An organic germanium ligand and samarium ion-functionalized antimony tungstate material, preparation method and application

Abstract

The present invention relates to an organic germanium ligand and samarium ion-functionalized antimony tungstate material with the chemical formula: Na4[H2N(CH3)2] 16 H 18 [Sm4(H2O) 12 W4O 14 Ge(CH2CH2COOH)]2[SbW9O 33 4[Ge(CH2CH2COOH)SbW 15 O 54 2·56H2O. The synthesis of this material uses an organic germanium ligand and an Sb 3+ ion double-template induced synthesis strategy, and is prepared by a one-step self-assembly reaction using antimony trichloride solution, sodium tungstate, di(carboxyethyl)germanium sesquioxide, dimethylamine hydrochloride and samarium nitrate. This preparation method is simple and easy to implement, and has a low cost. In addition, the organic germanium ligand and samarium ion-functionalized antimony tungstate material are compounded with gold nanoparticles to obtain a nanocomposite material with good stability and high photothermal conversion efficiency. The application of this composite material in the photothermal therapy of breast tumor cells shows good therapeutic effects, indicating that the organic ligand and rare earth-functionalized antimony tungstate material have certain application potential in tumor treatment, tumor drugs, photothermal therapy and other aspects.

Description

Technical Field

[0001] The present invention belongs to the technical field of the preparation of polyoxometalate nanomaterials, and particularly relates to an antimony tungstate material functionalized with an organogermanium ligand and samarium ions, a preparation method thereof, and an application thereof in tumor photothermal therapy. Background Technique

[0002] In the process of clinical tumor treatment, photothermal therapy has become an emerging treatment method. As an effective tumor treatment method, when the photothermal conversion material accumulates in tumor tissues, it can convert the absorbed light energy into heat energy under the irradiation of near-infrared light (750 - 1700 nm), and use local high temperature to ablate tumor cells. It has attracted much attention due to its advantages such as high treatment specificity, non-invasiveness, and accurate laser positioning (see G. Guedes, S. Q. Wang, H. A. Santos, et al, Adv. Mater .2021, 33 , 2007761; J. Q. Huang, Z. M. Deng, S. H. Bi, et al, Adv. Sci .2022, 9 , 2203902.).

[0003] Polyoxometalates are expected to become the next-generation nano-drugs for tumor treatment due to their rich microstructure, variable chemical composition, reversible redox activity, and good biocompatibility (see A. Bijelic, M. Aureliano, A. Rompel. Angew. Chem., Int. Ed .2019, 58 , 2980−2999; T. Sun, W. Cui, Q. Wu, et al, Adv. Mater .2016, 28 , 7397−7404). Some of these polyoxometalate skeletons contain abundant variable-valence transition metals (especially Mo V / VI and W V / VI ) centers, showing typical d−d transitions and intervalence charge transfer transitions between metal centers, resulting in strong near-infrared absorption (see J. H. Zhou, T. D. Sun, Z. B. Zha, et al, ACS Nano .2020, 14, 2126−2136), endows polyoxometalates with the ability of photothermal conversion, and thus can ablate solid tumors, making them a new type of photothermal agent. In 2017, the research group led by Professor Weibo Cai reported a polyoxomolybdate photothermal therapeutic agent. In the acidic and reducing microenvironment of tumors, polyoxomolybdate can self-assemble into larger nanostructures to enhance intratumoral accumulation. In addition, this polyoxomolybdate has no near-infrared absorption when molybdenum is in the hexavalent state, but shows strong near-infrared absorption when hexavalent molybdenum is reduced to pentavalent molybdenum in the tumor microenvironment, resulting in an increase in the internal temperature of the tumor and promoting tumor ablation (see D. L. Ni, D. W. Jiang, W. B. Cai, et al, Nano Lett .2017, 17 , 3282−3289). In 2018, the research group led by Professor Xiaoyuan Chen studied the self-assembly behavior of polyoxomolybdate-modified hollow mesoporous organosilica nanoparticles in the weakly acidic tumor microenvironment and their penetration and accumulation in tumors. More importantly, the reduction-activated Mo(VI) to Mo(V) conversion in polyoxomolybdate not only enables the anchored hollow mesoporous organosilica nanoparticles to exhibit good tumor microenvironment-responsive photothermal and photoacoustic imaging properties, but also plays an important role in controllably triggering the 10 efficient release of carbon monoxide, thus achieving the goal of synergistically enhancing carbon monoxide gas therapy with photothermal therapy to completely eradicate tumors. This research has important potential in realizing tumor microenvironment-responsive self-assembly to enhance tumor accumulation and tumor-specific synergistic therapy, and has broad application prospects in clinical applications (see W. Tang, W. P.Fan, X. Y. Chen, et al, ACS Nano .2018, 12 , 12269−12283). In 2022, the research group led by Professor Lixin Wu reported an ionic complex formed by the combination of a novel phosphomolybdate and 3,3',5,5'-tetramethylbenzidine. When the two are mixed, a reduced phosphomolybdate and an oxidized charge transfer complex are spontaneously formed. In the near-infrared region, the total sustainable photothermal conversion efficiency of the reduced phosphomolybdate and the oxidized charge transfer complex is 48.4%. This ionic complex shows good biocompatibility in in vitro cell viability assessment and is proven to enter tumor cells with sustained photothermal properties and complex stability. Due to the further interaction between reduced phosphomolybdates induced by local acidity, obvious accumulation of the ionic complex was observed at the tumor site after tail vein injection, and the significant reduction of mouse tumors proved the good photothermal therapy effect of this material (see X. Q. Kong, H. M. Yu, L. X. Wu, et al, Adv. Healthcare Mater .2022, 11 ,2102352.).

