Article pubs.acs.org/cm
Cation Exchange: A Facile Method To Make NaYF4:Yb,Tm-NaGdF4 Core−Shell Nanoparticles with a Thin, Tunable, and Uniform Shell Cunhai Dong,† Andreas Korinek,‡ Barbara Blasiak,# Boguslaw Tomanek,#,§ and Frank C. J. M. van Veggel*,† †
Department of Chemistry, the University of Victoria, P.O. Box 3065, Victoria, British Columbia, Canada V8W 3V6 Canadian Centre for Electron Microscopy, Brockhouse Institute for Materials Research, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4M1 # Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada T2N 4N1 § Institute for Biodiagnostics (West), National Research Council of Canada, Calgary, Alberta, Canada T2N 4N1 ‡
S Supporting Information *
ABSTRACT: Cation exchange was performed on upconversion NaYF4:Yb,Tm nanoparticles, resulting in NaYF4:Yb,Tm-NaGdF4 core−shell nanoparticles as indicated by electron energy-loss spectroscopy 2D mapping. Results show that core−shell nanoparticles with a thin, tunable, and uniform shell of subnanometer thickness can be made via this cation exchange process. The resulting NaYF4:Yb,Tm-NaGdF4 core− shell nanoparticles have an enhanced up-conversion intensity relative to the initial core nanoparticles. As potential magnetic resonance imaging (MRI) contrast agents, they were tested for their proton relaxivities. The r1 relaxivity per Gd3+ ion of the nanoparticles with a thin NaGdF4 shell (ca. 0.6 nm thick) measured at 9.4 T was found to be 2.33 mM−1·s−1. This r1 relaxivity is among the highest in all the reported NaYF4−NaGdF4 core−shell nanoparticles. The r1 relaxivity per nanoparticle is 1.56 × 104 mM−1·s−1, which is over 4000 times higher than commercial Gd3+-complexes. The very high proton relaxivity per nanoparticle is critical for targeted MRI as such nanoparticles provide strong contrast even in low concentrations. The presented cation exchange method is a promising way to manufacture core−shell nanoparticles with up-conversion NaYF4:Yb,Tm core and paramagnetic NaGdF4 shell for bimodal imaging, i.e. MR and optical imaging. KEYWORDS: cation exchange, sodium lanthanide fluoride nanoparticles, core−shell nanoparticles, magnetic resonance imaging, up-conversion optical imaging
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doping magnetic Gd3+ ions in the NaYF4 host matrix. However, maximum occupation of the surface of nanoparticles by Gd3+ ions is needed for MRI applications because the physical contact between Gd3+ ions and water molecules is the dominate factor for the shortening of the water relaxation time in MRI.9 By doping Gd3+ ions in the up-conversion nanoparticles, only a portion of the surface of nanoparticles is occupied by Gd3+ ions, and the Gd3+ ions available for water access are thus limited. Consequently, the paramagnetic properties of the nanoparticles are suboptimal.10−17 In contrast, core−shell nanoparticles with up-conversion NaYF4:Yb,Tm (or NaYF4:Yb,Er) nanoparticles in the core and magnetic NaGdF4 in the shell should provide increased magnetic properties through complete occupation of the surface by Gd3+ ions. Moreover, optical properties are also enhanced by the NaGdF4 shell through the reduction of the quenching by the surface organic groups, such as −OH and −CH. NaYF4−NaGdF4 core−shell nanoparticles can be
INTRODUCTION NaYF4:Yb,Tm-NaGdF4 core−shell nanoparticles that contain an up-conversion NaYF4:Yb,Tm core and a paramagnetic NaGdF4 shell are bifunctional nanoparticles, which enable bimodal imaging, i.e. optical bioimaging and magnetic resonance imaging (MRI).1 The bimodal imaging has recently been used as it takes advantage of high sensitivity and spatial resolution of MRI. Furthermore it allows noninvasive diagnosis using MRI and subsequent optical guidance for surgery.1 Upconversion nanoparticles that convert two or more lower energy near-infrared photons into one higher energy visible or near-infrared photon are suitable for optical imaging due to their low autofluorescence, good photostability, and possible deep tissue imaging,2 although a recent work by our group has indicated that practical issues remain for deep tissue imaging.3 Toxicity study and cell studies of this type of nanoparticles show no noticeable side effect.4−7 Gd3+-based positive contrast agents for MRI (T1 shortening) are advantageous over negative contrast agents (T2 shortening), such as iron oxide nanoparticles, due to hyperintense signal from the tissue of interest.8 The bifunctionality of the nanoparticles can be achieved by © 2012 American Chemical Society
Received: December 8, 2011 Revised: March 21, 2012 Published: March 21, 2012 1297
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cation-exchanged nanoparticles have a core−shell structure. The shell thickness of the NaYF4−NaGdF4 core−shell nanoparticles can be tuned by varying the conditions of the cation exchange process. Finally, we show that NaYF4−NaGdF4 core−shell nanoparticles prepared by the cation exchange process provide enhanced optical properties, and their relaxivities per Gd3+ ion are among the highest as compared to those prepared using a two- step direct core−shell synthesis method. Relaxivity measurements were performed at 9.4 T, a high field which provides high spatial resolution needed for small animal imaging although clinical MRI still uses 1.5 and 3 T.35 Contrast agents at high field are still to be optimized as high field is the current standard for small animal imaging.35,36
