Article pubs.acs.org/cm
Deep Tissue Imaging with Highly Fluorescent Near-Infrared Nanocrystals after Systematic Host Screening Fabian H. L. Starsich,† Pascal Gschwend,† Anton Sergeyev,‡ Rachel Grange,‡ and Sotiris E. Pratsinis*,† †
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Particle Technology Laboratory, Institute of Process Engineering, Department of Mechanical and Process Engineering, ETH Zurich, Sonneggstrasse 3, CH-8092 Zurich, Switzerland ‡ Optical Nanomaterials Group, Institute for Quantum Electronics, Department of Physics, ETH Zurich, Auguste-Piccard-Hof 1, CH-8093 Zurich, Switzerland S Supporting Information *
ABSTRACT: Photoluminescent inorganic nanoparticles are attractive as bioimaging contrast agents because they do not degrade by photobleaching and do not suffer from concentration quenching as clinically applied organic dyes. Here, for the first time, a large variety of oxide, phosphate, and vanadate nanocrystals doped with Nd3+ are systematically examined and compared as down-converting photoluminescent contrast agents to understand underlying physical properties and to identify the brightest composition. These inorganic crystals are particularly attractive for bioimaging in the near-infrared (NIR) window, where absorption and scattering by human tissue are reduced drastically. Through close control of their crystal size, the resulting fluorescence properties are quantitatively compared under NIR excitation. Most interestingly, BiVO4 doped with Nd3+ is shown to be the most efficient composition. Its application as a photoluminescent NIR imaging contrast agent is demonstrated ex vivo with chicken skeletal muscle and bovine liver tissues. Under a harmless laser power density (0.2 W/cm2), fluorescent BiVO4 particles could be clearly detected at an injection depth of 20 mm by a simple commercial camera.
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INTRODUCTION Photoluminescent inorganic nanoparticles consist of a host lattice doped with rare-earth ions as an active species. The characteristic luminescence from various doping elements ranges from the visible to the near-infrared (NIR) region, making such systems attractive in various biomedical applications. In particular, photoluminescent nanoparticles can be utilized as in vitro or in vivo imaging agents via absorption and emission of light. The emitted light can be detected with a standard camera (silicon detector). Photoluminescence imaging, therefore, requires only simple and costefficient equipment, compared to other clinically established imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI).1 Furthermore, this simple diagnostic method is characterized by high sensitivity,2 excellent planar resolution,3 and real-time imaging.4 However, in vivo optical imaging is restricted to the NIR range where light absorption, scattering, and autofluorescence by living tissue are drastically reduced.5 Hence, to achieve a large penetration depth, both excitation and emission spectra of the photoluminescent nanoparticles should peak at the so-called first (650−950 nm) or/and second (1000−1300 nm) biological windows. The first biological window is preferred as the required imaging equipment is cheaper than that for higher wavelengths. © 2017 American Chemical Society
Currently, the commercially used photoluminescent material is the organic dye indocyanine green (ICG).6,7 It is clinically applied for sentinel lymph node real-time mapping, tumor imaging,8and the intraoperative detection of tumor boundaries. It can serve as an adjunct intraoperative imaging modality (in addition to palpation and visual inspection) to detect small or superficial tumors or determine lesion margins that would be missed otherwise. Also, it does not disrupt the normal workflow, allowing surgeons to find tumors more easily. This reduces operating and therefore anesthesia time as well as overall costs. Despite these promising applications, ICG suffers from major drawbacks such as degradation, photobleaching,9 and concentration quenching10 that limit its biomedical use. Alternatively, quantum dots11 and rare-earth-doped inorganic materials, which do not have the limitations mentioned above, are quite attractive and can be classified into up- and down-converting systems. The former combine the energy of several absorbed photons of the incident irradiation to emit higher-energy light. Despite ongoing intensive research, the quantum yields (ratio of emitted to absorbed photons) of up-converting systems are Received: May 26, 2017 Revised: September 14, 2017 Published: September 15, 2017 8158
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Figure 1. Transmission electron microscopy images of (a) as-prepared and (b) annealed (600 °C, 2 h) BiVO4:Nd3+ nanoparticles. Primary particle size distributions as determined by image analysis of (c) as-prepared and (d) annealed BiVO4:Nd3+ nanoparticles. The inset shows the evolution of the geometric standard deviation as a function of counted nanoparticles.
