Intracellular pH-responsive and rituximab-conjugated mesoporous silica nanoparticles for targeted drug delivery to lymphoma B cells
- Shoubing Zhou†1,
- Dan Wu†2,
- Xiaodong Yin3,
- Xiaoxiao Jin1,
- Xiu Zhang1,
- Shiya Zheng1,
- Cailian Wang1Email author and
- Yanwen Liu1Email author
© The Author(s). 2017
Received: 20 August 2016
Accepted: 11 January 2017
Published: 6 February 2017
One of the main problems in B cell lymphoma treatment is severe adverse effects and low therapeutic efficacy resulting from systemic chemotherapy. A pH-sensitive controlled drug release system based on mesoporous silica nanoparticles was constructed for targeted drug delivery to tumor cells to reduce systemic toxicity and improve the therapeutic efficacy.
In this study, the doxorubicin (DOX) was filled into the mesopores of the functional MSNs (DMSNs). Furthermore, rituximab was introduced as the targeted motif of functional DMSNs using an avidin-biotin bridging method to evaluate the targetability to tumor cells. Then, the cell viability and apoptosis efficiency after treatment with rituximab-conjugated DMSNs (RDMSNs) were estimated by using CCK-8 assay and flow cytometry, respectively. Additionally, the research in vivo was performed to evaluate the enhanced antitumor efficacy and the minimal toxic side effects of RDMSNs. Also, TUNEL staining assay was employed to explore the mechanism of antitumor effects of RDMSNs.
This targeted drug delivery system exhibited low premature drug release at a physiological pH and efficient pH-responsive intracellular release under weakly acidic conditions. The in vitro tests confirmed that targeted RDMSNs could selectively adhere to the surface of lymphoma B cells via specific binding with the CD20 antigen and be internalized into CD20 positive Raji cells but few CD20 negative Jurkat cells, which leads to increased cytotoxicity and apoptosis of the DOX in Raji cells due to the release of the entrapped DOX with high efficiency in the slightly acidic intracellular microenvironment. Furthermore, the in vivo investigations confirmed that RDMSNs could efficiently deliver DOX to lymphoma B cells by pH stimuli, thus inducing cell apoptosis and inhibiting tumor growth, while with minimal toxic side effects.
This targeted and pH-sensitive controlled drug delivery system has the potential for promising application to enhance the therapeutic index and reduce the side effects of B cell lymphoma therapy.
KeywordsMesoporous silica nanoparticles pH-response Targeted drug delivery B cell lymphoma Rituximab
Lymphoma remains one of the primary causes of cancer mortality globally. Systemic chemotherapy is an indispensable treatment for many types of lymphoma. Rituximab, a chimeric monoclonal antibody that can specifically interact with the CD20 antigen , combined with doxorubicin (DOX) have been extensively used for improving the prognosis of B cell lymphoma over the past few decades . Although these treatments have favorable therapeutic effects in most cases, significant adverse effects may occur due to premature drug release prior to reaching the targeted sites and nonspecific biodistribution in normal tissues . Therefore, exploring new therapeutic strategies is necessary for preventing drugs from prematurely releasing during blood circulation, controlling drug nonspecific biodistribution, reducing off-target toxicity, and improving the therapeutic efficacy.
Nanoparticles have been reported to serve as drug delivery carriers in the nanomedicine field. Recently, mesoporous silica nanoparticles (MSNs) have attracted much attention due to their favorable properties including good biocompatibility, high stability, tunable pore diameter, unique porous structure, large loading capacity, and easy surface functionalization [4–9]. The ordered pore network of these MSNs can effectively load drug within the channels. Additionally, MSNs can also be designed to trigger the release of a loaded drug in response to either external or internal stimuli, such as temperature [10, 11], light [12, 13], redox reactions [14–16], enzymes [17, 18], pH value [19, 20], and biomolecules [21, 22]. Among these stimuli, pH-responsive drug release mechanisms are considered as a facile and convenient method for controlled drug release using a low pH signal, because endosomes and lysosomes formed in cells after internalization of drug delivery carriers are relatively more acidic with a pH of 4.5–5.5 . Therefore, various types of pH-responsive drug delivery carriers based on MSNs have been developed to control drug release via a pH signal in endosomes and lysosomes. However, the use of only single pH-responsive MSNs that are based on passive targetability via enhanced permeability and retention effects for drug delivery results in facile internalization by normal cells through an unspecific uptake method. Therefore, several studies have reported that the external surface of MSNs can be modified with tumor-specific ligands to improve the active targetability by increasing the affinity between the receptor and the ligand. Various types of targeted ligands, such as folate , peptides , glycyrrhetinic acid , hyaluronic acid , mannose , arginine-glycine-aspartate , DNA aptamer , and lactobionic acid , have been successfully conjugated to drug delivery carriers, leading to an enhanced anticancer drug therapeutic index. At present, these ligands primarily targeted solid tumors rather than lymphoma and were rarely used in clinical applications for cancer molecular targeting therapy due to unwanted immunogenicity. Therefore, the development of intracellular pH-responsive and active targeted drug-loaded MSNs is urgently needed for minimizing the side effects and maximizing the therapeutic efficacy for lymphatic system tumors.
