kept at this value for 1 h. Afterwards, 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 re-dispersed 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, solu-

tion A and B, were stirred and degassed under vacuum at 125 ºC for 30 min. Under Ar atmosphere, the temperature of solution A was raised to 330 ºC. Once solution A reached 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 down 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 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 ºC for 30 min. Under Ar atmosphere, the temperature of solution A was raised and maintained at 315 ºC 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:Ln3+/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 ºC for 30 min. Under Ar atmosphere, the temperature of solution A was raised to 315 ºC. 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 ºC for 30 min. Subsequent steps included cooling down, 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 polyacrylic acid (PAA; MW = 1,800 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-3phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (PEGDOPE) phospholipids (Avanti Polar Lipids, Inc., USA). The content was continuously mixed, following chloroform evaporation at 45 ºC under inert Ar atmosphere and the resulting dry film was hydrated with 5 mL of distilled water. The mixture was sonicated at 65 ºC for 60 min, and then successively passed through 0.45 µm 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 placed under magnetic stirring. PAA-coated UCNPs were precipitated via centrifugation (5,400 RCF for 20 min), and the obtained pellet was redisposed in 5 mL of distilled water. Structural and morphological characterization of UCNPs The crystal phase of the UCNPs was determined via X-ray powder 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 soft-



ware. 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 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 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 90º angle from the excitation beam and recorded with an Avaspec-ULS2048L spectrometer (Avantes, The Netherlands). Stray light from the excitation source was removed with 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. 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 (Perkin Elmer, USA). Upconversion photoluminescence lifetime measurements were performed on a FLS980 (Edinburgh Instruments, UK) spectrometer equipped with a double emission monochromator, single-photon counting photomultiplier (Hamamatsu R928, Japan), and a 1 W 980 nm pulsed laser diode MDL-III-980 (CNI, China) with 70µs pulse width and 100 Hz repetition rate.

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. Exclusively using OA as the ligand, the largest UCNPs were formed with size of 91 x 55 nm along their respective major and minor axis. Increasing the OM fraction from 0% to 30%, the UCNP size can be decreased gradually down to 69 x 44 nm (12.5% OM) and 49 x 37 nm (30% OM), respectively, still retaining the bi-pyramidal 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

Page 6 of 14

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 OARE 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 OARE, 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 relatively large UCNPs (42 x 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 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 tendencies 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 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 UCNPs’ size from 90 to 50 nm (along the major axis; Table S3). Meanwhile sub-10 nm UCNPs, barely feature any upconversion photoluminescence due to the high surface-to-volume ratio that leads to 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 treat-


Page 7 of 14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


ment.62-63 Therefore, the obtained sub-10 nm UCNPs require further modification to improve their optical performance 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 activecore/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.

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%. The size of the UCNPs decreases with increasing OM%, 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.

Therefore, it is desirable to be able to precisely optimize the photoluminescence 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 a OA/OM mixture composed by 50% of 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 con-

trollable if directly performed on the sub-5 nm cores. Various approaches of shell precursor injection were systematically 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 enhance the upconversion photoluminescence,50 it becomes practically impossible to carefully optimize the photoluminescence 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

Page 8 of 14

S3C). Second, shell precursors dissolved in a 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 LiYbF4:Tm3+ first nuclei by sequential injection of a pure OA/ODE mixture in the reaction flask.

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+ 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 TEM images is 20 nm.

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-


Page 9 of 14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


free) is injected in the dispersion of first nuclei, their size increases to 9.4 x 8.0 nm and a more noticeable bi-pyramidal 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 mmol to 0.25 mmol, immersing 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 best of our knowledge these particles constitute the smallest sub-10 nm pure-phase LiYbF4:Tm3+ UCNPs reported so far. Based on 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 x 7.8 nm immediately, without further size alteration. However, when LiYF4 first nuclei were annealed using the one-pot method, no small 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 candi-

date 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 alike 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 activecore/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 two-fold increase of upconversion emission intensity compared to parent LiYbF4:Tm3+ cores, primarily owing to the increased UCNP size and with it associated larger number of sensitizer ions available. 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. Prominently, 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 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 x 8.2 nm to 13.8 x 13.2 nm, 17.7 x 16.7 nm and 19.6 x 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 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 multi-shell architectures is achievable. As observed from the comparison of the upconversion emission of different

Page 10 of 14

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 x 60 nm-sized LiYF4:Tm3+, Yb3+ UCNPs at the same mass concentration.