and co-workers23 presented a study of seven different host materials (LaF3, SrF2, NaGdF4, NaYF4, KYF4, GdVO4, and YAG) doped with Nd3+; the emission efficiencies, however, were not characterized. Because of the complexity of the underlying physical processes, the clear relationship between photoluminescence efficiency and host matrix properties has not yet been investigated. Because emission intensities of materials reported in the literature strongly depend on the equipment and measurement procedure, comparisons in general are difficult to make. Methods for quantifying the efficiency such as determining the quantum yield have been developed but are not established and still challenging to implement and compare. Major issues are the lack of well-established standards, especially in the NIR region, for relative methods or proper calibrations of integrating sphere setups for absolute methods.24,25 Furthermore, quantum yields strongly depend on particle concentrations26 and laser power densities.27 Therefore, direct comparisons of different host materials produced by the same technique and characterized in an identical setup are needed. Common nanoparticle synthesis methods may be limiting for a quantitative comparison of various photoluminescent materials. In particular, wet-phase procedures typically suffer from limited versatility in the achievable material characteristics. Flame aerosol technology, on the other hand, is known for synthesis of nanoparticles with precise control over size, composition, and morphology.28 Furthermore, it is a scalable (up to kilograms per hour), high-purity, and dry process,29 all of which are key requirements for a potential translation of the nanomaterial into clinics. Here, we demonstrate a comparative study of the NIR downconverting photoluminescent efficiency of 18 flame-made host crystals doped with Nd3+ quantifying their bioimaging performance. The outstanding photoluminescent properties of biocompatible Nd-doped BiVO4 are revealed, and its performance for NIR deep tissue imaging is demonstrated ex vivo with chicken muscle and bovine liver tissue.
an order of magnitude lower than those of their competitors.12,13 More specifically, the highest efficiency for upconverting nanoparticles reported so far was 7.6%.14 Surprisingly, alternative down-converting photoluminescent inorganic nanoparticles, which absorb higher-enrgy light and emit lowerenergy light, have not been investigated in much detail, even though efficiencies of ≤80% have been reported.15 However, photoluminescent efficiencies in general are challenging to compare, as they have been shown to strongly depend on measurement conditions, which are discussed here in detail. So far, Nd3+ (neodymium) is the most promising dopant for down-converting photoluminescent materials for NIR optical imaging.16 It can be excited at 808 nm, and its fluorescence emission peaks are around 900 nm. Chen et al.17 produced core−shell NaGdF4:Nd3+-NaGdF4 particles and used the fluorescent emission at 900 nm to image subcutaneously injected nanoparticles in mice at a depth of 3 mm. Rocha et al. 18 used the 1060 nm emission peak of LaF 3 :Nd 3+ nanoparticles to demonstrate deep tissue in vivo imaging up to 10 mm after intravenous injection in mice. Apart from the fluorescent performance, the toxicity of such materials in biological applications also has to be considered carefully. For example, materials containing gadolinium exhibit promising fluorescence but are potentially harmful to patients suffering from advanced renal failure attributed to released ions.19 This has led the European Medicine Agency to recommend the replacement of linear Gd chelates as MRI contrast agents. Most of the literature on photoluminescent nanoparticles so far is focused on dopant effects, using a single host matrix. To optimize photoluminescence efficiency for a given dopant, various host crystal matrices should be evaluated. Such comprehensive comparisons of different host systems are so far available for only bulk materials used in laser applications.20 Comparisons of hosts at the nanoscale focus either on a few different ones or on only qualitative differences in the photoluminescent properties. Rambabu et al.21,22 studied the effect of three host crystal materials (YPO4, LaPO4, and GdPO4) doped with either Tb3+ or Eu3+. Recently, del Rosal 8159
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Figure 2. Normalized photoluminescence spectra of the 4F9/2 → 4I3/2 transition of Nd3+ in all host matrices produced under 808 nm excitation. The spectra are ordered according to the crystal phase of the host matrix, and their space groups are indicated.
