Article pubs.acs.org/IC
A General Strategy for Ligand Exchange on Upconversion Nanoparticles Wei Kong,† Tianying Sun,† Bing Chen,† Xian Chen,† Fujin Ai,‡ Xiaoyue Zhu,†,§ Mingyu Li,∥ Wenjun Zhang,†,§ Guangyu Zhu,‡ and Feng Wang*,†,⊥ †
Department of Physics and Materials Science, ‡Department of Biology and Chemistry, and §Center of Super-Diamond and Advanced Films, City University of Hong Kong, 83 Tat Chee Avenue, Hong Kong SAR, China ∥ State Key Laboratory of Modern Optical Instrumentation, Zhejiang University, Hangzhou 310027, China ⊥ City Universities of Hong Kong Shenzhen Research Institute, Shenzhen 518057, China S Supporting Information *
ABSTRACT: Lanthanide-doped upconversion nanoparticles with a suitable surface coating are appealing for biomedical applications. Because high-quality upconversion nanoparticles are typically prepared in an organic solvent and passivated by hydrophobic oleate ligands, a convenient and reliable method for the surface modification of upconversion nanoparticles is thus highly desired to satisfy downstream biological investigations. In this work, we describe a facile and versatile strategy for displacing native oleate ligands on upconversion nanoparticles with a diversity of hydrophilic molecules. The ligand-exchange procedure involves the removal of original oleate ligands followed by the attachment of new ligands in a separate step. The successful coating of relevant ligands was confirmed by Fourier transform infrared spectroscopy, thermogravimetry analysis, and ζ-potential measurement. The surface-modified nanoparticles display high stability and good biocompatibility, as revealed by electron microscopy, photoluminescence spectroscopy, and cytotoxicity assessment. Our study demonstrates that functional biomolecules such as biotin can be directly immobilized on the nanoparticle surface using this approach for the quick and effective detection of streptavidin.
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INTRODUCTION
Upconversion nanoparticles synthesized in the organic solvents are typically capped with oleate and/or oleylamine ligands that render the nanoparticles hydrophobic. Surface modifications of the nanoparticles are therefore necessary prior to subsequent biological studies that are carried out in aqueous solutions.38,39 A common strategy for surface modification is depositing an additional coating layer (e.g., silica or polymeric shells) around the nanoparticles, which can provide reactive functional moieties for further conjugation with biomolecules in addition to permitting aqueous dispersion. However, the coating layer increases the spatial separation between the upconversion nanoparticles and the surface tethered molecules and impairs their energy-exchange interactions. The strategy of ligand exchange that involves replacement of the original capping ligands with hydrophilic ones is thus developed to facilitate applications such as energy-transfer-based biodetection that uses upconversion nanoparticles as energy donors. The ligand-exchange preparation reported in the literature is usually a one-step procedure accomplished by directly substituting new ligands for the native ones. In order for the ligand-exchange reaction to proceed, the experimental parameters such as temperature and composition of the reaction
Lanthanide-doped upconversion nanoparticles, which emit a higher-energy photon after absorption of multiple low-energy photons, have attracted increasing research interest in the past decades.1,2 When compared to semiconductor quantum dots and organic dyes, upconversion nanoparticles display distinct advantages including large anti-Stokes shifts, sharp emission bandwidths, long excited-state lifetimes, high photochemical stability, and low cytotoxicity. Therefore, upconversion nanoparticles have been selected as superb candidates for biological research and biomedical applications, such as bioimaging,3−9 biodetection,10−15 drug delivery,16−19 and photodynamic therapy (PDT).20−22 High-quality upconversion nanoparticles that are required for bioapplications are generally synthesized in organic solvents.23−30 More specifically, most upconversion nanoparticles were prepared by thermal decomposition of metal trifluoroacetate precursors in an oleic acid/oleylamine/1-octadecene system or by precipitation of metal oleate complexes with fluorides in a binary solvent mixture of oleic acid and 1octadecene. These methods are now routinely used for the preparation of upconversion nanoparticles with tunable size, shape, composition, and layer-by-layer hierarchical structures.31−37 © XXXX American Chemical Society
Received: October 12, 2016
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DOI: 10.1021/acs.inorgchem.6b02479 Inorg. Chem. XXXX, XXX, XXX−XXX
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Inorganic Chemistry
Figure 1. Schematic illustration of the experimental design for the surface modification of upconversion nanoparticles with various ligands.
