- Nano Express
- Open Access
Fabrication of NaYF4:Yb,Er Nanoprobes for Cell Imaging Directly by Using the Method of Hydrion Rivalry Aided by Ultrasonic
© The Author(s). 2016
- Received: 15 July 2016
- Accepted: 21 September 2016
- Published: 1 October 2016
A novel method of fabricating water-soluble bio-probes with ultra-small size such as NaYF4:Yb,Er (18 nm), NaGdF4:Yb,Er (8 nm), CaF2:Yb,Er (10 nm), PbS (7 nm), and ZnS (12 nm) has been developed to provide for the solubility switch of nanoparticles from oil-soluble to water-soluble in terms of hydrion rivalry aided by ultrasonic. Using NaYF4:Yb,Er (18 nm) as an example, we evaluate the properties of as-prepared water-soluble nanoparticles (NPs) by using thermogravimetric analyses (TGA), Fourier transform infrared spectroscopy (FTIR), zeta potential (ζ) testing, and 1H nuclear magnetic resonance (1HNMR). The measured ζ value shows that the newly prepared hydrophilic NaYF4:Yb,Er NPs are the positively charged particles. Acting as reactive electrophilic moiety, the freshly prepared hydrophilic NaYF4:Yb,Er NPs have carried out the coupling with amino acids and fluorescence labeling and imaging of HeLa cells directly. Experiments indicate that the method of hydrion rivalry aided by ultrasonic provides a simple and novel opportunity to transform hydrophobic NPs into hydrophilic NPs with good reactivity, which can be imaging some specific biological targets directly.
- Hydrion rivalry aided by ultrasonic
In recent years, fluorescent label materials focus on the up-conversion (UC) phosphors represented by NaYF4:Yb,Er owing to their unique properties of emission light at shorter wavelengths (visible and near-infrared) after excitation in the near-infrared. Compared with conventional fluorescent materials, such as rhodamine, fluorescein, isothiocyanates, cyanine dyes [1, 2], and quantum dots [3–7], the luminous feature of up-conversion nanoparticles (UCNPs) dramatically reduces background autofluorescence since endogenous fluorophores are not excited by the longer excitation wavelengths, which results in high target-to-background ratios [8, 9], minimizing photodamage  and good tissue penetration [8, 9, 11–13]. UCNPs have become a kind of highly promising fluorescence labeling materials for biological applications.
Acting as bio-probes, the prepared UCNPs should meet some requirements of high fluorescent intensity [9, 14], small diameter , water-soluble [16, 17], low cytotoxicity [15, 18–21], etc. So, the control synthesis of UCNPs becomes to be crucial and attracts considerable interest in recent years [22–29]. To date, employing oleic acid (OA, C17H33COOH) to act as reaction media to obtain UCNPs with controlled size and morphology has been still a popular synthesis route [30–33]. Despite going well, the inherent shortcomings of OA layer covered on the as-prepared UCNP surface may prevent widespread use of UCNPs in practical biological settings. It is known that the OA layer covered on the surface of as-prepared UCNPs not only decreases the fluorescence intensity of UCNPs [16, 18] but also hinders their bio-application directly because of the water-soluble environment of biological fluids, namely, it is the necessary prerequisite to modify the surface of these NPs before applying into biomedical science. The advantages of surface functionalization of these NPs are not only to render them reasonably water-soluble and biocompatible but also to provide active sites for subsequent coupling with biological or chemical moieties [34–41]. So far, many attempts have been made to transform the oil-soluble OA-capped UCNPs into water-soluble, such as polymer capping [42, 43], surface silanization , OA-capped NaYF4:Yb,Er NP coating by hydrophilic group [45, 46], ligand exchange , ligand oxidation [48–50], hydrochloric acid , and layer-by-layer method . Unfortunately, all of the post-treatments are time-consuming and may lead to aggregation; furthermore, the surface modified UCNPs always have bigger size than that of before.
