Second Near-Infrared Conjugated Polymer Nanoparticles for

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Second Near-Infrared Conjugated Polymer Nanoparticles for Photoacoustic Imaging and Photothermal Therapy Tingting Sun, Jinhu Dou, Shi Liu, Xin Wang, Xiaohua Zheng, Yapei Wang, Jian Pei, and Zhigang Xie ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b01458 • Publication Date (Web): 09 Feb 2018 Downloaded from http://pubs.acs.org on February 12, 2018

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ACS Applied Materials & Interfaces

Second Near-Infrared Conjugated Polymer Nanoparticles for Photoacoustic Imaging and Photothermal Therapy Tingting Sun,†,‡ Jin-Hu Dou,§ Shi Liu,† Xin Wang,

⊥,†

Xiaohua Zheng,†,‡ Yapei Wang,║ Jian

Pei,*,§ and Zhigang Xie*,† †

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied

Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, China ‡

University of Chinese Academy of Sciences, Beijing 100049, China

§

Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry

and Molecular Engineering of Ministry of Education, Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, Center of Soft Matter Science and Engineering, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China

⊥

Department of Thyroid Surgery, The First Hospital of Jilin University, 71 Xinmin Street,

Changchun 130021, China ║

Department of Chemistry, Renmin University of China, Beijing 100872, China

ACS Paragon Plus Environment

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Abstract: Photothermal conversion in the second near-infrared (NIR-II) window allows deeper penetration and higher exposure to laser, but examples of NIR-II photothermal agents are mainly formulated by inorganic compounds. In view of the underlying influence of inorganic materials, a novel NIR-II photothermal nano-agent based on a narrow bandgap D-A conjugated polymer (TBDOPV-DT) with 2,2-bithiophene as the donor and thiophene-fused benzodifurandione-based oligo(p-phenylenevinylene) as the acceptor has been developed. More importantly, TBDOPVDT nanoparticles (TBDOPV-DT NPs) are demonstrated to combine excellent photoacoustic imaging (PAI) and photothermal therapy (PTT) ability in the meantime. TBDOPV-DT NPs exhibit dramatic photostability and heating reproducibility with photothermal conversion efficiency of 50%. Especially, the nanoparticles possess remarkable PTT effect toward cancer cells in vitro and can eliminate tumor cells completely in vivo under 1064 nm laser irradiation, while no appreciable side effect has been observed. This study achieves PAI-guided cancer therapy and sheds light on the future of using organic polymer nanoparticles for NIR-II photothermal therapy of cancer.

Keywords: conjugated polymer, second near-infrared, self-assembly, photoacoustic imaging, photothermal therapy


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Introduction Cancer is becoming one of the diseases threating human health, and some traditional tumor therapies including chemotherapy, radiotherapy and surgery usually cause serious side effects to cancer patients.1-4 Therefore, the development of more efficient and noninvasive tumor therapies are highly desired. Photothermal therapy (PTT), as one of the noninvasive therapies for malignant tumors, has attracted extensive attention due to the high specificity and efficiency in tumor destruction.1,5-11 Abundant photothermal agents (PTA) including inorganic gold12-17 or carbon18-25 based materials, and organic dyes,26-29 have been widely used. Compared with them, polymeric PTA,30-33 such as conjugated polymers have distinct advantages owing to their high absorption coefficient, superior photostability, and good biocompatibility. 5,30,34-41 Near-infrared (NIR) light has been generally applied in the field of PTT, because of its irreplaceable advantages of remote manipulation and high transparency in the “biological window”.11,42,43 In the past few decades, PTT in the first NIR (NIR-I, 750-1000 nm) optical window has been extensively studied.7,40,44-48 Recently, photothermal conversion in the second NIR (NIR-II, 1000-1700 nm) optical window, particularly within 1000-1100 nm, has received more and more attention, because it allows deeper tissue penetration and higher maximum permissible exposure to laser.6,42,49-51 However, only a few examples of NIR-II photothermal materials have been demonstrated, which are mainly based on inorganic materials, including transition metal sulfide/oxide semiconductors,52-54 noble metal nanomaterials,55-58 and semimetal nanomaterials.6 As far as we know, there were few organic polymer nanomaterials having been reported for PTT of cancer in the NIR-II window, although a very few polymer nanocomposites were utilized in other fields.59,60