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 x 55 nm in size) with core/shell LiYbF4:Tm3+/LiYF4 (~20 x 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.

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 and S9B. 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 photoluminescence 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 1 I6 → 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 x 20 nm in size) compared to the classical LiYF4:Tm3+, Yb3+ ones (~ 91x 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 - 1I6 → 3 F4 - band to that of 800 nm one - 3H4 → 3H6) as displayed in Figure S9A’ and S9B’. 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 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-


Page 11 of 14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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 oneweek 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-time 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 still retain the capability to initiate secondary photo-chemical processes through NIR generated UV upconversion emission.

CONCLUSIONS We have successfully tuned the size of LiYF4:Tm3+, Yb3+ UCNPs from 90 nm 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 nanostructures, we anticipate that this ripening 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.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. 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 * [email protected]

Author Contributions ‡

C.T., R.M. and A.S. contributed equally.

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT 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. Artūras Katelnikovas (Faculty of Chemistry and Geosciences, Vilnius University, Lithuania) for assistance with the lifetime measurements.

REFERENCES 1. Wang, C.; Cheng, L.; Liu, Z., Upconversion Nanoparticles for Photodynamic Therapy and Other Cancer Therapeutics. Theranostics 2013, 3 (5), 317-330. 2. Cheng, T.; O'Rorke, R.; Ortiz, R. F.; Tay, Y. Y.; Hemmer, E.; Vetrone, F.; Marks, R. S.; Steele, T. W. J., Self-Assembled Photoadditives in Polyester Films Allow Stop and Go Chemical Release. Acta Biomater. 2017, 54, 186-200. 3. Skripka, A.; Benayas, A.; Marin, R.; Canton, P.; Hemmer, E.; Vetrone, F., Double Rare-Earth Nanothermometer in Aqueous Media: Opening the Third Optical Transparency Window to Temperature Sensing. Nanoscale 2017, 9 (9), 3079-3085. 4. Jalani, G.; Naccache, R.; Rosenzweig, D. H.; Haglund, L.; Vetrone, F.; Cerruti, M., Photocleavable Hydrogel-Coated Upconverting Nanoparticles: A Multifunctional Theranostic Platform for NIR Imaging and On-Demand Macromolecular Delivery. J. Am. Chem. Soc. 2016, 138 (3), 1078-1083. 5. Chen, G.; Qiu, H.; Prasad, P. N.; Chen, X., Upconversion Nanoparticles: Design, Nanochemistry, and Applications in Theranostics. Chem. Rev. 2014, 114 (10), 5161-5214. 6. Chatterjee, D. K.; Rufaihah, A. J.; Zhang, Y., Upconversion Fluorescence Imaging of Cells and Small Animals Using Lanthanide Doped Nanocrystals. Biomaterials 2008, 29 (7), 937-943. 7. Wu, S.; Han, G.; Milliron, D. J.; Aloni, S.; Altoe, V.; Talapin, D. V.; Cohen, B. E.; Schuck, P. J., Non-Blinking and Photostable Upconverted Luminescence from Single LanthanideDoped Nanocrystals. Proc. Natl. Acad. Sci. U.S.A. 2009, 106 (27), 10917-10921. 8. Park, Y. I.; Kim, J. H.; Lee, K. T.; Jeon, K. S.; Na, H. B.; Yu, J. H.; Kim, H. M.; Lee, N.; Choi, S. H.; Baik, S. I.; Kim, H.; Park, S. P.; Park, B. J.; Kim, Y. W.; Lee, S. H.; Yoon, S. Y.; Song, I. C.; Moon, W. K.; Suh, Y. D.; Hyeon, T., Nonblinking and Nonbleaching Upconverting Nanoparticles as an Optical Imaging Nanoprobe and T1 Magnetic Resonance Imaging Contrast Agent. Adv. Mater. 2009, 21 (44), 4467-4471. 9. Hwan, N. S.; Mi, B. Y.; Il, P. Y.; Hyun, K. J.; Min, K. H.; Sig, C. J.; Taek, L. K.; Taeghwan, H.; Doug, S. Y., Long‐Term Real‐ Time Tracking of Lanthanide Ion Doped Upconverting Nanoparticles in Living Cells. Angew. Chem. Int. Ed. 2011, 50 (27), 6093-6097. 10. Nyk, M.; Kumar, R.; Ohulchanskyy, T. Y.; Bergey, E. J.; Prasad, P. N., High Contrast in Vitro and in Vivo Photoluminescence Bioimaging Using Near Infrared to Near Infrared Up-Conversion in Tm3+ and Yb3+ Doped Fluoride Nanophosphors. Nano Lett. 2008, 8 (11), 3834-3838. 11. Liu, Q.; Sun, Y.; Yang, T.; Feng, W.; Li, C.; Li, F., Sub-10 nm Hexagonal Lanthanide-Doped NaLuF4 Upconversion


