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Gd3+ doped CuInS2/ZnS nanocrystals with high quantum yield for bimodal fluorescence/magnetic resonance imaging YU Caiyan (郁彩艳)1, XUAN Tongtong (宣曈曈)2, LOU Sunqi (楼孙棋)1, LIU Xiaoxiao (刘潇潇)3, LIAN Guohai (廉国海)4, LI Huili (李会利)1,* (1. Engineering Research Center for Nanophotonics & Advanced Instrument, Ministry of Education, School of Physics and Materials Science, East China Normal University, Shanghai 200062, China; 2. Ministry of Education Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Optoelectronic Materials and Technologies, KLGHEI of Environment and Energy Chemistry, School of Chemistry, Sun Yat-Sen University, Guangzhou 510275, China; 3. Engineering Department, Hunan Electric Power Research Institute of State Grid, Changsha 410007, China; 4. Marketing Department, Hunan Electric Power Company of State Grid, Changsha 410007, China) Received 23 July 2016; revised 19 October 2016

Abstract: Recently, CuInS2/ZnS nanocrystals (CISZ NCs) have been widely used in many fields due to their excellent properties, such as tunable photoluminescence (PL) spectra, broad absorption, and non-toxicity. In order to expand the application of CISZ NCs, Gd3+ was introduced into the host serving as paramagnetic modules to achieve magnetic resonance imaging (MRI) enhancement. MRI probes could provide high-resolution anatomical information. The derived Gd-Cu-In-S/ZnS nanocrystals (GCISZNCs) exhibited the strong orange photoluminescence with a quantum yield of 57.6% and significantly high longitudinal relaxivity (r1=20.4 mmol/s) in comparison with commercial Magnevist (Gd-DTPA, r1=4.5 mmol/s). Effective enhancement of MRI and improved longitudinal relaxivity as well as lower cytotoxicity mode GCISZ NCs an ideal MRI probe, suggesting its potential and significance in practical biological and clinic applications in the future. Keywords: Gd-Cu-In-S/ZnS nanocrystals; longitudinal relaxivity; magnetic resonance imaging; rare earths

Owing to their unique optical and electronic properties such as tunable photoluminescence (PL) by controlling their size, a very broad absorption band and relatively good photostability, semiconductor nanocrystals (NCs) have been widely used in the field of light-emitting diodes (LED)[1], biological imaging[2] and solar cells[3]. Although II-VI Cd-based NCs exhibit prominent advantages, the inherent toxicity of heavy metal elements limits their widespread applications, especially in the biological and medical fields. Hence, Cd-free I-III-VI ternary compounds such as Cu-In-S (CIS) NCs have been considered as promising alternatives to traditional Cd-based ones[4]. The band gap of CIS NCs can be tuned by changing their size, shape and composition[5]. That is to say, the emission wavelength variation of NCs can be easily achieved by optimizing the reaction temperature, time, and stoichiometric ratio of Cu/In[4–6]. However, as-prepared CIS-core NCs usually exhibit low PL quantum yield (PLQY) and fluorescence intensity due to a large number of surface defects which can dramatically lower the PL brightness of CIS-core NCs[4]. In order to overcome the shortcomings, researchers select ZnS as a

protective shell to enhance their fluorescence and stability, mainly due to its inherent chemical stability, nontoxicity, wide bulk band gap to localize the charge carriers inside the core region, the same as zinc blende structure and a smaller lattice mismatch of ~2.2% between ZnS and CuInS2[6,7]. The PL spectra of CIS/ZnS (CISZ) core/shell NCs can be tuned from the whole visible region to near-infrared (NIR) region with the enhanced PLQY and excellent photostability[1–3,8], which have been proven to be an outstanding candidate for fluorescence imaging (FI) by many researchers[9–14]. For example, Liu’s group evaluated orange-emission CuInS2/ZnS core/shell quantum dots as FI probes for successfully identifying living HeLa cells and elegans[9]. Reiss and his co-workers reported successful highly efficient redemitting CuInS2/ZnS core/shell nanocrystals application in in vivo imaging[10]. In view of this, the work paid little attention on FI application of CISZ NCs, but laid emphasis on expanding its new application in the field of magnetic resonance imaging (MRI). MRI is one of the most powerful techniques in modern diagnostic medicine because it can penetrate deeply into