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Moreover, photoacoustic imaging (PAI), which combines optical excitation with ultrasonic detection, has attracted considerable attention.61-64 Both PAI and PTT are on the basis of the heat generated by NIR radiation, therefore, the ideal combination of PAI and PTT in the same system would be beneficial for imaging-guided cancer therapy.65-66 Herein, a narrow bandgap D-A conjugated polymer (TBDOPV-DT), with 2,2bithiophene

as

the

donor

and

thiophene-fused

benzodifurandione-based

oligo(p-

phenylenevinylene) as the acceptor42 (Scheme S1) was exploited as NIR-II photothermal material. TBDOPV-DT has been served as NIR-II adsorbing antenna to actuate thermodependent devices.42 In this work, TBDOPV-DT nanoparticles (TBDOPV-DT NPs) were prepared and used for PAI and PTT of tumors. TBDOPV-DT NPs exhibited high photothermal conversion efficiency (50%), thus possessing remarkable photothermal therapeutic effect under 1064 nm laser irradiation. Furthermore, this nanoparticle was an excellent PAI agent with strong photoacoustic signals, which provided guidance for choosing the optimal time for laser irradiation and guaranteeing the best PTT efficacy.

Results and Discussion Conventional nanoprecipitation method was exploited to prepare TBDOPV-DT NPs by using methoxypoly(ethylene glycol)2K-block-poly(d,l-lactide)2K (mPEG2K-PDLLA2K) as the carrier, and the prepared nanoparticles were used for PAI and PTT under 1064 nm laser irradiation (Scheme 1). The block copolymer of mPEG2K-PDLLA2K facilitates the formation of nanoparticle formulations. As characterized by transmission electron microscopy (TEM), vesicular nanoparticles were observed in Figure 1a. The size distribution of TBDOPV-DT NPs was determined by dynamic light scattering (DLS) with the average hydrodynamic diameter of 171.6 nm and the polydispersity index (PDI) of 0.148, which is in agreement with the results of


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TEM image. The assembly of the TBDOPV-DT polymers into hollow spheres should be ascribed to the presence of mPEG2K-PDLLA2K, because similar phenomenon has been reported previously.5 The loading content of TBDOPV-DT in NPs was 5% by calculating the weight ratio of TBDOPV-DT in TBDOPV-DT NPs. Furthermore, energy-dispersive X-ray spectroscopy (EDS) also confirmed the chemical composition of the as-synthesized TBDOPV-DT NPs (Figure S1). The diameter and PDI of the nanoparticles show negligible changes after storage in water or PBS (pH 7.4) containing 10% FBS for two weeks (Figure S2), demonstrating that TBDOPV-DT NPs possess good stability not only in water but also in physiological environment. Scheme 1. The preparation a) and application in PTT and PAI in vivo b) of TBDOPV-DT NPs.

The successful preparation of TBDOPV-DT NPs was further validated by absorption and Fourier transform infrared (FTIR) spectra. The absorption spectrum of TBDOPV-DT NPs (Figure 1b) in water was similar with that of TBDOPV-DT in tetrahydrofuran (THF), but with a


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little hypochromatic shift due to the aggregation of TBDOPV-DT molecules. The strong absorbance of both TBDOPV-DT NPs and TBDOPV-DT in the NIR-II region is beneficial for their photothermal performance. Moreover, a high absorption coefficient of 39.5 L g-1 cm-1 (1064 nm) was achieved for TBDOPV-DT NPs in water. FTIR spectrum of TBDOPV-DT NPs (Figure S3) has the characteristic peaks of both mPEG2K-PDLLA2K and TBDOPV-DT, which ulteriorly confirms the successful formation of nanoparticles. The content of TBDOPV-DT in NPs could be determined according to the standard curve (Figure S4). The photothermal performance of TBDOPV-DT NPs in water upon laser irradiation was investigated with the variation of concentration and the power density of 1064 nm laser. When the power density of 1064 nm laser was fixed at 0.90 W cm-2, an obvious concentrationdependent temperature increase was observed, whereas pure water without materials showed insignificant change in temperature (Figure 1c). A high temperature increase of 25.7 oC has been detected at a low concentration (10 µg mL-1) within 10 min. Similarly, temperature variation of the nanoparticles at a constant concentration (10 µg mL-1) also exhibit laser power-dependent behavior (Figure 1d). The temperature of TBDOPV-DT NPs could be increased by about 53.7 oC when the laser power used was 1.96 W cm-2. Photothermal conversion efficiency (η) is an essential parameter for the assessment of PTA, so it is determined according to reported method.5,11 The calculated η value is 50% (Figure 1e and S5), which shows distinct advantage over inorganic NIR-II photothermal materials (Table S1), demonstrating good photothermal performance of TBDOPV-DT NPs. Then multiple cycles of laser irradiation were conducted to investigate the photothermal stability of TBDOPV-DT NPs. After 10 heating/cooling cycles, the temperature changes were consistent (Figure 1f). The excellent photothermal conversion behavior of TBDOPV-DT NPs affords great promise for potential use in cancer PTT.


