Optically Detected Degradation of NaYF4:Yb,Tm-Based Upconversion

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Optically Detected Degradation of NaYF4: Yb, Tm Based Upconversion Nanoparticles in Phosphate Buffered Saline Solution Olivija Plohl, Marco Kraft, Janez Kovac, Blaž Belec, Maja PonikvarSvet, Christian Würth, Darja Lisjak, and Ute Resch-Genger Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.6b03907 • Publication Date (Web): 19 Dec 2016 Downloaded from http://pubs.acs.org on December 21, 2016

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Optically Detected Degradation of NaYF4: Yb, Tm Based Upconversion Nanoparticles in Phosphate Buffered Saline Solution Olivija Plohl,a b ‡ Marco Kraft, c ‡ Janez Kovač, a Blaž Belec, a b Maja Ponikvar-Svet, a Christian Würth, c Darja Lisjak, a* and Ute Resch-Genger c * a

Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia.

b

Jožef Stefan International Postgraduate School, Jamova 39, SI-1000 Ljubljana, Slovenia

c

Federal Institute of Materials Research and Testing (BAM), Division 1.10 Biophotonics, 12489

Berlin, Germany

ABSTRACT: In a proof-of-concept study, we assessed different analytical and spectroscopic parameters for stability screening of differently sized β-NaYF4: 20 mol % Yb3+, 2 mol % Tm3+ upconversion nanoparticles (UCNPs) exemplarily in the bioanalytically relevant buffer phosphate buffered saline (PBS; pH 7.4) at 37 and 50 ° C. This included the potentiometric determination of the amount of released fluoride ions, surface analysis with X-ray photoelectron spectroscopy (XPS), and steady state and time-resolved fluorescence measurements. Based upon these results, the luminescence lifetime of the 800 nm upconversion emission was identified as optimum parameter for stability screening of UCNPs and changes in particle surface chemistry.

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Introduction Luminescent upconversion nanoparticles (UCNPs), especially fluorides, have received a vivid interest due to their fascinating optical properties, making them suitable reporters for diagnostic assays 1, 2, 3 as well as for optical 4, 5 and multimodal imaging, 6, 7, 8 and chemical sensing. 9, 10 Among the many advantages of this emerging class of fluorophores are near infrared (NIR) excitation, minimizing autofluorescence in complex biological media and providing a large penetration depth in tissue, emission of a multitude of sharp emission lines in the ultraviolet (UV), visible (vis), and NIR as well as long luminescence lifetimes. 11, 12, 13, 14 Moreover, typically also a very high photochemical and thermal stability and a chemical inertness are claimed. Although the solubility products (Ksp) of binary lanthanide (Ln) fluorides in water are very low (e.g., for LaF3: Ksp = 3.26∙10-21 at 25 ° C) and increase with increasing atomic number of the Ln ion, 15 the solubility (rate) of nanoparticles can be, however, higher than that of the bulk material due to their larger surface-to-volume ratio (SA/Vol). 16 In addition, the solubility can be affected by pH and the presence of other chemical species like certain anions or ligands, which can form complexes with Ln3+, thereby favoring a dissolution process. 17, 18 Even though studies on a potential leakage of Ln3+ and/or fluoride anions (F–) from fluoride-based Ln-UCNPs in water or in physiological media are still rare, some of them already raised concerns about a potential cyto(toxicity) of UCNPs. 19, 20, 21, 22 This is related to the fact that F– can induce oxidative stress, modulate intracellular redox homeostasis, cause apoptosis, and alter gene expression. 23 One example suggesting the partial dissolution of UCNPs like -NaYF4, LaF3 and GdF3, co-doped with Yb3+ and Tm3+ in water at room temperature (RT) was only recently reported by us. 24 Another recent example presents a stability study of commercial β-NaYF4: Yb3+, Er3+ particles in acidic cellular compartments and simulated lysosomal fluid, revealing