Mesoporous silica nanoparticles were purchased from Anhui JingYe Nano Technology Co., Ltd. N-(trimethoxysilylpropyl) ethylenediamine triacetic acid was obtained from J&K Scientific Ltd. Doxorubicin hydrochloride was obtained from Shenzhen Wanle Pharmaceutical Co., Ltd. N-hydroxysuccinimide (NHS) was purchased from Aladdin Industrial Corporation. Amine-Peg2000-Biotin, the EZ-Link™ Sulfo-LC Biotinylation Kit and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) were purchased from Thermo Fisher Scientific. Dylight 488-Avidin was obtained from Wuhan Boster Biological Engineering Co., Ltd. Rituximab was obtained from Hoffmann-La Roche, Ltd. The DAPI (4,6-diamidino- 2-phenylindole) staining solution, Cell Counting Kit-8 and the Annexin V-FITC/PI cell apoptosis detection kit were purchased from Beyotime Biotechnology Co., Ltd.
Preparation of carboxyl-modified MSNs
The surfaces of the obtained MSNs were modified with carboxyl groups via hydrolyzation of N-(trimethoxysilylpropyl) ethylenediamine triacetic acid. Briefly, the MSNs (100 mg) were dispersed in anhydrous alcohol (20 mL), and 0.1 mL of N-(trimethoxysilylpropyl) ethylenediamine triacetic acid was added under continuous stirring with a magnetic stirring apparatus at room temperature for 24 h. Then, the resulting MSN-COOH were collected by repeated centrifugation and rinsed with a sterile PBS solution three times to remove the reaction impurities.
The morphological characterization of MSN-COOH was performed using a scanning electron microscope (SEM, Hitachi S-4800; Japan). The structures of MSN-COOH were investigated using transmission electron microscopy (TEM, Hitachi H-7600; Japan). The size distribution and zeta potential of the MSN-COOH resuspended in PBS (pH 7.4) were measured using a Malvern Zetasizer Nano ZS unit (Malvern Instruments, UK). Fourier transform infrared (FTIR) analyses of MSN and MSN-COOH were carried out on a Bruker Vertex 70 FTIR spectrometer. The pore size distributions and surface areas of different MSNs materials were characterized by Brunauer–Emmett–Teller (BET) and Barrett–Joyner–Halenda (BJH) analyses (ASAP2020M, USA).
To load MSN-COOH with DOX, 5 mg of DOX hydrochloride was dissolved in 2 mL of PBS (pH 7.4), and MSN-COOH was added to the solution. The mixture was stirred on a magnetic stirring apparatus at room temperature for 24 h under dark condition. The DOX molecules can diffuse into the mesoporous channels with carboxyl groups. The dispersion was detached by centrifugation and washed with PBS to remove the unloaded DOX. The DMSNs were resuspended in PBS. The amount of supernatant DOX was estimated by absorbance measurement at 488 nm using a TECAN Infinite F50 Microplate Reader. Loading efficiency = (initial weight of DOX - supernatant weight of DOX)/weight of particles × 100%. Encapsulation efficiency = (initial weight of DOX - supernatant weight of DOX) / initial weight of DOX.