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RESULTS AND DISCUSSION Nd3+ Fluorescence in Various Host Crystal Compositions and Sizes. Rare-earth metals Ce, Gd, La, and Y as well as Bi are produced by flame synthesis as Nd3+-doped oxides, phosphates, and vanadates. The metals were chosen because their ionic radii are similar to that of Nd3+, enabling their easy incorporation into the matrix. Pure Nd2O3, NdPO4, and NdVO4 particles were also prepared. First, the effect of the Nd3+ doping concentration on photoluminescence efficiency is investigated for representative hosts (Y2O3, LaPO4, YVO4, and BiVO4). An optimum Nd concentration of 1 atom % is found for all of them (Figure S1). At low dopant concentrations, the emission intensity increases with an increasing number of active sites. Extensive doping, however, leads to an increased level of nonradiative decay via energy transfer within the Nd3+ ions, which lowers the overall fluorescence efficiency.30 For all
doping contents, no formation of Nd-containing crystals (e.g., Nd2O3, NdVO4, and NdPO4) was observed in the obtained Xray diffraction patterns (not shown here). This indicates that Nd3+ was homogeneously incorporated into the various hosts. All as-prepared flame-made materials here had primary particle sizes (dBET) between 11 and 32 nm, consistent with their respective crystal sizes (dXRD) indicating monocrystallinity (Figure S2). Annealing these nanoparticles at different temperatures and for different durations allows further finetuning of their size and phase composition (Table S2 and Figures S3−S8). Figure 1 exemplarily depicts transmission electron images of (a) as-prepared and (b) annealed BiVO4:Nd3+ nanoparticles, and the corresponding primary particle size distributions (c and d) as determined by image analysis. 8160
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crystal growth (resulting dXRD in Table S2). As a representative example, Figure 3a shows the emission spectra (λex = 808 nm)
As one can see in Figure 1, the average primary particle size increases from 24 nm for as-prepared BiVO4:Nd3+ nanoparticles to 76 nm after annealing. This corresponds to the reported dBET (Figure S2) and dXRD values (Table S2). The morphology remains similar, indicating that it is not influenced by the sintering process. The geometric standard deviation (σg) decreases slightly from 1.36 for the as-prepared sample to 1.28 after annealing. This can be explained by the faster sintering of smaller nanoparticles to larger structures. The difference between the particle size distributions based on the small and large particle axes is not significant (Figure S9). Figure 2 shows the normalized emission spectra (λex = 808 nm) of the various as-prepared Nd3+-doped nanoparticles, grouped according to their crystal structure: (a) tetragonal, (b) monoclinic, (c) hexagonal, and (d) cubic. In all materials, the characteristic peaks of Nd3+ between 850 and 950 nm can be detected originating from the 4F9/2 → 4I3/2 transition.31 The emission peaks are in excellent agreement with the literature for several hosts, e.g., LaPO432 or GdVO4.23 Various host crystals produce different electric fields surrounding the Nd3+ ions, which influence fluorescence properties (Stark splitting).33 As one can see in Figure 2, different spectra reveal a close relationship between the crystal structure and emission pattern. All vanadates with tetragonal structure and in space group I41/amd (Figure 2a) exhibit almost the same spectral characteristics. The emission of tetragonal YPO4, which has the same space group, is comparable featuring an additional peak around 870 nm. A similar behavior can be observed for the monoclinic crystals (Figure 2b). Phosphates in space group P21/c (NdPO4, LaPO4, GdPO4, and CePO4) show very similar spectra, which are slightly shifted to higher wavelengths for LaVO4 and BiVO4, which have the same space group. However, monoclinic Bi2O3, which also has the same space group, has a quite distinct spectrum. On the other hand, hexagonal crystals (Figure 2c) show only minor similarities in emission spectra even though both have the same space group. Cubic Y2O3 and CeO2 (Figure 2d), however, have quite comparable emission spectra. Figure 2 also depicts the influence of the host crystal on the broadness of the emission spectrum. For cubic Y2O3, the difference from the lowest (879 nm) to the highest observed peak (946 nm) is 67 nm, whereas the difference for YVO4 is only 35 nm (from 879 to 914 nm). Emission patterns correlate with the interaction force of the metal and oxygen ions in the host matrices.34 Stronger interaction forces decrease the level of polarization of rare-earth ions by the oxygen atoms and result in a broader emission range. The degree of this spectral broadening gradually decreases from oxides over phosphates to vanadates.34 Chemical bonding between doping ions and host crystal atoms influences the absorption and photoluminescence spectra.35 Peaks shift toward longer wavelengths for materials with a decreasing difference in electronegativity between Nd3+ and the ligand, e.g., from phosphates to oxides.34 A similar trend can be observed by comparing monoclinic structures of P21/c symmetry (Figure 2b): the phosphates show emission peaks below 875 nm, LaVO4 shows a peak around 875 nm, while Bi2O3 shows a peak at only 890 nm. This indicates stronger covalent bonding of rare-earth ions with the host.34 The fluorescence efficiency of nanoparticles depends not only on host composition but also on crystal size.36 This effect was closely analyzed by annealing the as-prepared nanoparticles at different temperatures and durations, leading to controllable
Figure 3. (a) Emission spectra of NdVO4 with dXRD values of 30, 53, and 78 nm. (b) Integrated emission intensity (850−1000 nm) obtained from panel a as a function of crystal size (dXRD). (c) Predicted emission intensity of all materials for a crystal size of 50 nm excited at their optimized wavelengths (Figure S11, circles). Respective crystal phases are indicated (M, monoclinic; C, cubic; H, hexagonal; T, tetragonal).