media need to be stringently controlled, such that a stronger interaction between the nanoparticles and new ligands is established. In addition, substantial modification of the equipment setup and experimental variables is needed for ligand exchange with different types of molecules. Herein, we report a facile and versatile ligand-exchange protocol for replacing native oleate ligands on upconversion nanoparticles with a diversity of hydrophilic molecules. In our protocol, the removal of oleate ligands and the attachment of new ligands were conducted in separate steps. This ensures reliable attachment of different ligands at mild and consistent experimental conditions. Notably, functional biomolecules such as biotin can be directly attached to the nanoparticles for quick and effective biodetection through affinity interactions.
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RESULTS AND DISCUSSION The design of our strategy for displacing oleate ligands is composed of three key operations, as shown in Figure 1. The original oleate ligands are first removed through the treatment of the as-synthesized nanoparticles in a hydrochloric acid solution (0.1 M).40 After purification, the ligand-free nanoparticles are added to an aqueous solution of the new ligands whose pH is adjusted to weak basic (∼8) in advance. The ligand-exchange procedure is accomplished by transferring the mixture to a diethylene glycol solution, followed by the evaporation of water at 105 °C for 1 h and successive incubation in a Teflon-lined stainless steel autoclave at 160 °C for 2 h. As a proof-of-concept experiment, oleate-passivated NaYF4 nanoparticles was used as the model platform for ligand exchange with poly(acrylic acid) (PAA). The upconversion nanoparticles with a composition of NaYF4:Yb/Er (38/2 mol %)@NaYF4 are synthesized through coprecipitation in a binary solvent mixture of oleic acid and 1-octadecene.41 Figure 2a shows a typical transmission electron microscopy (TEM) image of the as-synthesized upconversion nanoparticles, which reveals a highly uniform morphology with an average particle size of 25 nm. The powder X-ray diffraction (XRD) pattern of the nanoparticles exhibits peak positions and intensities that can be well indexed in accordance with hexagonal-phase NaYF4 crystals, suggesting high crystallinity of the nanoparticles (Figure S1, Supporting Information). Fourier transform infrared (FTIR) spectroscopy confirms the existence of oleate ligands on the nanoparticle surface, which are mostly removed after acidic treatment (Figure 2b). After removal of oleate ligands, the nanoparticles are determined to be positively charged (33.6 mV) due to surface protonation,40 which favors the absorption of negatively charged ligands such as PAA. Accordingly, the new ligands are dissolved in water with sodium hydroxide at pH = 8 prior to
Figure 2. (a) Typical TEM image of the as-synthesized NaYF4:Yb/ Er@NaYF4 nanoparticles. (b) FTIR spectra of the upconversion nanoparticles before and after removal of oleate ligands. (c) TGA curves of PAA-coated nanoparticles prepared under different experimental conditions. (d) Dispersion stability of PAA-coated nanoparticles prepared under different experimental conditions. The intensities were obtained by recording the emission at 543 nm from aqueous dispersions of the nanoparticles (12.5 mM). The solid lines are intended to guide the eye. Error bars represent the standard deviations from three sets of repeated measurements.
reaction with the nanoparticles. The weakly basic solution promotes the ionization of functional groups on the ligands and enhances the solubility of the ligands in water (Figure S2, Supporting Information), thereby making the ligands more accessible to the nanoparticles. The importance of adjusting the pH for the reaction was verified by thermogravimetry (TGA) and dispersibility analyses (Figure 2c,d), which reveals a reduced abortion of the PAA molecule and a decreased dispersion stability without pH adjustment. It is worth noting that the adjustment of the pH must precede the mixing of the ligands and nanoparticles. Otherwise, the uncoated nanoparticles would be deprotonated before the ligands could be absorbed, leading to aggregation of the nanoparticles (Table S1, Supporting Information). A postsolvothermal processing is also found to be essential for achieving an effective surface coating of the new ligands (Figure 2c,d). Prior to solvothermal treatment, most ligands may not form a strong bond with the nanoparticles, probably because of the concurrent influence of steric hindrance and electrostatic repulsion. The weakly absorbed ligands may be B
DOI: 10.1021/acs.inorgchem.6b02479 Inorg. Chem. XXXX, XXX, XXX−XXX
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Figure 3. (a) FTIR spectra of upconversion nanoparticles coated with different types of ligands. (b) TEM images of upconversion nanoparticles coated with different types of ligands. The scale bars are 50 nm. (c) Photographs of upconversion nanoparticles coated with different types of ligands in water dispersions (12.5 mM). (d) Viability of human lung adenocarcinoma cell incubated with different concentrations of surface-modified upconversion nanoparticles for 48 h.