8


Nanocrystals for Sensitive Bioimaging in Vivo. J. Am. Chem. Soc. 2011, 133 (43), 17122-17125. 12. Shang, Y.; Hao, S.; Yang, C.; Chen, G., Enhancing Solar Cell Efficiency Using Photon Upconversion Materials. Nanomaterials 2015, 5 (4), 1782-1809. 13. de Wild, J.; Meijerink, A.; Rath, J. K.; van Sark, W. G. J. H. M.; Schropp, R. E. I., Towards Upconversion for Amorphous Silicon Solar Cells. Sol. Energy Mater. Sol. Cells 2010, 94 (11), 1919-1922. 14. Shan, G. B.; Demopoulos, G. P., Near‐Infrared Sunlight Harvesting in Dye‐Sensitized Solar Cells via the Insertion of an Upconverter‐TiO2 Nanocomposite Layer. Adv. Mater. 2010, 22 (39), 4373-4377. 15. Yuan, C.; Chen, G.; Li, L.; Damasco, J. A.; Ning, Z.; Xing, H.; Zhang, T.; Sun, L.; Zeng, H.; Cartwright, A. N.; Prasad, P. N.; Ågren, H., Simultaneous Multiple Wavelength Upconversion in a Core–Shell Nanoparticle for Enhanced Near Infrared Light Harvesting in a Dye-Sensitized Solar Cell. ACS Appl. Mater. Interfaces 2014, 6 (20), 18018-18025. 16. Raj, J. G. J.; Quintanilla, M.; Mahmoud, K. A.; Ng, A.; Vetrone, F.; Zourob, M., Sensitive Detection of ssDNA Using an LRET-Based Upconverting Nanohybrid Material. ACS Appl. Mater. Interfaces 2015, 7 (33), 18257-18265. 17. Vetrone, F.; Naccache, R.; Zamarrón, A.; Juarranz de la Fuente, A.; Sanz-Rodríguez, F.; Martinez Maestro, L.; Martín Rodriguez, E.; Jaque, D.; García Solé, J.; Capobianco, J. A., Temperature Sensing Using Fluorescent Nanothermometers. ACS Nano 2010, 4 (6), 3254-3258. 18. Liu, Q.; Peng, J.; Sun, L.; Li, F., High-Efficiency Upconversion Luminescent Sensing and Bioimaging of Hg(II) by Chromophoric Ruthenium Complex-Assembled Nanophosphors. ACS Nano 2011, 5 (10), 8040-8048. 19. Zhang, J.; Li, B.; Zhang, L.; Jiang, H., An Optical Sensor for Cu(II) Detection with Upconverting Luminescent Nanoparticles as an Excitation Source. Chem. Commun. 2012, 48 (40), 4860-4862. 20. van de Rijke, F.; Zijlmans, H.; Li, S.; Vail, T.; Raap, A. K.; Niedbala, R. S.; Tanke, H. J., Up-Converting Phosphor Reporters for Nucleic Acid Microarrays. Nat. Biotechnol. 2001, 19, 273. 21. Auzel, F., Upconversion and Anti-Stokes Processes with f and d Ions in Solids. Chem. Rev. 2004, 104 (1), 139-174. 22. Zhu, X.; Su, Q.; Feng, W.; Li, F., Anti-Stokes Shift Luminescent Materials for Bio-Applications. Chem. Soc. Rev. 2017, 46 (4), 1025-1039. 23. Marin, R.; Labrador-Paéz, L.; Skripka, A.; Haro-González, P.; Benayas, A.; Canton, P.; Jaque, D.; Vetrone, F., Upconverting Nanoparticle to Quantum Dot Förster Resonance Energy Transfer: Increasing the Efficiency through Donor Design. ACS Photonics 2018. 24. Lin, Q.; Huang, Q.; Li, C.; Bao, C.; Liu, Z.; Li, F.; Zhu, L., Anticancer Drug Release from a Mesoporous Silica Based Nanophotocage Regulated by Either a One- or Two-Photon Process. J. Am. Chem. Soc. 2010, 132 (31), 10645-10647. 25. Mal, N. K.; Fujiwara, M.; Tanaka, Y., Photocontrolled Reversible Release of Guest Molecules from Coumarin-Modified Mesoporous Silica. Nature 2003, 421, 350. 26. Agasti, S. S.; Chompoosor, A.; You, C.-C.; Ghosh, P.; Kim, C. K.; Rotello, V. M., Photoregulated Release of Caged Anticancer Drugs from Gold Nanoparticles. J. Am. Chem. Soc. 2009, 131 (16), 5728-5729. 27. Ikeda, T.; Tsutsumi, O., Optical Switching and Image Storage by Means of Azobenzene Liquid-Crystal Films. Science 1995, 268 (5219), 1873-1875. 28. Katagiri, K.; Koumoto, K.; Iseya, S.; Sakai, M.; Matsuda, A.; Caruso, F., Tunable UV-Responsive Organic−Inorganic Hybrid Capsules. Chem. Mater. 2009, 21 (2), 195-197. 29. Ren, L.; Qi, X.; Liu, Y.; Huang, Z.; Wei, X.; Li, J.; Yang, L.; Zhong, J., Upconversion-P25-Graphene Composite as an Advanced Sunlight Driven Photocatalytic Hybrid Material. J. Mater. Chem. 2012, 22 (23), 11765-11771. 30. Cheng, T.; Ortiz, R. F.; Vedantham, K.; Naccache, R.; Vetrone, F.; Marks, R. S.; Steele, T. W. J., Tunable Chemical Release from Polyester Thin Film by Photocatalytic Zinc Oxide and Doped

