Hafnium-based nanosheet with excellent performance in NIR-II window as well as preparation method and application of hafnium-based nanosheet

Abstract

The invention discloses a hafnium-based nanosheet with excellent performance in an NIR-II window as well as a preparation method and application of the hafnium-based nanosheet, and the preparation method of the hafnium-based nanosheet comprises the following steps: firstly preparing a hafnium hydride nanosheet, and then carrying out surface modification on the hafnium hydride nanosheet by using Pluronic F127 to obtain a target product. The thickness of the hafnium-based nanosheet prepared by the invention is only 1-3nm, and the hafnium-based nanosheet has a higher surface area and a better in-vivo distribution characteristic, and is beneficial to improvement of tumor targeting and metabolism efficiency. The hafnium hydride nanosheet is modified by Pluronic F127, so that the stability and biocompatibility of the nanosheet are improved, and meanwhile, the cytotoxicity and the blood dissolution risk are reduced. The hafnium-based nanosheet has the photothermal conversion efficiency as high as 29.4%, shows excellent light absorption capacity and thermal conversion performance in an NIR-II window, and can make full use of the deep tissue penetration advantage of the window.

Description

Technical Field

[0001] The invention belongs to the technical field of nanomaterials, and in particular relates to a hafnium-based nanosheet having excellent performance in a NIR-II window, and a preparation method and application thereof. Background Art

[0002] Photothermal therapy (PTT) is a non-invasive tumor treatment method based on photothermal conversion. Photothermal transduction agents (PTAs) convert near-infrared light energy into thermal energy to induce hyperthermic damage or apoptosis of tumor cells. In recent years, PTT has attracted widespread attention due to its good tissue penetration, high selectivity and low side effects.

[0003] Traditional PTAs (such as gold nanoshells, copper sulfide nanoparticles, and polypyrrole) have performed well in laboratory studies, but face the following problems in actual clinical applications:

[0004] 1. Poor biocompatibility and biosafety: Many nanomaterials are prone to cause toxic reactions in the body, limiting their potential for clinical transformation.

[0005] 2. Limited photothermal conversion efficiency: Some PTAs have low photothermal efficiency, resulting in the need for higher laser power to achieve therapeutic effects, which may cause damage to normal tissues.

[0006] 3. Insufficient adaptability of laser wavelength: The absorption peaks of most PTAs are located in the first near-infrared window (NIR-I, 750-1000nm), while the second near-infrared window (NIR-II, 1000-1700nm) has better tissue penetration and biosafety. Therefore, it is urgent to develop efficient PTAs suitable for the NIR-II window.

[0007] In recent years, hafnium (Hf)-based nanomaterials (such as hafnium oxide nanoparticles) have shown great potential in medical applications due to their high Z number and good chemical stability, especially in enhancing radiotherapy and photothermal therapy. NBTXR3 (hafnium oxide nanoparticles) has been approved by the FDA as a radiotherapy enhancer, which further stimulated the research of hafnium-based nanomaterials in the field of photothermal therapy.

[0008] At present, the closest implementation scheme to the present invention is to use metal oxides or metal-organic frameworks (MOFs) as PTAs. Among these schemes, some attempts have been made to use hafnium-based materials to improve biocompatibility and photothermal conversion efficiency, but the following problems still exist:

[0009] 1. Large particle size: Many hafnium-based PTAs (such as Hf-MOFs) have large particle sizes (usually >100 nm), which may affect their distribution and clearance in the body.

[0010] 2. Low photothermal conversion efficiency: The current photothermal conversion efficiency of hafnium-based materials is usually less than 30%, which has not yet reached the ideal level.

[0011] 3. Complex preparation process: The synthesis process of some hafnium-based PTAs requires complex multi-step reactions or high temperature and high pressure conditions, which limits the feasibility of large-scale production.