of NdVO4 nanoparticles with crystal sizes of 30, 53, and 78 nm. The emission intensities clearly increase with crystal size, while their pattern is not affected. This can be explained by the increased electromagnetic light volume inside a larger structure and the decreased level of nonradiative relaxation for larger particles.3 As the crystal size increases, the surface to volume ratio decreases, leading to lower local concentrations of crystal defects that dissipate the absorbed energy of the excited dopant ion.37 Furthermore, the number of surface hydroxyl groups per mass, which quench photoluminescence,38 is decreased.39 A linear relationship between NdVO4 crystal size and overall fluorescence intensity is revealed by integrating the emission spectra between 850 and 1000 nm (Figure 3b, squares). Such a relationship holds for all materials produced (Figure S10c) and allows determination of the emission intensity for each material at a dXRD of 50 nm (Figure 3b, e.g., circle for NdVO4). Furthermore, it was shown that besides the emission, the excitation profiles of photoluminescent nanoparticles depend on the host crystal-phase composition. To this end, excitation profiles of all samples were recorded between 770 and 825 nm 8161
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host material, is investigated as a potential fluorescent imaging agent for biomedical applications. Deep Tissue Imaging with BiVO4:Nd3+. Figure 4a shows a dilute aqueous suspension of highly fluorescent BiVO4:Nd3+
(Figure S11). Thereafter, the emission intensities obtained under a λex of 808 nm were scaled to the optimized excitation wavelength. In agreement with the literature,40,41 the excitation profile patterns were thought to be constant over the range of investigated crystal sizes. Figure 3c shows the calculated emission intensity at a dXRD of 50 nm [at optimized excitation wavelength (Figure S11, circles)] for all materials. There, it can be seen that BiVO4 clearly emerges as the most efficient of all hosts investigated (first column in Figure 3c). YVO4, GdVO4, monoclinic Y2O3, YPO4, and La2O3 perform quite well also. More specifically, monoclinic Y2O3 is much stronger (four times) than its cubic phase as the host for Nd3+ doping. The same phase dependency is observed42 for flame-made Y2O3:Tb3+ nanoparticles, while for Y2O3:Eu3+ nanoparticles, the cubic phase leads to an emission intensity higher than that of the monoclinic form.43 NdVO4 shows decent emission intensity, though it is more effective to use the active material (e.g., Nd) as a dopant.44 The comparison of the fluorescence efficiencies of various host materials is not straightforward. The down-conversion luminescence can be separated into three steps: (i) absorption of an incident photon leading to the excitation of an electron to a higher state, (ii) nonradiative losses via dopant energy transfer or lattice phonons,34,45 and (iii) emission of a lower-energy photon. Steps (ii) and (iii) are coupled directly as the the number of emitted photons increases when losses decrease. The level of dopant energy transfer can be reduced by decreasing the dopant interionic distance, i.e., adapting the doping concentration (Figure S1). Phonon-induced losses, on the other hand, increase for materials with higher phonon energies. Hence, host materials with lower phonon energies should be favored for efficient fluorescence.17 Generally, oxides (Y2O3, 430−550 cm−1)35 have phonon energies lower than those of vanadates (YVO4, 890 cm−1)46 or phosphates (LaPO4, 1050 cm−1).46 Interestingly, in this study, there is no clear correlation between phonon energy and emission intensity, and therefore, no experimental