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deposition of amorphous YPO4 on the particle surface which can introduce pro-inflammatory effects in cells. 25 These observations and the concomitant need to perform screening studies of UCNP stability in different environments encouraged us to search for parameters, which respond very sensitively to changes in particle surface and SA/Vol and are easily and quickly accessible as a prerequisite for the straightforward long-term control and monitoring of this application-relevant key parameter. Of particular use can be here the photoluminescence properties of UCNPs that are affected by the crystal field encountered by the Ln ions and UCNP surface chemistry. 12, 26, 27 For example, upconversion (UC) luminescence spectra and efficiencies are known to be size- and environment/matrix-dependent 7, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 and only recently, Yb3+ luminescence lifetimes have been utilized to determine the amount of water in organic solvents. 39

Moreover, compared to many other analytical techniques, luminescence measurements are

very fast and can be principally performed with rather simple and inexpensive instrumentation, even in the case of UC luminescence, and provide a unique sensitivity enabling the detection of single molecules. In order to identify suitable optical screening parameters, we performed a first proof-of-concept study of exemplarily chosen β-NaYF4: 20 mol. % Yb3+, 2 mol. % Tm3+ nanoparticles of two different sizes stored in the common bioanalytical buffer phosphate buffered saline (PBS) at pH 7.4 for two days at 37 and 50 ° C, using potentiometry, X-Ray photoelectron spectroscopy (XPS), and steady state and time resolved luminescence spectroscopy for the monitoring of changes in surface composition and a possible particle dissolution. A quantification of changes in surface chemistry from luminescence measurements, although tempting, was beyond the scope of this study. With our results, we were able to demonstrate the general need to perform systematic stability studies with UCNPs. In addition,


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we could underline particularly the potential of Tm3+ lifetimes for stability monitoring and screening of these materials. The knowledge of material stability is crucial for future applications of UCNPs e.g., as biosensing and bioimaging studies. 40, 41, 42

Experimental Methods Chemicals. All reagents were used as received without further purification. LnCl3∙(nH2O) (Ln = Y (99.99 %), Yb (99.9 %), Tm (99.9 %)), NH4F (98 %), oleic acid (OA, 90 %), chloroform, 1octadecene (ODE, 90 %), and phosphate buffered saline (PBS, 10x, pH = 6.8 with molar concentrations of Na2HPO4 : KH2PO4 : NaCl : KCl of about 1.0 : 0.18 : 1.4 : 0.27) were purchased from Alfa Aesar. The PBS stock solution was diluted 8.5-times to adjust the pH to 7.4. NaOH (≥ 99 %), and methanol were purchased from Merck, and ethanol (≥ 99.9 %), acetone (99.8 %), and cyclohexane (> 95 %) from CarloErba Reagents. Hydrochloric acid (HCl) and diethyl ether (DE) (99.5 %) were obtained from Applichem. All experiments were performed with UCNPs dispersed in deionized water except for the optical measurements, where milliQ water was used. In order to ensure a proper stoichiometry of the products, prior to use, the Ln3+ content of the reagents used for UCNP synthesis was determined using optical emission spectroscopy with inductively coupled plasma (ICP-OES; instrument Agilent 720). Preparation of UCNPs. In order to prevent previous contact of our UCNPs with water, a modified synthesis of β-NaYF4 nanoparticles, co-doped with 20 mol. % Yb3+ and 2 mol. % Tm3+ 43

was used. 12 mL of OA and 30 mL of ODE were added to a total amount of 2 mmol of

lanthanide chlorides (in stoichiometric ratio of Y : Yb : Tm = 0.78 : 0.20 : 0.02) in a 100 mL flask. The solution was heated to 156 ° C for 30 min to form a yellow transparent solution, cooled to 70 ° C, and a solution of NH4F (8 mmol) and NaOH (5 mmol), dissolved in 10 mL of


