Phytate-based ternary complex biomimetic nanomaterials, methods of making and uses thereof

Abstract

The present application relates to the field of biological medicine, and particularly relates to a kind of phytic acid-based ternary complex biomimetic nanomaterial, the ternary complex biomimetic nanomaterial is composed of phytic acid, metal ion and protein / polypeptide, which is connected by metal cation as cation bridge to connect protein / polypeptide and phytic acid to form ternary complex.The present application is synthesized by a variety of metal ions as bridge to synthesize different protein / polypeptide-based phytic acid ternary complex, constructs highly biocompatible new type of nanodiagnosis and treatment probe, can be reassembled, long-term aggregation at tumor site, and the imaging / therapeutic metal ion of coordination loading can realize long-acting tumor imaging, treatment or diagnosis and treatment integrated application function, and is expected to be used as a kind of new biomimetic nanomaterial in biomedical field.Meanwhile, the nanomaterial preparation process of the present application is simple, and easy to realize industrial production.

Description

Technical Field

[0001] The present invention relates to the preparation of a nano material, in particular to the preparation and application of a ternary composite biomimetic nano material based on phytic acid. Background Art

[0002] As cancer treatment gradually enters the era of "precision medicine," the delivery of imaging and therapeutic drugs via biomimetic nanomaterials holds broad promise for accurate tumor diagnosis and treatment. However, insufficient tumor accumulation time and poor biocompatibility are major limitations hindering the further development and clinical translation of biomimetic nanomaterials. While targeted molecular modification and the construction of stimuli-responsive probes can enhance the accumulation of nanoparticles in tumors, prolong tumor retention, and improve therapeutic efficacy, the retention time of these nanoparticles in tumors remains unsatisfactory because they can reenter the bloodstream or diffuse into surrounding tissues, preventing long-term and real-time tumor monitoring and treatment. Furthermore, their suboptimal biocompatibility results in drug retention in the body, potentially leading to long-term toxicity. Therefore, the development of biocompatible therapeutic probes that can reside at the tumor site for a long time is essential to overcome these temporal and spatial limitations and achieve precise treatment and tumor monitoring.

[0003] Phytic acid (PA), a type of vitamin B, also known as inositol hexaphosphate, is widely found in plants such as legumes, cereals, dried fruits, vegetables, and fruits. It is also present in most mammalian cells, making it highly biocompatible. Phytic acid is an inositol hexaphosphate ester with an asymmetric six-carbon ring structure. Its molecular structure contains six phosphates and twelve hydroxyl groups, giving it strong chelating properties. PA also exhibits inherent anti-cancer properties, inhibiting the growth of various cancer cells, including leukemia, prostate cancer, breast cancer, liver cancer, colon cancer, and skin cancer.

[0004] Phytic acid has a strong chelating property due to its molecular structure. It has a negative charge in a wide range of pH values ​​and can bind to positively charged Mg. 2+ 、Fe 2+ 、Cd 2+Many divalent or multivalent metal ions, such as phytates, chelate to form complexes with very low solubility, known as phytates. Some phytates are widely used in biomedicine, such as technetium [99mTc] phytate injection, which is used as a PET contrast agent for liver, spleen, and bone marrow imaging. Low solubility limits the conversion of phytates into further biomedical applications. After food is ingested by the human body, under the alkaline conditions of the intestine, both protein and phytic acid are negatively charged. At this point, metal cations can serve as bridges to form ternary complexes of phytic acid, metal cations, and protein. The addition of protein imparts advantages such as good biocompatibility, biodegradability, low antigenicity, high stability, and drug-loading capacity to the complexes. The formation of these complexes provides a biomimetic synthesis strategy for constructing biomimetic nanomaterials based on ternary complexes. Summary of the Invention

[0005] The biomimetic nanomaterials constructed in the prior art have poor biocompatibility, insufficient accumulation time, and safety issues associated with in vivo accumulation. The present invention provides a biomimetic nanomaterial that is highly biocompatible, possesses multiple biological functions such as tumor targeting, treatment, and magnetic resonance imaging, and can maintain a long retention time at the tumor site. This biomimetic nanomaterial can be used to simultaneously deliver continuous radiotherapy and chemotherapy to tumors while providing long-term imaging monitoring of therapeutic changes in the tumor.

[0006] In order to solve the above technical problems, the present invention proposes a ternary complex biomimetic nanomaterial based on phytic acid, which is a ternary complex composed of phytic acid, metal ions and proteins / polypeptides, wherein the molar ratio of phytic acid to metal ions is 1:(1-6), and the molar ratio of protein / polypeptide to phytic acid is 1:25; the ternary complex is formed by connecting the protein / polypeptide and phytic acid with metal cations as cationic bridges.

[0007] Furthermore, the phytic acid-based ternary composite biomimetic nanomaterial of the present invention comprises:

[0008] The metal ions are multivalent metal cations.

[0009] The protein / polypeptide is a negatively charged protein / polypeptide at a pH value of 7-10.

[0010] The selection of the multivalent metal cations includes several situations as shown in Table 1.

[0011] Table 1 Selection of polyvalent metal cations for different imaging and therapeutic applications

[0012]

[0013] At the same time, the present invention also provides two preparation methods of the phytic acid-based ternary composite biomimetic nanomaterial.

[0014] Preparation method 1 comprises the following steps:

[0015] S1-1, mixing phytic acid and a metal ion solution in a molar ratio of phytic acid to metal ion of 1:(1-6), stirring uniformly to obtain a mixed solution A;

[0016] S1-2, adding the protein / polypeptide solution to the mixed solution A at a molar ratio of protein / polypeptide to phytic acid of 1:25, and adjusting the pH of the solution to 7-10 to obtain a mixed solution B;

[0017] S1-3, centrifuging the mixed solution B to remove the precipitate, and repeatedly ultrafiltering / dialyzing the supernatant to obtain a ternary complex solution, which is the biomimetic nanomaterial.

[0018] Preparation method 2 comprises the following steps:

[0019] S2-1. Take a certain amount of phytic acid solution, adjust the pH value of the phytic acid solution to 7-10, add the protein / polypeptide solution to the phytic acid solution at a molar ratio of protein / polypeptide to phytic acid of 1:25, and stir evenly to obtain a mixed solution C;

[0020] S2-2, adding a metal ion solution to the mixed solution C at a molar ratio of metal ions to phytic acid of 3:1, and stirring uniformly to obtain a mixed solution D; the metal ions in the metal ion solution are metal ions that can produce precipitation after mixing with the phytic acid solution;

[0021] S2-3. Centrifuge the mixed solution D to remove the precipitate, and repeatedly ultrafilter / dialyze the supernatant to obtain a ternary complex solution, which is the biomimetic nanomaterial.