prepared by a direct core−shell synthesis procedure, i.e. making core nanoparticles first and then growing a shell on the core nanoparticles.18−20 However, the core−shell structure is generally concluded based on the size increase from transmission electron microscopy (TEM) and the enhanced optical properties, which has been shown to be inappropriate.21 Recent work by our group has shown that these directly synthesized core−shell nanoparticles do not have a uniform shell, and in a significant portion of nanoparticles, the core is only partially covered by the shell.22,23 Moreover, only one shell thickness is normally reported for the core−shell nanoparticles prepared using the direct synthesis method, which then gives only one measured relaxivity. Different thicknesses and the corresponding proton relaxivities are needed to investigate the effect of the shell thickness on both the per-ion and the per-nanoparticle relaxivity so that optimal conditions can be obtained for this type of core−shell nanoparticles. A very recent work has reported different shell thicknesses made by the direct synthesis method.20 However, again only unconvincing evidence, such as the size increase and the increased optical properties, was provided as support for the core−shell structure, which is very likely anisotropic.22,23 Hence, in order to maximize the surface occupation of Gd3+ ions and optimize the nanoparticle conditions for relaxivity, a different method is needed to prepare the bifunctional core−shell nanoparticles with a tunable shell thickness. Cation exchange in nanomaterials was first reported on CdS semiconductor nanoparticles exchanging with Hg+ to make CdS-HgS-CdS core−shell−shell nanoparticles with a layered structure at room temperature.24 It has then been highlighted with CdSe semiconductor nanoparticles exchanging completely and reversibly with Ag+ at room temperature,25 followed by preparation of some novel nanomaterials, such as CdE (CdE = CdS, CdSe, and CdTe) octapod nanocrystals,26 PtTe2 nanotubes, Se-MSe core−shell (M = Ag, Cd, Pd, Zn),27,28 PbSeCdSe core−shell,29 and PbS-CdS core−shell nanoparticles.30,31 Recently, we reported cation exchange in LnF3 nanoparticles that were synthesized in aqueous media, i.e. upon exposure to an aqueous medium containing Ln3+ ions, the Ln3+ ions in LnF3 nanoparticles are replaced by the Ln3+ ions in the solution.32 One of the potential advantages of the cation exchange is to make nanomaterials that cannot be made via a direct synthesis method, such as core−shell nanoparticles with a thin, tunable, and uniform shell. The cation exchange process has been carried out to incorporate some Gd3+ ions in NaYF4:Yb,Er nanoparticles using a rather complicated 4-step procedure: synthesis of oleyl amine-stabilized nanoparticles, removal of the surface oleyl amine, mixing of noncoordinated nanoparticles with Gd3+, and mixing with new organic ligands for dispersibility recovery.13 However, a core−shell structure has not been shown. In this work, we report cation exchange of water-dispersible NaYF4:Yb,Tm nanoparticles with Gd3+ salt (GdCl3) in water. Water-dispersibility was obtained by a ligand exchange reaction of the as-prepared oleate-stabilized NaYF4:Yb,Tm nanoparticles with polyvinylpyrrolidone (PVP) using a procedure modified from recent work.33 The ligand exchange method was chosen rather than silica coating34 or intercalation3 for the convenience of the following cation exchange reactions and the water access for MRI applications. PVP was chosen because of its good biocompatibility, ease of incorporating a functional end group, and solubility in various solvents, such as water, DMF, ethanol, etc.7 Electron energy-loss spectroscopy (EELS) 2D elemental mapping was used to prove that the
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EXPERIMENTAL SECTION
The lanthanide acetate salts and polyvinylpyrrolidone-10 (PVP) were purchased from Aldrich in the highest purity available (>99.9%). All the chemicals were used as received without further purification. The percentage of the dopant ions is atomic concentration relative to the total concentration of all Ln3+ ions. Synthesis of Oleate-Stabilized NaYF4:Yb(20%):Tm(2%) Nanoparticles. Nanoparticles were prepared by a procedure modified from the literature.37 In a 100 mL flask, a total of 2 mmol of Ln(OAc)3·xH2O [1.56 mmol Gd(OAc)3·xH2O, 0.4 mmol Yb(OAc)3·xH2O, and 0.04 mmol Tm(OAc)3·xH2O] were added, followed by the addition of 12 mL of oleic acid and 34 mL of octadecene. This mixture was stirred at 120 °C under vacuum to make a clear solution. Once it was clear, the solution was kept stirring for another 90 min. It was then cooled down to room temperature, followed by the addition of the solution of 5 mmol of NaOH and 8 mmol of NH4F in 20 mL of methanol. After having been stirred overnight, the methanol