CN107381580A - A kind of preparation method of the interior doping metal net shaped Biodegradable silica dioxide granule of polyphenol - Google Patents

Abstract

The invention belongs to the field of nanomaterial preparation, and in particular relates to a method for preparing degradable silica nanoparticles internally doped with polyphenol-metal mesh. In the present invention, the metal-polyphenol coordination complex network structure is incorporated into the silica polycondensation network system in a doping manner, thereby increasing the porosity of the silica and further weakening the silica through the hydrogen bond between the phenolic hydroxyl group and the silanol. The degree of polycondensation can achieve the purpose of accelerating the hydrolytic degradation of silica. In a weakly acidic and high glutathione environment, the metal-polyphenol coordination complex network structure can dissociate, inducing the collapse of the silica skeleton structure, degrading the nanoparticles into smaller fragments and further degrading and extracting The release of silicic acid molecules, polyphenol molecules and metal ions, so as to realize the self-degradation of the drug carrier in the tumor microenvironment.

Description

Preparation of Degradable Silica Particles with Internal Doping Polyphenol-Metal Network method

technical field

The invention belongs to the field of nanomaterial preparation, and in particular relates to a method for preparing silicon dioxide nanoparticles with uniform particle size, monodispersity, good biocompatibility and biodegradability doped with polyphenol-metal mesh.

Background technique

As an emerging nanomaterial, nano-silicon dioxide exhibits many impressive characteristics in the medical and biological fields, such as good biological affinity and easy surface modification. However, due to the compact structure of silica, silica particles have quite good thermal stability, and it takes a long time to decompose in cells and living bodies, which can easily cause dose accumulation in tissues and organs, thereby causing DNA damage, Protein denaturation, etc. and lead to a series of bad results. Therefore, the in vivo degradation and clearance of silica nanomaterials using biologically relevant factors has become a research topic worldwide, which is an important prerequisite for promoting its successful transformation into clinical applications, and has important research significance.

The porosity of silica particles or the degree of condensation and aggregation of particles is the key factor to achieve effective degradation. Therefore, the current solution to the in vivo degradation and removal of silicon nanomaterials is mainly to use doping methods to increase the porosity of silicon dioxide or build a degradable structural framework, especially to develop and utilize the internal factors of the tumor microenvironment (such as high active oxygen environment , low pH, high glutathione concentration) degradable silicon nanocarriers. Polyphenolic compounds are rich in ortho-phenolic hydroxyl structures, which can be used as a complex reaction with metal ions to form a metal-polyphenol coordination complex network structure. This type of structure has a large molecular weight and a network porosity. High, and the network structure can be dissociated in weakly acidic and high glutathione environment. Therefore, the present invention intends to increase the porosity of silica by doping the metal-polyphenol coordination complex network structure into the silica polycondensation network system and further weaken the porosity through the hydrogen bond between phenolic hydroxyl groups and silanols. The degree of polycondensation of silica can achieve the purpose of accelerating the hydrolytic degradation of silica. In a weakly acidic and high glutathione environment, the metal-polyphenol coordination complex network structure can dissociate, inducing the collapse of the silica skeleton structure, thereby realizing the self-degradation of the drug carrier in the tumor microenvironment.

Contents of the invention

The purpose of the present invention is to provide a method for preparing degradable silica nanoparticles with internally doped polyphenol-metal complex network structure. By doping the silica skeleton structure with the polyphenol-metal network, the porosity of the silica is increased, the polycondensation degree of the silica is weakened, and the purpose of accelerating the hydrolysis degradation of the silica is achieved. The obtained composite nanoparticles have the advantages of good biocompatibility, monodispersity, degradability and the like. This process realizes one-step synthesis of degradable silica nanoparticles, without adding template or pore expander during the synthesis process, the synthesis steps are simple and easy, and the cost is low.

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

A method for preparing internally doped polyphenol-metal network degradable silica nanoparticles: including reacting polyphenol molecules and silicon sources in an alkaline solution for a certain period of time to form internally doped polyphenol oligomers Synthesis step (1) of the primary silica structure; add metal ions to the above reaction solution, continue the reaction for a certain period of time, and centrifuge the reactant to obtain the synthesis step of silica nanoparticles internally doped with polyphenol-metal mesh (2).