[0022] The main factor to be considered in selecting preparation method 1 or preparation method 2 is whether precipitation occurs when the selected metal ion solution and phytic acid solution are mixed at a molar ratio of phytic acid to metal ion of 1:(1-6); if precipitation does not occur, either preparation method 1 or preparation method 2 can be used; if precipitation occurs, preparation method 2 is selected.

[0023] Furthermore, in the above preparation method 2, the metal ion is preferably Gd 3+ 、Bi 3+ and 223 Ra 2+ One or more of .

[0024] The present invention also proposes that the above-mentioned phytic acid-based ternary complex biomimetic nanomaterial can be used to prepare one or more imaging contrast agents of MRI imaging, CT imaging, radionuclide imaging and optical imaging, and to prepare drugs for chemotherapy, radiotherapy or photothermal therapy, wherein the selection of the polyvalent metal cations is shown in Table 1.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] The present invention proposes a construction strategy for a multifunctional bionic nanomaterial based on phytic acid. By simulating the formation of a ternary complex in the intestine, the biomimetic synthesis of the ternary complex biomimetic nanomaterial not only has the characteristics of high biocompatibility, but also has multiple biological functions such as tumor targeting, treatment, magnetic resonance, etc. The prepared biomimetic nanomaterial can be reassembled in situ at the tumor site to maintain a longer residence time, so as to achieve long-term MRI imaging monitoring and radiotherapy and chemotherapy of the tumor. Moreover, the biomimetic nanomaterial has excellent biocompatibility, can significantly reduce the toxicity of radiotherapy and chemotherapy drugs, and has good clinical transformation value. In addition, the preparation method of the biomimetic nanomaterial is simple and easy, easy to operate, low cost, easy to achieve industrial production, and is expected to be used as a new type of nano-diagnostic probe in the biomedical field. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is the construction principle of the phytic acid ternary complex bionic nanomaterial of the present invention.

[0028] Figure 2 This is a transmission electron micrograph of PA-Mn-BSA (PA:Mn=1:3) prepared in Example 1.

[0029] Figure 3 This is a transmission electron microscope image of PA-Gd-BSA prepared in Example 2.

[0030] Figure 4 This is a transmission electron micrograph of PA-Mn / Pt-BSA (PA:Mn:Pt=1:1:2) prepared in Example 4.

[0031] Figure 5 These are the actual images and hydrated particle size images of PA-Bi-BSA prepared in Example 3.

[0032] Figure 6 PA-Mn / 223 Actual image and hydrated particle size diagram of Ra-BSA.

[0033] Figure 7 These are the actual images and hydrated particle size images of PA-Mn / Pt-RGD prepared in Example 6.

[0034] Figure 8 The in vitro magnetic resonance imaging of PA-Mn-BSA (PA:Mn=1:3) and PA-Mn / Pt-BSA (PA:Mn:Pt=1:1:2) prepared in Examples 1 and 4 is shown.

[0035] Figure 9 This is the in vitro magnetic resonance imaging of PA-Gd-BSA prepared in Example 2.

[0036] Figure 10 PA-Mn / 223 In vitro magnetic resonance imaging of Ra-BSA.

[0037] Figure 11 This is the in vitro magnetic resonance imaging of PA-Mn / Pt-RGD prepared in Example 6.

[0038] Figure 12 This is the in vitro CT imaging of PA-Bi-BSA prepared in Example 3.

[0039] Figure 13 The particle size stability of PA-Mn-BSA (PA:Mn=1:3) and PA-Mn / Pt-BSA (PA:Mn:Pt=1:1:2) prepared in Examples 1 and 4 in PBS and FBS, respectively.

[0040] Figure 14 This is the acidic environment reassembly response of PA-Mn-BSA (PA:Mn=1:3) prepared in Example 1, wherein (a) is a physical picture of the PA-Mn-BSA (PA:Mn=1:3) at pH 7.4 and 5.0, (b) is the particle size change of the PA-Mn-BSA (PA:Mn=1:3) at pH 7.4 and 5.0, and (c) is a transmission electron microscopy image of the PA-Mn-BSA (PA:Mn=1:3) at pH 5.0.

[0041] Figure 15 The killing effects of PA-Mn-BSA (PA:Mn=1:3) of Example 1, PA-Mn / Pt-BSA (PA:Mn:Pt=1:1:2) of Example 4 and the chemotherapy drug cisplatin CDDP on prostate cancer PC-3 cells.

[0042] Figure 16 PA-Mn / 223 The killing effect of Ra-BSA on prostate cancer PC-3 cells.

[0043] Figure 17 The killing effect of PA-Mn / Pt-RGD in Example 6 on prostate cancer PC-3 cells.

[0044] Figure 18 The in vivo magnetic resonance imaging effects of PA-Mn-BSA (PA:Mn=1:3) of Example 1 and PA-Mn / Pt-BSA (PA:Mn:Pt=1:1:2) of Example 4 are shown, wherein (a) is the in vivo magnetic resonance imaging effect of PA-Mn-BSA (PA:Mn=1:3), and (b) is the in vivo magnetic resonance imaging effect of PA-Mn / Pt-BSA (PA:Mn:Pt=1:1:2).

[0045] Figure 19 Figure 2 is the in vivo tumor inhibition effect of the four drugs, wherein (a) is the anatomical diagram of the tumor in PC-3 tumor-bearing mice treated with PBS, PA-Mn-BSA (PA:Mn=1:3) of Example 1, CDDP, and PA-Mn / Pt-BSA (PA:Mn:Pt=1:1:2) of Example 4 for 14 days, and (b) is the growth curve of the tumor in PC-3 tumor-bearing mice treated with PBS, PA-Mn-BSA (PA:Mn=1:3) of Example 1, CDDP, and PA-Mn / Pt-BSA (PA:Mn:Pt=1:1:2) of Example 4.

[0046] Figure 20 Comparison of Pt content in tumors after 14 days of treatment with CDDP and PA-Mn / Pt-BSA (PA:Mn:Pt=1:1:2) of Example 4.

[0047] Figure 21 PC-3 tumor-bearing mice were treated with PBS, PA-Mn-BSA (PA:Mn=1:3) of Example 1, 223 RaCl2, PA-Mn / 223 Anatomical images of tumors after 10 days of Ra-BSA treatment.