Foundation item: Project supported by the National Natural Science Foundation of China (51472087), Shanghai Municipal Natural Science Foundation (13ZR1412500), Innovation Program of Shanghai Municipal Education Commission (14ZZ050), and the ECNU Reward for Out-standing Doctoral Dissertation Cultivation Plan of Action ( PY2015041) * Corresponding author: LI Huili (E-mail: [email protected]; Tel.: +86-21-62235465) DOI: 10.1016/S1002-0721(17)60923-2

YU Caiyan et al., Gd3+ doped CuInS2/ZnS nanocrystals with high quantum yield for bimodal fluorescence/magnetic …

tissue, providing anatomical details and high quality three-dimensional images of soft tissue in a non-invasive monitoring manner[11,12]. Rare earth element gadolinium (Gd) has been confirmed to exhibit excellent contrast efficiency because of its unique magnetic property[13,14]. Hence, Gd3+ was introduced into the NCs host serving as paramagnetic modules to achieve MRI enhancement. Many Gd-containing nanoparticles have been developed as effective probes for MR/fluorescence dual-modality diagnosis[11,15,16]. For instance, Li and his co-workers developed gadolinium-doped CdTe NCs dual-modal probes with a QY of 37% for MRI/FI by an aqueous synthesis approach [15]. Peng’s group reported Gd:CdTeNCs imaging modalities with a QY of 42.5%[17]. However, the intrinsic toxicity of such cadmium-containing NCs can not be ignored because they easily disintegrate in biological systems, causing leakage of cadmium ions as well as heavy-metal accumulation in subcellular regions, and might actually cause the extinction of biological systems. Therefore, current trend in the development of MRI probe suggests that an ideal probe should not only own higher relaxivity and contrast efficiency, but also should possess low toxicity and excellent stability in a biological environment[12]. Based on above, Gd-doped Cu-In-S/ZnS (GCISZ) NCs should be the ideal alternates to establish MRI/FI probe in vivo due to their low toxicity and near-infrared fluorescence[4,11]. In previous works, Gdcontaining Cu-In-S/ZnS or Zn-Cu-In-S/ZnS NCs have been proven to have much reduced toxicity compared with Cd-based ones and have been successfully applied for tumor targeted MR/fluorescence dual-modal in vivo imaging[11,18,19]. However, these reported dual-modal nanoprobes suffered from the decreased PLQY with a maximum of 50% when paramagnetic Gd ions were introduced and gave the highest longitudinal relaxivity of r1=15.8 mmol/s. Consequently, it still remains a challenge to fabricate dual-modal Gd doped CISZ NCs without compromising the properties of each component in isolation needed for fluorescence imaging and MRI[20–26]. Here we developed a simple synthesis of Gd-doped CISZ NCs with optimized fluorescence/MR properties through a hot-injection approach. The obtained NCs exhibit significantly higher longitudinal relaxivity (r1=20.4 mmol/s), in comparison with commercial Magnevist (GdDTPA, r1=4.5 mmol/s)[27,28], while the PLQY can be as high as 57.6%. The great MR enhancement without significantly compromising the fluorescence properties of the initial CISZ NCs after incorporating Gd into host and lower cytotoxicity indicate the promise of GCISZ NCs for great potential applications in biological and medical fields.