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methanol, was added slowly. Subsequently, the reaction mixture turned turbid. The reaction mixture was stirred at 50 ° C for 40 min, and methanol was removed by evaporation. Then, the solution was heated to 300 ° C under argon (Ar) atmosphere for 1.5 h and cooled to RT. The UCNPs were precipitated by addition of acetone, collected after centrifugation (at 5000 rpm for 5 min), washed with ethanol to remove the excess of OA and deionized water to remove NaCl, and finally redispersed in cyclohexane or chloroform. Oleate-capped UCNPs were transferred from cyclohexane or chloroform into water with a modified ligand-free phase transfer protocol. 44 For this purpose, the dried UCNPs were immersed in 0.1 M HCl (10 mL, pH = 1) and the mixture was sonicated in an ultrasound bath for about 3 h while maintaining a pH of 1 by adding 0.1 M HCl every 30 min. Subsequently, the aqueous solution was mixed with DE to extract OA. The procedure was repeated several times until the solution turned transparent. After precipitation with acetone, the ligand-free, bare UCNPs were recovered by centrifugation at 5000 rpm for 5 min and washed with water. UCNPs were collected from water by ultracentrifugation (10000 rpm, 5 min) and dried at 70 ° C for 3 h. Dissolution studies. Aging studies of bare (ligand-free) UCNPs with sizes of 24, 25, and 36 nm were conducted in PBS (pH 7.4) at 37 or 50 ° C for 2 days using a defined particle concentration (1.4 mg/mL). Then, the aged UCNPs were removed from PBS by centrifugation (5000 rpm for 5 min) and the supernatant was ultrafiltrated (filter MW 30kDa) to eliminate any remaining UCNPs from the PBS solution. The collected aged UCNPs were dried, washed with water to remove traces of salts potentially remaining from PBS, separated from the washing water by centrifugation, and dried again. For optical measurements, the samples were dispersed in milliQ water (see Table 1).


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Analytical characterization. The crystal structure of as-synthesized UCNPs was verified by Xray diffraction (XRD; X-ray diffractometer Philips X’Pert PRO MPD Diffractometer, PANanalytical with CuKα radiation, λCuKα1 = 1.5406 Å). The morphology of the UCNPs was examined with a transmission electron microscope (TEM, Jeol 2100) and their crystal structure was confirmed with selected area electron diffraction (SAED). TEM samples were prepared by dropping a diluted dispersion of UCNPs onto a copper grid, followed by solvent evaporation. The size of the UCNPs (given as diameter distribution) was determined from about 150 UCNPs per sample using the Gatan Digital Micrograph Software. For the determination of the elemental composition of the UCNPs, energy dispersive X-ray spectroscopy (EDXS) was performed during TEM analysis. The concentration of dissolved F–, used as a measure of UCNP dissolution, was determined potentiometrically in the filtrates (supernatants) of the aged samples. These measurements were done with an Orion 960 Autochemistry System with a temperature sensor and a combined fluoride ion selective electrode (Thermo, Orion model 96-09). For F– quantification, we used the multiple addition method 45 and performed at least three independent measurements per sample. Surface analysis. The surface chemistry of fresh and aged UCNPs was analyzed with X-ray photoelectron spectroscopy (XPS) using a PHI-TFA XPS spectrometer from Physical Electronics Inc. equipped with a monochromatic Al source as X-ray excitation source (photon energy of 1486.6 eV). The diameter of the analyzed area was 0.4 mm and the information depth about 3 to 5 nm, respectively. The surface composition was quantified from XPS peak intensities employing the simple model of homogeneous solids and taking into account relative sensitivity factors provided by the instrument manufacturer. 46 Peaks of Na 1s, F 1s, O 1s, Y 3d, C 1s, Yb 4d, and P 2p were used to calculate the average surface composition of the as-synthesized and


