Er@ NaGdF4 Nanodumbbells for

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Sequential Growth of NaYF4:Yb/Er@NaGdF4 Nanodumbbells for Dual-Modality Fluorescence and Magnetic Resonance Imaging Huiqin Wen, Huangyong Peng, Kun Liu, Maohong Bian, Yun-Jun Xu, Liang Dong, Xu Yan, Weiping Xu, Wei Tao, Jilong Shen, Yang Lu, and Haisheng Qian ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.6b16842 • Publication Date (Web): 28 Feb 2017 Downloaded from http://pubs.acs.org on March 2, 2017

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ACS Applied Materials & Interfaces

Sequential Growth of NaYF4:Yb/Er@NaGdF4 Nanodumbbells for Dual-Modality Fluorescence and Magnetic Resonance Imaging †‡▽

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Hui-Qin Wen, , , Huang-Yong Peng,§, Kun Liu,§ Mao-Hong Bian, Yun-Jun Xu, Liang Dong, ∥⊥ ∥⊥ † ⊥ Xu Yan, , Wei-Ping Xu, , Wei Tao,§ Ji-Long Shen, ,* Yang Lu, ,* and Hai-Sheng Qian§,*

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†

Department of Pathogen Biology, Provincial Laboratories of Pathogen Biology and Zoonoses Anhui, and Clinical Laboratory of the First Affiliated Hospital, Anhui Medical University. Department of Immunology, Anhui Medical University, Hefei, Anhui 230022, China ‡

Department of Blood Transfusion, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China School of Biological and Medical Engineering, Hefei University of Technology, Hefei, Anhui 230009, China

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Department of Radiology, Anhui Provincial Hospital, Hefei, Anhui 230001, China

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School of Chemistry and Chemical Engineering, Hefei University of Technology, Hefei, Anhui 230009, China

ABSTRACT: Upconversional core-shell nanostructures have gained considerable attention owing to their distinct enhanced fluorescence efficiency, multi-functionality and specific applications. Recently, we have developed a sequential growth process to fabricate unique upconversion core-shell nanoparticles. Time evolution of morphology for the NaYF4:Yb/Er@NaGdF4 nanodumbbells has been extensively investigated. An Ostwald ripening growth mechanism has been proposed to illustrate the formation of NaYF4:Yb/Er@NaGdF4 nanodumbbells. The hydrophilic NaYF4:Yb/Er@NaGdF4 core-shell nanodumbbells exhibited strong upconversion fluorescence and showed higher magnetic resonance longitudinal relaxivity (r1 = 7.81 mM-1s-1) than commercial contrast agents (Gd-DTPA). NaYF4:Yb/Er@NaGdF4 nanodumbbells can serve as good candidates for high efficiency fluorescence and magnetic resonance imaging. KEYWORDS: upconversion nanoparticles, nanodumbbells, sequential growth, MR imaging, compatibility

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ow dimensional nanostructures with controllable size and shape are of great scientific and technological importance due to their unique chemical and physical property.1 In the past two decades, lanthanide-doped upconversion (UC) nanomaterials have been widely investigated for their extensive applications in bioimaging,2,3 biosensor,4 bioprobe,5,6 photothermal therapy7,8 and photodynamic therapy9,10 owing to their low autofluorescence background and high tissue penetration depth of the near-infrared excitation light.11-12 Much effort has been paid to prepare UC core-shell nanostructures with tunable fluorescence emissions or paramagnetic properties for multimodal bioimaging, chemotherapy and photodynamic therapy.13-16 In particular, fluorescent-magnetic UC nanomaterials have received intense interests due to their significant paramagnetic properties and improved upconversional fluorescence for targeted detection,17 multimodal imaging18 and therapeutic delivery.19-20 However, most of these upconversion nanomaterials have been fabricated via a seed-mediated growth process, which is time consuming and generally involves complex process and more organic solvent needed.21 Recently, one pot successive layer-by-layer (SLBL) strategy has been developed to synthesize β-NaGdF4:Yb,Er@NaYF4 core/shell upconversion nanoparticles (NPs) using high boiling point RE-OA and