[0048] Figure 22 Figure 4 is the biochemical analysis of mice after injection of PA-Mn / Pt-BSA (PA:Mn:Pt=1:1:2) of Example 4, wherein (a) is aspartate aminotransferase (AST), (b) is alanine aminotransferase (ALT), (c) is urea nitrogen (BUN), and (d) is blood creatinine (CRE). DETAILED DESCRIPTION

[0049] The design idea of ​​the method for preparing a bionic nanomaterial proposed in the present invention is: to adopt a biomimetic synthesis strategy to prepare highly biocompatible multifunctional biomimetic nanomaterials for use in the biomedical field. The biomimetic nanomaterial can be coordinated and loaded with a variety of imaging / therapeutic drugs to meet the requirements of various biomedical applications. The preparation method of the present invention is to simulate the formation of a phytic acid ternary complex in the intestine, and use various metal ions such as manganese and gadolinium as bridges to biomimetically synthesize phytic acid ternary complexes of different protein / polypeptide bases to construct a highly biocompatible nano-diagnostic and therapeutic probe, which can achieve long-term aggregation at the tumor site and has multiple functions such as tumor imaging and treatment. It is expected to be used as a new type of biomimetic nanomaterial in the biomedical field. At the same time, the preparation process of the diagnostic and therapeutic agent of the present invention is simple and easy to realize industrial production.

[0050] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, but the following embodiments are by no means intended to limit the present invention in any way.

[0051] In the present invention, the biomimetic nanomaterial refers to a synthesized material that is a nanoparticle and can be used for imaging, treatment or integrated diagnosis and treatment of tumors.

[0052] The biomimetic nanomaterial described in the present invention is a phytic acid ternary complex, which includes phytic acid, metal ions coordinated and chelated with phytic acid, and proteins / polypeptides, wherein the molar ratio of phytic acid to metal ions is 1:(1-6), and the molar ratio of protein / polypeptide to phytic acid is 1:25; the ternary complex is formed by connecting the protein / polypeptide and phytic acid using metal cations as cationic bridges, and is used as a biomimetic nanomaterial for imaging, diagnosis and treatment of tumors.

[0053] In the biomimetic nanomaterial of the present invention, the metal ions are multivalent metal cations, and the proteins / polypeptides are negatively charged proteins / polypeptides at a pH value of 7-10.

[0054] The present invention provides two methods for preparing the above-mentioned biomimetic nanomaterials, wherein:

[0055] The first method comprises the following steps: mixing phytic acid and metal ion solutions at a molar ratio of phytic acid to metal ions of 1:(1-6), stirring uniformly to obtain a mixed solution A; adding a protein / polypeptide solution to the mixed solution A at a molar ratio of protein / polypeptide to phytic acid of 1:25, and adjusting the pH value of the solution to 7-10 to obtain a mixed solution B; centrifuging the mixed solution B to remove precipitates, and repeatedly ultrafiltrating / dialyzing the supernatant to obtain a ternary complex solution, which is the biomimetic nanomaterial.

[0056] The second method comprises the following steps: taking a certain phytic acid solution, adjusting the pH value of the phytic acid solution to 7-10, adding a protein / polypeptide solution to the phytic acid solution at a molar ratio of protein / polypeptide to phytic acid of 1:25, stirring evenly, to obtain a mixed solution C; adding a metal ion solution to the mixed solution C at a molar ratio of metal ions to phytic acid of 3:1, stirring evenly, to obtain a mixed solution D; the metal ions in the metal ion solution are metal ions that can produce precipitation after mixing with the phytic acid solution; centrifuging the mixed solution D to remove the precipitate, and repeatedly ultrafiltering / dialyzing the supernatant to obtain a ternary complex solution, which is the biomimetic nanomaterial.

[0057] In the preparation process of the biomimetic nanomaterial of the present invention, the multivalent metal cations include one or more elements listed in Table 1. Those skilled in the art can apply them to different imaging and treatment schemes according to the physical and chemical properties of the elements used. Among them, the preferred metal cations for magnetic resonance imaging (MRI) are Fe 2+ 、Fe 3+ 、Mn 2+ 、Gd 3+ .

[0058] In the preparation process of the biomimetic nanomaterial of the present invention, the preferred molar ratio of phytic acid to multivalent metal cations is 1:3; the protein / polypeptide can be any protein / polypeptide: such as common bovine serum albumin (BSA), human serum albumin (HSA), targeted protein transferrin (Tf), phycocyanin with photothermal properties, targeting peptide RGD, etc.

[0059] During the preparation of the biomimetic nanomaterial of the present invention, the pH is adjusted within a certain range. The pH value is determined based on the isoelectric point of the protein / polypeptide, and the pH range is selected between 7 and 10. For the convenience of biomedical applications, the preferred pH value is 7-7.5 within the allowed pH range.

[0060] The biomimetic nanomaterials described herein can be designed with diverse functionalities for use in tumor imaging diagnosis, tumor treatment, and integrated tumor diagnosis and treatment. Applications for tumor imaging include, but are not limited to, the following imaging modalities: MRI, CT, radionuclide imaging, and optical imaging. Applications for tumor treatment include, but are not limited to, chemotherapy, radiotherapy, and photothermal therapy.

[0061] The present invention is further described below with reference to the following examples. It should also be understood that the following examples are only used to further illustrate the present invention and are not to be construed as limiting the scope of protection of the present invention. Any non-essential improvements and adjustments made by those skilled in the art based on the above contents of the present invention fall within the scope of protection of the present invention.

[0062] The construction of the phytic acid ternary complex biomimetic nanomaterial in the present invention is to connect the protein / peptide and phytic acid by using metal cations as bridges to form phytic acid-metal-protein / peptide ternary complex nanoparticles. The principle is as follows Figure 1 As shown in FIG, when phytic acid coexists with metal cations and proteins / peptides, they can form a ternary complex under certain conditions. The formation of the ternary complex is through the metal cation serving as a cationic bridge to connect the negatively charged phytic acid and the protein / peptide.

[0063] Example 1

[0064] (1) According to the method 1, PA-Mn-BSA biomimetic nanomaterials were prepared, and the specific steps are as follows:

[0065] 125 μl of 0.1 M PA solution was added to a reaction vial containing 9 ml of ddH₂O. Then, 125 μl, 250 μl, 375 μl, 500 μl, 625 μl, and 750 μl of 0.1 M MnCl₂ solution were added dropwise at different PA:Mn ratios (1:1, 1:2, 1:3, 1:4, 1:5, and 1:6), respectively, and stirred thoroughly. Then, 500 μl of 1 mM BSA solution was added to the reaction vial and the pH was quickly adjusted to 7 with 1 M NaOH solution. The mixture was stirred at room temperature for 10 minutes. The solution was collected and centrifuged at 10,000 rpm / min for 20 minutes. The supernatant was transferred to an ultrafiltration tube and ultrafiltered three times at 4,000 rpm / min to remove impurities, yielding six PA-Mn-BSA solution samples.