[0012] In addition, most existing approaches fail to fully combine the physicochemical properties of nanomaterials, such as thickness and surface modification, to optimize photothermal performance and biocompatibility. For example, hafnium oxide nanoparticles have good radiotherapy enhancement effects, but their performance in photothermal therapy is not optimal. Summary of the invention

[0013] In view of the shortcomings of the prior art, the purpose of the present invention is to provide a hafnium-based nanosheet having excellent performance in the NIR-II window, and a preparation method and application thereof. The hafnium-based nanosheet prepared by the present invention has excellent photothermal conversion efficiency and light absorption capacity of the NIR-II window. In addition, the surface modification of Pluronic F127 improves the stability and biocompatibility of the nanomaterial, while reducing the risk of cytotoxicity and hemolysis. Compared with the above-mentioned existing solutions, the present invention provides a hafnium-based photothermal transducer with a smaller size, higher photothermal efficiency, and a simpler preparation process, which successfully overcomes the shortcomings of the existing solutions in biosafety, photothermal performance, and clinical feasibility.

[0014] To achieve the above object, the technical solution adopted by the present invention is:

[0015] A method for preparing hafnium-based nanosheets having excellent performance in the NIR-II window comprises the following steps:

[0016] Liquid phase exfoliation: adding hafnium hydride powder to deionized water, exfoliating to form hafnium hydride nanosheets by ultrasonic treatment to obtain a mixed solution; subjecting the mixed solution to low-speed centrifugation to remove unexfoliated particles, and then collecting the supernatant to obtain a hafnium hydride nanosheet aqueous dispersion.

[0017] Surface modification: Pluronic F127 powder is added to the aqueous dispersion of hafnium hydride nanosheets, and stirred at room temperature to complete the surface modification. Unmodified Pluronic F127 can be removed by high-speed centrifugation to prepare the target product hafnium-based nanosheets. The Pluronic F127 used in the present invention has good biocompatibility and can improve the dispersibility of hafnium-based nanosheets.

[0018] The thickness of the hafnium-based nanosheets prepared by the liquid phase exfoliation method is only 1 to 3 nm, which significantly improves the photothermal conversion efficiency of the material and the light absorption capacity of the NIR-II window. The hafnium-based nanosheets have good application prospects in the preparation of photothermal transduction agents for photothermal therapy and in the preparation of tumor treatment drugs.

[0019] The beneficial effects of the present invention are as follows:

[0020] (1) The present invention prepares hafnium hydride nanosheets by liquid phase exfoliation, which simplifies the synthesis steps, reduces raw material consumption and processing costs, and improves production efficiency. The liquid phase exfoliation method is easy to operate and has mild reaction conditions, which can achieve large-scale continuous production and reduce industrialization barriers.

[0021] (2) The present invention uses Pluronic F127 to modify the surface of hafnium hydride nanosheets, which significantly reduces cytotoxicity and blood dissolution risks, improves the safety of the material in the body, and meets the requirements of clinical applications.

[0022] (3) The present invention uses Pluronic F127 to modify the surface of hafnium hydrogenated nanosheets to prepare hafnium-based nanosheets with a photothermal conversion efficiency of up to 29.4%, which is superior to most existing PTAs and can achieve efficient tumor ablation at low laser intensity.

[0023] (4) The hafnium-based nanosheets prepared by the present invention exhibit excellent light absorption capacity and thermal conversion performance in the NIR-II window (1064 nm), and can fully utilize the deep tissue penetration advantage of this window.

[0024] (5) The thickness of the hafnium-based nanosheets prepared by the present invention is only 1-3 nm, and they have a higher surface area and better in vivo distribution characteristics, which helps to improve tumor targeting and metabolic efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 HfH in the embodiment 1.983 @F127 Schematic diagram of the synthesis process of NSs;

[0026] Figure 2 HfH 1.983 @F127 TEM image of NSs;

[0027] Figure 3 HfH 1.983 @F127 Dynamic light scattering analysis results of NSs;

[0028] Figure 4 HfH 1.983 @F127 AFM image of NSs;

[0029] Figure 5HfH 1.983 @XRD pattern of F127 NSs;

[0030] Figure 6 HfH 1.983 Raman spectra (a), FTIR spectra (b) and XPS spectra (c) of @F127 NSs;

[0031] Figure 7 HfH 1.983 @F127 Zeta potential analysis results of NSs;