Na-TFA-OA as shell precursor solutions.22 Up to date, it is still challenging work for the fabrication of upconversion nanomaterials with well controlled morphologies and physical properties, such as dumbbell-like nanoparticles.23-25 Here, an Ostwald ripening process has been demonstrated to fabricate the NaYF4:Yb/Er@NaGdF4 core-shell nanodumbbells. The morphological evolution of the samples at early stages has been carefully investigated to illustrate the formation mechanism of nanodumbbells. The as-prepared NaYF4:Yb/Er@NaGdF4 core-shell nanodumbbells exhibit strong upconversion fluorescence and higher magnetic resonance relaxivity. Poly(ethylene glycol)-poly(acrylic acid) di-block polymers (PEG–PAA) have been used to modify the hydrophobic nanoparticles of NaYF4:Yb/Er@NaGdF4 to form hydrophilic ones. The hydrophilic NaYF4:Yb/Er@NaGdF4 nanodumbbells have been analyzed as contrast agent for magnetic resonance imaging. The fluorescent and magnetic multifunctional NaYF4:Yb/Er@NaGdF4 nanodumbbells will play a significant role in the practical application in multimodal bioimaging-guided biodetection. In addition, the compatibility of this gadolinium-based contrast agent was demonstrated. Recently, we have developed a sequential growth process to fabricate unique upconversion core-shell nanoparticles.231

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However, the growth process and mechanism are not clear. In this paper, the products at early stages have been collected and characterized using transmission electron microscopy (TEM), high resolution transmission electron microscopy (HRTEM) and energy dispersive X-ray spectrum (EDS). As shown in Figure 1a, before the injection of Gd-oleate (Gd-OA), the TEM image showed that the diameter of as-obtained NaYF4:Yb/Er nanoparticles is 35 nm, which is in good accordance with the previous reported protocol. Figure 1b showed the TEM image of the sample obtained at the earliest stage for the synthesis of the NaYF4:Yb/Er@NaGdF4 nanodumbbells only one minute after injection of the Gd-OA, and many tiny nanoparticles were formed immediately including the pre-formed NaYF4:Yb/Er nanoparticles have been observed. Prolonging the duration time, the tiny nanoparticles gradually disappeared and the core NaYF4:Yb/Er nanoparticles grew larger to form dumbbell-like nanoparticles (shown in Figure 1c-e). Therefore, the shell growth via this process is dependent dissolution and growth driven by Ostwald ripening.26 Figure 1f showed the dumbbell-like NaYF4:Yb/Er@NaGdF4 core-shell nanoparticles (denoted as UCNPs-OA) have a length of 50 nm and a diameter of 45 nm for the two ends. The intensity distribution of the diameter of the as-prepared NaYF4:Yb/Er@NaGdF4 nanodumbbells was summarized in Figure S1 (in the Supporting Information). The X-ray diffraction (XRD) pattern of the sample obtained 10 minutes after the injection of Gd-OA precursor was shown in Figure S2 (in the Supporting Information), which illustrated that the sample was only comprised of hexagonal phase NaYF4 crystal (JCPDS standard card no. 28-1192) and no any impurities were observed.27 As shown in Figure S3 (in the Supporting Information), the structure and components of the as-prepared NaYF4:Yb/Er@NaGdF4 nanodumbbells were further characterized by X-ray photoelectron spectroscopy (XPS). In addition, as shown in the inset of Figure 1e, the HRTEM analysis of the tiny nanoparticle show that the nanoparticle is monocrystalline and hexagonal phase of NaGdF4, which are precipitated immediately from the reaction Gd-OA and sodium fluoride at 280 oC. The HRTEM analysis of dumbbell-like core-shell nanoparticles were shown in inset of Figure 1f, demonstrating that the core nanoparticles (NaYF4:Yb/Er) preferentially grow along the [001] direction at the first stage and grow along [010] or [100] direction as follows to result into formation of nanodumbbells-like nanostructures. Based on the above analysis, the growth mechanism for the dumbbell-like NaYF4:Yb/Er@NaGdF4 core-shell nanoparticles has been schematic illustrated in Scheme 1. Figure 2a shows scanning transmission electron microscopy image of the as-prepared nanodumbbells and the elemental mapping images for elements including Gd, Y, Yb