detached from the nanoparticles by washing. After solvothermal treatment, however, these weakly absorbed ligands form a tight attachment with the nanoparticle surface by overcoming the obstruction, which recedes because of the stretch of firmly combined ligands under high temperature and pressure. The successful coating of PAA ligands on the nanoparticle surface is confirmed by FTIR (Figure 3a). The spectrum shows clear absorption bands of PAA at 2957 and 2925 cm−1 (asymmetric and symmetric stretching vibrations of CH2), 1638 cm−1 (asymmetric stretching vibrations of CO2), and 1563 cm−1 (asymmetric stretching vibrations of CO).42 In our ligand-exchange process, the oleate ligands are not directly replaced by the new molecules. Thus, any molecules can principally be attached to the nanoparticle surface as long as they can form chemical bonds with lanthanide ions, irrespective of the bonding strength relative to that of oleate ligands. This is substantiated by coating a variety of molecules, including poly(ethylenimine) (PEI), poly(vinylpyrrolidone), cysteine, glycine, citric acid, biotin, and 2-aminoethyl dihydrogen phosphate, on the nanoparticle surface. The same coating procedure was used for these ligands except PEI, which is alkaline and is exempted from pH adjustment (Table S2,
Supporting Information). The successful coating of various new ligands is verified by FTIR (Figure 3a) and TGA (Figure S3, Supporting Information) analyses. The nanoparticles comprising various surface coating layers were further characterized by TEM, which reveals an essentially unaffected nanoparticle size and morphology (Figure 3b). The well-separated particles in the TEM images validate effective surface protection by the coating molecules that prevent the nanoparticles from aggregation. In line with the TEM observations, these surface-modified nanoparticles are well dispersed in aqueous solutions, as shown in Figure 3c. In addition, the whole set of nanoparticles exhibit consistent emission spectra closely resembling that of the ligand-free counterpart (Figure S4, Supporting Information). The results are primarily attributed to the inert crystalline shell of NaYF4, which remains intact during the ligand-exchange process. The epitaxial shell of NaYF4 in the nanoparticles shield the dopant ions from perturbation by surface oscillators, thereby preserving the optical integrity of the nanoparticles.43 We also assessed the cytotoxicity of the nanoparticles by MTT assay. As shown in Figure 3d, the ligand-free nanoparticles exhibit good biocompatibility. The cell viability C
DOI: 10.1021/acs.inorgchem.6b02479 Inorg. Chem. XXXX, XXX, XXX−XXX
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Inorganic Chemistry remains 88.9% at a high nanoparticle concentration of 500 μg mL−1. The results are ascribed to the low toxicity of the constituent elements as well as the high chemical stability of the crystal. After surface coating, a noticeable variation in the cell viability was detected. In general, the surface-modified nanoparticles show cytotoxicity similar to that of the corresponding capping ligands, in good agreement with literature reports.44,45 For example, PEI has been identified as a cytotoxic polymer, and the PEI-coated nanoparticles are found to be the least biocompatible. A notable advantage of our ligand-exchange approach is the direct functionalization of upconversion nanoparticles with biomolecules such as biotin, which should simplify related biological study procedures. 1H NMR analyses confirm that the biomolecules all survived the solvothermal process (Figure S5, Supporting Information). In order to further validate the bioactivity of the functionalized nanoparticles, we designed an energy-transfer-based biosensor using biotinylated upconversion nanoparticles to detect Cy3-conjugated streptavidin. As illustrated in Figure 4a, the biosensor makes use of affinity
upconversion nanoparticles through biotin−streptavidin binding other than nonspecific absorption.