1 Experimental 1.1 Chemicals

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Cuprous iodide (CuI), sulfur powder (S), oleic acid (OA), octadecene (ODE), zinc acetate (Zn(OAC)2), 1dodecanethiol (C12H26S), indium acetate (In(AC)3), gadolinium chloride (GdCl3), n-hexane, acetone, 3-mercaptopropionic acid (MPA) and tetra-methyl-ammonium hydroxide pentahydrate (TMAH) were purchased from Aladdin Biological Technology Co. Ltd.. Cell counting kit-8 (CCK-8) and HeLa cells were purchased from Sigma-Aldrich Trading Co. Ltd.. Fetal bovine serum (FBS) and dulbecco’s modified eagle’s medium (DMEM) were obtained from Gibco Life Technologies Co.. All reagents were of analytical regent and used as received without further experimental purification. 1.2 Synthesis of GCISZ NCs High quality GCISZ NCs were synthesized by hot-injection method in organic phase. First, 0.002323–0.046 g GdCl3, corresponding to the doping molar ratio of Gd3+: 1%–20%, 0.02 g S powder, 0.095–0.02375 g CuI (corresponding to various Cu/In from 1:1, 1:2, 1:3 to 1:4), and 0.146 g In(AC)3 were mixed with 4 mL OA and 6 mL ODE in a three-neck flask at 220 ºC for 5 min under N2 flow to allow the growth of GCIS NCs. Then, the reaction solution was cooled to 100 ºC, and GCIS core NCs were obtained. Here, it was found that the sample with 2 mol.% Gd3+ and 1:4 of Cu/In contained the optimum photoluminescence. Thus, in the following experiments, 2 mol.% Gd3+ and 1:4 of Cu/In was fixed. Second, 0.0053 g S powder and 0.03 g Zn(OAC)2 were dissolved in 10 mL ODE at 120 ºC for 15 min to yield a transparent ZnS precursor solution. It was subsequently injected into the as-prepared GCIS core NCs solution under a vigorous stirring, and directly heated to 220 ºC for 15 min to produce GCISZ NCs. Third, the resultant GCIS and GCISZ NCs were purified by the standard precipitation method using acetone as a precipitant, and re-dispersed in n-hexane for further characterization and application. 1.3 Surface ligand exchange with MPA The ligand exchange reaction was performed according to previously reported method[2]. First, the pH of 0.2 mol/L MPA methanol solution was adjusted to 8 with TMAH. Then, 20 mL GCISZ NCs n-hexane solution (1 μmol/L) and 20 mL MPA methanol solution were loaded into a flask under a vigorous stirring under N2 for 2 h at room temperature. Finally, excess TMAH and MPA were removed by centrifugation and GCISZ NCs wrapped by MPA were re-dispersed in water for further characterization and application. 1.4 Characterizations The absorption spectra of as-prepared NCs in n-hexane solution were measured by using a UV/Vis spectrophotometer (Hitachi U-3900). PL spectra were measured using a fluorescences pectrophotometer (Horiba Jo-

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binYvon, FluoroMax-4). The phase evolution was characterized by an M21XVHF2Z (Mac Science Co. Ltd.) X-ray diffractometer (XRD), using Cu Kα radiation (λ= 0.15405 nm) at a voltage of 40 kV and a current of 40 mA with 2θ scanning mode. The morphology and particle size of NCs were observed by a JEM-2100 high-resolution transmission electron microscope (HRTEM, JEOL, Japan) at an operating voltage of 200 kV. X-ray photoelectron spectroscopy (XPS) data were obtained by a multifunction imaging photoelectron spectrometer (Thermo ESCALAB 250XI) with monochromatic Al Kα radiation (1486.6eV). PLQY was calculated by the following equation: QYQDs = QYdye ×

AQDs Adye

2

⎛ nQDs ⎞ 1 − 10 ⎟ × −D ⎝ ndye ⎠ 1 − 10

×⎜

− Ddye

(1)

QDs

Where QY, D, A, and n are the quantum yield, the optical density, the integrated area of PL spectrum, and the refractive index, respectively[1,2]. The optical density at the first absorption peak of both sample and dye was kept in the range of 0.05 to 0.1 for avoiding reabsorption. In this paper, the dye of Rhodamine 6G was used as a standard sample and its QYdye=95%[5,6]. 1.5 Cell toxicity test CCK-8 assay was carried out to evaluate the cytotoxicity of as-prepared GCISZ NCs on HeLa cells according to the following procedure. Briefly, HeLa cells were seeded in 96-well plates at 1×104 cells per well in DMEM medium with 10% FBS and incubated at 37 ºC in a humidified atmosphere with 5% CO2. After incubating the cells for 24 h, the medium was replaced with 100 μL of fresh medium containing different concentrations of GCISZ NCs. After 24 h or 48 h, the medium was removed, and fresh medium containing CCK-8 was added into each cell, and then the cells were incubated at 37 ºC for another 4 h. The relative viability of cells was assessed by measuring the absorbance of the solution at 450 nm using a micro-platereader (Multiskan MK3, Thermo).