Page 12 of 14

LiYF4 Upconverting Nanoparticles. Biomacromolecules 2015, 16 (1), 364-373. 31. Lv, R.; Yang, D.; Yang, P.; Xu, J.; He, F.; Gai, S.; Li, C.; Dai, Y.; Yang, G.; Lin, J., Integration of Upconversion Nanoparticles and Ultrathin Black Phosphorus for Efficient Photodynamic Theranostics under 808 nm Near-Infrared Light Irradiation. Chem. Mater. 2016, 28 (13), 4724-4734. 32. Hou, Z.; Zhang, Y.; Deng, K.; Chen, Y.; Li, X.; Deng, X.; Cheng, Z.; Lian, H.; Li, C.; Lin, J., UV-Emitting Upconversion-Based TiO2 Photosensitizing Nanoplatform: Near-Infrared Light Mediated in Vivo Photodynamic Therapy via Mitochondria-Involved Apoptosis Pathway. ACS Nano 2015, 9 (3), 2584-2599. 33. Guo, H.; Qian, H.; Idris, N. M.; Zhang, Y., Singlet Oxygen-Induced Apoptosis of Cancer Cells Using Upconversion Fluorescent Nanoparticles as a Carrier of Photosensitizer. Nanomedicine: NBM 2010, 6 (3), 486-495. 34. Sordillo, L. A.; Pu, Y.; Pratavieira, S.; Budansky, Y.; Alfano, R. R., Deep Optical Imaging of Tissue Using the Second and Third Near-Infrared Spectral Windows, J. Biomed. Opt. 2014; 19 (5), 056004. 35. Dong, N. N.; Pedroni, M.; Piccinelli, F.; Conti, G.; Sbarbati, A.; Ramírez Hernández, J. E.; Maestro, L. M.; Iglesias de la Cruz, M. C.; Sanz Rodriguez, F.; Juarranz, A.; Chen, F.; Vetrone, F.; Capobianco, J. A.; Solé, J. G.; Bettinelli, M.; Jaque, D.; Speghini, A., NIR-to-NIR Two-Photon Excited CaF2:Tm3+,Yb3+ Nanoparticles: Multifunctional Nanoprobes for Highly Penetrating Fluorescence BioImaging. ACS Nano 2011, 5 (11), 8665-8671. 36. Naczynski, D. J.; Tan, M. C.; Zevon, M.; Wall, B.; Kohl, J.; Kulesa, A.; Chen, S.; Roth, C. M.; Riman, R. E.; Moghe, P. V., Rare-Earth-Doped Biological Composites as in Vivo Shortwave Infrared Reporters. Nat. Commun. 2013, 4, 2199. 37. Skripka, A.; Marin, R.; Benayas, A.; Canton, P.; Hemmer, E.; Vetrone, F., Covering the Optical Spectrum through Collective Rrare-Earth Doping of NaGdF4 Nanoparticles: 806 and 980 nm Excitation Routes. Phys. Chem. Chem. Phys. 2017, 19 (19), 1182511834. 