was evaporated under heating at ca. 65 °C in argon followed by heating up to 300 °C. The reaction mixture was stirred for 110 min and cooled down to room temperature. Nanoparticles were precipitated using ethanol and isolated using Spinchron 15 centrifuge from Beckman Coulter at 5000 rpm with a F0850 rotor (a centrifugal force of 2700 × g) for 5 min. The supernatant was poured off. The nanoparticles in the bottom of centrifuge tube were redispersed in chloroform, precipitated using anhydrous ethanol, and isolated using the above centrifuge settings. This washing process was repeated twice. After the purification, nanoparticles were stored as dispersion in chloroform with a concentration of ca. 50 mg/mL. Preparation of PVP-Stabilized NaYF4:Yb,Tm Nanoparticles. PVP-stabilized nanoparticles were prepared by ligand exchange using a procedure modified from the literature.33 From the above as-prepared oleate-stabilized NaYF4:Yb,Tm nanoparticles dispersion, 0.2 mL was taken into a 50 mL round-bottom flask and diluted with 5 mL of DMF and 5 mL of dichloromethane, followed by the addition of 300 mg of PVP. The reaction mixture was refluxed at 80 °C for 8 h, followed by stirring at room temperature overnight. The resulting PVP-stabilized nanoparticles were precipitated using 60 mL of ethyl ether. The precipitate was washed once with ethyl ether and isolated using the same centrifuge settings described above. The precipitate was then dried under vacuum for 4 h so that it is ready for the following cation exchange reaction. Cation Exchange of PVP-Stabilized NaYF4:Yb,Tm Nanoparticles. The above PVP-stabilized NaYF4:Yb,Tm nanoparticles in the centrifuge tube were dispersed in 2 mL of DI water, followed by the addition of the respective amounts of GdCl3·6H2O in 1 mL of water. Gd3+ salt of 40-, 10-, and 2-fold over the total Ln3+ ions in NaYF4:Yb,Tm nanoparticles were designed to use. Based on the used volume and the concentration of the dispersion of the as-prepared nanoparticles, the mass of NaYF4:Yb,Tm nanoparticles was calculated to be 5 mg. The total amount of Ln3+ ions was thus calculated to be 20 μmol with the average molar mass of NaYF4:Yb(20%),Tm(2%) of 206 g/mol assuming 20 wt % ligand coverage based on TGA. Therefore, 40-, 10-, and 2-fold amount of Gd3+ salt was calculated to be ca. 287, 1298
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Figure 1. (a) TEM image and (b) XRD pattern of the as-prepared NaYF4:Yb,Tm nanoparticles [vertical bars at the bottom are positions of all the Bragg reflections of hexagonal NaYF4 (JCPDS 00-016-0334)]. 72, and 14.4 mg GdCl3·6H2O, respectively. The reaction mixture was heated up to 25, 50, 75, and 100 °C, respectively, and stirred for 1 h. After cooling down to room temperature, it was then transferred into a dialysis bag with a MWCO of 2000 D and dialyzed in water for 30 h. Control Experiment for Dialysis. This control experiment was done by dissolving 100 mg of PVP in 3 mL of DI water, followed by the addition of 287 mg of GdCl3·6H2O (40-fold Gd3+ for cation exchange). The resulting mixture was heated to 100 °C and stirred for 1 h. After having been cooled down to room temperature, it was transferred into a dialysis bag with a MWCO of 2000 D and dialyzed in water for 30 h. Transmission Electron Microscopy. Transmission electron microscopy (TEM) was done with a Hitachi H-7000 Transmission Electron Microscope operating at 200 kV. The nanoparticle dispersion was dropcasted onto a carbon grid and allowed to dry in air at room temperature. The carbon grid with samples on it was then mounted into the vacuum sample chamber for imaging. The size of nanoparticles with a standard deviation was calculated based on 50 nanoparticles. Powder X-ray Diffraction. Approximately 20 mg of a sample was gently stirred in an alumina mortar to break up lumps. The powdery samples of nanoparticles were smeared on to a zero-background holder using ethanol. Step-scan X-ray powder-diffraction data were collected over the 2θ range 20−100° with Cr (30 kV, 15 mA) radiation on a Rigaku Miniflex diffractometer with variable divergence slit, 4.2° scattering slit, and 0.3 mm receiving slit. The scanning step size was 0.02° 2θ with a counting time of 6 s per step. Three XRD peaks ([100], [111], and [201]) were used to calculate the size of nanoparticles and their standard deviation. High-Angle Annular Dark-Field Images and Electron Energy-Loss Spectroscopy. High-angle annular dark-field (HAADF) images combined with electron energy-loss spectroscopy (EELS) or energy dispersive X-ray spectroscopy (EDX) data were acquired on a FEI Titan 80-300 TEM (FEI company, Eindhoven, The Netherlands), equipped with a CEOS image corrector and operated at 300 kV. The microscope is equipped with a Gatan Tridiem ER energy filter (GIF) (GatanInc., Pleasanton, CA) and an Oxford EDX detector. EELS mapping was performed in STEM mode with a convergence angle of 8 mrad, and the collection angle was 15 mrad. The energy resolution of the system was 0.8 eV. Spectrum image acquisition and postprocessing was done using the Gatan Digital Micrograph Software. STEM micrograph collection was performed using the FEI TIA software. Nanoparticles in solution were deposited directly onto ultrathin carbon film supported on a copper mesh grid (Ted Pella, Inc., Redding, CA). Samples were plasma cleaned for 40 s to remove hydrocarbon contaminations using a O2/H2 gas mixture. The object pixel size for the EELS spectrum images was 3 Å with an acquisition time of 0.2 s, the dispersion per channel was 0.2 eV. During acquisition, the spatial drift of the specimen was compensated every 60