1.6 Cell bio-imaging HeLa cells were incubated overnight in DMEM supplemented with 10% FBS in a 5% CO2 humidified incubator at 37 ºC, and then the culture medium was replaced with fresh DMEM containing GCISZ NCs of 0.5 mg/mL. Subsequently, the HeLa cells were incubated for another 2 h and rinsed with PBS for three times to remove excess GCISZ NCs. Finally, the fluorescence photographs were taken by a confocal laser (473 nm) scanning microscope (Carl Zeiss LSM 700). 1.7 T1-weighted relaxivity and MRI The T1-weighted relaxivity of GCISZ NCs was obtained on a 0.5 T MRI instrument (MesoMR60, Shanghai Niumag Corporation, China). The samples were dispersed in double-distilled water with various Gd3+ concentrations (0, 0.05, 0.1, 0.15, 0.2 and 0.25 mmol/L). Relaxivity values of GCISZ NCs were obtained from the slope of the linear fitting of 1/T relaxation time (s−1) versus Gd3+ concentration. The T1-weighted images were acquired using the sequence of RARE-T1+T2-map under the following parameters: TE=12.5 ms, TR=100 ms, field of view (FOV)=10×10 cm2, flip angle (FA)=180°, and slice thickness=4 mm. Matrix=192×256 cm.

2 Results and discussion Fig. 1 presents the crystal structure and morphology of the obtained GCIS and GCISZNCs. From the XRD patterns in Fig. 1(a), it can be seen that the synthesized GCIS core NCs match well with the reported CIS (JCPDS 47-1372)[4,11,20], and belong to the face-centered cubic phase with the zinc blende structure (JCPDS 65-9585). Three major peaks at 27.8º, 47.2º and 56.1º correspond to (112), (220) and (312) planes, respectively. The growth of ZnS shell leads to a slight shift of the diffraction peaks to higher angle, indicating the formation of the ZnS shell around the GCIS cores. Broad diffraction peaks of CIS and GCISZ are attributed to the small

Fig. 1 (a) XRD patterns of GCIS and GCISZ NCs, and (b) HRTEM image of GCISZNCs, the top-right inset shows the corresponding SAED pattern

YU Caiyan et al., Gd3+ doped CuInS2/ZnS nanocrystals with high quantum yield for bimodal fluorescence/magnetic …

crystal size of NCs, which agrees well with the HRTEM result shown in Fig. 1(b). The average particle size is about 3 nm with a uniform size distribution. The corresponding selected area electron diffraction (SAED) displays three clear diffraction rings of (112), (220) and (312) planes from the inner to the outer. The result is in agreement with the XRD analysis of Fig. 1(a). To further confirm the Gd doping into GCISZ NCs, the X-ray photoelectron spectrometer (XPS) analysis of the constituent elements was carried out. The binding energy was calibrated with C 1s at 284.8 eV as a reference. As depicted in Fig. 2(a), all the characteristic photoelectron peaks corresponding to Gd 4d, S 2p, C 1s, In 3(d, p, s), Cu 2p and Zn 2p are observed clearly[4,11,21], confirming the successful introduction of Gd3+ in the product with 0.81 at.% Gd, 21.99 at.% S, 55.14 at.% C, 7.24 at.% In, 6.55 at.% Cu and 8.3 at.% Zn. The high-resolution spectrum of Gd 4d exhibits obvious peak at 140.4 eV (Fig. 2(b)), suggesting that the oxidation