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and Er in nanodumbbells have been clearly observed, indicating the co-existence of these elements in the as-prepared product and showing the shell containing gadolinium element and the uniformly doping of the ytterbium and erbium elements in the core. In addition, the scanning transmission electron microscopy-Energy dispersive X-ray spectra (STEM-EDS) elemental mapping images of the as-prepared NaYF4:Yb/Er@NaGdF4 core-shell nanodumbbells were shown in Figure 2b, confirming distribution of Gd element on the surface of the nanodumbbells. This dumbbells-like nanoparticle possessed a higher surface area, which is reasonable to exhibit higher longitudinal relaxation of water protons.28 For comparison, sphere-like NaYF4:Yb/Er@NaGdF4 core-shell nanoparticles with similar size (denoted as sphere-like NPs) have been synthesized successfully via a modified protocol and shown in Figure S4 (in the Supporting Information).

Figure 1. a) TEM images of the core nanoparticles, NaYF4:Yb/Er. b-f) TEM images of the samples obtained at early stages of forming NaYF4:Yb/Er@NaGdF4 core-shell nanoparticles. The corresponding reaction durations after injection of Gd-OA precursor are b) 1 min, c) 5 min d) 10 min e) 15 min, and f) 30 min. Inset of e) and f) were the high resolution images of tiny nanoparticle and dumbbell-like core-shell nanoparticle. The scale bar in inset of e) and f) represent 10 nm and 2 nm, respectively.

Scheme 1. Schematic illustration of the formation of the dumbbell-like NaYF4:Yb/Er@NaGdF4 core-shell nanoparticles.


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Figure 2. a) Scanning transmission electron microscopy image (STEM) of the NaYF4:Yb/Er@NaGdF4 nanodumbbells and element maps of Gd, Y, Yb, Er in the nanoparticles. The inset of a) shows the simulation structure of nanodumbbell. b) Line analysis of the elemental distribution in a typical UCNP dumbbell nanoparticle.

The as-prepared hydrophobic upconversion core-shell nanoparticles were necessary to be transferred into aqueous solution before application. In our work, ligand exchange method was chosen to modify the surface of NaYF4:Yb/Er@NaGdF4 nanodumbbells (denoted as modified nanodumbbells and abbreviated as mUCNDBs) using PEG-PAA double block copolymer. As shown in Figure S5 (in the Supporting Information), the bands centered at 1560 and 1460 cm-1 of FT-IR spectra were attributed to the stretching vibrations of the carboxylate group in PEG-PAA, indicating that the sufficient carboxylate groups were beneficial to the solubility in water. In addition, the new stretch at 1100 cm-1 could be assigned to the stretching vibration of the PEG chains on the surface of mUCNDBs. No aggregation of nanoparticles was observed from TEM image of mUCNDBs (Figure 3a). The hydrodynamic sizes of mUCNDBs in deionized water (DIW) were measured by dynamic light scattering (DLS). As shown in Figure 3b, narrow size distribution exhibited good water dispersibility of mUCNDBs. The obtained mUCNDBs were negatively charged due to the surface modification of PEG-PAA (Figure S6, Supporting Information). The chemical stability for the hydrophilic UC nanoparticles stabilized by polymers have attracted much attention.29 The TEM image of mUCNDBs stayed in water for seven days were shown in Figure S7 (in the Supporting Information) and the size and morphology of the product has not changed, indicating the good chemical stability for the as-prepared hydrophilic mUCNDBs. Fluorescence spectrum of UCNPs-OA and mUCNDBs was shown in Figure 3c. These peaks corresponded to respective blue, green, and red emissions, and led to an overall green color in aqueous solution (inset of Figure 3c). A paramagnetic behavior of mUCNDBs was exhibited by a superconducting quantum interference device (SQUID) magnetometer (Figure 3d), indicating the potential application in T1-weight magnetic resonance (MR) imaging. The fluorescence and magnetic