[0032] Figure 8 HfH 1.983 @F127 Thermogravimetric analysis results of NSs;

[0033] Fig. 9 HfH 1.983 @F127 Visible-NIR absorption spectrum of NSs;

[0034] Fig.10 It is HfH 1.983 @F127 Photothermal performance of NSs; Figure a shows different concentrations of HfH 1.983 @F127 Heating curve of NSs aqueous dispersion under laser irradiation over time; Figure b is the heating curve of HfH under different laser powers 1.983 @F127NSs heating curve over time; Figure c is the heating curve of HfH under laser irradiation 1.983 @F127 NSs infrared thermal image; d is HfH 1.983 @F127 NSs reaches peak temperature under near-infrared laser irradiation (1064nm, 1W) and then cools naturally to room temperature; Figure e is HfH 1.983 @F127 Photothermal stability test results of NSs.

[0035] Fig.11 HfH 1.983 @F127 NSs toxicity and hemolysis test results. Figure a shows the toxicity and hemolysis test results of NSs. 1.983 @Increase of F127NSs concentration gradient, cell viability of HUVEC cells and NCM460 cells; Figure b is HfH 1.983 @F127NSs hemolysis under different concentration gradients.

[0036] Fig.12 To evaluate HfH using CT26 tumor cells 1.983 @F127 The effect of NSs photothermal killing of cancer cells in vitro. Figure a is a live / dead staining image; Figure b is the cell viability after laser irradiation at different times.

[0037] Fig.13 This is an analysis of the in vivo therapeutic effects of different treatment groups on CT26 tumors. Among them: Figure a is the weight change curve of mice, Figure b is the relative tumor volume change curve, Figure c is the tumor weight in mice on day 14, Figure d is a photo of mice on day 14, and Figure e is a photo of the tumor removed from mice on day 14. DETAILED DESCRIPTION

[0038] In order to describe the embodiments of the present invention in detail below, the embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0039] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0040] The models and suppliers of the reagents used in this example are as follows:

[0041] Hafnium hydride powder is HfH 1.983 Powder, purchased from SUNANO Technology Co., Ltd.

[0042] F-127 was purchased from Sigma-Aldrich.

[0043] Calcein-AM and propidium iodide dyes were purchased from Thermo Fisher.

[0044] The above reagents are only for illustrating the sources and components of the reagents used in the experiments of the present invention so as to fully disclose the information, and do not mean that the present invention cannot be realized by using other similar reagents or reagents provided by other suppliers.

[0045] Example

[0046] A method for preparing hafnium-based nanosheets with excellent performance in the NIR-II window, and a reference to a schematic diagram of the synthesis process of the hafnium-based nanosheets Figure 1 , including the following steps:

[0047] 100 mg HfH 1.983 The powder was ground in a ball mill for 30 min, then added into 10 mL of water and ultrasonically treated at a power of 600 W for 12 h to make HfH 1.983 Powder exfoliation to form hafnium hydride nanosheets HfH 1.983 NSs to obtain a mixed solution; the obtained mixed solution was centrifuged (2000 rpm / min) to collect the supernatant to obtain a hafnium hydride nanosheet aqueous dispersion. F-127 powder was added to 1 mL of HfH nanosheet aqueous dispersion and stirred at room temperature for 4 h to modify the surface of HfH nanosheets. The obtained HfH nanosheets were denoted as HfH 1.983 @F127 NSs, and then centrifuged at 14000rpm for 20 minutes to remove unmodified Finally, the collected HfH 1.983 The supernatant of @F127NSs was stored at 4°C until use.