[0066] (2) Relaxation rate determination of PA-Mn-BSA prepared in different ratios

[0067] Screening for optimal phytic acid metal ion ratios (PA:Mn) in phytic acid ternary complexes. Using the six PA-Mn-BSA biomimetic nanomaterials with different PA:Mn ratios as examples, the relaxivity of each PA-Mn-BSA sample was measured to determine the optimal phytic acid metal ion ratio for the constructed phytic acid ternary complex biomimetic nanomaterials for magnetic resonance imaging.

[0068] The bionic nanomaterial samples with different PA:Mn concentrations were placed on the sample holder of a 1.5T nuclear magnetic resonance instrument for T1 value detection. According to the T1 values ​​of samples with different concentrations, a linear regression was performed with concentration (C) as the horizontal axis and T1 value as the vertical axis to construct a fitting curve and calculate the longitudinal relaxation rate (r1) value of each sample.

[0069] The results are shown in Table 2. When the PA:Mn ratio is 1:3, the PA-Mn-BSA nanoparticles exhibit a higher relaxivity and a higher Mn ion loading rate. While a 1:4 ratio exhibits a higher relaxivity, the Mn ion loading efficiency is significantly reduced. Therefore, a 1:3 ratio of PA to metal ions is optimal in the phytic acid ternary complex.

[0070] Table 2 Relaxation rates of PA-Mn-BSA samples with different ratios

[0071] PA / Mn <![CDATA[r1(mM -1 S -1 )]]> Mn (yield%) 1:1 8.32 59.07 1:2 5.76 50.14 1:3 14.72 23.60 1:4 32.16 1.31 1:5 18.79 1.37 1:6 5.3 0.96

[0072] Example 2

[0073] based on Figure 1 The construction principle of the phytic acid ternary complex biomimetic nanomaterial is shown in the figure. 3+ It acts as a cationic bridge to connect protein and phytic acid to form PA-Gd-BSA ternary complex nanoparticles.

[0074] PA-Gd-BSA nanoprobes were prepared according to the steps of Method 2. Specifically, 125 μl of 0.1 M PA solution was added to a reaction flask containing 9 ml of ddH₂O. The pH of the solution was adjusted to 7 with 1 M NaOH solution. 500 μl of 1 mM BSA solution was then added dropwise to the flask. The mixture was stirred at room temperature for 10 minutes. The solution was collected and centrifuged at 10,000 rpm / min for 20 minutes. The supernatant was collected and ultrafiltered three times at 4,000 rpm / min to remove impurities, yielding a PA-Gd-BSA solution.

[0075] Example 3

[0076] based on Figure 1 The construction principle of the bionic nanomaterial is to use high atomic number bismuth ions as cationic bridges to connect protein and phytic acid to form phytic acid-bismuth-protein ternary complex nanoparticles.

[0077] PA-Bi-BSA biomimetic nanomaterials were prepared according to the steps of method 2. Specifically, 125 μl of 0.1 M PA solution was added to a reaction flask containing 9 ml of ddH₂O. The pH of the solution was adjusted to 7 with 1 M NaOH solution. 500 μl of 0.1 M BSA solution was then added dropwise to the reaction flask. The mixture was stirred at room temperature for 10 minutes. The solution was collected and centrifuged at 10,000 rpm / min for 20 minutes. The supernatant was collected and ultrafiltered three times at 4,000 rpm / min to remove impurities, yielding a PA-Bi-BSA solution.

[0078] Example 4

[0079] (1) Based on Figure 1 This example uses paramagnetic manganese ions and the chemotherapeutic drug cisplatin as examples to prepare PA-Mn / Pt-BSA biomimetic nanomaterials according to the steps of Method 1. The optimal synthesis ratio was screened by varying the PA:metal ion ratio. The specific steps are as follows: 125ul of 0.1M PA solution is added to a reaction bottle containing 9ml of ddH2O, and then 125ul, 187.5ul, and 250ul of 0.1M MnCl2 solution and 250ul, 187.5ul, and 125ul of 0.1M cis-diaminedihydrate platinum (II) solution are added dropwise according to different molar ratios of PA:Mn:Pt, including PA:Mn:Pt of 1:1:2, 1:1.5:1.5, and 1:2:1, respectively, and stirred evenly; then 500ul of 1mM BSA solution is added to the reaction bottle, and the pH of the solution is quickly adjusted to 7 with 1M NaOH solution, and stirred at room temperature for 10 minutes. The solution was collected and centrifuged at 10,000 rpm / min for 20 minutes. The supernatant was placed in an ultrafiltration tube and ultrafiltered three times at 4,000 rpm / min to remove impurities, thereby obtaining six PA-Mn / Pt-BSA solution samples.

[0080] (2) Relaxation rate determination of PA-Mn / Pt-BSA prepared in different ratios

[0081] The optimal metal ion ratio in PA-Mn / Pt-BSA was screened for magnetic resonance imaging monitoring. Six PA-Mn / Pt-BSA biomimetic nanomaterial samples with varying PA:metal ion ratios were prepared as examples. The relaxivity of each PA-Mn / Pt-BSA sample was measured to determine the optimal metal ion ratio for the constructed phytic acid ternary complex biomimetic nanomaterial for magnetic resonance imaging.

[0082] Six PA-Mn / Pt-BSA biomimetic nanomaterial samples were placed on the sample holder of a 1.5T nuclear magnetic resonance instrument for T1 value detection. According to the T1 value of the proportioned samples, a linear regression was performed with concentration (C) as the horizontal axis and T1 value as the vertical axis to construct a fitting curve and calculate the longitudinal relaxation rate (r1) value of each sample.

[0083] The results are shown in Table 3. Under the condition of ensuring a certain Mn ion loading rate, the PA-Mn / Pt-BSA nanoparticles obtained with a ratio of PA:Mn:Pt = 1:1:2 have a higher relaxivity (11.88) than other ratios. Therefore, the ratio of PA:Mn:Pt in the PA-Mn / Pt-BSA ternary complex is better at 1:1:2.

[0084] Table 3 Relaxation rates of PA-Mn / Pt-BSA samples with different ratios

[0085] PA / Mn / Pt <![CDATA[r1(mM -1 S -1 )]]> Mn (yield%) 1:1:2 11.88 27.30 1:1.5:1.5 9.94 32.99 1:2:1 7.21 36.69

[0086] Example 5

[0087] based on Figure 1 Preparation principle diagram, this embodiment takes paramagnetic manganese ions and radiotherapy drug radium chloride as an example, and prepares PA-Mn / according to the steps of method 2. 223 The specific steps are as follows: add 125ul of 0.1M PA solution to a reaction bottle containing 9ml of ddH2O, adjust the pH of the solution to 7 with 1M NaOH solution, add 500ul of 1mM BSA solution to the reaction bottle, and then add 375ul of 0.1M MnCl2 solution and 250ul of radioactive 1Mkq / ml dropwise. 223 RaCl2 solution was stirred at room temperature for 10 minutes. The solution was collected and centrifuged at 10000 rpm / min for 20 minutes. The supernatant was placed in an ultrafiltration tube and ultrafiltered three times at 4000 rpm / min to remove impurities and obtain PA-Mn / 223 Ra-BSA solution.