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aged UCNPs that were always measured in duplicate. The relative standard deviation of the species concentration is estimated to be about 10 %. Optical properties. For optical measurements, the 24 and 36 nm-sized as-synthesized and aged samples were dispersed in milliQ water, using always the same concentration of solid material in the unaged and aged samples (c = 1.4 mg/ml). Luminescence decay measurements were carried out with an Edinburgh Instruments spectrofluorometer FSP-920 equipped with a μ-flash lamp 920H (pulse width of 3 μs; xenon lamp as excitation light) in the case of the downconversion (DC) luminescence (directly excited, Stokes shifted emission). UC emission spectra were recorded on spectrofluorometer FSP-920 using a 1 W 980 nm laser diode for sample excitation. For measurements of the lifetimes of the multiphotonic UC luminescence, an Edinburgh Instruments spectrofluorometer FLS980-xD2-stm equipped with an electrically pulsed 8 W 978 nm laser diode (long square pulses, pulse width of 400 µs) was used. The decay kinetics were recorded at different emission wavelengths with red sensitive PMTs (R2658P for DC and H10720-20 for UC luminescence) from Hamamatsu using the time correlated single photon counting (TCSPC) technique. The decay curves of the UC and DC luminescence were used as obtained without consideration of the instrument response function (no unfolding of the instrument response function done). For data analysis, the decay curves were normalized to one after the excitation pulse and integrated. All measurements were performed at the same excitation power density to prevent an influence of this parameter on measured luminescence spectra and decay kinetics/lifetimes. 27 In order to cover the period of time required for the performance of all luminescence measurements with the differently sized and aged UCNP samples, which resulted in the storage of the respective UCNPs in milliQ water for maximum 10 days, we performed also aging studies in this matrix as control experiments (see Results and


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discussion, section Luminescence decay behavior). Lifetime measurements with freshly prepared 36 nm-sized unaged samples and the corresponding samples stored in milliQ water for 10 days revealed closely matching decay curves, thereby confirming that sample storage in water barely affects the decay behavior.

Results and discussion UCNP dissolution and surface analysis

Figure 1. A) TEM image of exemplarily chosen 25 nm-sized aged UCNPs with the corresponding SAED and an amorphous solid side product (marked with arrows) and B) EDXS spectrum of the side product. Y-L and P-K peaks overlap (at around 2 keV), which can be seen in the inset. The additional Y-K peak at around 15 keV confirms the presence of Y, while the presence of Yb follows from the Yb-M peaks (0.5 and 1.0 keV). The Cu and C peaks originate from the TEM supporting grid. The solid side product (A) showed no distinct SAED, revealing its amorphous nature. Higher magnification TEM image C) shows UCNPs coated with an amorphous layer. Aging and dissolution studies. Prior to the aging studies, we characterized the key properties of all as-synthesized UCNPs. The hexagonal structure and phase purity of the as-synthesized UCNPs were confirmed by XRD analysis (see characterization in the SI, Figure S1). TEM data


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revealed the homogeneous size of the UCNPs. Particle size varied slightly among different batches (Table 1). Exemplarily, TEM images and particle-size distributions of the two UCNP batches with sizes of 24 and 36 nm are shown in SI, Figure S2. The as-synthesized 25 nm-sized UCNPs (Table 1) differ only very slightly from the 24 nm sized UCNP sample (see Figure 1). Potentiometric analysis of the supernatants of the UCNP samples aged at two different temperatures summarized in Table 1 demonstrated that all samples underwent a significant degree of dissolution with molar fractions of dissolved F per total F content relating to the nominal composition, NaY0.78Yb0.20Tm0.02F4 (XF; see x values in the equations given Scheme 1) amounting to values between 10 and 30 mol. %, respectively. Expectedly, a higher aging temperature and a smaller particle size, and hence, a larger SA/Vol, favored F release as indicated by the larger XF values. In particular, the 25 nm-sized UCNPs are more prone to dissolution (larger XF value) than the 36 nm UCNPs at 37 ° C; moreover, the 24 nm-sized UCNPs dissolve more strongly at 50 ° C than the comparable batch of 25 nm-sized UCNPs stored at 37 ° C. This behavior agrees very well with results from previously performed aging studies of hexagonal UCNPs with temperature and size. 47 Control experiments with 36 nm-sized UCNPs aged in water at RT for 10 days, performed to justify sample storage in water as done in the case of the spectroscopically studied samples, see Experimental (section Optical studies), revealed only minor dissolution (XF  2 mol. %). This was confirmed by the studies of UCNPs, stored in water after aging in PBS, yielding XF values that exceeded those of the aged samples only by about 2 mol. %. Table 1. Fluoride release obtained for three batches of differently sized UCNPs aged at different temperatures, and molar fraction XF of dissolved F per total F in NaY0,.78Yb0.20Tm0.02F4.