s. Line profiles were taken out of the spectrum images in two directions to make the signal difference clearer. Fluorescence Studies. Fluorescence analyses were done using an Edinburgh Instruments FLS 920 fluorescence system, which was combined with a 980 CW laser as excitation source for emission spectra. A power density of 350 W/cm2 was used for excitation. A redsensitive Peltier-cooled Hamamatsu R955 photomultiplier tube with a photon counting interface was used as a detector of the emission. All luminescence measurements were done with aqueous dispersion of nanoparticles. All spectra were corrected for the instrument sensitivity. In order to carry out appropriate optical intensity comparison, one batch of PVP-coated nanoparticle sample was split into two equal portions. One portion underwent cation exchange, and the other used as control. The concentration of NaLnF4 is thus the same (ca. 0.01 mmol/mL). The emission of the NaYF4:Yb,Tm nanoparticles that have undergone cation exchange with 10-fold Gd3+ ions at 75 °C was corrected by a factor of 1.2 (100/83.3) because they have 16.7% less emissive ions. Inductively Coupled Plasma Mass Spectroscopy. Inductively Coupled Plasma Mass Spectroscopy (ICP-MS) analysis was carried out using a Thermo X-Series II (X7) quadruple ICP-MS to determine elemental concentration in the nanoparticles. The water dispersion of ca. 2 mg of nanoparticles (or 2 mg of sample from control experiment for dialysis) was digested in concentrated nitric acid at 135 °C in sealed Teflon vials for 3 days and diluted with ultrapure water before analysis. Calibration was performed by analyzing serial dilutions of a mixed element synthetic standard containing known amount of elements. Each sample, standard and blank, was spiked with indium (to a concentration of about 7 ppb) as the internal standard to correct for signal drift and matrix effects. Accuracy was confirmed by analysis of a standard reference material (SLRS-4). Calculation of Shell Thickness of NaYF4:Yb,Tm-NaGdF4 Core−shell Nanoparticles. The NaGdF4 shell thickness of NaYF4:Yb,Tm-NaGdF4 core−shell nanoparticles was calculated based on the relative molar concentration of Gd3+ ion in relation to the total amount of Ln3+ ions along with the known size of nanoparticles (r = radius of nanoparticle). The relative molar concentration of Gd3+ ion (c) can be easily calculated once the elemental concentration was determined using ICP-MS. An example of shell thickness (x) calculation is as follows
4/3π(r − x)3 4/3πr 3
=
1−c 1
Relaxivity. Aqueous dispersions of nanoparticles were used to determine relaxivity. T1 and T2 relaxation measurements were obtained using a 9.4 T/21 cm bore magnet (Magnex, England) and Bruker (Bruker, Germany) console. A transmit/receive radio frequency volume birdcage coil was applied to excite protons and obtain resonant signal. For T2 measurements a multislice, multiecho pulse sequence was used. The pulse parameters were as follows: 1299
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Figure 2. (a) TEM image and (b) XRD pattern of the PVP-coated NaYF4:Yb,Tm nanoparticles [vertical bars at the bottom are positions of all the Bragg reflections of hexagonal NaYF4 (JCPDS 00-016-0334)]. repetition time (TR) 5 s, matrix size 128 × 128, field of view (FOV) 3 × 3 cm, slice thickness 2 mm, 128 echoes, 3 ms apart. T2 values were measured using a single exponential fitting of the echo train (Marevisi, Canada). For T1 measurement we used TRUE FISP pulse sequence with 3 mm slice thickness, FOV 30 × 30 mm, matrix size 128 × 128, TR 3 ms, TE 1.5 ms, 60 frames × 4 segments, segment time 192 ms. The single exponential fitting of the data was used (Marevisi, Canada) to calculate T1 values. The concentration of Gd3+ ion ([Gd3+]) in the nanoparticle dispersion was determined using ICP-MS, and r1 and r2 per Gd3+ ion were calculated by 1/(T1,2*[Gd3+]). For relaxivity per nanoparticle, the amount of Ln3+ ions in one nanoparticle with a known size was first calculated based on the volume, density, and molar mass, followed by the multiplication by the molar percentage of Gd3+ ion in the core−shell nanoparticles and relaxivity per Gd3+ ion.
The extent of the cation exchange was determined by ICP-MS, and the results are given in Table 1. For instance, ICP MS data Table 1. Gd3+ Concentration (%) in NaYF4:Yb,Tm Nanoparticles Cation-Exchanged under Different Conditions Based on ICP MS Dataa 40-fold Gd3+ 10-fold Gd3+ 2-fold Gd3+ a
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25 °C
50 °C
75 °C
100 °C
9.1 ± 0.1
14.6 ± 0.1
29.7 ± 0.1 16.7 ± 0.1 12.0 ± 0.1
45.8 ± 0.2
The concentration is relative to the total amount of Ln3+ ions.