[0088] Example 6

[0089] based on Figure 1The preparation principle diagram shows the preparation of PA-Mn / Pt-RGD biomimetic nanomaterials using the peptide RGD as a carrier, carrying paramagnetic manganese ions and the chemotherapeutic drug cisplatin (CDDP) according to Method 2. The specific steps are as follows: 125 μl of 0.1 M PA solution was added to a reaction flask containing 9 ml of ddH₂O. The pH of the solution was adjusted to 10 with 1 M NaOH solution. 500 μl of 1 mM RGD solution was then added dropwise to the reaction flask. Then, 125 μl of 0.1 M MnCl₂ solution and 250 μl of 0.1 M cisplatin (II) diamine dihydrate solution were added dropwise. The reaction was stirred at room temperature for 10 minutes. The solution was collected and centrifuged at 10,000 rpm / min for 20 minutes. The supernatant was collected and ultrafiltered three times at 4,000 rpm / min to remove impurities, resulting in a PA-Mn / Pt-RGD solution.

[0090] Example 7

[0091] Characterization of the phytic acid ternary complex prepared by the present invention and verification of its in vitro and in vivo diagnostic and therapeutic effects

[0092] (1) Transmission electron microscopy examination of the particle size and morphology of the phytic acid ternary complex

[0093] Taking the PA-Mn-BSA with a PA:Mn ratio of 1:3 prepared in Example 1, the PA-Gd-BSA prepared in Example 2, and the PA-Mn / Pt-BSA with a PA:Mn:Pt ratio of 1:1:2 prepared in Example 4 as examples, the morphology of the phytic acid ternary complex was observed by transmission electron microscopy. The solution was diluted to an appropriate concentration, titrated onto a carbon grid, and the morphology and particle size of the PA-Mn-BSA, PA-Gd-BSA, and PA-Mn / Pt-BSA nanoparticles were observed under a transmission electron microscope. The results were as follows: Figure 2 、 Figure 3 and Figure 4 As shown, the three phytic acid ternary complex biomimetic nanomaterials all have a small particle size, with a diameter of about 10 nm, and the particle size is relatively uniform and has good dispersion.

[0094] (2) Dynamic light scattering detection of particle size monitoring of phytic acid ternary complex

[0095] The phytic acid ternary composite biomimetic nanomaterials PA-Bi-BSA, PA-Mn / 223 The hydrated particle size of Ra-BSA and PA-Mn / Pt-RGD was characterized and their particle size was observed. The solution was diluted to an appropriate concentration and placed under a Malvern particle size analyzer to measure the hydrated particle size of the biomimetic nanomaterial. The results are shown in Figure 2. Figure 5 、 Figure 6 、 Figure 7As shown, PA-Bi-BSA, PA-Mn / 223 Ra-BSA and PA-Mn / Pt-RGD biomimetic nanomaterials are clear and transparent solutions, which indicates that they have good solubility. The particle sizes of the three materials are all in line with the normal distribution. The particle size of PA-Bi-BSA is about 80nm, and that of PA-Mn / 223 The particle size of Ra-BSA is about 27 nm, and the particle size of PA-Mn / Pt-RGD is about 8 nm. Both particle sizes are small and meet the requirements of bionanomedicine applications.

[0096] (3) In vitro MRI imaging effect

[0097] PA-Mn-BSA (PA:Mn=1:3), PA-Gd-BSA, PA-Mn / Pt-BSA (PA:Mn:Pt=1:1:2), PA-Mn / 223 Ra-BSA and PA-Mn / Pt-RGD were used as examples to verify the in vitro magnetic resonance imaging effect of single metal or multi-metal phytic acid ternary complexes. The ternary complex solutions were diluted to different concentrations and placed under GE 3.0T magnetic resonance imaging for T1WI imaging. The results showed that PA-Mn-BSA ( Figure 8 )、PA-Mn / Pt-BSA( Figure 8 )、PA-Gd-BSA( Figure 9 )、PA-Mn / 223 Ra-BSA( Figure 10 )、PA-Mn / Pt-RGD( Figure 11 ) solution with increasing concentration, its T1WI signal gradually increased, and finally showed extremely high brightness on the T1WI image. Figure 8 Comparison of MRI images of PA-Mn-BSA and PA-Mn / Pt-BSA revealed that the MRI performance of PA-Mn-BSA and PA-Mn / Pt-BSA was essentially similar, indicating that the doping of the imaging metal ion Mn and the therapeutic metal Pt has negligible effects on the MRI performance of Mn. These results demonstrate that phytic acid ternary complex biomimetic nanomaterials, whether prepared with a single metal ion or multiple metal ions, can exhibit superior T1 imaging in vitro.

[0098] (4) In vitro CT imaging effect of phytic acid ternary complex

[0099] In order to verify that the phytic acid ternary complex prepared by metal ions imaged in other ways also has good imaging effects, such as bismuth with a high atomic number, can be imaged by CT, the PA-Bi-BSA prepared in Example 3 was used as an example for verification. PA-Bi-BSA solutions were prepared into different concentrations and placed under a 64-slice CT scan for CT imaging: 100kev, 90ms. The results are shown in Figure 3. Figure 12 As shown, the brightness of the PA-Bi-BSA solution gradually increased with increasing concentration, reaching a high brightness at a concentration of 12 mg / ml, demonstrating good CT imaging results. This indicates that the prepared PA-Bi-BSA solution has the potential to be used as a CT contrast agent, and also provides a reference for the preparation of phytic acid ternary complex biomimetic nanomaterials with various other imaging metal ions.

[0100] (5) Stability of phytic acid ternary complex biomimetic nanomaterials

[0101] In order to confirm the stability of phytic acid ternary complex biomimetic nanomaterials, PA-Mn-BSA (PA:Mn=1:3) and PA-Mn / Pt-BSA (PA:Mn:Pt=1:1:2) prepared in Examples 1 and 4 were used as examples to verify the particle size changes of biomimetic nanomaterials in different environments (PBS, FBS). PA-Mn-BSA and PA-Mn / Pt-BSA nanoparticles were placed in PBS and FBS solutions respectively, and the turbidity changes of the solutions were observed at different time points (30min, 4h, 8h, 1d, 3d, 7d, 14d), and their hydrated particle size was monitored by a dynamic light scattering particle size analyzer. The results are shown in Figure 2. Figure 13 As shown in the figure, the particle size of PA-Mn-BSA and PA-Mn / Pt-BSA nanoparticles did not change significantly during the 14-day monitoring in PBS and FBS environments, indicating good stability.