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Particle size

Aging conditions

XF (mol. %)

(36 ± 1) nm

PBS, 2 days, 37 °C

(9.90 ± 0.02)

PBS, 2 days, 37 °C +

(11.88 ± 0.14)

water, 10 days, RT

(24 ± 1) nm

water, 10 days, RT

(1.98 ± 0.12)

PBS, 2 days, 50 °C

(27.29 ± 0.06)

PBS, 2 days, 50 °C +

(29.29 ± 0.18)

water, 10 days, RT (25 ± 1) nm

PBS, 2 days, 37 °C

(13.83 ± 0.05)

This observation agrees well with results from a recent dissolution study of -NaYF4: Yb, Tm in PBS, where these effects were ascribed to an incongruent dissolution of the UCNPs’ surfaces, accompanied by the formation of stable Ln-phosphate compounds. 47 Such a dissolution is shown in Scheme 1 (reactions indicated with red arrows). This explanation is in accordance with other studies, where binary Ln-fluorides and Ln-oxides were transformed into more stable Lnphosphates in the presence of phosphate ions, 48, 49 and is also confirmed with this study. TEM analysis of the 25 nm-sized aged UCNPs revealed an amorphous side product (Figures 1A and C) composed of Y, Yb, P, and O (see EDXS spectrum in Figure 1B), suggesting that the side product is Y/Yb phosphate. These Ln-phosphates could be formed heterogeneously at the UCNP surface or homogeneously in solution. For example, Figure 1A shows an agglomerate of UCNPs, an amorphous precipitate and UCNPs embedded in an amorphous matrix, while Figure 1C reveals UCNPs coated with an amorphous layer. TEM analyses did not show any changes in the


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crystal structure (see SAED in Figure 1A) and any significant size reduction of the UCNPs upon the dissolution. The reduction of the UCNP diameter, estimated from the F release (i.e., from the XF values) amounts, to about 1-2 nm, which is too small to be reliably detected with our analytical approach. The significantly smaller XF values found for aging in water, i.e., our control experiments, are attributed to hydrolysis of the UCNPs surfaces 47 (reaction indicated with a blue arrow in Scheme 1).

Scheme 1. Schematic presentation of the processes and products involved in the dissolution of UCNPs in PBS; here Ln3+ denotes Y3+, Yb3+ and Tm3+, red arrows mark the dissolution processes and the blue arrow indicates surface hydrolysis by water while the formed phosphates are highlighted in grey.

Subsequently, the chemical composition of the surfaces of the exemplarily chosen batch of 25 nm-sized UCNPs before and after aging in PBS for 2 days at 37 ° C was determined with XPS (Figure 2). All constituting elements (except for Tm) were detected in the unaged and the aged


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sample. Note that the amount of Tm3+ (0.33 at. %) was below the detection limit of XPS (around 0.5 at. %). Additionally, there is a strong overlap of the Tm3+ 4d peak with the Yb3+ 4d peak. Both, unaged and aged, samples revealed a Na/(Y + Yb) ratio < 1, suggesting a substoichiometric fraction of Na+ at the UCNPs surface. Complete removal of OA by our ligand exchange procedure was confirmed by the relatively low C peak. As follows from Figure 2, the main difference between unaged and aged samples is the lower fraction of F in the aged sample. This is accompanied by a significantly higher fraction of O present in the aged sample. Obviously, the dissolved F is substituted by O2 and/or (OH) during UCNP hydrolysis (Scheme 1). The large increase of the O fraction (almost one order of magnitude with respect to the  25 % decrease of the F fraction, Figure 2B) in the aged sample cannot be attributed solely to hydrolysis of the particles. An additional P peak in the aged sample indicates the phosphate (PO4) formation during aging, which is also consistent with the at. % ratio of O/P  4 (Figure 1B). Therefore, we assume that the surfaces of the aged UCNPs must be, to a large extent, coated with Ln-phosphate, thereby confirming the results from the TEM analysis shown in Figure 1C. This agrees well with the results of a recent study of the stability of commercial NaYF4:Yb3+, Er3+ UCNP upon exposure to phosphate at a neutral or physiological pH in lysosomes and simulated lisosomal fluid. 25