The preparation method of the internally doped polyphenol-metal mesh degradable silica nanoparticles of the present invention, the specific experimental steps are as follows:

a) Add TEOS and a certain amount of polyphenols to the ethanol-water solution with a volume ratio of 60:1, stir for 10 minutes to make it evenly mixed; add ammonia water drop by drop, react at 25°C for 0.5 h, pass the polyphenol molecules The hydrogen bond between the phenolic hydroxyl group and the silanol makes the polyphenol oligomer easily doped into the polycondensation network structure of silica, thereby obtaining primary SiO ₂ particles internally doped with polyphenol oligomer.

b) Add metal ions to the above mixture, continue to react for 5.5 h in a water bath at 25°C, and use the coordination between metal ions and polyphenol catechol groups to form a polyphenol-metal network, which can immobilize more The polyphenol molecules are inside the silica spheres, while further increasing the porosity of the silica. After centrifugation, the precipitate is washed with absolute ethanol and deionized water, and finally silicon dioxide nanoparticles doped with polyphenol-metal mesh are obtained.

In the preparation method provided by the present invention, the doping mass ratio of polyphenols in the finally obtained polyphenol-metal mesh-doped silica nanoparticles should be less than 20%.

In the preparation method provided by the present invention, the polyphenol can be any one of epigallocatechin gallic acid (EGCG), tannic acid (TA), and gallic acid (GA); the metal ion can be iron ion, manganese Any one or more of gadolinium ions, europium ions, copper ions, zinc ions, and cadmium ions.

In the preparation method provided by the present invention, the molar ratio of metal ions to polyphenols is 1:4-1:10, and the most preferred ratio is 1:5.

The morphology characteristics of the internally doped polyphenol-metal mesh silica nanoparticles obtained according to the preparation method provided by the present invention are: when the polyphenol molecules are EGCG and GA, the silica nanoparticles are monodisperse solid Porous balls, when the polyphenol molecule is TA, the shape of the silica nanoparticles is a monodisperse hollow eccentric porous spherical shape, the size of the nanoparticles is 80-100 nm, and the potential is -35±5 mv.

In the preparation method provided by the present invention, the internal dopant molecules are not limited to polyphenol molecules, and can be extended to compounds or drug molecules containing polyhydroxyl or polymercapto structures; the metal ions are not limited to the few described in the present invention. a metal ion.

The preparation method provided by the present invention does not introduce a template agent and a pore-enlarging agent, so the subsequent process of removing the template agent and the pore-enlarging agent is not required, and the disadvantages of reduced particle yield and poor degradability are avoided.

The silica nano-particles doped with polyphenol-metal nets obtained according to the preparation method of the present invention have biodegradable properties. Under acidic and glutathione dual stimulus response conditions, the polyphenol-metal network structure doped inside the silica nanoparticles undergoes reduction and protonation reactions, and the network structure dissociates first, leading to the collapse of the SiO ₂ structure , the particles degrade into smaller fragments and further degrade, extracting silicic acid molecules, polyphenol molecules and metal ions. The degradation condition is pH≤6, the glutathione concentration is 10 mM, and the degradation time is 3-7 days.

In the preparation method provided by the present invention, the doped polyphenol molecules not only play the role of skeleton doping, but also have certain antioxidant and tumor inhibitory activities; in addition, doped metal ions such as Mn ²⁺ , Fe ³⁺ , Gd ³⁺ , etc., can provide the nuclear magnetic or fluorescence imaging function of the silica system, so that the composite particles can be used in biomedical diagnosis and treatment.