[0004] Therefore, the development of novel polyoxometalates with pharmacological potential is very important. Research has confirmed that organogermanium compounds have a wide range of pharmacological effects, such as anti-cancer, anti-viral, anti-inflammatory, anti-malarial, etc. (see A. K. Sijpesteijn, F. Rijkens, A. Manten, et al, Nature 1964, 201 , 736). Among them, carboxyethylgermanium sesquioxide is a well-known low-toxicity broad-spectrum anti-cancer drug (see F. Suzuki, R. R. Brutkiewicz, R. B. Pollard, Br. J. Cancer 1985, 52 , 757−763). Considering the coordinating active carboxyl groups in its structure, carboxyethylgermanium sesquioxide should be a very promising ligand to construct novel polyoxometalates with enhanced anti-cancer activity and less side effects on normal tissues. Inspired by the above viewpoints, the present invention for the first time proposes a new idea of inducing the synthesis of novel polyoxometalate materials with organogermanium ligands, and synthesizes an organogermanium ligand and samarium ion functionalized antimony tungstate material Na4[H2N(CH3)2] 10 H 24 [Sm4(H2O) 12 W4O 14 Ge(CH2CH2COOH)]2[SbW9O 33 4[Ge(CH2CH2COOH)SbW 15 O 54 2·54H2O (target material), and prepares its nanocomposite with gold nanoparticles (r-PANC) by a chemical reduction method. This r-PANC nanocomposite shows good effects in the photothermal therapy of breast tumor cells. SUMMARY OF THE INVENTION

[0005] The object of the present invention is to overcome the defects of the prior art and provide an organogermanium ligand and samarium ion functionalized antimony tungstate material. Its r-PANC nanocomposite formed with gold nanoparticles exhibits good photothermal conversion performance, and its application in the photothermal therapy of breast tumor cells is explored.

[0006] The present invention also provides a preparation method of the above organogermanium ligand and samarium ion functionalized antimony tungstate material.

[0007] To achieve the above object, the present invention adopts the following technical solutions:

[0008] An organic germanium ligand and samarium ion-functionalized antimony tungstate material, with the chemical formula: Na4[H2N(CH3)2] 16 H 18 [Sm4(H2O) 12 W4O 14 Ge(CH2CH2COOH)]2[SbW9O 33 4[Ge(CH2CH2COOH)SbW 15 O 54 2·56H2O. This material belongs to the monoclinic system, C space group 2 / m, and the unit cell parameters are a a = 39.0056(14) Å, b b = 23.5158(8) Å, c c = 24.9641(10) Å, α α = 90º, β= β = 92.056(2)º, γ γ = 90º, V V = 22883.5(15) Å 3 , Z Z = 2, R ρ1 = 0.0446, wR ρ2 = 0.0997.

[0009] The preparation method of the above-mentioned organic germanium ligand and samarium ion-functionalized antimony tungstate material adopts a synthetic strategy induced by organic germanium ligand and Sb 3+ ion double templates. The specific steps are as follows:

[0010] Under stirring conditions, dissolve Na2WO4·2H2O, di(carboxyethyl)germanium sesquioxide, and dimethylamine hydrochloride in distilled water. Add an aqueous solution of antimony trichloride to the reaction system, adjust the pH of the reaction system to 1.8 - 2.4, continue stirring for 10 - 20 minutes, then add Sm(NO3)3∙6H2O to the system, adjust the pH of the reaction system to 1.8 - 2.4 again, stir for 20 - 30 minutes, then place it in a water bath at 85 - 95 °C and heat for 100–140 minutes. Take it out, cool it to room temperature, filter, and let the filtrate stand and volatilize. After a few days, light green cuboid-shaped crystals will precipitate, which is the target material, the organic germanium ligand and samarium ion-functionalized antimony tungstate material.

[0011] In the above method for preparing the target material, specifically, the molar ratio of Na2WO4·2H2O, bis(carboxyethyl)germanium sesquioxide, dimethylamine hydrochloride, antimony trichloride, Sm(NO3)3∙6H2O, and distilled water is 13.642−15.159︰0.442−0.884︰14.717−24.528︰0.8−1.2︰0.337−0.900︰1110−1700.