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Figure 2. A) XPS spectra of exemplarily chosen 25 nm-sized unaged and aged UCNPs. B) Respective surface composition given in at. %. The relative uncertainty was estimated from duplicate measurements to be about 10 %. Note that the Yb3+ 4d peak at an energy of 190 eV overlaps with the P 2s peak.

Impact of UCNP aging on the optical properties

Figure 3. A) Normalized UC emission intensities (normalization at 800 nm) of the 36 and 24 nm-sized unaged and aged UCNP samples. The inset shows the strong 800 nm emission. B)


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Decay curves of the NIR-excited 800 nm luminescence of the 36 and 24 nm-sized unaged and aged UCNP samples, respectively. The areas under the normalized decay curves subsequently used for data evaluation and comparison of aging-induced effects are highlighted. Upconversion luminescence. The responsivity of the UC luminescence, originating from the different energy levels of the sensitizer and activator ions Yb3+ and Tm3+ (see energy level diagram displayed in Figure S3), to UCNP size, i.e., more specifically to SA/Vol, and to microenvironment 7, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 encouraged us to assess the potential of steady state and time-resolved luminescence measurements for stability screening of UCNPs. As summarized in Figure 3A, comparative spectroscopic studies of the differently sized fresh and differently aged UCNP samples revealed only a small influence of SA/Vol and aging on the normalized emission spectra obtained at the same excitation power density for comparison purposes. We noticed, however, a significant influence of SA/Vol on the luminescence intensity of the particles, i.e., a decrease in UC luminescence with increasing SA/Vol (see comparison of the luminescence intensities of 36 nm- and 24 nm-sized fresh UCNP in the SI, Figure S4A). The observation that the intensities of the UC emission arising from unaged and aged 36 nm UCNPs exceed that of unaged and aged 24 nm-sized UCNPs by about one order of magnitude agrees well with previous studies on size-/surface-related luminescence quenching of other UCNP systems. 30, 35, 50, 51 This intensity comparison of dispersions containing the same mass of particles is, however, partly hampered by the fact that the aged samples contained also the solid side product(s), i.e., the Ln-phosphates formed upon aging (see Scheme 1 and Figure 1), and hence, does not allow for a quantitative assessment- of the observed changes. Luminescence decay behavior. In contrast to luminescence intensities, which always depend on emitter concentration and absorption as well as on excitation power density in the case of


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multiphotonic emitters like UCNPs, luminescence lifetime measurements are not affected by emitter concentration. Moreover, according to our experience, the luminescence decay behavior of UCNPs is less strongly affected by excitation power density, particularly in the low power regime, than measurements of luminescence intensities. In order to assess the potential of luminescence lifetime measurements for stability monitoring of UCNPs, we determined the UC luminescence decay kinetics of the Tm3+ activator and the DC luminescence decay kinetics of the Yb3+ sensitizer of the differently sized unaged and aged UCNP samples under identical measurement conditions. The results are summarized in Figure 3B and in the SI (Figure S4B-D). Due to the fact that the energy transfer between the sensitizer Yb3+ and the activator Tm3+ proceeds via long lived excited states, we always observed an additional rise component in the decay kinetics immediately after the excitation pulse (pulse width of ~ 400 µs). Furthermore this luminescence rise can vary for different samples as displayed in Figure 3B. This makes the fitting of the lifetimes of UCNPs very challenging. Therefore, for the desired comparison of the decay curves, we chose to utilize integrated decay curves consistently normalized after 400 ms. This is exemplarily shown in Figure 3B. This figure clearly reveals aging-induced changes. In order to quantify the influence of the aging process, we also calculated the quenching efficiency (𝜂a) from the integrated luminescence decay curves of all UC and DC bands, see equation 1 (eq. 1). In equation 1, (eq. 1), Ia equals the integrated luminescence decay curve obtained in the presence of a fluorescence quencher/quenching process and I0 the initially measured integrated luminescence decay curve in the absence of a quencher/quenching process, respectively.