Recently, we have studied the relationships between coating layer (OA) and NaYF4:Yb,Er in detail and come up with an easily operated physical method, ultrasonic separation, to remove the oleate ligand from the surface of OA-capped NaYF4:Yb,Er NPs . Unfortunately, the ultrasonic separation method is hardly applied to the particles whose sizes are smaller than 20 nm, because a smaller NaYF4 particle will have a greater surface-to-volume ratio than the bigger one, and therefore displays a much greater surface free energy, which induces the growth and aggregation under the function of ultra-sound treatment. For application in vivo imaging, the size of UCNPs should be less than 10 nm . In general, particles with dimension of 6 nm in diameter are the renal excretion limit size , and these ultra-small particles are excreted via the kidney and mostly excreted through the liver and into the bile without significant metabolism . Even if UCNPs can be made especially small, these particles may become very bigger after water-soluble modification by currently common method, and the size of particles cannot meet the requirements for acting as nanobiotag to apply to the intracellular tracking of biomolecules. Recognizing the importance of water-soluble post-treatment of OA-capped UCNPs and how to develop a facial way to achieve for the solubility switch of NPs from oil-soluble to water-soluble meanwhile keeping the size and optical properties unchanged after treatment is challenging.
As known to all, the surface of NaYF4:Yb,Er NPs synthesized in OA reaction medium exists a fair amount of electron-poor metal atoms Y, which can coordinate with the carboxy groups of oleate anions. Considering OA is a weak acid, H+ will bond with oleate anions (C17H33COO−) easily if H+ is added into the above solution. Or rather, the positively charged NaYF4:Yb,Er NPs coming from electron-poor metal atoms Y and H+ have competitive reaction with C17H33COO− in the solution. Considering “ultrasonic separation” also works well, it is expected that removing the oleate ligand from the surface of OA-capped NPs will be much easier by using of hydrion rivalry aided by ultrasonic.
Herein, we present a universal protocol, hydrion rivalry aided by ultrasonic, to remove the oleate ligand from the surface of OA-capped NPs. OA-capped ultra-small NPs, including NaYF4:Yb,Er (18 nm), NaGdF4:Yb,Er (8 nm), CaF2:Yb,Er (10 nm), PbS (7 nm), and ZnS (12 nm), act as examples to illustrate the transformation from oil-soluble NPs to water-soluble NPs. Considering after the removing of negatively charged oleate from the surface of NaYF4:Yb,Er, the newly prepared OA-free NaYF4:Yb,Er NPs may carry some positive charges, which will turn into reactive electrophilic moiety. We test the zeta potential of the freshly prepared water-soluble NaYF4:Yb,Er NPs and demonstrate the newly prepared OA-free NaYF4:Yb,Er NPs how to couple with amino acids and mark HeLa cells directly.
All of the commercially available reagents are purchased and unpurified. Rare-earth oxide (Y2O3, Yb2O3, Er2O3, Gd2O3, 99.9 %, Sigma), dichloride (CaCl2, PbCl2, ZnCl2, 99.9 %, Sigma), Na2S (99.9 %, Sigma), oleic acid (OA; 90 %, Sigma), 1-octadecene (ODE; >90 %, Sigma), absolute ethanol (>99.5 %, Sigma), cyclohexane (>90 %, Sigma), and rare-earth chlorides (LnCl3·6H2O, Ln = Y, Yb, Er, Y:Yb:Er = 80:18:2 in molar ratio) are prepared by ourselves.
Synthesis of OA-Capped NaYF4:Yb,Er NPs
At first, the molar ratio of Er2O3, Yb2O3, and Y2O3 is 2 %:18 %:80 %, which are mixed and dissolved in hydrochloric acid solution and heated to form a clear solution. The above solution is evaporated and crystallized to obtain rare-earth chlorides (LnCl3). Second, 1 mmol dried LnCl3 with 6 ml of OA and 14 ml of ODE are added into a three-necked flask. The mixture is stirred and heated under vacuum to 150 °C to form a homogeneous solution A and then cooled down to room temperature. Then, another mixed transparent solution B (0.1 g NaOH, 0.148 g NH4F, and 10 ml of methanol) is added into solution A and then heated to 100 °C for 10 min. After methanol is evaporated thoroughly, the mixture is heated to 331 °C under nitrogen atmosphere for 60~90 min. Finally, the OA-capped NaYF4:Yb,Er NPs are obtained after the precipitate is centrifuged and washed with ethanol/cyclohexane (v/v = 1:1) for three times, which can be easily redispersed in various nonpolar organic solvents (e.g., hexane, cyclohexane, toluene).