show that after NaYF4:Yb,Tm nanoparticles were mixed with 10-fold Gd3+ ions at 75 °C, the nanoparticles contain 16.7% Gd3+ ions. TEM shows that the cation-exchanged nanoparticles have essentially the same morphology as the PVP-coated NaYF4:Yb,Tm nanoparticles (Figure 3a,3b), which is expected because the cation exchange process is not supposed to change the lattice formed by the anions.31 To confirm that all the detected Gd3+ ions are from the inorganic grain of nanoparticles and PVP does not hold any Gd3+ ions after dialysis, PVP was mixed with GdCl3 in water and stirred at 100 °C for 1 h. The mixture was then cooled down, followed by dialysis for the same amount of time (30 h) as for the cation-exchanged nanoparticles. After dialysis, no Gd3+ ion was found in PVP using ICP MS, which has a detection sensitivity of parts per trillion. This clearly shows that all the Gd3+ ions detected for the cation-exchanged nanoparticles are from the inorganic grain of nanoparticles, which confirms that Gd3+ ions in the solution did indeed replace Ln3+ ions in NaYF4:Yb,Tm nanoparticles. The above cation exchange reaction did not lead to a 100% replacement by Gd3+ ions, but only 16.7% were replaced. The important question is then where the Gd3+ ions are located in the cation-exchanged nanoparticles. As a matter of fact, the partial cation exchange has been used to make PbSe-CdSe core−shell semiconductor nanoparticles by partially replacing Pb2+ in PbSe nanoparticles with Cd2+ ions.29 Based on the blueshifted photoluminescence and the enhanced quantum yield, it has been concluded that the shell contains only CdSe. In contrast to semiconductor nanoparticles owning size-dependent optical properties, it is relatively hard to confirm convincingly a core−shell structure of lanthanide-based nanoparticles. In addition to size increase and optical enhancement, EELS and EDX line scans on randomly chosen nanoparticles
RESULTS AND DISCUSSION Oleate-stabilized NaYF4:Yb,Tm nanoparticles were synthesized using a coprecipitation method in organic media at 300 °C. As shown by the TEM image in Figure 1a, NaYF4:Yb,Tm nanoparticles are near-monodisperse with a size of 19.8 ± 1.2 nm. XRD pattern shows that NaYF4:Yb,Tm nanoparticles have the hexagonal phase, which is preferred to the cubic phase for optical applications.38 Using the Scherrer equation, the size of the nanoparticles was calculated to be 18.7 ± 0.7 nm, which is consistent with the size based on TEM. In order to make oleate-stabilized NaYF4:Yb,Tm nanoparticles water-dispersible, a ligand exchange process with polyvinylpyrrolidone (PVP) was carried out using a procedure modified from literature.33 After exchanging with PVP, as shown by the TEM image in Figure 2a, NaYF4:Yb,Tm nanoparticles look essentially the same as the as-prepared oleate-stabilized nanoparticles in morphology, and XRD pattern in Figure 2b shows that the PVP-coated NaYF4:Yb,Tm nanoparticles have the same hexagonal phase as the oleatestabilized nanoparticles (the broad hump peaked at 32° is due to amorphous PVP). These are expected results because the change in surface coordination should not change the crystal structure of nanoparticles. Due to the high solubility of PVP in water, the PVP-coated NaYF4:Yb,Tm nanoparticles can readily be dispersed in water, which is also consistent with our previous work.33 Cation exchange was performed by simply mixing the waterdispersible PVP-coated NaYF4:Yb,Tm nanoparticles with Gd3+ ions in water. Gd3+ ions were used in 40-, 10-, and 2-fold excess over the total Ln3+ ions in the precursor nanoparticles. After cation exchange, excess Gd3+ ions were removed by dialysis. 1300
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Figure 3. (a) TEM image, (b) HAADF image, and (c, d) EELS 2D elemental maps and line profiles of Gd3+ in NaYF4:Yb,Tm-NaGdF4 core−shell nanoparticles prepared by cation exchange of NaYF4:Yb,Tm nanoparticles with 10-fold Gd3+ ions at 75 °C.
have also been used,39 which could overlook the real structure of nanoparticles.22 In this article, to confirm that Gd3+ ions are in the surface layers, i.e. NaYF4:Yb,Tm-NaGdF4 core−shell nanoparticles had indeed been made, 2-dimensional mapping of Gd by electron energy-loss spectroscopy (EELS) was carried out on randomly chosen nanoparticles from the HAADF image that shows that all the nanoparticles are similar in morphology. Due to the higher concentration of the shell element(s) at the edge of core−shell nanoparticles in a 2D projection of the nanoparticles, the signal from the shell is higher than that from
the center of the core−shell nanoparticles. The signal difference between the shell and the center gives rise to a contrast with the shell being brighter. As shown in Figure 3c,d, EELS 2D mapping does show a brighter shell at the edge of the nanoparticle, which proves that NaYF4:Yb,Tm-NaGdF4 core− shell nanoparticles had indeed been made by the cation exchange process. The variation in brightness at the edge may suggest imperfectly uniform shell. However, the core is completely covered, which is further confirmed by the later relaxivity data. The EELS line profiles taken out of 2D mapping 1301
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To achieve shells of various thicknesses by the cation exchange process, two methods were carried out systematically. The first method is to apply different temperatures. As shown in Table 1, as the temperature for the cation exchange increases from 25 to 100 °C, the Gd3+ concentration in cation-exchanged nanoparticles increases from 9.1 to 45.8%, which corresponds to an average shell thickness increase from 0.3 to 1.9 nm. The other method is to use different amount of Gd3+ ions for the cation exchange reactions. As the amount of Gd3+ increases from 2- to 40-fold over Ln3+ ions in NaYF4:Yb,Tm nanoparticles, the Gd3+ concentration in the cation-exchanged nanoparticles increases from 12.0 to 29.7%, which corresponds to an average shell thickness increase from 0.4 to 1.1 nm. In Figure 4, TEM images again show that there is no obvious change in the morphology of the nanoparticles. To characterize the core−shell structure of these cation-exchanged nanoparticles, the nanoparticles that had undergone cation exchange with 40-fold Gd3+ ions at 75 and 100 °C were used to perform EELS 2D mapping. It can be seen in Figure 5a,b that cationexchanged nanoparticles prepared at 75 °C have an overall core−shell structure although the shell is not perfectly uniform as indicated by the light spots in the core area on the 2D mapping image and the line profiles. Moreover, those prepared at 100 °C, as shown in Figure 5c,d, have irregular surface morphology. The very uneven bright spots on 2D mapping image and the line profiles clearly show nonuniform distribution of Gd3+ (for more images, see Figure S2),
spectrum image in two different directions makes the core− shell structure clearer. Moreover, the complete coverage of the core nanoparticles by the shell is in sharp contrast to the incomplete shell of the core−shell nanoparticles synthesized using a direct synthesis procedure.22,23 In this case, with 16.7% Gd3+, the NaGdF4 shell thickness is only 0.6 nm (Table 2). The Table 2. Relaxivity (r1) of the NaYF4:Yb,Tm-NaGdF4 Core− Shell Nanoparticles Made by Cation-Exchange at Different Conditions (Measured at 9.4 T) parameter concentration (%) of Gd3+ in the nanoparticles calculated shell thickness (nm) r1 per Gd3+ ion (mM−1·s−1) r1 per nanoparticle (× 104 mM−1·s−1) r2 per Gd3+ ion (mM−1·s−1)
value 12
16.7
29.7
0.4
0.6
1.1
2.30 ± 0.01 1.07 ± 0.01
2.33 ± 0.01 1.50 ± 0.01
1.36 ± 0.01 1.56 ± 0.01
49.0 ± 0.5
160 ± 7
106 ± 5
thin shell is also indirectly confirmed by EDX measurements that were not able to distinguish the shell from the core due to the larger interactive volume size as compared to the thickness of the shell (Figure S1). These results clearly show that cation exchange is a very effective method to make genuine core−shell nanoparticles with a very thin shell. A subnanometer thin shell of NaGdF4 is crucial for MRI applications as shown later.