[0102] (6) pH-responsive reassembly properties of phytic acid ternary complexes

[0103] The PA-Mn-BSA (PA:Mn=1:3) prepared in Example 1 was used as an example for verification. Based on the physiological pH of the human body (7.4) and the pH of tumor cell endosomes (5.0) as references, the pH was adjusted to 7.4 and 5.0, and the particle size changes of the nanoparticles at different pH values ​​were observed using a particle size analyzer. The results showed that when the pH was adjusted from 7.4 to 5.0, the solution changed from clear to turbid. Figure 14 (a), and its particle size shows explosive growth, see Figure 14 (b). At the same time, the nanoparticles at pH 5.0 were observed by transmission electron microscopy. Figure 14 (c), with PA-Mn-BSA (PA:Mn=1:3) at physiological pH ( Figure 2), the ternary complex PA-Mn-BSA exhibited significant aggregation at pH 5.0, demonstrating pH-responsive reassembly. This suggests that under the acidic conditions of tumors, the nanotheranostic probe can undergo pH-responsive aggregation, preventing it from re-entering the blood circulation. This increases the aggregation and retention of nanoparticles at the tumor site, enabling long-term and effective retention at the tumor site, enabling continuous imaging, monitoring, and treatment of the tumor.

[0104] (7) Inhibition rate of tumor cell growth

[0105] 1) The growth inhibition rate of tumor cells by PA-Mn-BSA and PA-Mn / Pt-BSA biomimetic nanomaterials.

[0106] In order to verify in vitro that after loading chemotherapeutic metals through ternary complexes, biomimetic nanomaterials can still maintain their anti-tumor activity and effectively inhibit the growth of tumor cells. Using cisplatin as a control, different concentrations of PA-Mn-BSA (PA:Mn=1:3) and PA-Mn / Pt-BSA (PA:Mn:Pt=1:1:2) nanomaterials were co-incubated with PC-3 tumor cells for 72 hours, and the survival rate of tumor cells was detected by MTT assay. The results are shown in Figure 2. Figure 15 The results showed that due to the inherent anti-cancer effect of phytic acid, as the concentration increased, although PA-Mn-BSA could also inhibit the growth of tumor cells, its inhibitory effect was not obvious; while the cell killing activity of the PA-Mn / Pt-BSA group was close to that of the cisplatin group, which indicated that the PA-Mn / Pt-BSA bionic nanomaterial loaded with cisplatin maintained the killing effect of cisplatin on tumor cells, providing a basis for its further use in living tumor treatment, and also providing the possibility for the construction of multifunctional phytic acid ternary complex bionic nanomaterials.

[0107] 2)PA-Mn / 223 The growth inhibition rate of tumor cells by Ra-BSA biomimetic nanomaterials.

[0108] In order to verify in vitro that after loading radiotherapeutic metals through ternary complexes, biomimetic nanomaterials can still maintain their anti-tumor activity and effectively inhibit the growth of tumor cells. 223 RaCl2 was used as a control, and the PA-Mn / 223 Ra-BSA with different radioactivity was co-incubated with PC-3 tumor cells for 72 h, and the survival rate of tumor cells was detected by MTT assay. Figure 16 Shows: With the increase of radioactivity, PA-Mn / 223 After treatment with Ra-BSA, the proliferation of PC-3 cells was significantly inhibited, and its inhibitory effect on tumor cell growth was similar to that of 223RaCl2, which indicates that it is loaded with radioactive elements 223 PA-Mn / Ra 223 Ra-BSA maintains 223 The killing effect of Ra on tumor cells provides a basis for the construction of multifunctional phytic acid ternary complex biomimetic nanomaterials.

[0109] 3) The growth inhibition rate of tumor cells by PA-Mn / Pt-RGD bionic nanomaterials.

[0110] In order to verify in vitro that the ternary complex biomimetic nanomaterial constructed with polypeptide as carrier can still maintain the anti-tumor activity of the loaded metal drug and effectively inhibit the growth of tumor cells, the PA-Mn / Pt-RGD biomimetic nanomaterial prepared in Example 6 was co-incubated with PC-3 tumor cells at different concentrations for 72 hours, and the survival rate of tumor cells was detected by MTT method. The results are shown in Figure 2. Figure 17 It shows that with the increase of PA-Mn / Pt-RGD concentration, the growth of tumor cells is significantly inhibited, which indicates that the PA-Mn / Pt-RGD bionic nanomaterial loaded with cisplatin retains the killing effect of cisplatin on tumor cells, which provides a basis for constructing multifunctional phytic acid ternary complex bionic nanomaterials through polypeptides.

[0111] (8) In vivo tumor imaging monitoring

[0112] In vivo tumor imaging monitoring using PA-Mn-BSA and PA-Mn / Pt-BSA biomimetic nanomaterials

[0113] In order to attempt to confirm that the phytic acid ternary complex biomimetic nanomaterial of the present invention can achieve excellent imaging effects at the in vivo level when loaded with imaging metal ions, this example uses PA-Mn-BSA (PA:Mn=1:3) and PA-Mn / Pt-BSA (PA:Mn:Pt=1:1:2) prepared in Examples 1 and 4 as examples to verify their in vivo magnetic resonance imaging effects.

[0114] PA-Mn-BSA or PA-Mn / Pt-BSA solution was injected into PC-3 tumor-bearing mice via the tail vein, and the tumors were monitored by continuous magnetic resonance T1 imaging using a 3.0T magnetic resonance scanner before and at different time points after injection. Figure 18 As shown in Figure a, after PA-Mn-BSA treatment, the T1WI signal of the tumor site of PC-3 tumor-bearing mice showed a significant enhancement effect after administration. The enhancement effect continued to increase and reached its peak at 12 hours. The enhancement effect at the tumor site lasted for a long time and was still visible at 14 days. Figure 18Figure b shows that after PA-Mn / Pt-BSA treatment, the T1WI signal of the tumor site in PC-3 tumor-bearing mice also showed a significant enhancement. The enhancement method was similar to that of PA-Mn-BSA treatment, reaching a peak at 12 hours. As time went on, the tumor signal began to decline, but it still maintained an enhancement effect for a long time. This long-term enhancement effect suggests that the bionic nanomaterial can be retained at the tumor site for a long time. The above results show that both PA-Mn-BSA and PA-Mn / Pt-BSA bionic nanomaterials can achieve good magnetic resonance imaging effects in vivo, and can achieve long-term enhancement effects in tumor retention. This confirms that the phytic acid ternary complex bionic nanomaterial of the present invention can achieve imaging, diagnosis and monitoring of living tumors after loading imaging metals; and can be retained at the tumor site for a long time, and is expected to achieve a long-term therapeutic effect on the tumor to enhance the therapeutic effect of the drug.