[0012] The present invention provides the application of the above-mentioned organic germanium ligand and samarium ion-functionalized antimony tungstate material in the preparation of photothermal therapy drugs for tumor cells, that is, it can be used in the photothermal therapy of tumor cells.

[0013] A method for preparing a nanocomposite material (r-PANC) formed by the above-mentioned organic germanium ligand and samarium ion-functionalized antimony tungstate material and gold nanoparticles, the specific steps are as follows:

[0014] Mix a certain amount of the organic germanium ligand and samarium ion-functionalized antimony tungstate material, HAuCl4 solution (0.1 g∙L –1 ) with acetone, stir and heat at 40−60 °C for 3−5 h, add 0.18−0.22 mL of hydrazine hydrate solution (80 wt%), continue to stir for 30–50 minutes, centrifuge and wash, and dry at 40−60 °C to obtain the nanocomposite material (r-PANC).

[0015] Furthermore, in the above method for preparing the nanocomposite material r-PANC, the dosage ratio of the organic germanium ligand and samarium ion-functionalized antimony tungstate material, HAuCl4 solution, acetone, and hydrazine hydrate solution is 8–12 mg︰0.2–0.4 mL︰2.–3 mL︰0.18–0.22 mL.

[0016] The present invention provides the nanocomposite material prepared by the above preparation method.

[0017] The present invention also provides the use of the nanocomposite material r-PANC as a photothermal agent in the photothermal therapy of tumors (especially breast cancer), and its application in the photothermal therapy of breast tumor cells to achieve the inhibition and ablation of breast tumor cells.

[0018] The present invention adopts a synthetic method induced by an organic germanium ligand and Sb 3+ ion double templates, introduces the organic germanium ligand ((CH2CH2COOHGe)2O3) and SbCl3 into the reaction system at the same time, and uses the organic germanium ligand and Sb 3+The template-induced effect of ions and the bridging effect of tungsten atoms and samarium ions with strong coordination ability were used to prepare a material of organogermanium ligand and samarium ion-functionalized antimony tungstate under certain experimental conditions and molar ratios. During this reaction process, the introduction of the organogermanium ligand not only acts as a template agent, which can orderly induce the assembly of tungstate groups, thus generating tungstate fragments centered on organogermanium atoms. In addition, the organic chain groups in the organogermanium ligand can further connect adjacent tungsten atoms, samarium ions, and antimony tungstate fragments, playing an important role in stabilizing the structure of the target material. And an r-PANC nanocomposite was prepared by a chemical reduction method, which showed good effects in the photothermal therapy of breast tumor cells.

[0019] The present invention provides a preparation method of a material of organogermanium ligand and samarium ion-functionalized antimony tungstate and a study on its tumor photothermal therapy performance. Compared with the prior art, the present invention has the following advantages:

[0020] (1) The molecular structure of the material of organogermanium ligand and samarium ion-functionalized antimony tungstate provided by the present invention can be accurately determined by X-ray single crystal diffraction technology;

[0021] (2) The material of organogermanium ligand and samarium ion-functionalized antimony tungstate provided by the present invention adopts a synthesis method induced by an organogermanium ligand and Sb 3+ ion double templates, and the synthesis process is simple, easy to operate, and low in cost;

[0022] (3) The r-PANC nanocomposite provided by the present invention exhibits good photothermal conversion ability and shows good effects in the photothermal therapy of breast tumor cells. Brief Description of the Drawings

[0023] Figure 1 In, (a) the molecular structure diagram of the target material, (b) the asymmetric molecular structure unit diagram of the target material, (c) the splitting schematic diagram of the asymmetric molecular structure unit of the target material;

[0024] Figure 2 is the comparison between the powder X-ray diffraction pattern and the single crystal X-ray diffraction pattern of the target material;

[0025] Figure 3 is the infrared spectrum diagram of the target material;

[0026] Figure 4 is the thermogravimetric curve of the target material;

[0027] Figure 5Among them, (a) the inhibitory effect of the target material on mouse breast cancer cells (4T1), (b) the inhibitory effect of the target material on human hepatic stellate cells (LX-2), human hepatoma cells (HepG-2) and human cervical cancer cells (HeLa);

[0028] Figure 6 Among them, (a) field emission scanning electron microscope photographs of r-PANC nanocomposites, (b) comparison of the hydrodynamic diameters and Zeta potentials of gold nanoparticles and r-PANC nanocomposites, (c) stability of r-PANC nanocomposites in physiological saline over time, (d) stability of r-PANC nanocomposites in Dulbecco's medium containing 10% fetal bovine serum over time;

[0029] Figure 7 Among them, (a) infrared spectrum comparison of the target material and r-PANC nanocomposites, (b) powder X-ray diffraction pattern comparison of the target material, gold nanoparticles and r-PANC nanocomposites; in the figure, POM refers to the target material;