𝜂a(quenching)a = 100 % ∙ (1 – Ia/I0)

(eq. 1)

As follows from Figure 4, UCNP aging results in a decrease of all integrated normalized luminescence decay curves measured at matching excitation power densities. A comparison of


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the 𝜂a values derived for the different UC bands of Tm3+ and the Yb3+ emission at 980 nm excited at 940 nm (DC emission) reveals that the strongest luminescence quenching results for the 700 nm and 800 nm emission bands (UC excitation) and the directly excited Yb3+ emission at 980 nm, amounting to 𝜂a of about 15 % and 20 % for the 36 nm- and 24 nm-sized UCNP samples, respectively. In the case of the 24 nm-sized UCNPs, the luminescence decay at 475 nm, arising from a three photonic process, is clearly less affected, although we had initially anticipated a stronger quenching of the three photonic 475 nm emission compared to the 800 nm emission. In contrast, for the 36 nm-sized UCNP, 𝜂a amounts to the same values as derived for the other UC luminescence bands, i.e., to about 15 %. Overall, the luminescence quenching derived from the particle concentration independent time-resolved luminescence measurements seems to correlate with the loss in F. We did not find, however, a quantitative correlation between the size of the luminescence quenching and the UCNP dissolution degree (XF). This requires a more systematic study, beyond the goal of this first proof-of-concept study on optical screening parameters signalizing aging-induced changes of the UCNP surfaces. This will be addressed by us in the future.


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Figure 4. Luminescence quenching efficiency 𝜂a (see equation 1) derived from integrated decay curves of the 475, 700, and 800 nm UC emission and the 980 nm DC luminescence of Yb3+ (excitation at 940 nm), respectively.

Conclusion and Outlook In summary, our proof-of-concept study clearly reveals that UCNPs can release fluoride ions upon storage and aging in the bioanalytically relevant buffer phosphate buffered saline (PBS), with the loss in fluoride ions being more pronounced for smaller particles with a higher SA/Vol and for storage at elevated temperatures. Based upon TEM and XPS analysis, this partial dissolution was ascribed to the simultaneous formation of lanthanide phosphates homogeneously in solution and heterogeneously at the surface of the UCNP (see Scheme 1), favored by the low solubility product of these species. UCNP aging also resulted in changes of the upconversion (UC) and downconversion (DC) luminescence intensities and lifetimes. Particularly lifetime measurements and the accordingly determined integrated decay curves revealed a considerable potential for the monitoring and screening of the stability of UCNPs as demonstrated by the correlation of this parameter with the potentiometrically measured fluoride release. This is most likely similarly true for other effects resulting in changes in UCNP surface chemistry. Particularly suited for this purpose seem to be measurements of the luminescence decay kinetics of the 700 nm and 800 nm UC emission of Tm3+ or the 980 nm DC luminescence of Yb3+. In order to derive a clear correlation between particle dissolution, fluoride release, and optical properties, systematic studies of the aging of UCNPs of different size will be performed for


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typical material compositions (i.e., common dopant ions and dopant ion concentrations), crystal phases, and surface coatings in different buffers and in cell culture media. Moreover, UCNPs doped with Er3+ and other lanthanide ions and UCNPs prepared by different synthetic methods will be similarly assessed by us. Finally, our results clearly indicate that a protective coating is needed for applications in aqueous environments in order to prevent the dissolution of UCNPs, particularly in in vitro and in vivo studies. Such a protective coating can be for example realized with inorganic shells like silica shells or organophosphorous ligands that can bind to lanthanide surface atoms with a high affinity. AUTHOR INFORMATION Corresponding Author *Ute Resch-Genger* [email protected] Federal Institute of Materials Research and Testing (BAM), Division 1.10 Biophotonics, 12489 Berlin, Germany *Darja Lisjak [email protected] Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ‡These authors contributed equally. Notes The authors declare no competing financial interest. Acknowledgment