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state of Gd remains +3 in GCISZ NCs[22,23]. In the highresolution Cu 2p XPS spectrum of Fig. 2(c), two peaks at 932.9 and 952.8 eV with a separation of 19.9 eV are observed, confirming the presence of monovalent copper[7,21]. The In 3d XPS spectrum in Fig. 2(d) contains two peaks at 445.4 and 453 eV with a standard separation of 7.6 eV, suggesting that the oxidation state of the element In in the GCISZ is +3[6,11]. The S 2p XPS spectrum can be resolved into two peaks (Fig. 2(e)): one peak at 162.1 eV (2p3/2) is attributed to the sulfide ions in the NCs, and the other at 163.1 eV (2p1/2) can be assigned to thiolate sulfur which is bonded to the NCs surface[24,25]. Binding energies located at 1022.8 and 1045.9 eV with a standard separation of 23.1 eV (Fig. 2(f)) match well with the 2p signals of Zn2+ in ZnS, implying that the oxidation state of the element Zn in the NCs is +2[2,7]. Fig. 3 presents UV/Vis absorption and PL spectra of the synthesized CIS, GCIS and GCISZ NCs. It can be seen that the absorption and PL peak positions of both

Fig. 2 XPS survey spectrum (a) and high resolution of GCISZ nCs of Gd 4d (b), Cu 2p (c), In 3d (d), S 2p (e) and Zn 2p (f)

Fig. 3 UV/vis absorbance (a) and PL spectra (λex=450 nm) (b) of as-prepared CIS, GCIS, GCISZ NCs

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CIS and GCIS synthesized under the same condition resemble completely each other, implying that the incorporation of Gd ions does not have obviouses influence on the particle size distribution and compositions of CIS NCs. PL intensity of GCIS is not obviously reduced but only less than 5%, which is largely different from the previously reported GCIS NCs[11,18,19]. After coating ZnS shell, PL intensity of GCISZ NCs increases dramatically because of evident removal of the surface trap states[4,26]. PLQY of as-prepared GCISZ NCs reaches 57.6%, which is higher than the maximum of 50% reported by Yang and his/her co-workers[11]. Simultaneously, a blue-shift of the PL peak position from the original 654 to 591 nm during the ZnS shell growth indicates that a small amount of zinc ions diffuse into the GCIS cores, which enlarges the band gap of NCs. Furthermore, when the GCISZ NCs in n-hexane are transferred into an aqueous solution through ligand exchange by 3-Mercaptopropionic acid (MPA) for applications such as cell imaging, both the position and shape of the absorption spectra as well as the body color of samples do not undergo any obvious variations. Besides this, the PL intensity of the resultant water-soluble NCs is only slightly decreased (~5%), when compared with that of the initial oil-soluble sample, as shown in Fig. 4. Obviously, the resultant water-soluble NCs exhibit strong orange photoluminescence under 365 nm UV light in the inset photographs. Thus, it suggests that, no matter what solvents are used, the as-prepared GCISZ NCs exhibit good PL stability and excellent fluorescent properties, which make it serve as a potential candidate for imaging probe. For fluorescence imaging probe and MRI contrast agent, toxicity is a bottleneck problem, which limits its practical applications. Therefore, we evaluated the inherent cytotoxicity of GCISZ NCs using HeLa cells

Fig. 4 PL intensity (λex=450 nm) of the GCISZ before and after surface ligand exchange (The inset gives photograph of the resultant water-soluble NCs taken under 365 nm UV light)

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Fig. 5 (a) Effect of GCISZ NCs on HeLa cells viability and cell imaging of GCISZ NCs; (b) bright-field microphotograph; (c) confocal fluorescence microphotograph; (d) overlap of corresponding bright-field image and fluorescence image of HeLa cells incubated with the GCISZ NCs in a concentration of 1 mg/mL for 2 h