Preparation of targeting DMSNs
The resulting DMSNs were dissolved in PBS, and an equimolar amount of EDC and NHS was added to the solution. The carboxyl groups on the surface of the DMSNs were activated for 1 h at room temperature in a shaker. The supernatant was removed after the mixture was centrifuged. The resulting precipitants were resuspended in PBS, and Amine-Peg2000-Biotin (5 mg) was added to the solution. Next, the mixture was allowed to react for 1 h at room temperature in a shaker to afford the biotinylated DMSNs. The biotinylated DMSNs were incubated with DyLight 488-labeled avidin for 10 min. The biotinylated DMSNs were collected by repeated centrifugation and rinsed three times to remove the redundant DyLight 488-labeled avidin. Then, rituximab was biotinylated through the EZ-Link™ Sulfo- LC-Biotinylation Kit according to the manufacturer’s instructions. Finally, biotinylated rituximab was added to the biotinylated DMSNs suspension and incubated for 10 min. The mixture was rinsed and purified to afford the RDMSNs. Rituximab-conjugated MSNs (RMSNs) were prepared using the same method but without DOX hydrochloride.
The conjugation of rituximab on the surface of the DMSNs was determined by measuring the absorbance of the free DyLight 488-avidin solution and DyLight 488-avidin conjugated DOX-loaded MSNs with a fluorescence spectrophotometer at a maximum excitation wavelength of 493 nm and a maximum emission wavelength of 518 nm. The binding efficiency of rituximab on the DyLight 488-avidin conjugated DMSNs was estimated as the ratio of the intensity of the DyLight 488-avidin conjugated DMSNs to the intensity of the free DyLight 488-labeled avidin samples.
In vitro test of drug release
The DMSN and RDMSN samples were dissolved in 5 mL of PBS buffer (pH 5.5 or pH 7.4) or medium and shaken at 37 °C under dark conditions. The samples were centrifuged at certain intervals, and the amount of released DOX in the supernatant was determined using a TECAN Infinite F50 Microplate Reader.
Raji and Daudi (CD20-positive) cell lines and Jurkat (CD20-negative) cell lines, which were purchased from the Type Culture Collection of the Chinese Academy of Sciences (Shanghai, People’s Republic of China), were cultured in RPMI 1640 medium with 10% FBS (v/v) and 1% PS (v/v) at 37 °C under a humid atmosphere containing 5% CO2 at 37 °C. The cells used in the experiments were in the logarithmic growth phase.
Cell recognition and cellular uptake of RDMSNs and DMSNs
The Raji cells and Jurkat cells were seeded in a 12-well plate (50,000 per well) and incubated with RDMSNs and DMSNs with a DOX concentration of 0.5 μg/mL for 2 h at 37 °C. After the medium was removed and the cells were washed with PBS three times, flow cytometry (FCM) was employed to quantify the mean fluorescence intensity (MFI) of the RDMSNs and DMSNs internalized into the cells based on DOX autofluorescence. Additionally, the Raji cells and Jurkat cells were incubated with a nuclear staining agent (DAPI) in NEST glass culture dishes for 30 min followed by observation under a confocal laser scanning microscope (CLSM FV1000; Olympus, Japan) using a 100 × oil objective at excitation wavelengths of 410 and 488 nm, respectively. Competitive experiments were performed by pre-incubation of Raji cells with excessive rituximab to block the CD20 antigen for 30 min followed by washing. Jurkat cells were employed as a control.
Transmission electron microscopy was further employed to observe cell uptake and intracellular distribution of the nanoparticles. After the Raji cells were incubated with RDMSN and DMSN for 24 h, these cells were collected by repeated centrifugation and rinsed with PBS buffer. Then, the Raji cells were immobilized with 2.5% glutaraldehyde and observed using TEM.
Cell viability assay of RDMSNs and DMSNs
The cell viability was measured according to the instructions provided with the Cell Counting Kit-8 (CCK-8). The Raji, Daudi and Jurkat cells were seeded in 24-well plates (1 × 105 per well). The cells were incubated with various concentrations of MSNs or rituximab-conjugated MSNs (RMSNs) (i.e., 10, 20, 40, 80, or 100 μg/mL), Free DOX, RDMSNs and DMSNs containing various DOX concentrations (i.e., 0.1, 0.5, 1.0, 2.0, or 4.0 μg/mL). After incubation for 24 h, the cells were washed with PBS buffer three times and placed in fresh culture medium. Then, 10 μL of the CCK-8 solution were added to each well followed by incubation for an additional 4 h. The absorbance of the solution was measured at 450 nm using a TECAN Infinite F50 Microplate Reader.