Figure 4. TEM of PVP-coated NaYF4:Yb,Tm nanoparticles after cation exchange at different conditions. 1302
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Figure 5. EELS 2D map and two line profiles of Gd3+ in NaYF4:Yb,Tm-NaGdF4 core−shell nanoparticles prepared by cation exchange of NaYF4:Yb,Tm nanoparticles with 40-fold Gd3+ ions at (a,c) 75 °C and (b,d) 100 °C (for more images, see Figure S2).
Figure 6 corresponds to the transition of 3H4 to 3H6. The peaks from the transitions of 1D2 to 3H6, 1G4 to 3H6, 1D2 to 3F4, and 1 G4 to 3F4 are overshadowed by the peak at 800 nm. The upconversion properties of the PVP-coated NaYF4:Yb,Tm nanoparticles from the same batch that had not undergone cation exchange were also measured as a control to compare with the cation-exchanged nanoparticles. Figure 6 shows that the cation-exchanged nanoparticles by 10-fold Gd3+ ions have a higher intensity than the precursor nanoparticles. Note that the shell thickness of the cation-exchanged nanoparticles is only 0.6
indicating a non-core−shell or incomplete core−shell structure. Thus, a trend can be seen that as the extent of cation exchange increases, the shell tends to become non-uniform or incomplete. From the above results, it can be concluded that core−shell nanoparticles with a tunable, uniform, and complete shell of up to ca. 1 nm thick can easily be made via cation exchange. The up-conversion properties of the cation-exchanged nanoparticles were tested by exciting with a 980 nm CW laser. The emission peak at 800 nm from Tm3+ ions shown in 1303
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also consistent with the size of unit cell (6.02 × 6.02 × 3.601 Å3), i.e. roughly one monolayer of NaGdF4 is needed on the surface. The extra NaGdF4 shell (1.1−0.6 = 0.5 nm) is not contributing to the relaxivity and thus makes the per-ion relaxivity lower. These results are consistent with a very recent work, in which core−shell nanoparticles with 0.2−0.7 nm thick NaGdF4 shell were made using a direct core−shell synthesis procedure and their per-ion relaxivities are also very similar (6.14−6.18 mM−1·s−1 at 3 T) despite their shell being likely anisotropic or incomplete.20 As their shell thickness further increases, the per-ion relaxivity decreases.20 From the above results, a rough trend can be seen that core−shell nanoparticles with a NaGdF4 shell thinner than ca. 0.6 nm should have the same per-ion relaxivity, and core−shell nanoparticles with a NaGdF4 shell thicker than ca. 0.6 nm should have the same pernanoparticle relaxivity. We would like to note that these analyses are possible because nanoparticles with the same size and different shell thicknesses can be made using the cation exchange process, which is otherwise very challenging using direct synthesis. The situation here is different from those based on nanoparticles made using direct synthesis, in which different shell thicknesses arise from different sizes, and, thus, the increase in shell thickness affects both the per-ion and pernanoparticle relaxivities. In order to compare these core−shell nanoparticles prepared via cation exchange with those prepared using a direct core− shell synthesis procedure, their relaxivities are listed in Table 3.