38. Guan, M.; Dong, H.; Ge, J.; Chen, D.; Sun, L.; Li, S.; Wang, C.; Yan, C.; Wang, P.; Shu, C., Multifunctional UpconversionNanoparticles-Trismethylpyridylporphyrin–Fullerene Nanocomposite: a Near-Infrared Light-Triggered Theranostic Platform for Imaging-Guided Photodynamic Therapy. NPG Asia Mater. 2015, 7, e205. 39. Lu, S.; Tu, D.; Hu, P.; Xu, J.; Li, R.; Wang, M.; Chen, Z.; Huang, M.; Chen, X., Multifunctional Nano‐Bioprobes Based on Rattle‐Structured Upconverting Luminescent Nanoparticles. Angew. Chem. Int. Ed. 2015, 54 (27), 7915-7919. 40. Huang, Y.; Skripka, A.; Labrador-Paez, L.; SanzRodriguez, F.; Haro-Gonzalez, P.; Jaque, D.; Rosei, F.; Vetrone, F., Upconverting Nanocomposites with Combined Photothermal and Photodynamic Effects. Nanoscale 2018, 10 (2), 791-799. 41. Mai, H. X.; Zhang, Y. W.; Si, R.; Yan, Z. G.; Sun, L. D.; You, L. P.; Yan, C. H., High-Quality Sodium Rare-Earth Fluoride Nanocrystals: Controlled Synthesis and Optical Properties. J. Am. Chem. Soc. 2006, 128 (19), 6426-6436. 42. Liu, C.; Gao, Z.; Zeng, J.; Hou, Y.; Fang, F.; Li, Y.; Qiao, R.; Shen, L.; Lei, H.; Yang, W.; Gao, M., Magnetic/Upconversion Fluorescent NaGdF4:Yb,Er Nanoparticle-Based Dual-Modal Molecular Probes for Imaging Tiny Tumors in Vivo. ACS Nano 2013, 7 (8), 7227-7240. 43. Dühnen, S.; Rinkel, T.; Haase, M., Size Control of Nearly Monodisperse β-NaGdF4 Particles Prepared from Small α-NaGdF4 Nanocrystals. Chem. Mater. 2015, 27 (11), 4033-4039. 44. Wang, J.; Song, H.; Xu, W.; Dong, B.; Xu, S.; Chen, B.; Yu, W.; Zhang, S., Phase Transition, Size Control and Color Tuning of NaREF4:Yb3+, Er3+ (RE = Y, Lu) Nanocrystals. Nanoscale 2013, 5 (8), 3412-3420. 45. Wang, F.; Han, Y.; Lim, C. S.; Lu, Y.; Wang, J.; Xu, J.; Chen, H.; Zhang, C.; Hong, M.; Liu, X., Simultaneous Phase and Size Control of Upconversion Nanocrystals through Lanthanide Doping. Nature 2010, 463, 1061.