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Figure 1. Basic physical properties and photothermal performance of TBDOPV-DT NPs. a) DLS results (inset) and TEM image of TBDOPV-DT NPs. b) Absorption spectra and picture (inset) of TBDOPV-DT NPs (water, right) and TBDOPV-DT (THF, left). Photothermal conversion behavior of TBDOPV-DT NPs at c) various concentrations and d) laser power densities. e) The photothermal response of TBDOPV-DT NPs under 1064 nm laser irradiation (0.90 W cm-2) and 10 min later laser was shut off. f) Temperature variations of TBDOPV-DT NPs (10 µg mL-1) in water over ten cycles of heating and natural cooling.

The NIR-II laser has higher tissue penetration than the generally explored NIR-I one. To explore its advantage over NIR-I laser (such as 808 nm) in PTT, IR780 was selected as a representative NIR-I photosensitizer, which was also encapsulated in mPEG2K-PDLLA2K (IR780 NPs), and chicken breast muscles were used as model biological tissues. Then, the deep tissue photothermal capability under 808 and 1064 nm irradiation was further assessed by covering 300 µL of IR780 NPs or TBDOPV-DT NPs in water with chicken breast muscles of varying


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thicknesses (0, 1, 2, 3, 4, 6 and 8 mm). The nanoparticles were irradiated by 808 and 1064 nm laser respectively at 1 W cm−2, and the changes in temperature were detected. As shown in Figure 2 and S6, a faster trend in temperature decrease can be observed for 808 nm laser than 1064 nm laser after penetration through the tissues of increasing thicknesses. This suggests that laser in the NIR-II window can achieve much stronger tissue penetration and less attenuation of photothermal heating than that in NIR-I window.

Figure 2. Relative temperature elevations of IR780 NPs and TBDOPV-DT NPs in water upon exposure to 808 and 1064 nm laser under chicken breast muscles of varying thicknesses (0, 1, 2, 3, 4, 6 and 8 mm).

For investigation of the cellular uptake of TBDOPV-DT NPs, nile red (NR) was chosen as the environment-dependent fluorescent probe67 and NR labled TBDOPV-DT NPs (NR@NPs) were prepared. Figure S7 shows the DLS results of NR@NPs and the photoluminescence (PL) spectra of TBDOPV-DT NPs and NR@NPs, which validates the successful loading of NR. Human liver hepatocellular carcinoma (HepG2) and cervical carcinoma (HeLa) cells were selected and cultured with NR@NPs for 0.5 and 2 h respectively, followed by staining the nuclei