verification of the described theories can be reported. It is suggested that the light absorption properties of the host crystals have a strong influence on their fluorescence efficiency as seen by the outstanding performance of BiVO4, which is well-known for its bright yellow color47 and has been investigated as an up-converting photoluminescent system for improved photocatalysis.48 This hypothesis requires a careful investigation and will be topic for future research. The photoluminescence decay of our BiVO4:Nd3+ nanoparticles follows a double-exponential profile with an average lifetime of 87 μs (Figure S12). In comparison to other materials doped with 1 atom % Nd3+ (e.g., 19 μs for NaYF4,23 0.84 μs for YAG,23 and 59 μs for YF331), this value is high, indicating minor quenching and nonradiative decay.17 A quantum yield of 1.58% (at a power density of 0.1 W/cm2) was measured for our BiVO4:Nd3+ nanoparticles, which compares well to the literature.26 However, quantum yields strongly depend on excitation density,27 which unfortunately is rarely reported. Furthermore, they are affected by concentration in colloidal dispersions, making an objective evaluation even more complicated.26 This highlights the necessity of constant measurement conditions for a fair comparison of photoluminescent nanomaterials, which is done here. In the following, BiVO 4:Nd3+, which has not been identified previously as an outstanding down-converting fluorescent
Figure 4. Fluorescence of BiVO4:Nd3+ nanoparticles. (a) Aqueous particle suspension under NIR excitation showing local fluorescence even at a low concentration (0.1 mg/mL). (b) Schematic of the experimental setup used for ex vivo experiments. (c) Fluorescence of BiVO4:Nd3+ nanoparticles (aqueous suspensions, 3 mg/mL) injected ex vivo into chicken skeletal muscle tissue at depths of 3−20 mm and imaged with a camera after harmless 808 nm excitation (0.2 W/cm2). Integrated emission intensities acquired by adding the intensities of each pixel in the insets follow an exponential decay. (d) Particles were patterned in form of the letter “P” and placed 5 mm behind bovine liver tissue. (e) Under 808 nm excitation, the particles could be clearly imaged. (f) Overlay of panels d and e showing a possible application during surgery.
(0.1 mg/mL) under NIR excitation from the side. The local fluorescence can be clearly detected in the middle of the cuvette, at the path of the incident laser beam. The BiVO4:Nd3+ nanoparticles remain in suspension without any surface treatment, as shown by dynamic light scattering (Figure S13). During all ex vivo experiments, no substantial temperature increase (>1 °C) of the particle suspensions due to illumination was detected (measured with an IR camera). The potential of BiVO4:Nd3+ as a bioimaging agent was assessed by injecting 100 μL of its aqueous suspension (3 mg/mL) ex vivo into chicken skeletal muscle tissue at depths of 3−20 mm. The particles were excited at 808 nm and 0.2 W/cm2, which is a harmless skin exposure for up to 8 h,49 and their emission was detected by a camera (Figure 4b). The insets in Figure 4c show the acquired images with and without particles. In the absence of particles, no autofluor8162
DOI: 10.1021/acs.chemmater.7b02170 Chem. Mater. 2017, 29, 8158−8166
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Figure 6. Comparison of the performance of fluorescent nanoparticles (BiVO4:Nd3+, circles) and a commercial NIR dye [indocyanine green (ICG), triangles]: (a) under constant laser exposure (2.5 W/cm2) at different intervals, (b) as a function of material concentration, and (c) for suspensions stored in the dark (λex = 808 nm) at different times after preparation.