9

Page 13 of 14 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


46. Huang, X., Tuning the Size and Upconversion Luminescence of NaYbF4:Er3+/Tm3+ Nanoparticles through Y3+ or Gd3+ Doping. Opt. Mater. Express 2016, 6 (7), 2165-2176. 47. Johnson, N. J. J.; Oakden, W.; Stanisz, G. J.; Scott Prosser, R.; van Veggel, F. C. J. M., Size-Tunable, Ultrasmall NaGdF4 Nanoparticles: Insights into Their T1 MRI Contrast Enhancement. Chem. Mater. 2011, 23 (16), 3714-3722. 48. Naccache, R.; Yu, Q.; Capobianco, J. A., The Fluoride Host: Nucleation, Growth, and Upconversion of Lanthanide‐Doped Nanoparticles. Adv. Opt. Mater. 2015, 3 (4), 482-509. 49. Mahalingam, V.; Vetrone, F.; Naccache, R.; Speghini, A.; Capobianco, J. A., Colloidal Tm3+/Yb3+‐Doped LiYF4 Nanocrystals: Multiple Luminescence Spanning the UV to NIR Regions via Low‐ Energy Excitation. Adv. Mater. 2009, 21 (40), 4025-4028. 50. Hong, A. R.; Kim, S. Y.; Cho, S. H.; Lee, K.; Jang, H. S., Facile Synthesis of Multicolor Tunable Ultrasmall LiYF4: Yb, Tm, Er/LiGdF4 Core/Shell Upconversion Nanophosphors with Sub-10 nm Size. Dyes Pigm. 2017, 139, 831-838. 51. Zou, Q.; Huang, P.; Zheng, W.; You, W.; Li, R.; Tu, D.; Xu, J.; Chen, X., Cooperative and Non-Cooperative Sensitization Upconversion in Lanthanide-Doped LiYbF4 Nanoparticles. Nanoscale 2017, 9 (19), 6521-6528. 52. Wang, J.; Wang, F.; Xu, J.; Wang, Y.; Liu, Y.; Chen, X.; Chen, H.; Liu, X., Lanthanide-Doped LiYF4 Nanoparticles: Synthesis and Multicolor Upconversion Tuning. C. R. Chim. 2010, 13 (6), 731736. 53. Xue, X.; Uechi, S.; Tiwari, R. N.; Duan, Z.; Liao, M.; Yoshimura, M.; Suzuki, T.; Ohishi, Y., Size-Dependent Upconversion Luminescence and Quenching Mechanism of LiYF4: Er3+/Yb3+ Nanocrystals with Oleate Ligand Adsorbed. Opt. Mater. Express 2013, 3 (7), 989-999. 54. Barua, S.; Mitragotri, S., Challenges associated with penetration of nanoparticles across cell and tissue barriers: A review of current status and future prospects. Nano Today 2014, 9 (2), 223243. 55. Shun, Y. G.; Moog, C. G., Synthesis of Hexagonal‐Phase NaYF4:Yb,Er and NaYF4:Yb,Tm Nanocrystals with Efficient Up‐ Conversion Fluorescence. Adv. Funct. Mater. 2006, 16 (18), 23242329. 56. Bu, W.; Chen, Z.; Chen, F.; Shi, J., Oleic Acid/Oleylamine Cooperative-Controlled Crystallization Mechanism for Monodisperse Tetragonal Bipyramid NaLa(MoO4)2 Nanocrystals. J. Phys. Chem. C 2009, 113 (28), 12176-12185. 57. Xu, Z.; Shen, C.; Hou, Y.; Gao, H.; Sun, S., Oleylamine as Both Reducing Agent and Stabilizer in a Facile Synthesis of Magnetite Nanoparticles. Chem. Mater. 2009, 21 (9), 1778-1780. 58. Mourdikoudis, S.; Liz-Marzán, L. M., Oleylamine in Nanoparticle Synthesis. Chem. Mater. 2013, 25 (9), 1465-1476. 59. Boyer, J.-C.; Vetrone, F.; Cuccia, L. A.; Capobianco, J. A., Synthesis of Colloidal Upconverting NaYF4 Nanocrystals Doped with Er3+, Yb3+ and Tm3+, Yb3+ via Thermal Decomposition of Lanthanide Trifluoroacetate Precursors. J. Am. Chem. Soc. 2006, 128 (23), 74447445. 60. Liu, B.; Li, C.; Xie, Z.; Hou, Z.; Cheng, Z.; Jin, D.; Lin, J., 808 nm photocontrolled UCL imaging guided chemo/photothermal synergistic therapy with single UCNPs-CuS@PAA nanocomposite. Dalton Trans. 2016, 45 (33), 13061-9. 61. Bogdan, N.; Vetrone, F.; Ozin, G. A.; Capobianco, J. A., Synthesis of ligand-free colloidally stable water dispersible brightly