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with Hoechst 33258. Then, cellular uptake was visualized via confocal laser scanning microscopy (CLSM). As indicated in Figure S8 and S9, bright red fluorescence was observed in all the cells, manifesting the efficient uptake of NR@NPs by cells. To further quantify the cellular uptake, flow cytometry was carried out. The internalization of NR@NPs by both cell lines was enhanced with time (Figure S10), exhibiting a time-dependent endocytosis. For exploring TBDOPV-DT NPs as PTA to treat cancer diseases, the PTT effect of TBDOPV-DT NPs toward cancer cells was first verified via MTT assays at various concentrations (0-10 µg mL-1) without or with 1064 nm laser irradiation (0.90 W cm-2, 10 min). For cells without laser irradiation, no significant cytotoxicity was observed after 24 h of incubation (Figure 3a, b). While crescent cells were dead with the increase of concentration for cells treated with laser irradiation, and TBDOPV-DT NPs at 10 µg mL-1 was effective enough to kill the majority of both cells. As expected, cells only treated by laser at 0.90 W cm-2 or 1.30 W cm-2 lived well (Figure S11). To further validate that cell death was triggered by both treatment with TBDOPV-DT NPs and laser irradiation, live cells (green) and dead ones (red) were also differentiated by Calcein AM and propidium iodide (Figure 3c and S12). Cells treated with only 1064 nm laser irradiation or TBDOPV-DT NPs in the dark were in healthy state as those in the control group, showing green fluorescence. Nevertheless, almost all the cells incubated with TBDOPV-DT NPs followed by treatment with laser irradiation were dead, exhibiting red fluorescence. These results intuitively confirmed the outstanding PTT efficacy of TBDOPV-DT NPs with 1064 nm laser irradiation.


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Figure 3. Cytotoxicity against cancer cells. Cell viabilities of a) HeLa and b) HepG2 cells under incubation of TBDOPV-DT NPs without or with 1064 nm laser irradiation. c) Fluorescence images of live (green) and dead (red) HeLa cells co-stained by Calcein AM and propidium iodide after various treatments. Scale bars: 100 µm.

For exploring the bio-distribution of TBDOPV-DT NPs in vivo, IR780 was loaded in TBDOPV-DT NPs, and ex vivo near-infrared fluorescence (NIRF) imaging was used to indicate the bio-distribution of TBDOPV-DT NPs. As shown in Figure S13, in the early stages (2 and 6 h after injection), the nanoparticles are mainly accumulated in liver and lung. It was worth noting that the fluorescense of the nanoparticles in the tumor gradually increased within 12 h and then decreased, which demonstrated that 12 h after injection should be the optimal time for laser irradiation. Thereafter, motivated by the intense absorption of TBDOPV-DT NPs and the excellent PTT efficacy, we investigated its potential in PAI. At first, the photoacoustic signals from TBDOPV-DT NPs in water were evaluated by varying concentrations. Higher PA signal was detected with increasing concentrations of the nanoparticles, and the PA signals of TBDOPV-DT


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NPs are linearly strengthened with concentrations (Figure S14). Next, PAI was further implemented on HeLa tumor bearing nude mouse. The mouse was intravenously injected with TBDOPV-DT NPs, and PA images were obtained at 0, 2, 7, 12, 24 and 36 h. As seen from Figure 4a, TBDOPV-DT NPs was an excellent PAI agent with strong photoacoustic signals. Notably, the PA signal reached maximum accumulation after intravenous injection of TBDOPVDT NPs for 12 h (Figure 4b), when the variation of photoacoustic signals was quantified versus time. This is in accordance with the NIRF imaging results, which is of great importance for providing guidance about the time when accumulation of TBDOPV-DT NPs reaches its maximum at the tumor site, thus choosing the optimal time for laser irradiation and guaranteeing the best PTT efficacy.

Figure 4. a) PA images and b) signal intensities of tumor obtained at appointed time points after administration of TBDOPV-DT NPs (1.94 mg kg-1). Scale bar in a), 3 mm.

Encouraged by the above results, we continued in vivo phototherapy of HeLa tumorbearing nude mice, and tumor inhibition effect was assessed upon 1064 nm laser illumination. The mice with tumors were divided into five groups randomly: control group (Control); groups treated with only TBDOPV-DT NPs (NPs) or 1064 nm laser (Laser); combinations of NPs and