A system resolution of 119 μm for BiVO4:Nd3+ and 77 μm for ICG was calculated as detailed in the Experimental Section and in Figure S15. This resolution is well preserved for at least 90 min by the BiVO4:Nd3+ nanoparticles, while it has faded away within 60 min for ICG. For larger imaging depths, the square pattern of both BiVO4:Nd3+ and ICG could not be clearly detected (data not shown).52 The resolution of optical imaging systems is theoretically limited by the Abbe diffraction limit to ∼λ/2.53 Practically, the resolution decreases because of equipment limitations and for in vivo applications by optical scattering through the tissue (through which imaging is performed).18 The latter effect depends only on the wavelength of the traveling light (excitation and emission). For BiVO4:Nd3+ nanoparticles, both of these wavelengths and therefore also the resolution are very similar to those of the fluorescent dye ICG, which is already clinically used for imaging at submillimeter resolution (e.g., capillaries).9 This suggests that despite any limitations in deep tissue resolution, our nanoparticles are as applicable for in vivo photoluminescent imaging as ICG is. The photoluminescent nanoparticles were contrasted in further detail to the clinically applied NIR dye ICG that is readily used for the intraoperative detection of tumor boundaries.6 Figure 6 compares the photoluminescence performance of this dye (triangles) to that of BiVO4:Nd3+ nanoparticles (circles) under various conditions. Figure 6a shows the evolution of the emission intensities of ICG and BiVO4:Nd3+ under constant laser exposure (2.5 W/cm2). After illumination for 20 min, the emission of the dye disappears while that of BiVO4:Nd3+ remains unaffected near its maximum for >4 h. The performance of ICG can be attributed to photobleaching9 that severely limits its use for long-term exposure, for example, during surgery.54
Figure 5. NIR fluorescence images of BiVO4:Nd3+ (top) and surgical dye ICG (bottom) patterned in a square, through 5 mm of optical phantom under harmless 808 nm excitation (0.2 W/cm2) after (a) 0, (b) 60, and (c) 90 min.
and 90 min (Figure 5c) under constant illumination. The photoluminescence of both materials can be clearly detected initially. At increasing illumination times, the intensity of the signal generated by the surgical dye ICG is drastically decreased (Figure 5b) and becomes completely undetectable after 90 min (Figure 5c). Flame-made BiVO4:Nd3+, on the other hand, can be localized sharply even after 90 min, with minor fluctuations in intensity compared to the initial image. These can be explained by instabilities in the utilized laser and detector equipment, changes in the surrounding light (both are also reproducibly detected for aqueous particle dispersions (Figure 6a,c)), and slight degradation of the agar matrix. 8163
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Chemistry of Materials The dependence of material concentration on fluorescence is depicted in Figure 6b. The ICG (triangles) shows a linear dependence up to a concentration of 0.1 g/L (0.13 mM). For higher concentrations, quenching occurs and the emission steadily decreases.10 As a result, the measured ICG emission cannot be correlated reliably to its concentration at a specific location. In contrast, the nanoparticles’ fluorescence scales linearly with concentration to 10 g/L. To compare optical stabilities of ICG and BiVO4:Nd3+, we shine light on both samples and record the obtained fluorescence signal in the dark at room temperature. Figure 6c shows the obtained measurements for ICG (triangles) and BiVO 4 :Nd 3+ (circles). BiVO4:Nd3+ does not show any attenuation of its luminescence for 90 h. On the other hand, ICG is steadily degrading. These three main drawbacks of ICG, namely, photobleaching, concentration quenching, and degradation, clearly render fluorescent nanoparticles a superior biomedical NIR imaging system. Despite these major drawbacks, ICG is widely used during surgery, indicating the potential clinical impact of a photostable alternative, such as the nanoparticles described here. Finally, the cytotoxicity of BiVO4:Nd3+ nanoparticles was tested with macrophages.55 Low toxicity was exhibited for particle concentrations of ≤50 μg/mL (Figure S16). This is in agreement with the reported oral LD50 value of BiVO4 tested in rats to >5000 mg/kg.56 Furthermore, BiVO4 is currently used for food packaging, indicating its low toxicity.56