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CONCLUSIONS In conclusion, we have demonstrated a convenient and reliable strategy for the exchange of capping ligands on upconversion nanoparticles. We show that, by prior removal of the original ligands, a wide variety of molecules can be attached to upconversion nanoparticles through a general solvothermal process. This protocol eliminates the inconvenience associated with direct ligand-exchange reactions that require a complicated equipment setup and stringent control over experimental variables. At the same time, the solvothermal treatment ensures firm bonding between the nanoparticles and ligands, leading to good aqueous dispersibility and high stability of the nanoparticles. We believe that the strategy described here can be readily extended to other nanoparticle/ligand systems for applications ranging from biological imaging to lighting and solar cells.
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EXPERIMENTAL METHODS
Reagents. Ytterbium(III) acetate hydrate (99.9%), erbium(III) acetate hydrate (99.9%), yttrium(III) acetate hydrate (99.9%), sodium hydroxide (NaOH; 98+%), ammonium fluoride (NH4F; 98+%), 1octadecene (90%), oleic acid (90%), dimethyl sulfoxide (DMSO; 99+ %), poly(acrylic acid) (PAA; MW ≈ 1800), poly(ethylenimine) (PEI; branched, MW ≈ 800), poly(vinylpyrrolidone) (MW ≈ 10,000), citric acid (99.5+%), diethylene glycol (DEG; 99%), (2-aminoethyl)phosphonic acid (99%), L-cysteine (97+%), glycine (97+%), biotin (99+%), streptavidin−Cy3 in a phosphate-buffered saline solution were purchased from Sigma-Aldrich. 3-[4,5-Methylthiazol-2-yl]-2,5diphenyltetrazolium bromide (MTT) and A549, the human lung adenocarcinoma cell line, were purchased from ThermoFisher Scientific HK. All chemicals were used as received without any purification. Synthesis of NaYF4:Yb/Er (38/2 mol %) Nanoparticles. In a typical procedure, 2 mL of a water solution of Ln(CH3CO2)3 (0.2 M, Ln = Y, Yb, and Er) was added to a 50 mL flask containing 3 mL of oleic acid and 7 mL of 1-octadecene. The mixture was heated at 150 °C for 40 min to form lanthanide oleate complexes and then cooled to 50 °C naturally. Thereafter, 5 mL of a methanol solution containing NH4F (1.55 mmol) and NaOH (1 mmol) was added, and the resultant solution was stirred for 30 min. After the methanol was evaporated, the solution was heated to 290 °C under argon for 1 h and then cooled to room temperature. The resulting nanoparticles were precipitated by the addition of ethanol, collected by centrifugation at 6000 rpm for 5 min, washed with ethanol several times, and redispersed in 2 mL of cyclohexane. Synthesis of NaYF4:Yb/Er@NaYF4 Nanoparticles. The shell precursor was first prepared by mixing 2 mL of a water solution of yttrium acetate (0.2 M) with 3 mL of oleic acid and 7 mL of 1octadecene in a 50 mL flask, followed by heating at 150 °C for 40 min. After cooling to 50 °C, preformed NaYF4:Yb/Er core nanoparticles dispersed in 2 mL of cyclohexane were added along with 5 mL of a methanol solution of NH4F (1.55 mmol) and NaOH (1 mmol). The resulting mixture was stirred at 50 °C for 30 min, at which time the solution was heated to 290 °C under argon for 1 h and then cooled to room temperature. The resulting nanoparticles were precipitated by the addition of ethanol, collected by centrifugation at 6000 rpm for 5 min, washed with ethanol several times, and redispersed in 2 mL of cyclohexane. Synthesis of Ligand-Free Nanoparticles. A total of 1 mL of a cyclohexane dispersion of the core−shell nanoparticles was precipitated by the addition of ethanol and redispersed in 2 mL of a HCl solution (0.1 M in deionized water). The slurry was then sonicated at 45 °C for 1 h to remove the oleate ligands. After the reaction, the nanoparticles were collected via centrifugation at 14000
Figure 4. Streptavidin detection using biotinylated upconversion nanoparticles. (a) Schematic illustration of the experiment design of an energy-transfer-based biosensor for streptavidin detection. (b) Emission spectra of the biotinylated nanoparticle sensor in the presence of varying concentrations of streptavidin−Cy3. (c) Integrated emission intensity of Er3+ in the 515−565 nm range as a function of the streptavidin concentration (0.3−1.25 nM). The straight line is the linear regression of the measured data. Error bars represent the standard deviations from three sets of repeated measurements.