Cell apoptosis assay of RDMSNs and DMSNs
The nuclear morphological changes due to apoptosis were detected in Raji cells using CLSM. The Raji cells were seeded in a 6-well plate (4 × 105 per well) and incubated with PBS buffer, MSNs (50 μg/mL), Free DOX, DMSNs and RDMSNs containing a DOX concentration of 2.0 μg/mL for 24 h. Next, the cells were rinsed with cold PBS buffer three times and fixed with 4% paraformaldehyde at room temperature for 30 min. Then, the samples were washed with PBS and stained with DAPI (20 μg/mL) in NEST glass culture dishes for 30 min. Finally, the stained Raji cells were observed under CLSM.
The cell apoptosis assay was analyzed by FCM with a commercial Annexin V-FITC detection kit. The Raji cells were treated using the same method. In addition, the Raji cells were incubated with different concentrations of RDMSNs (i.e., 0, 10, 20, 30, and 50 μg/mL). After incubation for 24 h, the Raji cells were rinsed twice with cold PBS buffer, resuspended in 195 μl of binding buffer solution and stained with 5 μl of FITC-labeled Annexin V and 10 μl of PI for 15–20 min at room temperature in the dark. Raji cells incubated in PBS buffer were considered the control group.
RMSNs biological safety study in vivo
Female Babl/c mice were treated with RMSNs by tail vein injection (100 μL, 100 mg/kg) one dose every 3 days for 3 weeks. The nude mice treated with saline were used as controls (3 mice per group). The body weight was monitored every week. The main organs including the heart, liver, spleen, lungs and kidneys were acquired after the final treatment followed by Hematoxylin and eosin (H&E) staining to detect the toxicity in vivo.
DOX distribution in tumors
Lymphoma model were established by subcutaneous injection with 6 × 107 Raji cells into the right axillary space of mice. When lymphoma volume reached approximately 100 mm3, the intravenous injection of Free DOX, DMSNs and RDMSNs was then carried out at the DOX dose of 2 mg / kg at 1, 6, and 24 h, respectively (9 mice per group). After the sacrifice of 3 mice per group for each time points, the tumors were excised and homogenized with RIPA buffer. Subsequently, the supernatant was collected by centrifugation and quantified for DOX content by fluorimetry and normalized with the tumor weight.
In vivo antitumor efficacy
Raji lymphoma bearing mice were established as described above. When lymphoma volume reached approximately 100 mm3, Raji lymphoma bearing mice were randomly divided into 4 groups (5 mice per group), respectively : saline group, Free DOX group, DMSNs group and RDMSNs group. Each Raji lymphoma bearing mouse was treated with DOX related formulations (the dose was 2 mg / kg) once every 4 days for a total four times. The lymphoma sizes of all mice were monitored by a digital caliper and calculated by the equation: Vtumor = LW2/2 (L: tumor length, W: tumor width). The lymphoma volume and body weight were determined every other day. After 16 days of treatment, all the mice were sacrificed and the lymphoma were extracted and fixed with 4% paraformaldehyde. Additionally, To detect cell apoptosis in lymphoma tissue, lymphoma tissue was sliced into thin sections and stained with a TUNEL apoptosis detection kit. Next, the sample was stained with DAPI solution to visualize cell nuclei under a fluorescence microscope.
All experiments were performed in triplicate. Results were presented as mean ± standard deviation and analyzed using SPSS 16.0 software (SPSS, Chicago, IL, USA). Statistical analysis was carried out using a student’s t-test. P < 0.05 was determined to be statistically significant.
Preparation and characterization of nanoparticles
Characterization of nanoparticles drug loading and release
To investigate the drug loading behavior of MSNs, an anticancer drug (i.e., DOX) was chosen as a model drug. The properties of the MSNs as a drug delivery system were estimated by the DOX loading and encapsulation efficiencies. The encapsulation efficiency was approximately 45.2 ± 3.1%, and the loading efficiency was approximately 23.5 ± 1.3%. The data are similar to that of the previous study . These results demonstrated that the MSNs possessed a large storage space for the effective loading of DOX.