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Laser intratumorally (IT + Laser) or intravenously (IV + Laser). An IR thermal camera was utilized to monitor the change of temperature during laser irradiation (Figure 5a, b). The temperature of tumors with injections of TBDOPV-DT NPs (IT: 0.56 mg kg-1; IV: 1.94 mg kg-1) showed rapid increase under irradiation (0.90 W cm-2 for IT + Laser and 1.30 W cm-2 for IV + Laser). On the contrary, the temperature exhibited tiny change for mice only treated with 1.30 W cm-2 of 1064 nm laser (Figure S15). Then, the tumor volumes were monitored during subsequent 20 days. Tumor volumes of mice in the Control, NPs and Laser groups increased gradually during the entire treatment period (Figure 5c). Differently, the tumor volumes of mice in IT/IV + Laser groups increased a little in the first two days, but they descended gradually thereafter and disappeared on the 10th day. After that, there was no recurrence of the tumors during the next 10 days, and only scars were left (Figure S16), indicating that TBDOPV-DT NPs with laser irradiation could completely inhibit the growth of tumors. On the 20th day, the mice were sacrificed and the tumors were excised. The photo of the excised tumors was shown in Figure 5d, and there was no tumor in IT/IV + Laser groups. Hematoxylin and eosin (H&E) staining of tumor regions (Figure 5g) ulteriorly certified the complete elimination of tumor cells. The weight of the tumors were in accordance with the volumes (Figure 5e). Changes of body weight were measured to evaluate the potential adverse effect of photothermal agents. In Figure 5f, only body weight of mice in IV + Laser group showed insignificant reduction in the first two days, but increased rapidly afterwards. Besides, the body weight of treated mice was a little higher than that of control group, suggesting that these treatments have no significant toxic effects to animals. H&E staining showed that intravenous injection of TBDOPV-DT NPs has no obvious damage to main organs (Figure S17). The potential long-term toxicity of TBDOPV-DT NPs in vivo were also investigated via measurement of the serum biochemistry and complete blood


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panels. The serum parameters of TBDOPV-DT NPs treated group have no obvious difference with those of control group (Figure S18), including the liver function makers of aspartate aminotransferase (AST) and alanine transaminase (ALT), the kidney function labels of uric acid (UA), creatinine (CREA) and urea nitrogen (UREA). Moreover, all parameters of complete blood tests are in normal range (Figure S19). It is clearly demonstrated from these results that TBDOPV-DT NPs would be efficient therapeutic agent for tumor PTT without any appreciable side effect.

Figure 5. In vivo PTT of tumors. The whole-body IR images of mice after injection of TBDOPV-DT NPs a) intratumorally (0.56 mg kg-1) and irradiated by 1064 nm laser (0.90 W cm2

) or b) intravenously (1.94 mg kg-1) and irradiated by laser (1.30 W cm-2). c) Growth rates of

tumors after different treatments. d) Representative photo of excised tumors. e) Tumor weight of


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each group. f) Changes in body weight of mice with tumors after various treatments. Statistical significance: **P≤0.01; ***P≤0.001. g) H&E staining of tumor regions in different groups. Scale bars: 100 µm.

Conclusions In conclusion, we have exhibited an example of organic NIR-II photothermal nano-agent based on conjugated polymer (TBDOPV-DT NPs), which has strong absorbance in the NIR-II window and exhibits excellent NIR-II photothermal properties. TBDOPV-DT NPs possess good physiological stability, ultrahigh photothermal conversion efficiency (50%) and photostability, which show excellent potential as candidate agents for PTT based cancer treatment. In addition, TBDOPV-DT NPs have favourable PAI ability, and could be used for imaging-guided cancer therapy. This study demonstrates an elegant example of organic polymer photothermal agents in NIR-II optical window, and offers an alternative system for forming NIR-II photothermal agents by rational design of organic polymers.

Materials and Methods Materials and characterization: mPEG2K-PDLLA2K and TBDOPV-DT were synthesize according to previous methods.42,68 Cell viability (live-dead cell staining) assay kit was purchased from Jiangsu KeyGEN Biotechnology Co., Ltd.. The other chemicals were used as obtained commercially. The absorption spectra were obtained by using a UV-3600 UV-vis-NIR spectrophotometer (Shimadzu). FTIR was measured by Nicolet Impact 410 Fourier transform infrared spectrometer. An MSOT inVision 128 small animal imaging system (iThera Medical