luminescent lanthanide-doped upconverting nanoparticles. Nano Lett. 2011, 11 (2), 835-40. 62. Chauhan, V. P.; Stylianopoulos, T.; Martin, J. D.; Popović, Z.; Chen, O.; Kamoun, W. S.; Bawendi, M. G.; Fukumura, D.; Jain, R. K., Normalization of Tumour Blood Vessels Improves the Delivery of Nanomedicines in a Size-Dependent Manner. Nat. Nanotech. 2012, 7 (6), 383-388. 63. Hoshyar, N.; Gray, S.; Han, H.; Bao, G., The Effect of Nanoparticle Size on in Vivo Pharmacokinetics and Cellular Interaction. Nanomedicine 2016, 11 (6), 673-692. 64. Kale, V.; Lastusaari, M.; Hölsä, J.; Soukka, T., Intense UV Upconversion through Highly Sensitized NaRF4: Tm (R: Y, Yb) Crystals. RSC Adv. 2015, 5 (45), 35858-35865. 65. Johnson, N. J.; He, S.; Diao, S.; Chan, E. M.; Dai, H.; Almutairi, A., Direct evidence for coupled surface and concentration quenching dynamics in lanthanide-doped nanocrystals. J. Am. Chem. Soc. 2017, 139 (8), 3275-3282. 66. Würth, C.; Fischer, S.; Grauel, B.; Alivisatos, A. P.; ReschGenger, U., Quantum Yields, Surface Quenching, and Passivation Efficiency for Ultrasmall Core/Shell Upconverting Nanoparticles. J. Am. Chem. Soc. 2018, 140 (14), 4922-4928. 67. Hudry, D.; Busko, D.; Popescu, R.; Gerthsen, D.; Abeykoon, A. M.; Kübel, C.; Bergfeldt, T.; Richards, B. S., Direct Evidence of Significant Cation Intermixing in Upconverting Core@ Shell Nanocrystals: Toward a New Crystallochemical Model. Chem. Mater. 2017, 29 (21), 9238-9246. 68. Razgoniaeva, N.; Yang, M.; Garrett, P.; Kholmicheva, N.; Moroz, P.; Eckard, H.; Royo Romero, L.; Porotnikov, D.; Khon, D.; Zamkov, M., Just Add Ligands: Self-Sustained Size Focusing of Colloidal Semiconductor Nanocrystals. Chem. Mater. 2018. 69. Damasco, J. A.; Chen, G.; Shao, W.; Ågren, H.; Huang, H.; Song, W.; Lovell, J. F.; Prasad, P. N., Size-Tunable and Monodisperse Tm3+/Gd3+-Doped Hexagonal NaYbF4 Nanoparticles with Engineered Efficient Near Infrared-to-Near Infrared Upconversion for in Vivo Imaging. ACS Appl. Mater. Interfaces 2014, 6 (16), 13884-13893. 70. Du, Y. P.; Zhang, Y. W.; Sun, L. D.; Yan, C. H., Optically Active Uniform Potassium and Lithium Rare Earth Fluoride Nanocrystals Derived from Metal Trifluroacetate Precursors. Dalton Trans. 2009, (40), 8574-8581. 71. Johnson, N. J. J.; van Veggel, F. C. J. M., LanthanideBased Heteroepitaxial Core–Shell Nanostructures: Compressive versus Tensile Strain Asymmetry. ACS Nano 2014, 8 (10), 1051710527. 72. Hai, G.; Zhengquan, L.; Haisheng, Q.; Yong, H.; Idris Niagara, M., Seed-Mediated Synthesis of NaYF4 :Yb, Er / NaGdF4 Nanocrystals with Improved Upconversion Fluorescence and MR Relaxivity. Nanotechnology 2010, 21 (12), 125602. 73. Yin, A.; Zhang, Y.; Sun, L.; Yan, C., Colloidal Synthesis and Blue Based Multicolor Upconversion Emissions of Size and Composition Controlled Monodisperse Hexagonal NaYF4 : Yb,Tm Nanocrystals. Nanoscale 2010, 2 (6), 953-959. 74. Zhao, J.; Jin, D.; Schartner, E. P.; Lu, Y.; Liu, Y.; Zvyagin, A. V.; Zhang, L.; Dawes, J. M.; Xi, P.; Piper, J. A.; Goldys, E. M.; Monro, T. M., Single-Nanocrystal Sensitivity Achieved by Enhanced Upconversion Luminescence. Nat. Nanotech. 2013, 8, 729. 75. Wang, Y. F.; Sun, L. D.; Xiao, J. W.; Feng, W.; Zhou, J. C.; Shen, J.; Yan, C. H., Rare-Earth Nanoparticles with Enhanced Upconversion Emission and Suppressed Rare-Earth-Ion Leakage. Chemistry 2012, 18 (18), 5558-64.


10


Page 14 of 14

Table of Contents artwork


11

Small and Bright Lithium-Based Upconverting Nanoparticles - Journal

Recommend Documents