[0048] HkDJ 1.983 @F127 Characterization of NSs

[0049] Figure 2 HfH 1.983 @F127 TEM image of NSs. The TEM image shows that the obtained HfH 1.983 @F127 The lateral size of NSs is about 100nm. Figure 3 HfH 1.983 @F127 Dynamic light scattering analysis results of NSs show that HfH 1.983 The hydrated particle size of @F127 is about 50.75nm. Figure 4 HfH 1.983 @F127 Atomic force microscopy (AFM) image of NSs showing HfH 1.983 @F127 The thickness of NSs is 1-3nm. Figure 5 HfH 1.983 @F127 X-ray diffraction (XRD) pattern of NSs shows that the obtained HfH 1.983 The XRD pattern of @F127 NSs is consistent with that of standard hafnium hydride crystals (PDF#07-0369). Figure 6 Figure a, b, and c are HfH 1.983 @F127 Raman, FTIR and XPS spectra of NSs. Raman spectrum shows HfH 1.983 The peak value of @F127 nanosheet is 125.26cm -1 , FTIR spectroscopy confirmed the successful modification of Pluronic F127, and XPS spectroscopy indicated the presence of Hf[2+] and Hf[0]. Figure 7 HfH 1.983 Zeta potential analysis results of @F127 NSs. The Zeta potential results showed that the modification of F127 slightly increased the negative charge of the nanosheets. Figure 8 HfH 1.983 @F127 Thermogravimetric analysis results of NSs. Thermogravimetric analysis shows that HfH 1.983The content of F127 on the @F127 nanosheets is about 28.21%. These results demonstrate that ultrathin HfH 1.983 @Successful preparation of F127 nanosheets.

[0050] HkDJ 1.983 @F127 NSs photothermal performance

[0051] Fig. 9 HfH 1.983 @F127 The visible-near infrared absorption spectrum of NSs shows that HfH 1.983 @F127 NSs has light absorption at 1064nm. Based on this, HfH 1.983 The photothermal performance of @F127 NSs was evaluated by second near-infrared (NIR-II) laser. Fig.10 It is HfH 1.983 @F127 Photothermal performance of NSs, where: Figure a shows different concentrations of HfH 1.983 @F127 Heating curve of NSs aqueous dispersion under laser irradiation over time; Figure b is the heating curve of HfH under different laser powers 1.983 @F127 NSs heating curve over time; Figure c is the HfH under laser irradiation 1.983 @F127 NSs infrared thermal image; d is HfH 1.983 @F127NSs reaches peak temperature under near-infrared laser irradiation (1064nm, 1W) and then cools naturally to room temperature. Figure e is HfH 1.983 @F127 NSs light and heat stability test results. Fig.10 As can be seen in Figure a, different concentrations of HfH 1.983 @F127 NSs aqueous dispersion exhibited a rapid temperature increase under NIR-II laser (1064 nm) irradiation, which is consistent with Fig.10 The infrared thermal imaging results in Figure c are consistent. For example, HfH 1.983 The temperature of the aqueous dispersion of @F127 NSs (20 μg / mL) increased from 24.8°C to 61.4°C. In sharp contrast, only a 5.2°C temperature change was observed for deionized water. Fig.10 As can be seen in Figure b, HfH 1.983 @F127 The temperature rise of NSs aqueous dispersion is positively correlated with the laser power. Fig.10 As can be seen in Figure d, HfH 1.983 The photothermal conversion efficiency (PTCE) of @F127 NSs was calculated to be 29.4%; then, the HfH 1.983 @F127 Photothermal stability of NSs, such as Fig.10As shown in Figure e, after 5 cycles of laser on / off irradiation, HfH 1.983 @F127 NSs temperature can still reach the maximum, indicating that HfH 1.983 @F127 NSs are stable under laser irradiation.

[0052] HkDJ 1.983 @F127 Cytotoxicity and hemolysis of NSs

[0053] Fig.11 HfH 1.983 @F127 Toxicity and hemolysis test results of NSs. Good biocompatibility of nanomaterials is crucial for biomedical applications. In order to evaluate the 1.983 @F127 The cytotoxicity of NSs was determined by standard MTT ((3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay using human colon epithelial NCM460 cells and human umbilical vein endothelial cells (HUVEC). The results are shown in Fig.11 As shown in Figure a, no obvious cytotoxicity was observed. 1.983 @F127 NSs concentration was as high as 200 μg / mL, and the cell viabilities of NCM460 and HUVEC were also 98% and 97%, respectively, indicating extremely low toxicity. Fig.11 Figure b is HfH 1.983 @F127 The hemolysis test results of NSs at different concentration gradients show that different concentrations of HfH 1.983 The hemolysis rates of @F127 NSs were all lower than 5%, indicating good blood biocompatibility.