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Part of this work was supported by the COST Action CM1403, the European upconversion network from the design of photon-upconverting nanomaterials to (biomedical) applications. URG acknowledges also financial support by research grants RE 1203/18-1 (German research council; DFG) and RE 1203/20-1 (project NANOHYPE; DFG and M-Eranet). Slovenian Research Agency is acknowledged for its financial support within Research Programs P2-0089, P1-0045 and P02-0082. ABBREVIATIONS UCNP upconversion nanoparticle, NIR near-infrared, UV ultraviolet, VIS visible, Ln lanthanide, SA/Vol surface area-to-volume ratio, RT room temperature, UC upconversion, PBS phosphate buffered saline, XPS X-Ray photoelectron spectroscopy, OA oleic acid, ODE octadecene, DE diethyl ether, XRD X-ray diffraction, TEM transmission electron microscope, SAED selected area electron diffraction, EDXS energy dispersive X-ray spectroscopy, DC downconversion, 𝜂a quenching efficiency. Supporting Information. A basic characterization of the UCNPs with representative XRD pattern, TEM images with SAEDs and particle-size distribution, non-normalized UC luminescence and normalized UC and DC decay kinetics. The following files are available free of charge. Langmuir_Stability Screening_SI (PDF)


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TEM image of exemplarily chosen 25 nm-sized aged UCNPs with the corresponding SAED and an amorphous solid side product (marked with arrows). Figure 1A 80x67mm (300 x 300 DPI)


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EDXS spectrum of the side product. Y-L and P-K peaks overlap (at around 2 keV), which can be seen in the inset. The additional Y-K peak at around 15 keV confirms the presence of Y, while the presence of Yb follows from the Yb-M peaks (0.5 and 1.0 keV). The Cu and C peaks originate from the TEM supporting grid. The solid side product (A) showed no distinct SAED, revealing its amorphous nature. Figure 1B 40x30mm (600 x 600 DPI)


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Higher magnification TEM image C) shows UCNPs coated with an amorphous layer. Figure 1C 40x29mm (300 x 300 DPI)


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A) XPS spectra of exemplarily chosen 25 nm-sized unaged and aged UCNPs. B) Respective surface composition given in at. %. The relative uncertainty was estimated from duplicate measurements to be about 10 %. Note that the Yb3+ 4d peak at an energy of 190 eV overlaps with the P 2s peak. Figure 2 63x24mm (300 x 300 DPI)


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Normalized UC emission intensities (normalization at 800 nm) of the 36 and 24 nm-sized unaged and aged UCNP samples. The inset shows the strong 800 nm emission. Figure 3A 59x45mm (300 x 300 DPI)


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ecay curves of the NIR-excited 800 nm luminescence of the 36 and 24 nm-sized unaged and aged UCNP samples, respectively. The areas under the normalized decay curves subsequently used for data evaluation and comparison of aging-induced effects are highlighted. Figure 3B 59x45mm (300 x 300 DPI)


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Luminescence quenching efficiency ߟa (see equation 1) derived from integrated decay curves of the 475, 700, and 800 nm UC emission and the 980 nm DC luminescence of Yb3+ (excitation at 940 nm), respectively. Figure 4 59x45mm (300 x 300 DPI)


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Schematic presentation of the processes and products involved in the dissolution of UCNPs in PBS; here Ln3+ denotes Y3+, Yb3+ and Tm3+, red arrows mark the dissolution processes and the blue arrow indicates surface hydrolysis by water while the formed phosphates are highlighted in grey. Scheme 1 76x37mm (300 x 300 DPI)


Optically Detected Degradation of NaYF4:Yb,Tm-Based Upconversion

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