Synthesis of Oleate-Capped and OA-Free CaF2:Yb,Er, PbS, ZnS, and NaGdF4:Yb,Er Nanocrystals
The detailed experimental procedural is in the Additional file 1.
Fabrication of Ligand-Free NPs
The as-obtained OA-capped NPs (0.5 g) is added into 10 ml ethanol, then adjusting the pH value of the solution to 4.5 by using diluted hydrochloric acid (0.1 mol/l). Simultaneously, the mixture is stirred vigorous and ultrasonic (power outlet 25–50 W) for 10~30 min, and then, the precipitate is separated by centrifugation. Finally, the hydrophilic NPs were washed with deionized water for two times and dried under vacuum at 60 °C.
UCNPs Coupling with Amino Acid
Fifty-milligram amino acid is added into 10-ml water, and the mixture is stirred to form a homogeneous and transparent solution. Then, 20 mg of new-UCNPs (18 nm) is added into the above solution and vigorously stirred for overnight at 25 °C. The complex of amino acid UCNPs is obtained by centrifugation.
Cell Culture, Fluorescent Labeling, and Imaging
The HeLa cells are cultured (at 37 °C, 5 % CO2) on glass chamber slides in RPMI 640 medium containing 10 % fetal bovine serum and 1 % penicillin/streptomycin overnight in a culture box (Heraeus BB16UV). The cells are gently washed three times with PBS and blocked in PBS containing 1 % bovine serum albumin (BSA) for 20 min at 4 °C. Then, HeLa cells are incubated with new-UCNPs (18 nm, 10 μg/ml) at 4 °C for 0.5–24 h. Prior to imaging, the live cells are washed thoroughly with PBS to remove any unbound reagents. Cell imaging is performed on a Leica DMIL inverted fluorescence microscope (with a ×40/0.5 objective) equipped with a 980-nm NIR laser and a Nikon digital camera.
The samples are characterized by X-ray powder diffractometer (XRD) through using a Brucker D8-advance X-ray Diffractometer with Cu Kα radiation (λ = 1.5418 Å); the operation voltage and current are, respectively, 40 kV and 40 mA. The 2θ range scan is swept from 10° to 70° in 0.02° steps with a count time of 0.2 s.
Particle sizes and shapes are characterized by an H-7650 (HITACHI, Japan) low- to high-resolution transmission electron microscope (HRTEM) operated at 100 kV. Samples are prepared by drying a drop of nanocrystal dispersion in cyclohexane/toluene (1/1) or ethanol on amorphous carbon-coated copper grids.
Thermogravimetric analyses are recorded on a TA Instrument SDT 2960 simultaneous DTA-thermogravimetric analyses (TGA) at a heating rate of 10 °C/min under N2.
The IR spectrum is obtained by using Brucker TENSOR Infrared Spectrometer.
The NMR measurement is carried out on Bruker BioSpin GmbH Spectrometer.
The zeta potential measurements are carried out on a Zeta PALS zeta potential analyzer (Brookhaven Instruments Corporation) at room temperature.
Confocal Fluorescence Imaging of Incubated Living Cells
UCNP-labeled HeLa cells are characterized by a modified Olympus FV1000 laser scanning confocal microscope equipped a continuous-wave (CW) NIR laser operating at 980 nm (Connet Fiber Optics, China). A ×60 oil-immersion objective lens is used to carry out the FL imaging of UCNP-labeled HeLa cells. The emission of active UCNPs is collected at 540 ± 20 and 660 ± 20 nm under the 980-nm CW laser excitation.