through CCK-8 assay. In Fig. 5(a), cell viability is above 80% even when GCISZ NCs concentration reaches 2 mg/mL and incubation time prolongs 48 h. In contrast, CdS:Cu+ NCs cause a 5% reduction in cell viability at a concentration of 1.5 μg/mL after 1 h of exposure time[29], hence they are safe for in vitro and in vivo applications as contrast agent. It confirms good biocompatibility and negligible cytotoxicity of GCISZ NCs towards HeLa cells, not like free gadolinium ions. The strong Gd3+ incorporation into CISZ NCs is expected to effectively block the leakage of Gd3+ into the surroundings, which obviously decreases the toxicity of free Gd3+ [30]. Figs. 5(b–d) present the fluorescence images of living HeLa cells incubated with 0.5 mg/mL GCISZ NCs aqueous solution for 2 h. No fluorescence is observed for the control bright-field image (Fig. 5(b)). On the contrary, as depicted in Fig. 5(c), the phase contrast image of HeLa cells at λex=473 nm clearly shows the strong orange fluorescence. From the overplayed fluorescence and brightfield images (Fig. 5(d)), strong orange PL signals can still be seen, and also no morphological damage of the HeLa cells appears after being labelled with GCISZ NCs, which suggests that the cells are live as before. All these results firmly demonstrate again that the as-synthesized GCISZ NCs in this work possess good biocompatibility and can serve as an outstanding candidate for fluorescence imaging. After Gd3+ doping, the unique PL properties of GCISZ NCs are well preserved. More importantly, the introduction of Gd3+ renders CISZ NCs the MRI modality because it can accelerate longitudinal (T1) relaxation of water protons and exert bright contrast in regions where

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3 Conclusions In summary, a high quality bimodal bio-imaging nanoprobe based on Gd-CIS/ZnS was synthesized through a simple hot-injection method. The average size of prepared GCISZ NCs was –3 nm with a PLQY as high as 57.6 %. The strong incorporation of Gd3+ into CISZ NCs led to a stable structure of Gd-CISZ which caused an enhanced MRI contrast with an r1 value as high as 20.4 mmol/s. Furthermore, the result of CCK-8 assay revealed the weak toxicity of GCISZ NCs. In vitro relaxivity characterization and excellent PL properties demonstrated that GCISZ NCs possessed not only the high sensitivity of fluorescence imaging but also the high spatial resolution of MRI, providing a great potential for its practical applications in biological and clinical fields.

References: T1–1

3+

Fig. 6 (a) Linear relationship between and Gd concentrations; (b) T1-weighted MRI (top) and corresponding pseudo-color images (bottom) of GCISZ NCs with different Gd3+ concentrations (The value of T1–1 was collected basing on readings from (b))

the nano-probes localize. Thus, we investigate the T1 contrast capability of GCISZ NCs as MRI contrast agents on a 0.5 T MRI instrument and the results are shown in Fig. 6. Obviously, longitudinal relaxivity of GCISZ NCs is enhanced linearly along with the increase of equivalent Gd concentration (Fig. 6(a)). The relaxivity values (r1) evaluated from a plot of the relaxation time (T1–1) versus Gd3+ ion concentration is determined to be 20.4 mmol/s, which is much larger than commercially available MRI agent Magnevist (r1=4.5 mmol/s)[27,28] and recently reported Gd-CIS NCs (r1=3.72–15.78 mmol/s)[11]. In the case of the obtained GCISZ NCs based MRI contrast agent, small size is important to reach a high longitudinal relaxivity because longitudinal relaxivity is largely dependent upon direct interactions between Gd3+ and hydrogen protons[11,16,28]. The ultra-small GCISZ NCs with high specific surface ratios could maximize dipole-dipole interactions between Gd3+ and hydrogen protons, thus, are responsible for the high r1. Consistently, the gray-scaled T1-weighted images of GCISZ NCs with different Gd3+ concentrations clearly show a positive contrast enhancement, and the brightness becomes more prominent with Gd3+ concentration increasing from 0 to 0.25 mmol/L (Fig. 6(b)). But, no such signal enhancement is observed for bare CISZ core NCs. Therefore, combining with the results of MRI, cell viability and imaging, we can conclude that the as-prepared GCISZ NCs in this study hold greater potential as fluorescence/MR bimodal nanoprobe in medical imaging for a better diagnosis.

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