Figure 6. Emission spectra of (a) the cation-exchanged NaYF4:Yb,Tm nanoparticles with 10-fold Gd3+ ions at 75 °C and (b) the unexchanged PVP-coated NaYF4:Yb,Tm nanoparticles.
nm, and thus the quenching by the surface organic group, such as −OH and −CH, still occurs.20 This could be overcome by making NaYF4:Yb,Tm-NaYF4 core−shell nanoparticles first, followed by cation exchange to incorporate a thin NaGdF4 shell for bifunctional applications. The NaYF4:Yb,Tm-NaGdF4 core−shell nanoparticles with a shell thickness of up to 1.1 nm made by the cation exchange process, as potential MRI contrast agents, were also tested for their relaxivity, and the results are shown in Table 2. The r1 relaxivity per Gd3+ ion is up to 2.33 mM−1·s−1 at 9.4 T, which is similar to that of clinically used Gd3+-complexes, such as GdDOTA (3.0 mM−1·s−1 at 9.4 T36) and Gd-DTPA (3.1 mM−1·s−1 at 9.4 T36). The r1 relaxivity per nanoparticle of the cation-exchanged nanoparticles is up to 1.56 × 104 mM−1·s−1, which is over 4000 times higher than these Gd3+complexes. The very high relaxivity per nanoparticle enables very high local contrast in MRI with a low dose, which is crucial for the targeted contrast imaging.1,40 The r2 relaxivity per Gd3+ ion measured at 9.4 T is in the range of 49−160 mM−1·s−1, which is significantly higher than r1. This is expected for nanoparticles at a high magnetic field.41 Unfortunately, due to lack of data at 9.4 T, it cannot be compared directly with Gd3+complexes. From Table 2, it can also be seen that as the shell thickness increases from 0.4 to 0.6 nm, the per-ion relaxivity remains almost the same (only 1.3% difference) whereas the pernanoparticle relaxivity changes dramatically. The very similar per-ion relaxivity of the nanoparticles with 0.4 and 0.6 nm thick shell suggests that Gd3+ ions in these nanoparticles are very likely fully utilized for the relaxivity. The increased pernanoparticle relaxivity indicates that a 0.4 nm thick NaGdF4 shell is not sufficient to cover fully the surface of the nanoparticles, i.e. the surface of the nanoparticles is not fully occupied by Gd3+ ions. As the shell thickness further increases from 0.6 to 1.1 nm, the per-nanoparticle relaxivity remains almost the same (3.8% difference) whereas the per-ion relaxivity decreases dramatically. The very similar per-nanoparticle relaxivity suggests that the increase in NaGdF4 shell thickness from 0.6 nm to 1.1 does not change the total relaxivity. Thus, 0.6 nm thick NaGdF4 shell seems sufficient to cover fully the surface of the nanoparticles, i.e. the surface is fully occupied by Gd3+ ions, which confirms the complete shell as suggested by the EELS 2D map in Figure 3. This thickness is
Table 3. Comparison of the Relaxivity (r1) of Gd3+-Based Inorganic Nanoparticles nanoparticles NaYF4:Yb,Tm-NaGdF4 core−shell NaGdF4:Yb,Er-NaGdF4 core−shell NaGdF4:Yb,Er-NaGdF4 core−shell NaYF4:Yb,Er-NaGdF4 core−shell NaYF4:Yb,Er-NaGdF4 core−shell NaYF4:Yb,Er-NaGdF4 core−shell
size (nm)
r1 (mM−1·s−1)
field (T)
ref
20
2.33
9.4
this work
20
1.4
1.5
Heyon et al.10
41
1.05
1.5
Heyon et al.10
28
0.48
3.0
12
2.6
4.7
Muhammad et al.19 Prasad et al.18
24
6.18
3
Shi et al.20
It can be seen that the per-ion relaxivities in the work by Heyon et al.10 and by Muhammad et al.19 are lower than this work. The per-ion relaxivity of 2.6 mM−1·s−1 at 4.7 T by Prasad et al. looks higher than this work.18 However, the per-ion relaxivity of Gd3+-based nanoparticles decreases significantly as the applied magnetic field increases,41 and this number is thus expected to be lower at 9.4 T. The reason for these core−shell nanoparticles having lower per-ion relaxivities is that their NaGdF4 shell is relatively thick (a few nanometers18,19) and in the case of Heyon’s work, a large portion of Gd3+ ions are in the core.10 The very recently reported core−shell nanoparticles with 0.2−0.7 nm thick NaGdF4 shell prepared by Shi et al., as aforementioned, have relaxivities of 6.14−6.18 mM−1·s−1 at 3 T, which should be roughly the same as our work at 9.4 T because they have the similar thin NaGdF4 shell to our core− shell nanoparticles made by cation exchange as described above. 1304
dx.doi.org/10.1021/cm2036844 | Chem. Mater. 2012, 24, 1297−1305