[0030] Figure 8 are the visible near-infrared spectra of the target material, the target material in the reduced state, gold nanoparticles and r-PANC nanocomposites;

[0031] Figure 9 Among them, (a) heating curves of water, the target material (solid square line), the target material in the reduced state (solid equilateral triangle line), gold nanoparticles (solid inverted triangle line) and r-PANC nanocomposites (solid circle line) in aqueous solution, (b) radiation optical power at 1.0 W·cm –2 when, heating curves of r-PANC nanocomposites with different concentrations in aqueous solution, (c) effects of radiation light with different powers on the heating curves of r-PANC nanocomposites (concentration fixed at 400 μ g·mL –1 ) in aqueous solution, (d) r-PANC nanocomposites (concentration of 400 μ g·mL –1 , radiation optical power of 1.0 W·cm –2 ) cycle stability;

[0032] Figure 10 is the photothermal conversion efficiency curve of gold nanoparticles and r-PANC nanocomposites under the conditions of a concentration of 400 μ g·mL –1 and a radiation optical power of 1.0 W·cm –2 ;

[0033] Figure 11Tumor-bearing mice with breast cancer cells were injected with saline and r-PANC nanocomposites via the tail vein, and then subjected to near-infrared light (808 nm, 1.0 W·cm –2 ) irradiation for different durations, and the corresponding photothermal imaging results are shown;

[0034] Figure 12 Establishment of a mouse breast cancer tumor model: (a) Mice were inoculated with breast cancer cells 7 days before intravenous injection of drugs; (b, c) Tumor-bearing mice were randomly divided into groups. During the 14-day treatment period, the tumor-bearing mice were intravenously injected with saline or r-PANC nanocomposites every other day, and the tumor sites were irradiated with light; (d) Tumors of mice in each experimental group were excised.

[0035] Figure 13 Among them, (a) shows the body weight changes of tumor-bearing mice in the saline intravenous injection group, saline intravenous injection + light irradiation group, r-PANC nanocomposite intravenous injection group, r-PANC nanocomposite intravenous injection + light irradiation group, and doxorubicin intravenous injection group; (b) shows the tumor volume changes of tumor-bearing mice in the above-mentioned groups; (c) shows the tumor inhibition rates of mice in the above-mentioned groups.

[0036] Figure 14 Comparison of hematoxylin-eosin staining of tumor tissues excised from mice in the saline intravenous injection group, saline intravenous injection + light irradiation group, r-PANC nanocomposite intravenous injection group, r-PANC nanocomposite intravenous injection + light irradiation group, and doxorubicin intravenous injection group 14 days after treatment. Specific implementation method

[0037] The present invention will be further described below through specific examples, but the protection scope of the present invention is not limited thereto.

[0038] In the following examples, all raw materials used are ordinary commercially available products that can be directly purchased. Room temperature refers to 25 ± 5 o °C.

[0039] Example 1:

[0040] The chemical formula of the target material is Na4[H2N(CH3)2] 16 H 18 [Sm4(H2O)12 W4O 14 Ge(CH2CH2COOH)]2[SbW9O 33 4[Ge(CH2CH2COOH)SbW 15 O 54 2·56H2O。

[0041] The above target material was obtained by using an organic germanium ligand and an Sb 3+ ion double-template induced synthesis strategy, and its preparation method is as follows:

[0042] (1) Preparation of antimony trichloride solution: 2.281 g of solid antimony trichloride was dissolved in 10.0 mL (6.0 mol∙L –1 ) hydrochloric acid solution;

[0043] (2) Under stirring conditions, 4.750 g (14.400 mmol) of Na2WO4·2H2O, 0.200 g (0.590 mmol) of dicarboxyethyl germanium trioxide, and 1.750 g (21.460 mmol) of dimethylamine hydrochloride were added to 25 mL of distilled water. After complete dissolution, 1.0 mL (1.0 mol∙L –1 ) of the prepared antimony trichloride solution was added to the reaction system. Subsequently, the pH of the reaction system was adjusted to 2.0 with 6.0 mol·L –1 hydrochloric acid solution, and stirring was continued for 10 minutes. Then, 0.200 g (0.450 mmol) of Sm(NO3)3∙6H2O was added to the system, and the pH of the reaction system was adjusted to 2.0 again with 2 mol·L –1 sodium hydroxide solution. After stirring for 30 minutes, it was finally heated in a 90 °C water bath for 120 minutes, taken out, and cooled to room temperature. The reaction solution was filtered, and the filtrate was slowly volatilized. After several days, light green cuboid crystals were precipitated, which was the target material.