Characterization of the MSNs
Size distribution (nm)
Zeta potential (mV)
40.7 ± 19.1
−32.6 ± 5.7
45.3 ± 17.6
−27.1 ± 3.8
56.3 ± 11.2
−31.5 ± 5.2
Cell recognition and internalization of DMSNs and RDMSNs
Cell viability study of DMSNs and RDMSNs
Cell apoptosis study of DMSNs and RDMSNs
RMSNs biological safety study in vivo
Enhanced DOX accumulation in tumors and antitumor efficacy in vivo
In the war against lymphoma, chemotherapy is presently the most common treatment. However, its efficiency is hampered by severe toxic side effects. These adverse effects often lead to a drug dose reduction or discontinuation of treatments in clinical applications. Nanoparticles as excellent drug delivery carriers have been reported to serve as an effective approach to enhance the drug efficacy and reduce adverse effects [36, 37]. The drug-loaded MSNs have been reported to serve as a promising drug carrier for all types of solid tumors therapy. However, the ligands conjugated to targeted drug-loaded MSNs had the unwanted immunogenicity. In this study, we successfully designed and constructed an intracellular pH-responsive and targeted drug delivery system based on DOX-loaded MSNs to enhance the therapeutic index and reduce the side effects of B cell lymphoma therapy.
The prepared RDMSNs have several advantages. First, PEG as a polymer protective layer could suppress plasma protein adsorption. Furthermore, rituximab as tumor-targeting components could carry out CD20 antigen-mediated cell internationalization. Additionally, DOX-loaded RDMSNs could be released by a low pH signal at the targeted site. Thus, after the multifunctional RDMSNs reach their targeted sites, the rituximab on the outer layer can specifically adhere to the CD20 antigen on the membranes of lymphoma B cells, leading to receptor-mediated cell pinocytosis or endocytosis and endosome or lysosome formation inside the tumor cells. Then, the loaded drug can be rapidly released from the multifunctional RDMSNs due to a reduction of the electrostatic interaction triggered by the lower pH of the acidic environment of the endosome or lysosome. Therefore, these multifunctional RDMSNs have the potential for use as an intracellular pH-responsive and targeted drug delivery system for B cell lymphoma therapy.
In this study, the zeta potential results demonstrated that the MSNs were negatively charged at a pH of 7.4 due to the large amount of negatively charged silanol group on the MSNs, which is consistent with that reported in a previous study . Moreover, several studies confirmed that the isoelectric point (pI) of DOX is 8.2. It is important to note that the pI values of DOX are higher than pH 7.4, revealing that the DOX molecules are positively charged in the physiological microenvironment. Therefore, the DOX molecule can fill the mesoporous channels of the MSNs under pH 7.4 conditions via electrostatic interactions between the negative charges of the MSNs and the positive charges of the DOX molecules. Thus, the DMSNs further exhibit high loading and encapsulation efficiencies. In the drug release assay, no significant difference in the amount of released DOX was observed between the DMSNs and RDMSNs at the same pH value. Furthermore, the conjugation of rituximab did not influence the release of DOX at the different pH values. Interestingly, the release efficiency of DOX at a pH of 5.5 was higher than that at pH of 7.4 or in medium, indicating that a lower pH value was more beneficial to DOX release from the DMSNs or RDMSNs. These results were supported by those from previous studies . The pH-responsive DOX release was due to the weakly electrostatic attraction at acidic pH and the strongly electrostatic attraction at physiological pH between MSNs and DOX molecules. Due to this property, the pH-responsive and targeted drug release system could effectively decrease DOX release during blood circulation (pH 7.4) and improve DOX release in the endosomes or lysosomes (pH 4.5–5.5) of tumor cells. Therefore, reduced DOX side effects and enhanced intracellular DOX accumulation could be achieved via this pH-responsive and targeted drug delivery system.