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(12) Zhou, J.; Yu, M. X.; Sun, Y.; Zhang, X. Z.; Zhu, X. J.; Wu, Z. H.; Wu, D. M.; Li, F. Y. Biomaterials 2011, 32, 1148. (13) Liu, Q.; Sun, Y.; Li, C. G.; Zhou, J.; Li, C. Y.; Yang, T. S.; Zhang, X. Z.; Yi, T.; Wu, D. M.; Li, F. Y. ACS Nano 2011, 5, 3146. (14) Ryu, J.; Park, H. Y.; Kim, K.; Kim, H.; Yoo, J. H.; Kang, M.; Im, K.; Grailhe, R.; Song, R. J. Phys. Chem. C 2010, 114, 21077. (15) Cheng, L.; Yang, K.; Li, Y.; Chen, J.; Wang, C.; Shao, M.; Lee, S. T.; Liu, Z. Angew. Chem., Int. Ed. 2011, 50, 7385. (16) Johnson, N. J. J.; Oakden, W.; Stanisz, G. J.; Prosser, R. S.; van Veggel, F. C. J. M. Chem. Mater. 2011, 23, 3714. (17) Evanics, F.; Diamente, P. R.; van Veggel, F. C. J. M.; Stanisz, G. J.; Prosser, R. S. Chem. Mater. 2006, 18, 2499. (18) Chen, G. Y.; Ohulchanskyy, T. Y.; Law, W. C.; Agren, H.; Prasad, P. N. Nanoscale 2011, 3, 2003. (19) Guo, H.; Li, Z. Q.; Qian, H. S.; Hu, Y.; Muhammad, I. N. Nanotechnology 2010, 21, 125602. (20) Chen, F.; Bu, W.; Zhang, S.; Liu, X.; Liu, J.; Xing, H.; Xiao, Q.; Zhou, L.; Peng, W.; Wang, L.; Shi, J. Adv. Funct. Mater. 2011, 21, 4285. (21) Dong, C. H.; Pichaandi, J.; Regier, T.; van Veggel, F. C. J. M. Nanoscale 2011, 3, 3376. (22) Abel, K. A.; Boyer, J. C.; Andrei, C. M.; van Veggel, F. C. J. M. J. Phys. Chem. Lett. 2011, 2, 185. (23) Abel, K. A.; Boyer, J. C.; van Veggel, F. C. J. M. J. Am. Chem. Soc. 2009, 131, 14644. (24) Mews, A.; Eychmuller, A.; Giersig, M.; Schooss, D.; Weller, H. J. Phys. Chem. 1994, 98, 934. (25) Smith, A. M.; Nie, S. M. J. Am. Chem. Soc. 2011, 133, 24. (26) Deka, S.; Miszta, K.; Dorfs, D.; Genovese, A.; Bertoni, G.; Manna, L. Nano Lett. 2010, 10, 3770. (27) Jeong, U.; Kim, J. U.; Xia, Y. N. Nano Lett. 2005, 5, 937. (28) Camargo, P. H. C.; Lee, Y. H.; Jeong, U.; Zou, Z. Q.; Xia, Y. N. Langmuir 2007, 23, 2985. (29) Pietryga, J. M.; Werder, D. J.; Williams, D. J.; Casson, J. L.; Schaller, R. D.; Klimov, V. I.; Hollingsworth, J. A. J. Am. Chem. Soc. 2008, 130, 4879. (30) Ethayaraja, M.; Bandyopadhyaya, R. Ind. Eng. Chem. Res. 2008, 47, 5982. (31) Son, D. H.; Hughes, S. M.; Yin, Y. D.; Alivisatos, A. P. Science 2004, 306, 1009. (32) Dong, C. H.; van Veggel, F. C. J. M. ACS Nano 2009, 3, 123. (33) Johnson, N. J. J.; Sangeetha, N. M.; Boyer, J. C.; van Veggel, F. C. J. M. Nanoscale 2010, 2, 771. (34) Li, Z. Q.; Zhang, Y.; Jiang, S. Adv. Mater. 2008, 20, 4765. (35) Pautler, R. G. Physiology 2004, 19, 168. (36) de Sousa, P. L.; Livramento, J. B.; Helm, L.; Merbach, A. E.; Meme, W.; Doan, B.-T.; Beloeil, J.-C.; Prata, M. I. M.; Santos, A. C.; Geraldes, C. F. G. C.; Toth, E. Contrast Media Mol. Imaging 2008, 3, 78. (37) Li, Z. Q.; Zhang, Y. Nanotechnology 2008, 19, 345606. (38) Wang, G. F.; Peng, Q.; Li, Y. D. Acc. Chem. Res. 2011, 44, 322. (39) Wang, F.; Deng, R. R.; Wang, J.; Wang, Q. X.; Han, Y.; Zhu, H. M.; Chen, X. Y.; Liu, X. G. Nat. Mater. 2011, 10, 968. (40) Werner, E. J.; Datta, A.; Jocher, C. J.; Raymond, K. N. Angew. Chem., Int. Ed. 2008, 47, 8568. (41) Caravan, P.; Farrar, C. T.; Frullano, L.; Uppal, R. Contrast Media Mol. Imaging 2009, 4, 89.
CONCLUSIONS Cation exchange of NaYF4:Yb,Tm nanoparticles with Gd3+ ions was performed in aqueous media after the as-prepared oleatestabilized NaYF4:Yb,Tm nanoparticles were made waterdispersible by ligand exchange with PVP. The resulting nanoparticles have a core−shell structure. A thin, tunable, and uniform NaGdF4 shell of the NaYF4:Yb,Tm-NaGdF4 core−shell nanoparticles have been achieved via the cation exchange process. These core−shell nanoparticles have enhanced up-conversion properties, and their relaxivity per Gd3+ ion is among the highest in all the NaYF4−NaGdF4 core− shell nanoparticles due to the very thin NaGdF4 shell. The r1 relaxivity per nanoparticle of 1.56 × 104 mM−1·s−1 is over 4000 times that of Gd3+-complexes, which is crucial for targeted MR imaging. These NaYF4:Yb,Tm-NaGdF4 core−shell nanoparticles are promising for bimodal imaging, i.e. optical bioimaging and MRI.
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ASSOCIATED CONTENT
S Supporting Information *
EDX line scans, EELS 2D map, EELS line profiles, and Gd/Y molar ratio of cation-exchanged nanoparticles. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge the generous funding from the Natural Science and Engineering Research Council (NSERC), the Canada Foundation for Innovation (CFI), and the British Columbia Knowledge Development Fund (BCKDF) of Canada. The EELS and HAADF work was done at the Canadian Centre for Electron Microscopy, a facility supported by NSERC and McMaster University.
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