[0044] Example 2:

[0045] The chemical formula of the target material is Na4[H2N(CH3)2] 16 H 18 [Sm4(H2O) 12 W4O 14 Ge(CH2CH2COOH)]2[SbW9O 33 4[Ge(CH2CH2COOH)SbW 15 O 54 2·56H2O。

[0046] The above target material was obtained by using an organic germanium ligand and an Sb 3+Obtained by an ionic double-template induced synthesis strategy, and its preparation method is as follows:

[0047] (1) Preparation of antimony trichloride solution: 2.281 g of solid antimony trichloride is dissolved in 10.0 mL (6.0 mol∙L –1 ) hydrochloric acid solution;

[0048] (2) Under stirring conditions, 4.750 g (14.400 mmol) of Na2WO4·2H2O, 0.200 g (0.590 mmol) of germanium dioxide bis(carboxyethyl), and 1.750 g (21.460 mmol) of dimethylamine hydrochloride are added to 25 mL of distilled water. After complete dissolution, 1.0 mL (1.0 mol∙L –1 ) of the prepared antimony trichloride solution is added to the reaction system. Subsequently, the pH of the reaction system is adjusted to 2.0 with 6.0 mol·L –1 hydrochloric acid solution, and stirring is continued for 10 minutes. Then, 0.400 g (0.900 mmol) of Sm(NO3)3∙6H2O is added to the system, and the pH of the reaction system is adjusted to 2.0 again with 2 mol·L –1 sodium hydroxide solution. After stirring for 30 minutes, it is finally placed in a 90 °C water bath and heated for 120 minutes, taken out, and cooled to room temperature. The reaction solution is filtered, and the filtrate is slowly volatilized. After several days, light green cuboid crystals precipitate, which is the target material.

[0049] Example 3:

[0050] The chemical formula of the target material is Na4[H2N(CH3)2] 16 H 18 [Sm4(H2O) 12 W4O 14 Ge(CH2CH2COOH)]2[SbW9O 33 4[Ge(CH2CH2COOH)SbW 15 O 54 2·56H2O.

[0051] The above target material is obtained by an organic germanium ligand and Sb 3+ ionic double-template induced synthesis strategy, and its preparation method is as follows:

[0052] (1) Preparation of antimony trichloride solution: 2.281 g of solid antimony trichloride is dissolved in 10.0 mL (6.0 mol∙L –1 ) hydrochloric acid solution;

[0053] (2) Under stirring conditions, 4.750 g (14.400 mmol) of Na2WO4·2H2O, 0.200 g (0.590 mmol) of germanium dioxide bis(carboxyethyl) and 1.750 g (21.460 mmol) of dimethylamine hydrochloride were added to 30 mL of distilled water. After complete dissolution, 1.0 mL (1.0 mol∙L –1 ) of antimony trichloride solution prepared was added to the reaction system. Subsequently, the pH of the reaction system was adjusted to 2.0 with 6.0 mol·L –1 hydrochloric acid solution. After continuing to stir for 10 minutes, 0.400 g (0.900 mmol) of Sm(NO3)3∙6H2O was added to the system. Again, the pH of the reaction system was adjusted to 2.0 with 2 mol·L –1 sodium hydroxide solution. After stirring for 30 minutes, it was finally placed in a water bath at 90 °C and heated for 120 minutes, taken out, and cooled to room temperature. The reaction solution was filtered, and the filtrate was slowly volatilized. After a few days, light green cuboid crystals were precipitated, which was the target material.

[0054] Example 4:

[0055] The r-PANC nanocomposite formed by the above target material and gold nanoparticles was prepared by a chemical reduction method, and the specific steps are as follows:

[0056] 10.0 mg of the target material, 0.3 mL (0.1 g∙L –1 ) HAuCl4 solution and 2.7 mL of acetone were mixed and stirred and heated at 45 o °C for 4.0 hours. It was taken out, cooled to room temperature with continuous stirring, and 0.2 mL of hydrazine hydrate solution (80 wt%) was added to the solution. Stirring was continued for 40 minutes. After centrifugation, it was washed 3 times with ethanol, and finally dried overnight at 60 o °C to obtain the r-PANC nanocomposite.

[0057] The present invention determined and characterized the crystal structure of the target material prepared in the above Examples 1 – 3, and its unit cell parameters are as follows:

[0058] Na4[H2N(CH3)2] 16 H 18 [Sm4(H2O) 12 W4O 14 Ge(CH2CH2COOH)]2[SbW9O 33 4[Ge(CH2CH2COOH)SbW 15 O 54 2·56H2O is monoclinic,C 2 / m space group, unit cell parameters are a = 39.0056(14) Å, b = 23.5158(8)Å, c = 24.9641(10) Å, α = 90 o , β= 92.056(2) o , γ = 90 o , V = 22883.5(15) Å 3 , Z = 2, R 1=0.0446, wR 2= ​​0.0997.