Sigma-Aldrich, 99%) and ethanol for a metal molarity of 0.4.43 The vanadate precursor solution was prepared by dissolving nitrate salts together with stoichiometric amounts of ammonium metavanadate (Sigma-Aldrich, 99%) in a 2:1 volumetric ratio of 2-EHA to acetic anhydride (Sigma-Aldrich, puriss.) while the mixture was being stirred and heated to 100 °C for 1.5 h. This yielded a molarity of 0.4 for the metal and vanadium combined. The precursor for LaVO4 was prepared by dissolving the La and V salts listed above in a 2:1:1 2EHA:acetic anhydride:ethanol volumetric ratio. The phosphate precursor solutions were prepared by dissolving appropriate nitrate salts with tributyl phosphate (Sigma-Aldrich, 97%) in a 1:1 2EHA:ethanol volumetric ratio, giving again a 0.4 M solution for the metal and phosphorus combined. Nd3+ doping was performed by adding neodymium nitrate hexahydrate to the solutions listed above with 0.5−10 atom % Nd. The Nd atomic fraction (atom %) was defined with respect to the total metal ion concentration, including P or V. The precursor solution was fed into a spray nozzle (8 mL/min) and dispersed by 3 L/min oxygen (PanGAS, purity of >99.9%). The resulting spray was ignited and sustained by a premixed oxygen/methane (1.5/3.2 L/min) flamelet, sheathed by 20 L/min oxygen.57 The as-prepared particles were collected on a glass microfiber filter (Whatman GF) by a gas pump (Busch Mink MM 1202 AV). Production rates of the as-prepared nanoparticles were approximately 10 g/h. Characterization. X-ray diffraction (XRD) patterns were recorded with a Bruker AXS D8 Advance diffractometer (40 kV, 40 mA, Cu Kα radiation) at 2θ = 15−70° with a step size of 0.03°. The spectra and crystallite sizes were obtained using the TOPAS 4 software (Bruker) and Rietveld fundamental parameter refinement.58 The specific surface area (SSA) was determined according to the Brunauer−Emmett− Teller (BET) method at 77 K (Micromeritics, Tristar II Plus). The samples were degassed at 150 °C for 1 h prior to being analyzed. Scanning transmission electron microscopy images were recorded via an aberration-corrected, dedicated apparatus (Hitachi HD-2700VD) with a probe corrector (CEOS). Measurements were performed at an acceleration potential of 200 kV (electron gun, cold-field emitter) in ultra-high-resolution mode. The primary particle size distribution was determined by manually measuring and counting the longest dimensions (maximum length) of the particles in the obtained transmission electron images with ImageJ. Dynamic light scattering was performed on a Zetasizer (Malvern Instruments). NIR fluorescence emission spectra were recorded with a STS-NIR spectrometer (Ocean Optics) under excitation fixed at 808 nm from a laser diode (Shanghai Laser & Optics Century Co.). The fluorescence emission of the particles was measured in ethanol suspensions (1 mg/ mL) by a fiber-optic cable positioned at a 90° angle to the incident beam. Prior to measurements, the suspensions were dispersed by ultrasonication without any dispersing agents. To filter out the laser light, an 850 nm long-pass filter was used. As a background, the spectrum of undoped YVO4 nanoparticles was fitted at 850 nm and then subtracted. Excitation spectra were recorded on a different setup, which allowed the variation of the excitation wavelength. The nanoparticles were excited with a tunable femtosecond Ti:sapphire laser (Spectra-Physics Mai Tai HP DS), and the fluorescence emission was recorded with a Princeton ARC SP-2356 spectrometer with a PIXIS:256E camera. Quantum yield and lifetime measurements of BiVO 4 :Nd 3+ (annealed for 2 h at 600 °C) were performed on a double-emission monochromator system (FLS980, Edinburgh Instruments) equipped with an 808 nm laser (0.1 W/cm2, CNI) for excitation and a liquid nitrogen-cooled NIR-PMT detector (Hamamatsu). The quantum yield measurements were performed using the integrated sphere accessory, in which a PTFE plug was used as a reference. A PM1 pulse modulator box was used for the lifetime measurements (pulse width of 10 μs, laser frequency of 1000 Hz). Quantum yield measurements were performed on powder. Lifetime measurements were performed on powder and suspensions, leading to identical results. Ex Vivo Experiments. Chicken skeletal muscle and bovine liver tissues were used for the ex vivo experiments. One hundred microliters of a 3 g/L aqueous solution of the nanoparticles (BiVO4:Nd3+,
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CONCLUSIONS A quantitative analysis of down-conversion fluorescence in the NIR by 18 host nanocrystals (oxides, phosphates, and vanadates of Bi, Ce, Gd, La, Nd, and Y) doped with Nd3+ was performed for the first time to the best of our knowledge. The emission spectra of the 4F9/2 → 4I3/2 transition of Nd3+ were analyzed and correlated to their respective crystal structure. The emission intensity of all materials at a crystal size of 50 nm was compared. Interestingly, existing theories on photoluminescence efficiency could not be verified, opening the possibility for future detailed research on this matter. It was discovered, however, that BiVO4:Nd3+ was the most efficient fluorescent material. Subsequently, a suspension of these nanoparticles was injected ex vivo into chicken muscle and bovine liver tissues and excited at harmless power densities with an 808 nm light source. The signal could be detected at injection depths of ≤20 mm though not with micrometer precision. A detailed comparison to the “gold standard” dye, indocyanine green (ICG), proved that BiVO4:Nd3+ has a comparable spatial resolution but much higher photostability. These results highlight its strong potential as an optical imaging agent for biomedical applications and as a promising alternative to already clinically applied organic dyes. Further in vivo experiments are needed to fully address the performance of the developed materials.