[0115] (9) In vivo tumor inhibition effect

[0116] 1) In vivo tumor inhibition effect of PA-Mn / Pt-BSA biomimetic nanomaterials

[0117] In order to demonstrate that the biomimetic nanomaterial of the present invention can achieve tumor growth inhibition effect at the in vivo level when chelating chemotherapeutic metal ions, the PA-Mn / Pt-BSA (PA:Mn:Pt=1:1:2) prepared in Example 4 was used as an example to verify its in vivo tumor inhibition effect.

[0118] A PC-3 tumor-bearing mouse model was established. When the tumor grew to 100 mm 3 PA-Mn / Pt-BSA solution was injected into the rat tail vein at 14 days. PBS, CDDP, and PA-Mn-BSA (PA:Mn=1:3) prepared in Example 1 were used as controls. Tumor size was measured every other day for 14 days to observe the tumor growth inhibition effect of different groups. On day 14, the tumors of the mice were dissected and their sizes were observed. Figure 19 As shown in (a), compared with the PBS, CDDP, and PA-Mn-BSA groups, the tumor volume of the PA-Mn / Pt-BSA group was the smallest, showing a strong tumor growth inhibition effect; while the tumor volume of the PA-Mn-BSA group did not change significantly compared with the PBS group, and its growth inhibition effect was not obvious. Although the tumor volume of the CDDP group was smaller than that of the PBS group, its tumor inhibition effect was still not as good as that of the PA-Mn / Pt-BSA group. Figure 19(b) also shows that after treatment with PA-Mn / Pt-BSA, the tumor growth in the PA-Mn / Pt-BSA group was slow and significantly inhibited compared to the exponential growth of the tumor in the PBS group. The above results indicate that PA-Mn / Pt-BSA biomimetic nanomaterials chelated with therapeutic metals (cisplatin) have a significant growth inhibitory effect on living tumors. At the same time, the Pt content in the tumors of the CDDP group and the PA-Mn / Pt-BSA group was detected by ICP-MS on day 14. The results are as follows: Figure 20 As shown in the figure, the Pt content in the tumor site in the PA-Mn / Pt-BSA group was significantly higher than that in the CDDP-treated group at 14 days, which was confirmed by the magnetic resonance imaging results of PA-Mn-BSA (PA:Mn=1:3) and PA-Mn / Pt-BSA (PA:Mn:Pt=1:1:2) prepared in Examples 1 and 4, indicating that PA-Mn / Pt-BSA can cause the chemotherapy drug cisplatin to accumulate in the tumor site for a long time, thereby achieving a long-term chemotherapy effect.

[0119] 2)PA-Mn / 223 In vivo tumor inhibitory effect of Ra-BSA

[0120] In order to verify that the biomimetic nanomaterials of the present invention can achieve tumor growth inhibition effect at the living body level when chelating radioactive therapeutic metal ions, the PA-Mn / 223 Ra-BSA was used as an example to verify its in vivo tumor inhibition effect.

[0121] A PC-3 tumor-bearing mouse model was established. When the tumor grew to 100 mm 3 PA-Mn / 223 Ra-BSA solution, PBS, 223 RaCl2 and PA-Mn-BSA (PA:Mn=1:3) prepared in Example 1 were used as controls; the tumor size was measured every other day after injection for 10 days to observe the tumor growth inhibition effect of different groups. On the 10th day, the tumors of mice were dissected and their sizes were observed. Figure 21 As shown, compared with PBS, 223 RaCl2, PA-Mn-BSA group, PA-Mn / 223 The Ra-BSA group had the smallest tumor volume and showed a strong tumor growth inhibition effect; 223 Although the tumor volume of the RaCl2 group was smaller than that of the PBS group, its tumor inhibition effect was still not as good as that of the PA-Mn / 223 Ra-BSA group.

[0122] (10) Safety assessment

[0123] Since most chemotherapy drugs have certain toxic side effects, the safety of PA-Mn-BSA (PA:Mn=1:3) and PA-Mn / Pt-BSA (PA:Mn:Pt=1:1:2) prepared in Examples 1 and 4 were evaluated as examples.

[0124] Normal Kunming mice were injected with PBS, CDDP, PA-Mn-BSA, and PA-Mn / Pt-BSA through the tail vein, and blood biochemical analysis was performed 24 hours later. The results were as follows: Figure 22 As shown in the results, after CDDP treatment, the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea nitrogen (BUN), and blood creatinine (CRE) in mice were significantly higher than those in the PBS group, showing obvious liver and kidney toxicity; while after PA-Mn-BSA and PA-Mn / Pt-BSA treatment, their blood biochemical indicators did not change significantly compared with the PBS group, showing no obvious liver and kidney toxicity risk. The liver and kidney toxicity of mice treated with PA-Mn / Pt-BSA loaded with cisplatin was significantly reduced compared with that after free CDDP treatment, which suggests that the phytic acid ternary complex biomimetic nanomaterial of the present invention can significantly reduce the toxic and side effects of the loaded drug. The above results show that PA-Mn-BSA and PA-Mn / Pt-BSA have good biosafety, which shows that the biomimetic nanomaterial constructed by the phytic acid ternary complex has high biocompatibility.

[0125] In summary, the present invention provides a method for preparing a ternary biomimetic nanomaterial based on phytic acid. This method overcomes the low solubility of phytate and constructs a soluble biomimetic nanomaterial for tumor imaging diagnosis, treatment, and integrated diagnosis and treatment. The biomimetic nanomaterial prepared by this method is highly biocompatible and can reassemble in situ in the acidic environment of the tumor to maintain long-term retention at the tumor site, achieving long-term monitoring and treatment effects.

[0126] It is obvious to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the present invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the present invention. Therefore, from all perspectives, the embodiments should be regarded as exemplary and non-limiting. Those skilled in the art can make many variations based on the teachings of the present invention without departing from the spirit of the present invention, and all of these variations are within the scope of protection of the present invention.