[0059] The cluster anion unit of the target material [Sm4(H2O) 12 W4O 14 Ge(CH2CH2COOH)]2[SbW9O 33 ]4[Ge(CH2CH2COOH)SbW 15 O 54 ]2 38− ( Figure 1 a) consists of two identical [Sm4(H2O) 12 W4O 14 Ge(CH2CH2COOH)][SbW9O 33 ]2[Ge(CH2CH2COOH)SbW 15 O 54 ] 19− ( Figure 1 b) Subunits. Each subunit is composed of a novel triple-vacancy Dawson-type [Ge(CH2CH2COOH)SbW 15 O 54 ] 12− Building blocks and two triple-missing Keggin types [B- α -SbW9O 33 ] 9− Building blocks through a novel nuclear Sm-W-Ge heterometallic [Sm4(H2O) 12 W4O 14 Ge(CH2CH2COOH)] 11+ Cluster units are connected to form ( Figure 1 c). The most noteworthy is the organic germanium ligand in the triple-vacancy Dawson type [Ge(CH2CH2COOH)SbW 15 O 5412− The germanium atoms provided in the building block are embedded in [SbW 15 O 54 15− fragment and act as the second heteroatom. In [Ge(CH2CH2COOH)SbW 15 O 54 12− building block, the germanium atoms on the organogermanium ligand act as structural templates to construct a cyclic [GeW6O 27 14− fragment, and this cyclic fragment is combined with the three - vacancy Keggin - type [B - α -SbW9O 33 9− building block by sharing six oxygen atoms to form a three - vacancy Dawson - type [Ge(CH2CH2COOH)SbW 15 O 54 12− building block ( Figure 1 c)). At the same time, the carboxyl groups on the organogermanium ligand are combined with the surrounding tungsten atoms, samarium ions and antimonate fragments to form a Sm−W−Ge heterometallic [Sm4(H2O) 12 W4O 14 Ge(CH2CH2COOH)] 11+ cluster unit. Two identical [Sm4(H2O) 12 W4O 14 Ge (CH2CH2COOH)][SbW9O 33 2[Ge(CH2CH2COOH)SbW 15 O 54 19− sub - units form the cluster anion unit of the target material through the bridging action of samarium ions.

[0060] In the present invention, the powder X - ray diffraction spectrum of the target material is basically consistent with its single - crystal X - ray diffraction spectrum (see Figure 2 ), indicating that the synthesized target material is pure. In the infrared spectrum of the target material (see Figure 3 ), five characteristic peaks 952, 879, 849, 765 and 680 cm –1 appear in the low - wavenumber range of 1000−600 cm –1 , which are respectively attributed to the three - vacancy Dawson - type [Ge(CH2CH2COOH)SbW 15 O 54 12− building block and the three - vacancy Keggin - type [B - α -SbW9O​​​​​​​​33 9− W−O in the building block t , Ge–O, W−O b , W−O c and Sb−O a asymmetric stretching vibrations of the bonds; and a stretching vibration peak of the carboxylate group was observed at 1564 cm –1 , proving the presence of the organogermanium ligand in the target material. The results of the infrared spectroscopy analysis are consistent with those of its single crystal structure analysis. The thermogravimetric curve of the target material (see Figure 4 ) shows that its decomposition process undergoes three steps of weight loss. The first weight loss occurs between 25−200 °C, with a weight loss of 6.77% (the theoretical value is 6.39%), attributed to the loss of 56 crystal water molecules and 24 coordinated water molecules. The second weight loss occurs between 200−800 °C, with a weight loss of 7.35% (the theoretical value is 7.08%), attributed to the dissociation of 16 dimethylamine groups, the dehydration of 18 protons, and the loss of the organogermanium ligand. When the temperature continues to rise (>800 °C), the framework structure of the target material collapses.

[0061] To further explore the application potential of the target material in cancer treatment, the Cell Counting Kit-8 (CCK-8) method was first used to prove that the material has good inhibitory effects on tumor cells (the IC 50 for 4T1 cells is 0.7179 mg∙mL −1 ), and has low toxicity to normal cells (the IC 50 for LX-2 cells is 5.4030 mg∙mL −1 , the IC 50 for human hepatocellular carcinoma cells HepG-2 is 4.7040 mg∙mL −1 , the IC 50 for human cervical cancer cells HeLa is 2.7400 mg∙mL −1 , Figure 5 ). It can be found that under the same conditions, the survival rate of normal LX-2 cells is much higher than that of human hepatocellular carcinoma cells and human cervical cancer cells. Therefore, the target material has good biocompatibility and low side effects on normal biological tissues.

[0062] Subsequently, the r-PANC nanocomposite prepared in Example 4 was further characterized. It can be seen from the field emission scanning electron microscope images that the morphology of the r-PANC nanocomposite presents a sea urchin shape and is evenly distributed ( Figure 6 a in), and its particle size in aqueous solution is 168.17 ± 4.15 nm, meeting the requirements for intravenous injection of drugs into the mouse tail vein ( Figure 6 ​In b), in normal saline and Dulbecco's medium containing 10% fetal bovine serum, no significant change was found in the particle size of the r-PANC nanocomposite over time, indicating that the r-PANC nanocomposite has good stability in the physiological environment ( Figure 6 In c and d), it provides a prerequisite for subsequent intravenous injection to treat malignant tumors in mice.