[0054] HkDJ 1.983 @F127 Effects of NSs on PTT in vitro and in vivo

[0055] To evaluate HfH 1.983 Effects of @F127 NSs on photothermal therapy (PTT) A tumor-bearing mouse model was created by subcutaneously injecting CT26 cells into the right flank of each female Balb / c mouse. Once the tumor reached the specified size, the mice were randomly assigned to different treatment groups: (1) phosphate-buffered saline (PBS); (2) PBS+NIR-Ⅱ; (3) HfH 1.983 @F127 NSs; (4) HfH 1.983 @F127 NSs+NIR-Ⅱ. Tumor volume and body weight were monitored every two days, and digital images of the tumor site were captured on day 14. All animal experiments were approved by the Institutional Animal Care and Use Committee of Hefei University of Technology.

[0056] Thanks to HfH 1.983@F127 NSs have excellent photothermal performance and low toxicity, and HfH was evaluated using CT26 cells for the first time 1.983 @F127 The effect of NSs photothermal killing of cancer cells in vitro. Fig.12 As shown in Figure a, HfH 1.983 After treatment with @F127NSs and laser irradiation NIR for 3 min (1W, 1064 nm), a large number of dead CT26 cancer cells (red fluorescence) were observed. 1.983 @F127 After NSs or NIR treatment, almost all cells are alive (green fluorescence). This result is consistent with the MTT result ( Fig.12 (b), which should be attributed to HfH 1.983 @F127NSs has good light-to-heat conversion capability.

[0057] To further evaluate HfH 1.983 @F127 NSs photothermal ability against cancer cells, in vivo PTT experiment was performed using mice carrying CT26 as a model, the results are shown in Fig.13 As shown in Figure a, no significant changes in body weight were observed in different groups, further confirming that HfH 1.983 @F127 NSs have good biocompatibility. Fig.13 From Figures b to e in Figure 2, we can see that after HfH 1.983 @F127 NSs plus laser irradiation treatment effectively inhibited tumor growth. In contrast, the tumors in the PBS group grew rapidly, indicating that HfH 1.983 @F127 The photothermal effect of NSs can induce cancer cell death. These results clearly show that HfH 1.983 @F127 NSs can effectively inhibit tumor growth in vitro and in vivo.

[0058] Obviously, the described embodiments are only some embodiments of the present invention, but not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

Claims

1. A method for preparing hafnium-based nanosheets having excellent performance in the NIR-II window, characterized in that: The following steps are involved: Hafnium hydride nanosheets are prepared, and then the hafnium hydride nanosheets are modified by using Pluronic F127 to obtain the target product.

2. The preparation method according to claim 1, characterized in that: The method for preparing hafnium hydride nanoparticles is chemical vapor deposition, mechanical exfoliation or liquid exfoliation.

3. The preparation method according to claim 2, characterized in that: The method for preparing hafnium hydride nanosheets is a liquid exfoliation method, which includes the following steps: dispersing hafnium hydride powder in water, then ultrasonically exfoliating the hafnium hydride powder to form hafnium hydride nanosheets to obtain a mixed solution; centrifuging the mixed solution and collecting the supernatant to obtain a hafnium hydride nanosheet water dispersion.

4. The preparation method according to claim 1, characterized in that: The method for modifying the hafnium hydride nanosheets using Pluronic F127 is as follows: Pluronic F127 is added to the hafnium hydride nanosheet water dispersion and stirred at room temperature to complete the surface modification.

5. A hafnium-based nanosheet having excellent performance in the NIR-II window, characterized in that: The invention discloses a novel nanostructured carbon foam prepared by the preparation method described in any one of claims 1 to 4.

6. The hafnium-based nanosheet according to claim 5, characterized in that: The thickness of the hafnium-based nanosheets is 1-3 nm.

7. Use of the hafnium-based nanosheets as claimed in claim 5 in the preparation of a photothermal transduction agent for photothermal therapy.

8. Use of the hafnium-based nanosheets according to claim 6 in preparing drugs for treating tumors.

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