Mechanism of Removing Oleate Ligand from the Surface of NaYF4:Yb,Er NPs
During the synthesis of NPs, OA acts as reaction media and takes part in the reaction. Before the reaction, OA reacts with Ln3+ ions to form Ln(OA)3, which renders LnCl3 disperses into the reaction system to ensure the homogeneous nucleation in the reaction. After the reaction, the carboxy group of oleate anions act as electron donors to coordinate with the rear earth ions possessing electron-poor and unsaturated bonding located at the surface of NaYF4:Yb,Er, which leads to a layer of OA covered on the surface of as-prepared NaYF4:Yb,Er. The bonding force between oleate and rear earth ions is weaker than that of normal chemical bond, which lies between physisorption and chemisorption, and can be separated by high-power ultrasonic wave . However, the ultra-small particles, especially for the particles with their size less than 20 nm, have greater surface free energy, which always aggregate when using relatively high ultrasonic power to get rid of the OA layer from their surface. Therefore, how to eliminate the OA layer covered on the NaYF4:Yb,Er NPs under low ultrasonic power is an intractable problem.
The Characterization of Samples
In our experiments, NaYF4:Yb,Er (18 nm), NaGdF4:Yb,Er (8 nm), CaF2:Yb,Er (10 nm), PbS (7 nm), and ZnS (12 nm) have been synthesized to testify the removing OA effect by using the method of hydrion rivalry aided by ultrasonic (Additional file 1). Herein, the as-prepared NaYF4:Yb,Er (18 nm) acts as a typical example to demonstrate our research.
The measured FTIR absorption spectra of as-prepared NaYF4:Yb,Er NPs before and after removing OA layer are showed in Fig. 3b. The FTIR spectrum of oleic acid is measured acting as the comparison experiment, which is depicted as curve a. For oleic acid, the specific absorbing peak of the alkene stretchings (C=C) and the asymmetric and symmetric stretching vibrations of the methylene (CH2) group are located at 3008 and 2923 and 2853 cm−1, respectively. The C=O stretching vibration mode and the O–H stretching vibration mode of the carboxyl group are located at 1708 and 934 cm−1, respectively. The curve b is the FTIR spectrum of OA-capped NaYF4:Yb,Er NPs, the specific absorbing peak of the alkene stretchings (C=C), and the asymmetric and symmetric stretching vibrations of the methylene (CH2) group located at 2923 and 2853 cm−1 separately with remarkable clarity in the spectrum. The absorption peaks of 1562 and 1419 cm−1 associate with the asymmetric and symmetric stretching vibrations of the carboxylic group (–COO−), respectively, instead of the peak at 1708 cm−1, which attributes to the electrostatic attraction and chemical adsorption between the Ln3+ ions of the surface of OA-capped NaYF4:Yb,Er NPs and –COO− groups of the oleic acid. The results are lined with the previous reports [16, 55]. In Fig. 3c, the featured absorption peak of carboxyl at 1555 and 1459 cm−1 band cannot be found, which confirms that the sample c is OA-free NaYF4:Yb,Er NPs.
As analysis in the mechanism section, the surface of the freshly synthesized NaYF4:Yb,Er NPs exists unsaturated bonding of rear earth ions, which coordinates with the carboxy group of oleate anions to form OA-capped NaYF4:Yb,Er NPs. So, the freshly prepared OA-free NaYF4:Yb,Er NPs turn into positively charged particles after removing the covered layer, which can be predicted that the high activity dangling bond existed on the surface of particles will be neutralized by their storage environment if they are placed in the air for a long time and finally result in the loss of positive charge from the surface of the particles. As known, positive or negative of zeta potential represents the nanoparticles with what kind of charge according to the definition of zeta potential, normally, ζ > 0 means the positively charged particles, whereas the particles carry a negative charge. Herein, we prepare two samples, one is the freshly prepared OA-free NaYF4:Yb,Er NPs (new-UCNPs) and the other is OA-free NaYF4:Yb,Er NPs which are placed in the air for 2 months (aged-UCNPs). The measured zeta potential of new-UCNPs is +32.96 mV under aqueous solution of pH = 6, which indicates that the new-UCNPs are positively charged particles. Though the aged-UCNPs also have excellent water-solubility, they are negatively charged particles because its measured zeta potential is −29.50 mV. The results are lined with our prediction. In consideration of the positively charged new-UCNPs possess electrophilicity, it is possible that the freshly prepared OA-free NaYF4:Yb,Er NPs can react directly with negatively charged centers on biomolecules and form UCNP-biomolecule adducts.