[0063] By comparing the infrared spectra of the target material and the r-PANC nanocomposite, it can be found that ( Figure 7 In a, in the figure, POM refers to the target material): the characteristic absorption peaks of the infrared spectra of the r-PANC nanocomposite and the target material are the same, and they belong to the characteristic peaks of organogermanium and [B- α -SbW9O 33 fragment still remain, indicating that the structure of the target material has not changed during the preparation of the r-PANC nanocomposite. At the same time, X-ray powder diffraction analysis of the target material, gold nanoparticles) and the r-PANC nanocomposite found that: the X-ray powder diffraction of the r-PANC nanocomposite simultaneously contains the characteristic diffraction peaks of the target material (2θ = 5–10 o and the 2θ = 38.3 formed by the

[111] ,

[200] ,

[220] and

[311] crystal planes of gold nanoparticles o 、44.4 o 、64.6 o and 77.8 o diffraction peaks (PDF#04-0784, Figure 7 In b), which confirmed the successful composite of the target material and gold nanoparticles.

[0064] In addition, the visible near-infrared spectrum of the r-PANC nanocomposite shows significant absorption in the near-infrared region (about 750 nm), which makes it a promising candidate material for a photothermal agent ( Figure 8 ). Importantly, by comparing the visible near-infrared spectra of the target material, the reduced target material, gold nanoparticles and the r-PANC nanocomposite, almost no absorption in this region was observed in the spectrum of the reduced target material, while the r-PANC nanocomposite has stronger absorption at 808 nm than gold nanoparticles. Because of the synergistic absorption of infrared light by the mixed-valence target material and the formed gold nanoparticles, the absorption of the target material to near-infrared light is enhanced.

[0065] On this basis, the photothermal behaviors of different materials were studied under irradiation with near-infrared laser (808 nm). The system temperatures of the target material (solid square line), the target material in the reduced state (solid up triangle), gold nanoparticles (solid down triangle), and r-PANC nanocomposites (solid circle) increased to 37.8, 40.5, 54.1, and 76.1 o °C in 10 minutes, respectively. It can be seen that r-PANC nanocomposites exhibit better photothermal conversion ability ( Figure 9 in a)). At the same time, the effects of the concentration of r-PANC nanocomposites and the excitation light power on their photothermal conversion ability were also tested. When the radiation laser power was constant (1.0 W·cm –2 −2), the system temperature of r-PANC nanocomposites increased with the increase of their concentration ( Figure 9 in b)); when the concentration of r-PANC nanocomposites was constant (400 μ μg·mL –1 −1), the system temperature of r-PANC nanocomposites increased with the increase of the radiation laser power ( Figure 9 in c)). Five radiation laser on-off cycle tests showed that the photothermal conversion ability of r-PANC nanocomposites did not show an obvious increase or decrease, indicating that r-PANC nanocomposites have good photothermal conversion stability ( Figure 9 in d)). Moreover, at 808 nm and a radiation light power of 1.0 W·cm –2 −2, the photothermal conversion efficiency (43.31%) of r-PANC nanocomposites with a concentration of 400 μ μg·mL –1 −1 was much higher than that of gold nanoparticles (26.95%, see Figure 10 ), which indicates that the W 5 / 6+ -charge transfer transition in the target material in the reduced state improves the photothermal conversion performance of r-PANC nanocomposites.

[0066] The present invention also explored the photothermal performance of r-PANC nanocomposites in mouse tumors. By the tail vein injection method, saline and r-PANC nanocomposites (25 mg / kg) were respectively injected into tumor-bearing mice. After 24 hours, the tumor sites of the tumor-bearing mice were irradiated with near-infrared light at 808 nm with a radiation power of 1.0 W·cm –2 −2 for 10 minutes, and the temperature rise of the tumor sites of the tumor-bearing mice was recorded using a thermal imaging instrument ( Figure 11 ). Under near-infrared light irradiation, the tumor sites of the tumor-bearing mice injected with r-PANC nanocomposites rapidly heated up to 55.0 °C, and tumor ablation was achieved. While the temperature of the tumor sites of the tumor-bearing mice injected with saline only rose to 39.0 °C, and it was difficult to achieve tumor ablation.