Previous studies reported similar results whereby a targeted modification of ligand enhanced the internalization and cytotoxicity effect of nanoparticles via the receptor-mediated endocytosis pathway [40–42]. In our study, the results demonstrated that more RDMSNs were recognized and internalized by CD20 antigen positive Raji cells compared to DMSNs. Furthermore, the prepared RDMSNs exhibited higher cytotoxicity effect and apoptosis efficiency compared to those of Free DOX and DMSNs at the same DOX concentration in the CD20 antigen positive Raji cells. Also, Raji cell apoptosis increased when the concentration of the RDMSNs increased. These should be the covalent conjugations of Rituximab as a ligand which provide active targeting and improved endocytosis of RDMSNs by lymphoma B cells by overexpressing CD20 antigen, enhancing drug efficacy and promoting lymphoma B cells death. In this research in vivo, Free DOX only exhibited a moderate inhibition effect on lymphoma growth compared to that of DMSNs, which was different from the results of cell viability evaluation in vitro. It was attributed to the fact that Free DOX rapidly diffused into all tissues of mice after intravenous administration, leading to potential toxic side effect on healthy tissues, thus only small amount of DOX molecule could reach tumor sites in vivo. On the other hand, Free DOX has shorter half life in vivo, and would be eliminated during the blood circulation and metabolism. Additionally, the enhanced antitumor activity, increased cell apoptosis observed via TUNEL staining assay and reduced systemic toxicity of RDMSNs could probably be involved in the following factors: (1) DOX molecule loaded into the hole of MSNs effectively protected it from quick clearance during blood circulation; (2) Enhanced permeability and retention effect of stealth RDMSNs would passively and actively aggregate the RDMSNs at the tumor site; (3) CD20 antigen-mediated cell specific endocytosis or internalization of the RDMSNs were occurred via CD20 antigen positive Raji cells, improving cell uptake of RDMSNs, and promoting the local chemotherapeutics accumulation. (4) Due to the pH-responsive property, the intracellular DOX release of RDMSNs was improved in the endosomes or lysosomes (pH 4.5–5.5) of tumor cells. (5) The enhanced antitumor efficacy of RDMSNs was occurred through inducing lymphoma cells apoptosis. (6) Rituximab as a molecular targeted drug can induce the antibody-dependent cell-mediated cytotoxicity and complement dependent cytotoxicity. Thus, the synergistic effect of the DOX and Rituximab in the RDMSNs resulted in excellent tumor inhibition effect. (7) DOX is an anthraquinone anticancer agent that is commonly used for the treatment of various types of tumors. DOX can specifically inhibit topoisomeraseIIenzyme activity. However, topoisomeraseIIplays an important role in DNA replication . All these results demonstrated that RDMSNs exhibited both the excellent antitumor effect and the reduced systemic toxicity. Taken together, our study displayed that RDMSNs could serve as an effective and safe platform to improve the therapeutic effect of antitumor drugs and reduce the associated side effects.
In summary, we have designed and constructed a targeted and DOX-loaded drug delivery system based on MSNs with CD20 antigen-mediated cancer cell uptake and intracellular pH-responsive controlled drug release features. More DOX can be released in an acidic environment (pH 5.0) than in a neutral environment (pH 7.4). The in vitro experiments demonstrated that RDMSNs exhibited targeting accumulation and improved the cytotoxic effects on CD20 positive lymphoma B cells. Furthermore, the in vivo investigations confirmed that RDMSNs could efficiently deliver DOX to tumor cells by pH stimuli, thus inducing cell apoptosis and inhibiting tumor growth, while with minimal toxic side effects. These results suggest that this targeted drug delivery system has the potential for applications in B cell lymphoma therapy.
Cell Counting Kit-8
Confocal laser scanning microscope
Doxorubicin -loaded mesoporous silica nanoparticles
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride
Fourier transform infrared
Hematoxylin and eosin
Mean fluorescence intensity
Mesoporous silica nanoparticles
Phosphate buffer saline
Poly (ethylene glycol)
Rituximab-conjugated and doxorubicin-loaded mesoporous silica nanoparticles
Rituximab-conjugated mesoporous silica nanoparticles
Scaning electron microscope
Transmission electron microscopy
Terminal deoxynucleotidyl transferase dUTP nick end labeling
The authors are indebted to all the donors whose names were not included in the author list, but who participated in our study.
This study was supported by grants from the National Natural Science Foundation of China (No. 81271699).
Availability of data and materials
The data and materials supporting our findings can be found.
SZ and DW performed most of the experiments, analyzed data, and wrote the manuscript. SZ, DW and XY were participated in data acquisition, analysis and interpretation. XJ and XZ performed some experiments. SZ, XZ and SZ reviewed and edited the manuscript. CW and YL designed the experiments and edited the manuscript. All authors read and approved the final manuscript.
The authors declare that there is no competing interests.
Consent for publication
Ethics approval and consent to participate
The using of nude mouse was approved by Animal Ethics Committee of Southeast University.
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