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EXPERIMENTAL SECTION
Particle Synthesis. For synthesis of various host matrices of Nd3+, appropriate precursors were prepared by dissolving the corresponding nitrate salts {bismuth nitrate pentahydrate [Bi(NO3)3·5H2O], cerium nitrate hexahydrate [Ce(NO3)3·6H2O], gadolinium nitrate hexahydrate [Gd(NO3)3·6H2O], lanthanum nitrate hexahydrate [La(NO3)3· 6H2O], neodymium nitrate hexahydrate [Nd(NO3)3·6H2O], or yttrium nitrate hexahydrate [Y(NO3)3·6H2O], all from Sigma-Aldrich, 99.9%} in a 1:1 volume mixture of 2-ethylhexanoic acid (2-EHA, 8164
DOI: 10.1021/acs.chemmater.7b02170 Chem. Mater. 2017, 29, 8158−8166
Chemistry of Materials
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annealed for 2 h at 600 °C) was injected into the chicken breast tissue at varying depths (3−20 mm). The particles were excited with an 808 nm laser diode (Shanghai Laser & Optics Century Co.) using a power density of 0.2 W/cm2. The signal was detected by a commercially available CMOS camera (Basler acA1920-40um, integration time of 1 s) with an 850 nm long-pass filter attached (evaluation details in Figure S14 and Table S1). Prior to measurements, nanoparticles were dispersed via ultrasonication without any dispersing agents. Experiments that investigated the resolution of the applied imaging system were conducted by imaging ICG (0.05 mg/mL) and BiVO4:Nd3+ (annealed for 2 h at 600 °C, 5 mg/mL) in a 1% agar suspension patterned in a 5 mm × 5 mm × 5 mm cube through 5 mm Intralipid (0.5%) (light traveling distance, 1 cm). The particles and dye were excited with an 808 nm laser diode (Shanghai Laser & Optics Century Co.) using a power density of 0.2 W/cm2. The signal was detected by a commercially available CMOS camera (Basler acA192040um, integration time of 100 ms) with an 850 nm long-pass filter attached. The resolution was determined by converting the pixel to actual dimensions via the comparison of pattern center to center distance x. This allowed the calculation of the square dimensions (d1/ d2) in the image, which was again compared to the actual dimensions. The difference was reported as the resolution.
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ASSOCIATED CONTENT
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.chemmater.7b02170. Fluorescence measurements for various doping concentrations, primary particle size measurements by N2 adsorption, annealing experiments and X-ray diffraction patterns, extended primary particle size distributions, fluorescence intensities as a function of crystal size, excitation spectra, lifetime measurements, dynamic light scattering, spatial resolution evaluation, cytotoxicity measurements, evaluation of imaging depth, and crystal sizes (PDF)
AUTHOR INFORMATION
Corresponding Author
*Telephone: +41 44 632 31 80. Fax: +41 44 632 15 95. E-mail:
[email protected]. ORCID
Fabian H. L. Starsich: 0000-0003-0724-764X Author Contributions
F.H.L.S. and P.G. contributed equally to this work. Notes
The authors declare no competing financial interest.
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S Supporting Information *
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Article
ACKNOWLEDGMENTS
We thank Dr. Frank Krumeich for the TEM analysis, Anastasia Spyrogianni for the assistance with the cytotoxicity studies, and Dr. Robert Grass for particle synthesis. This research was funded by the Swiss National Science Foundation (Grants 205320_163243 and PP00P2_150609) and the ETH Zürich Research Grant (ETH-4317-1). We thank Edinburgh Instruments for the measurements of quantum yield and lifetime. This research received a Best Poster Award during the 2017 European Aerosol Conference from August 27 to September 1 in Zurich. 8165
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