[0067] Based on the advantages of the above r-PANC nanocomposites for tumor photothermal therapy, a mouse breast cancer tumor model ( Figure 12 ) was established to evaluate the in vivo pharmacodynamic evaluation and tumor photothermal therapy performance of the r-PANC nanocomposites. Seven days before intravenous injection of the drug, breast cancer cells (4T1) were inoculated into mice. When the tumor volume grew to approximately 100 mm 3 , the tumor-bearing mice were randomly divided into 5 groups, with 6 mice in each group. They were intravenously injected with normal saline or r-PANC nanocomposites respectively. During the 14-day treatment period, the changes in tumor volume and body weight of mice in the normal saline group (control group), normal saline + light irradiation group, r-PANC group, r-PANC + light irradiation group, and doxorubicin (DOX) group were recorded every other day. The results are as Figure 13 shown in a and Figure 13 b. Within 14 days, the body weight of mice in the normal saline group or the normal saline + light irradiation group remained basically unchanged, and the tumor volume continued to increase, indicating that simple near-infrared light irradiation would not damage the normal body functions of mice and had little effect on tumor growth. The body weight of mice intravenously injected with doxorubicin decreased continuously, and there was no obvious change in the body weight of mice in other experimental groups, indicating that doxorubicin had obvious toxic and side effects on mice, and the r-PANC nanocomposites had good biocompatibility. As Figure 13 shown in b and Figure 13 c, simple intravenous injection of the r-PANC group could inhibit tumor growth to a certain extent. In contrast, the tumor growth of the r-PANC + light irradiation treatment group was significantly inhibited, and the tumor was significantly smaller than that of the r-PANC treatment group, with a tumor inhibition rate as high as 78.36% ( Figure 13 shown in c), indicating that the photothermal heating of the r-PANC nanocomposites had an inhibitory and ablative effect on tumors. Finally, the tumor sections of mice in the normal saline group, normal saline + light irradiation group, r-PANC group, r-PANC + light irradiation group, and doxorubicin group were stained with hematoxylin-eosin. The results showed that obvious nuclear rupture or shrinkage was visible in the r-PANC + light irradiation treatment group ( Figure 14 ), further verifying the significant effect of the r-PANC material on photothermal therapy of tumors.

[0068] In summary, the present invention obtained a novel organogermanium ligand and samarium ion-functionalized antimony tungstate material with pharmacological potential through the induction and assembly of organogermanium ligands. In addition, the present invention also provides a multifunctional nanoplatform for breast cancer comprehensive diagnosis and treatment technology, and provides a promising strategy for constructing intelligent reactive therapeutic drugs for tumor-specific treatment.

Claims

1. An organic germanium ligand and samarium ion-functionalized antimony tungstate material, with the chemical formula: Na4[H2N(CH3)2] 16 H 18 [Sm4(H2O) 12 W4O 14 Ge(CH2CH2COOH)]2[SbW9O 33 4[Ge(CH2CH2COOH)SbW 15 O 54 2·56H2O。 2. The preparation method of the organogermanium ligand and samarium ion-functionalized antimony tungstate material according to claim 1, characterized in that, The specific steps are as follows: Under stirring conditions, dissolve Na2WO4·2H2O, dicarboxyethyl germanium sesquioxide, and dimethylamine hydrochloride in distilled water. Add an aqueous solution of antimony trichloride to the reaction system, adjust the pH of the reaction system to 1.8 - 2.4, continue stirring for 10 - 20 minutes, then add Sm(NO3)3∙6H2O to the system, adjust the pH of the reaction system to 1.8 - 2.4 again, stir for 20 - 30 minutes, place it in a water bath at 85 - 95 °C and heat for 100–140 minutes, take it out, cool to room temperature, filter, let the filtrate stand and volatilize to precipitate light green cuboid crystals, thus obtaining the product.

3. The preparation method of the organogermanium ligand and samarium ion-functionalized antimony tungstate material according to claim 2, wherein The molar ratio of Na2WO4·2H2O, dicarboxyethyl germanium sesquioxide, dimethylamine hydrochloride, antimony trichloride, Sm(NO3)3∙6H2O and distilled water is 13.642−15.159︰0.442−0.884︰14.717−24.528︰0.8−1.2︰0.337−0.900︰1110−1700.

4. A preparation method of a nanocomposite formed by a stibium tungstate material functionalized with the organogermanium ligand and samarium ions described in claim 1 and gold nanoparticles, characterized in that, The specific steps are as follows: Mix the organogermanium ligand and samarium ion-functionalized antimony tungstate material, HAuCl4 solution and acetone, stir and heat at 40−60 °C for 3−5 h, add hydrazine hydrate solution, continue stirring for 30–50 minutes, centrifuge, wash, and dry to obtain the product.

5. The preparation method of the nanocomposite material according to claim 4, characterized in that, The dosage ratio of the organogermanium ligand and samarium ion-functionalized antimony tungstate material, HAuCl4 solution, acetone and hydrazine hydrate solution is 8–12 mg︰0.2–0.4 mL︰2–3 mL︰0.18–0.22 mL.

6. The nanocomposite material prepared by the preparation method described in claim 4 or 5.

7. The application of the organogermanium ligand and samarium ion-functionalized antimony tungstate material described in claim 1 in the preparation of a photothermal therapy drug for tumor cells.

8. The application of the nanocomposite material described in claim 6 in the preparation of a photothermal agent for tumor photothermal therapy.

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