resonance imaging indicated that the mUCNDBs can be used as a dual-modality probe for in vivo imaging. In vitro MRI properties were evaluated by a Siemens 3 T clinic MR scanner. Figure 4a showed the T1-maps of mUCNDBs aqueous solution with different gadolinium concentrations in the range of 0.05-0.8 mM, as well as sphere-like NPs and Gd-DTPA. Higher signal intensity could be clearly observed as the concentration of gadolinium ions gradually increased. The r1 of mUCNDBs were calculated to be 7.81 mM-1s-1, which is 2-folds higher than the commercial Gd-DTPA (3.06 mM-1s-1) (Figure 4b), demonstrating that mUCNDBs could be the promising T1 contrast agent. Moreover, the r1 relaxivity of mUCNDBs was twice as high as that of sphere-like NPs (3.75 mM-1s-1) with similar size and modification, which might be benefited from the higher surface area. In vitro fluorescence study using HeLa cells was performed to test the feasibility of mUCNDBs in cellular imaging. After 24 h co-incubation, the uptake of mUCNDBs by HeLa cells was observed by confocal laser scanning microscopy (CLSM). Upon excitation at 980 nm, strong blue, green and red upconversion luminescence were clearly visualized (Figure 4c), indicating that the mUCNDBs could serve as a promising fluorescent probe. As a proof of concept experiment, the in vivo fluorescence and MR imaging were evaluated using 4T1 tumor-bearing mice. As shown in Figure S8 (in the Supporting Information), the fluorescence imaging of subcutaneous tumor was performed via intratumoral injection of the nanoparticles. T1-weighted MR images were recorded precontrast and postinjection of mUCNDBs with a 3.0 T MR instrument (Figure 4d). At the tumor site, a brightness effect could be observed after the injection of mUCNDB. Additionally, the signal-noise-ratio (SNR) of postinjection of mUCNDBs was enhanced a quarter in comparison with precontrast. The results revealed that the mUCNDBs possessed both obvious fluorescence and MR imaging ability, proving that mUCNDBs can be used for multimodal imaging.

Figure 3. a) TEM image of mUCNDBs. b) Intensity distribution of the diameter of the mUCNDBs in DIW. c) Fluorescence spectrum of the as-prepared UCNPs-OA (black line) and mUCNDBs (red line) excited by 980 nm laser. Inset is the corresponding luminescence photograph of solution containing mUCNDBs. d) M-H curve of mUCNDBs powder at room temperature.


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Figure 4. a) Pseudocolor T1-maps and b) responsive longitudinal relaxation curves of mUCNDBs, sphere-like NPs and Gd-DTPA with gadolinium ion concentration varying from 0.05 mM to 0.8 mM in aqueous solutions. Gradient column corresponds to quantitative T1 value. c) CLSM images of mUCNDBs with HeLa cells. Upper panels 1-3 show the red, green, blue upconversion luminescence under excitation of 980 nm. Lower panels 1-3 show the dyed nuclei under excitation of 405 nm, merge image and bright-field image, respectively. All the scale bars represent 20 µm. d) T1-weight images of the subcutaneous tumor and relative SNR histograms of the tumor. The tumor areas are marked by the white circle. Pre means precontrast, while post means postinjection. The results are the mean values from a representative of four evaluations (Mean ± S.E.M., n = 4, **p < 0.01).

Figure 5. a) MTT viability assay was used to determine the cell viability of MCF-7 cells after incubation with mUCNDBs for 24 h. b) Photographs and histograms of hematolysis tests. c) H&E-stained tissue sections from mice injected with mUCNDBs (n=3, dose=0.1 mmol Gd kg-1, 15 days postinjection) and control mice received a 200 µL intravenous injection of normal saline (n=3). All the scale bars represent 20 µm..