interaction between a biotin and a streptavidin, which brings the upconversion nanoparticles and Cy3 into close proximity and results in quenching of the upconverted emission. As expected, we detected an appreciable decline of the upconversion emission after the biotinylated nanoparticles were incubated with streptavidin−Cy3 for 1 h (Figure 4b). The linear response of the emission intensity to the streptavidin concentration (Figure 4c) indicates that an energy-transfer process is responsible for the sensing signal. We also conducted a control experiment using ligand-free nanoparticles as the energy donors. Under similar experimental conditions, we recorded a largely preserved upconversion emission in the presence of streptavidin−Cy3 (Figure S6, Supporting Information). The results confirm that the streptavidin−Cy3 molecules were primarily captured by the D
DOI: 10.1021/acs.inorgchem.6b02479 Inorg. Chem. XXXX, XXX, XXX−XXX
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Inorganic Chemistry rpm for 30 min, washed twice with deionized water, and redispersed in 1 mL of deionized water. New Ligand Deposition on Uncoated Nanoparticles. Typically, a certain amount of new ligands was first dissolved in 9 mL of deionized water by adjusting the pH to 8 using a NaOH solution (0.1 M in deionized water) under vigorous stirring at room temperature. Thereafter, 0.5 mL of ligand-free nanoparticles was added drop by drop, followed by stirring for another 2 h. The water dispersion was then added to 10 mL of DEG, and the mixture was stirred at 105 °C for 1 h to remove water. Finally, the DEG dispersion was transferred to a 20 mL Teflon-lined autoclave and incubated at 160 °C for 2 h. The obtained nanoparticles were collected via centrifugation at 14000 rpm for 30 min, washed several times with ethanol and deionized water, redispersed in 8 mL of deionized water, and stored in a fridge at 4 °C. The detailed experimental parameters for different ligands are summarized in Table S2 in the Supporting Information. Cytotoxicity of Surface-Modified Nanoparticles. A549 was maintained in Dulbecco’s modified Eagle’s medium supplemented with 10% fetal bovine serum, 100 units mL−1 of penicillin, and 100 μg mL−1 streptomycin. The cells were incubated in 5% CO2 humidified at 37 °C for growth. The number of viable A549 cells after treatment with surface-modified upconversion nanoparticles were evaluated by MTT assay. Briefly, A549 cells (1 × 104 cells well−1) were seeded in a 96-well plate and kept overnight for attachment. The next day the medium was replaced with a fresh medium with various concentrations of surface-modified upconversion nanoparticles (0.0016−10 μM), and the cells were allowed to grow for 48 h. A total of 4 h before the completion of incubation, 10 μL of MTT (10 mg mL−1) was added to each well. After incubation was completed, 100 μL of DMSO was added to each well and incubated for another 4 h at 37 °C. Color developed after the reaction was quantified by measuring the absorption at 540 nm using a UV−vis−IR microplate reader (Powerwave XS MQX200R). Characterizations. TEM measurements were carried out on a Philips CM-20 transmission electron microscope operating at an acceleration voltage of 200 kV. Photoluminescence (PL) spectra were obtained from water dispersion of the nanoparticles (0.1 wt %) on an F-4600 spectrophotometer (Hitachi). ζ-potential measurements were carried out on a Malven Zetasizer Nano ZS. FTIR spectra were obtained on a PE Spectrum 100 (PerkinElmer). 1H NMR measurements were carried out on a Bruker 400 MHz “AVANCE III” Nuclear Magnetic Resonance System (NMR-400). Unless otherwise stated, all measurements were carried out at room temperature.
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(CityU 11208215), and City University of Hong Kong (Grant 7004650).
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.6b02479. Listings of experimental variables, XRD patterns, TEM images, TGA curves, and FTIR, PL, and 1NMR spectra (PDF)
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REFERENCES
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Feng Wang: 0000-0001-9471-4386 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (Grants 21573185, 21303149, 21371145, and 51332008), the Research Grants Council of Hong Kong E
DOI: 10.1021/acs.inorgchem.6b02479 Inorg. Chem. XXXX, XXX, XXX−XXX
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DOI: 10.1021/acs.inorgchem.6b02479 Inorg. Chem. XXXX, XXX, XXX−XXX