Claims

1. A ternary composite biomimetic nanomaterial based on phytic acid, characterized in that: The biomimetic nanomaterial is a ternary complex composed of phytic acid, metal ions and protein / polypeptide, wherein the molar ratio of protein / polypeptide to phytic acid is 1:25; the ternary complex is formed by connecting the protein / polypeptide and phytic acid using metal cations as cationic bridges; The metal ions are polyvalent metal cations; The protein / peptide is selected from common bovine serum albumin, human serum albumin, targeted protein transferrin, phycocyanin with photothermal properties, and targeting peptide RGD; The polyvalent metal cation is selected from Cr 3+ 、Co 2+ 、Mn 2+ 、Fe 2+ 、Fe 3+ 、Cu 2+ 、Cu 3+ 、La 2+ 、Gd 3+ 、Ce 3+ , Tb 3+ 、Pr 3+ 、Dy 3+ 、Nd 3+ 、Ho 3+ 、Pm 3+ 、Er 3+ 、Sm 3+ 、Tm 3+ 、Eu 3+ 、Yb 3+ 、Lu 3+ 、Bi 2+ , Hf 4+ 、Re 4+ 、W 4+ 、Ta 5+ 、 177 Lu 3+ 、 68 Ga 3+ 、 99m Tc 7+ 、 111 In 3+ 、 62 Cu 2+ , Pt 2+ 、Ru 3+ 、Os 2+ 、 223 Ra 2+ 、 89 Sr 2+ 、 60 Co 2+ 、 192 Ir 3+ 、 137 Cs + 、 182 Ta 5+ ; When the selected metal ion solution and the phytic acid solution are mixed at a molar ratio of phytic acid to metal ion of 1:(1-6), if no precipitation occurs, use preparation method 1 or preparation method 2; if precipitation occurs, use preparation method 2: Preparation method 1 comprises the following steps: S1-1, mixing phytic acid and a metal ion solution in a molar ratio of phytic acid to metal ion of 1:(1-6), stirring uniformly to obtain a mixed solution A; S1-2, adding the protein / polypeptide solution to the mixed solution A at a molar ratio of protein / polypeptide to phytic acid of 1:25, and adjusting the pH of the solution to 7-10 to obtain a mixed solution B; S1-3, centrifuging the mixed solution B to remove the precipitate, and repeatedly ultrafiltering / dialyzing the supernatant to obtain a ternary complex solution, which is the biomimetic nanomaterial; Preparation method 2 comprises the following steps: S2-1. Take a certain amount of phytic acid solution, adjust the pH value of the phytic acid solution to 7-10, add the protein / polypeptide solution to the phytic acid solution at a molar ratio of protein / polypeptide to phytic acid of 1:25, and stir evenly to obtain a mixed solution C; S2-2, adding a metal ion solution to the mixed solution C at a molar ratio of metal ions to phytic acid of 3:1, and stirring uniformly to obtain a mixed solution D; the metal ions in the metal ion solution are metal ions that can produce precipitation after mixing with the phytic acid solution; S2-3. Centrifuge the mixed solution D to remove the precipitate, and repeatedly ultrafilter / dialyze the supernatant to obtain a ternary complex solution, which is the biomimetic nanomaterial.

2. The phytic acid-based ternary composite biomimetic nanomaterial according to claim 1, characterized in that: The selection of the polyvalent metal cation is: For preparing MRI imaging contrast agent, the multivalent metal cation is selected from Mn 2+ 、Fe 2+ 、Fe 3+ 、Gd 3+ ; For preparing contrast agents for CT imaging, the multivalent metal cation is selected from Yb 3+ 、Lu 3+ 、Bi 2+ , Hf 4+ 、Re 4+ 、W 4+ 、Ta 5+ ; For preparing a contrast agent for nuclear imaging, the multivalent metal cation is selected from 177 Lu 3+ 、 68 Ga 3+ 、 99m Tc 7+ 、 111 In 3+ 、 62 Cu 2+ ; For preparing contrast agents for optical imaging, the multivalent metal cation is selected from Yb 3+ 、Lu 3+ 、Er 3+ 、Nd 3+ ; For preparing a drug for chemotherapy, the multivalent metal cation is Pt 2+ 、Ru 3+ 、Os 2+ ; For preparing a drug for radiotherapy, the multivalent metal cation is selected from 177 Lu 3+ 、 223 Ra 2+ 、 89 Sr 2+ 、 60 Co 2+ 、 192 Ir 3+ 、 137 Cs + 、 182 Ta 5+ ; For preparing a drug for photothermal therapy, the multivalent metal cation is selected from Re 4+ 、W 4+ 、Bi 2+ .

3. A method for preparing a ternary composite biomimetic nanomaterial based on phytic acid according to any one of claims 1 or 2, characterized in that: When the selected metal ion solution and the phytic acid solution are mixed at a molar ratio of phytic acid to metal ion of 1:(1-6), if no precipitation occurs, use preparation method 1 or preparation method 2; if precipitation occurs, use preparation method 2: Preparation method 1 comprises the following steps: S1-1, mixing phytic acid and a metal ion solution in a molar ratio of phytic acid to metal ion of 1:(1-6), stirring uniformly to obtain a mixed solution A; S1-2, adding the protein / polypeptide solution to the mixed solution A at a molar ratio of protein / polypeptide to phytic acid of 1:25, and adjusting the pH of the solution to 7-10 to obtain a mixed solution B; S1-3, centrifuging the mixed solution B to remove the precipitate, and repeatedly ultrafiltering / dialyzing the supernatant to obtain a ternary complex solution, which is the biomimetic nanomaterial; Preparation method 2 comprises the following steps: S2-1. Take a certain amount of phytic acid solution, adjust the pH value of the phytic acid solution to 7-10, add the protein / polypeptide solution to the phytic acid solution at a molar ratio of protein / polypeptide to phytic acid of 1:25, and stir evenly to obtain a mixed solution C; S2-2, adding a metal ion solution to the mixed solution C at a molar ratio of metal ions to phytic acid of 3:1, and stirring uniformly to obtain a mixed solution D; the metal ions in the metal ion solution are metal ions that can produce precipitation after mixing with the phytic acid solution; S2-3. Centrifuge the mixed solution D to remove the precipitate, and repeatedly ultrafilter / dialyze the supernatant to obtain a ternary complex solution, which is the biomimetic nanomaterial.

4. The method for preparing the ternary composite biomimetic nanomaterial based on phytic acid according to claim 3, characterized in that: The metal ion in the preparation method 2 is Gd 3+ 、Bi 3+ and 223 Ra 2+ One or more of .

5. An application of a ternary composite biomimetic nanomaterial based on phytic acid, characterized in that: The biomimetic nanomaterial according to any one of claims 1 or 2 or the biomimetic nanomaterial prepared according to any one of claims 3 or 4 is used to prepare drugs for chemotherapy, radiotherapy or photothermal therapy, wherein the polyvalent metal cations are selected from: For preparing a drug for chemotherapy, the multivalent metal cation is Pt 2+ 、Ru 3+ 、Os 2+ ; For preparing a drug for radiotherapy, the multivalent metal cation is selected from 177 Lu 3+ 、 223 Ra 3+ 、 89 Sr 2+ 、 60 Co 2+ 、 192 Ir 3+ 、 137 Cs + 、 182 Ta 5+ ; For preparing a drug for photothermal therapy, the multivalent metal cation is selected from Re 4+ 、W 4+ 、Bi 2+ .

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