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Figure 6. a) The evaluation of blood routine tests of mice injected with mUCNDBs (n=3, dose=0.1 mmol Gd kg-1, 7days and 15 days postinjection) and control mice received a 200 µL intravenous injection of normal saline (n=3). (b) The evaluation of major liver and kidney function (n=3).

MTT viability assay was performed towards MCF-7 cells to determine the cell viability of mUCNDBs. The mUCNDBs were relatively non-toxic to MCF-7 cells within the tested concentration range even as high as 200 µg/mL (Figure 5a). To evaluate the haemolysis of mUCNDBs, deionized water and normal saline served as positive and negative control, respectively. As shown in Figure 5b, the haemolysis rate of mUCNDBs, as low as negative control, was much lower than the haemolysis limit (5%). The result showed that mUCNDBs have no haemocylolysis according to the standard. To investigate the in vivo biocompatibility, mUCNDBs were injected intravenously into Balb/c mice at a dose of 0.1 and 0.05 mmol Gd/kg. Tissue sections of lung, heart, liver, spleen and kidney were stained with hematoxylin and eosin (H&E) for morphological analyses. Compared with control groups, no morphological changes were observed in experimental groups, indicating no distinct toxic effects in vivo within two weeks (Figure 5c). The body weights of mice were recorded for 14 days to monitor the mature period. Compared with the control group, the body weights of experimental groups kept growing with similar growth rate (Figure S9, Supporting Information). No evident side effects were observed, implying that mUCNDB had basically no influence on the qualities of life. All the experimental groups showed a 100% viability, indicating a negligible toxicity. Tests of hematology

parameters as well as liver and kidney function indicators were taken to research the long-term compatibility of mUCNDBs at 2 weeks postinjection. The significant hematology parameters were evaluated to identify the blood compatibility (Figure 6a). No evident change was found between experimental groups injected with normal saline of mUCNDBs and control groups injected with normal saline. The vital liver and kidney function, including alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and blood urea nitrogen (BUN), were measured, and it showed a variation with normal levels in comparison to the control groups, indicating no obvious dysfunction caused by mUCNDB (Figure 6b). In summary, a facile sequential growth process has been successfully developed to fabricate uniform NaYF4:Yb/Er@NaGdF4 core-shell nanodumbbells. The modified hydrophilic nanodumbbells show good dispersibility and upconversion fluorescence and higher magnetic resonance longitudinal relaxivity (r1 = 7.81 mM-1s-1). Furthermore, fluorescence and MR dual-modal imaging studies in vitro and in vivo were demonstrated, and a satisfying compatibility was validated. The present study has provided an alternative to multimodal bioimaging.


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ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: Additional intensity distribution of the diameter of the UCNPs-OA; XRD, XPS and FT-IR spectrum of NaYF4:Yb,Er@NaGdF4 nanodumbbells; zeta potential of nanodumbbells; The responsive NaYF4:Yb,Er@NaGdF4 longitudinal relaxation curves of the aqueous solutions of prepared mUCNDBs, sphere-like NaGdF4 NPs and Gd-DTPA; In vivo upconversion luminescence image; Change in body weights over a period of 14 days of mice injected with mUCNDBs.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] (J.-L. S.) *E-mail: [email protected] (Y. L.) *Fax: +86-551-62901285. E-mail: [email protected] (H.-S. Q.) Author Contributions ∇ H.-Q.W. and H.-Y.P. Contributed equally to the work. Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS We acknowledge the funding support from the National Natural Science Foundation of China (Grant 21471043, 51572067, 21501039, 81471983, 81171606), the Fundamental Research Funds for the Central Universities (‘Chun-Hua Project’ 2015HGCH0009, WK2060190056), the National Basic Research Program of China (No. 2010CB530001), the Science Foundation of Anhui Province (No. KJ2014A106 and No. 1308085MH124) and the China Postdoctoral Science Foundation (2015M570540). H. Wen and H. Peng contributed equally to this work.

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