UCNPs Couple with Amino Acid
As known, adjacent amino and carboxy of amino acid can form into inner-salt in the aqueous solution. So, the group of −NH3 + will act as steric hindrance to hinder the electron-donating group, carboxylate ion, to couple with positively charged ions, and leads to CH3CH(OH)CH(NH2)COOH and NH2CH2COOH seldom react with new-UCNPs finally.
For HOOCCHNH2(CH2)2COOH and H2NCH2CH2CH2CH2CH(NH2)COOH, such as in Fig. 6 Eq. (3) and (4), one end of the molecules forms inner-salt, the existence of −NH3 + acting as steric hindrance will hinder the coupling between carboxyl and UCNPs; the other end of the molecules keeps the strong nucleophilicity group, carboxyl (Fig. 6 formula 3) and amino (Fig. 6 formula 4). Therefore, HOOCCHNH2(CH2)2COOH and H2NCH2CH2CH2CH2CH(NH2)COOH can couple with newly UCNPs directly, as shown in Fig. 1b. In Fig. 5, we also notice that curve d has a higher signal of amino acid than that of curve e, which indicates that the effect of HOOCCHNH2(CH2)2COOH coupling with UCNPs is better than that of H2NCH2CH2CH2CH2CH(NH2)COOH. The reason may be that carboxyl nucleophilic performance is better than that of amino.
Fluorescence Labeling and Imaging of HeLa Cells
To ascertain whether the new-UCNPs (18 nm) have been conjugated HeLa cells after incubation (CUCNPs = 10 mg/ml) for 16 h at 37 °C, the cells are washed five times using PBS to get rid of the residual UCNPs thoroughly and then imaged using a confocal microscope equipped with a 980-nm NIR laser. Figure 7b–e shows the confocal luminescence images of new-UCNP-labeled HeLa cells. As is shown, the surrounding cells exhibit bright green and red UC fluorescence, confirming the attachment of the new-UCNPs conjugates on the surface of cells. The morphology and position of the cells in bright field and dark field overlap very well, showing stronger interactions between the positively charged UCNPs and the negative charged phosphate groups on the surface of phospholipid of cells. In addition, considering a long incubation time of HeLa cells with the high concentration of new-UCNPs, the labeled cells also keep considerable viability, which indicates that the new-UCNPs have good biocompatibility and low cytotoxicity. However, the biological environment is more complex, has different pH, and has the presence of proteins as well as other macrophages and nonspecific binding molecules that are everywhere in vivo model. For the consideration of our experiments just to have a specific target, the further applications in the biomedical field after addressing specificity and selectivity to target an analyte or a cell of interest should be done in the future.
We present an effective method to carrying out the solubility switch of nanoparticles from oil-soluble to water-soluble in terms of hydrion rivalry aided by ultrasonic; furthermore, the method is suitable for the ultra-small particles. The measured zeta potential indicates that the newly prepared OA-free NaYF4:Yb,Er NPs have some positive charges, which is demonstrated to couple with amino acid and label and image the HeLa cells further. The biology experiment illustrates that the freshly prepared OA-free UCNPs can act as bio-probe for some specific target applications directly without any surface functional treatment.
We are very grateful for Prof. Fuyou Li (Fudan University, China) for the help to fulfill the confocal imaging of HeLa cells. This work is supported by the National Natural Science Foundation of China (Grant No. 21445001 and 21541014), 973 Program (2013CB933800), and the Open Project of the State Key Lab of Crystal Materials, Shandong University.
ZL is the director of the experiment group, who propounded the ideas and drafted the manuscript. HM carried out the series of experiments and characterized all the samples. YF participated in the related experiments. YL and RZ participated in the experiment of data analysis. BT participated in its design and coordination. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
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