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GmbH) was used for PAI. Other characterizations were conducted according to reported instruments and methods.5,69 Preparation of TBDOPV-DT NPs: TBDOPV-DT (0.5 mg) and mPEG2K-PDLLA2K (5 mg) were dissolved in 5 mL of THF. Then the solution was dropwise added to deionized water (10 mL) under stirring. After THF was fully evaporated, it was dialysed for 24 h. The powders of TBDOPV-DT NPs were obtained by freeze-drying. For the preparation of NR@NPs, nile red (NR), TBDOPV-DT and mPEG2K-PDLLA2K were all dissolved in the organic phase. In vitro PTT effects: TBDOPV-DT NPs in aqueous solution with different concentrations were under 1064 nm laser irradiation for 10 min at 0.90 W cm-2, and temperatures were recorded every minute. To a fixed concentration of TBDOPV-DT NPs (10 µg mL-1), the influence from different power density (0.90-1.96 W cm-2) was recorded as well. The photothermal response of TBDOPV-DT NPs in water (10 µg mL-1) was recorded with irradiation and then laser was shut off. Photothermal conversion efficiency (η) was determined in accordance with previous method.5,11 The photostability was investigated by measuring the temperature variations of TBDOPV-DT NPs (10 µg mL-1) in water over ten cycles of heating and natural cooling. Cell lines and cell culture: HepG2 and HeLa cells were cultured with common methods.69

Cellular uptake: CLSM was used to examine the cellular uptake of NR@NPs by HeLa and HepG2 cells via reported procedures.69 Cell nuclei were stained with Hoechst 33258. Cytotoxicity: MTT assays were conducted to determine the toxicity of TBDOPV-DT NPs in Laser and Dark groups according to previous methods.5 The power density of 1064 nm laser used here was 0.90 W cm-2, and the irradiation time was 10 min.


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Live-dead cell staining: Cells were treated with the same conditions in MTT assays with untreated cells as control. 24 h later, Calcein-AM/propidium iodide were used to stain cells for 30 min at room temperature. Finally, cell staining results were obtained by a fluorescence microscope. Biodistribution of TBDOPV-DT NPs: The Kunming (KM) mice with tumors were injected with IR780 labeled TBDOPV-DT NPs (1.94 mg kg-1). The heart, liver, spleen, lung, kidney and tumor of the mice were collected and NIRF imaging were conducted at 2, 6, 12, 24 and 48 h. Systemic Toxicity: 4 KM mice were used in each group and they were injected with TBDOPVDT NPs (1.94 mg kg-1) intravenously. After 20 days, the liver/kidney function makers (AST, ALT, UREA, CREA and UA) were obtained from an automatic biochemical analyzer. Besides, complete blood of the mice were obtained for hematology analysis. Photoacoustic imaging (PAI): In vitro and in vivo PAI experiments were all performed with the reported methods.65 For in vivo PAI, the tumor bearing nude mouse was injected with TBDOPVDT NPs (1.94 mg kg-1) intravenously by tail vein, and PA images were acquired at 0, 2, 7, 12, 24 and 36 h. The results were analyzed via ViewMOSTTM software. Tumor suppression experiments: All the procedures about animal experiments were according to the guidelines of the Regional Ethics Committee for Animal Experiments. Male nude mice were obtained and maintained under required conditions. To evaluate antitumor effects, the animal modal we used was subcutaneous HeLa tumor xenografts. The tumor-bearing mice were divided into five groups (four in each group) randomly for different formulations. They were intratumorally injected with PBS or TBDOPV-DT NPs (0.56 mg kg-1) or intravenously injected with TBDOPV-DT NPs (1.94 mg kg-1). After different treatments, the tumor dimensions (length


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and width) were measured every 2 days. Tumor volumes were calculated via length × width2/2 (mm3). 20 days later, they were all sacrificed, tumors and main organs were collected.

ASSOCIATED CONTENT

Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Synthesis of TBDOPV-DT, high-resolution TEM and EDS mapping images, stability and FTIR spectra of TBDOPV-DT NPs, the standard curve of TBDOPV-DT, photothermal response of TBDOPV-DT NPs, comparison of different photothermal agents, temperature increase curves of IR780 NPs and TBDOPV-DT NPs, characterization of NR@TBDOPV-DT NPs, CLSM images, flow cytometry analyses, cell viabilities at different power density, live-dead cell staining, bio-distribution, PA signal of TBDOPV-DT NPs, IR images, representative photos of mice, H&E staining of different organs, serum biochemical analysis, and hematology data (PDF) AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. *E-mail: [email protected]. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT


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The project was supported by the National Natural Science Foundation of China (Project No. 51522307).

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