More specifically, a method for preparing degradable silica nanoparticles with internally doped polyphenol-metal complex network structure comprises the following steps:

SiO ₂ -TA-Fe system

a) Add 430 μL TEOS and 1.2 mg TA (12% doping ratio) into ethanol-water solution with a volume ratio of 60:1, stir for 10 min to mix well; add 0.5 mL of ammonia water dropwise, at 25 The reaction was carried out at ℃ for 0.5 h to obtain primary SiO ₂ nanoparticles containing polyphenol oligomers.

b) Add 0.38 mg FeCl _{3 ·} 6H ₂ O (molar ratio: TA: Fe = 5: 1) to the reaction solution, continue to react in a water bath at 25°C for 5.5 h, after the reaction is complete. Centrifuge at 10,000 rpm for 10 min, wash the precipitate twice with absolute ethanol and ultrapure water, and disperse the precipitate in 10 mL deionized water to obtain degradable silica nanoparticles doped with TA-Fe.

SiO ₂ -EGCG-Fe system

a) Add 430 μL TEOS and 8.6 mg EGCG (doping ratio 8.66%) into ethanol-water solution with a volume ratio of 60:1, stir for 10 min to mix evenly; add 0.5 mL ammonia water dropwise, at 25 The reaction was carried out at ℃ for 0.5 h to obtain primary SiO ₂ nanoparticles containing polyphenol oligomers.

b) Add 1.01 mg FeCl _{3 ·} 6H ₂ O (the molar ratio is EGCG:Fe=5:1) to the reaction solution, and continue to react in a water bath at 25°C for 5.5 h, after the reaction is completed. Centrifuge at 10,000 rpm for 10 min, wash the precipitate twice with absolute ethanol and ultrapure water, and disperse the precipitate in 10 mL deionized water to obtain degradable silica nanoparticles doped with EGCG-Fe.

Compared with the preparation method of other degradable silica particles, the remarkable advantage of the present invention is:

(1) According to the method of the present invention, the preparation process of the internally doped polyphenol-metal mesh silica nanoparticles is simple, the synthetic particle size is uniform, and the monodispersity is good. The preparation method provided by the invention does not introduce a template agent, so the subsequent process of removing the template agent is not required, and the disadvantages of reduced yield of particles and poor degradability are avoided.

(2) In the process of synthesizing silicon spheres, polyphenol oligomers are first introduced, and then polyphenols are doped into the polycondensation network structure of silica by using the rapid complexation ability of polyphenols and metal ions. This process realizes the doping of oligomers inside the silicon spheres, and provides a universal method for subsequent doping of other oligomers inside the silica spheres.

(3) The silicon dioxide composite nanoparticles doped with metal-polyphenol network obtained by the method of the present invention have good biocompatibility and are easily degraded by acidic and glutathione dual stimulus responses. The internally doped polyphenols and metal ions can not only increase the porosity of SiO ₂ nanoparticles, but also the polyphenol molecules themselves have a certain antioxidant and tumor inhibitory activity. Doped metal ions such as Mn ²⁺ , Fe ³ The introduction of ⁺ , Gd ³⁺ , etc. can also provide the nuclear magnetic or fluorescence imaging function of the silica system, which is convenient for its application in the sustained release of drugs in tumors or inflammatory tissues, and nuclear magnetic imaging-guided treatment.

Description of drawings

Figure 1 shows the low magnification TEM characterization of composite nanoparticles synthesized when different polyphenol molecules are doped: (A) SiO ₂ -GA-Fe; (B) SiO ₂ -EGCG-Fe; (C) SiO ₂ -TA -Fe; the doping ratio of polyphenols is 8.66%, and the molar ratio of polyphenols to metals is 5:1;

Figure 2 shows the TEM characterization of the composite nanoparticles synthesized when doped with different metal ions using TA as the doped polyphenol molecule: (A) SiO ₂ -TA-Fe; (B) SiO ₂ -TA-Mn; ( C) SiO ₂ -TA-Gd;

Figure 3 shows the transmission electron microscope characterization of the morphology of SiO ₂ -TA-Fe composite nanoparticles obtained when TA is used as doped polyphenol molecules and the metal ion is selected as Fe ³⁺ , with different doping ratios of TA: (A) 4.33%; (B) 8.66%; (C) 12%; (D) 17.2%;

Figure 4 is the investigation of the degradation of SiO ₂ -EGCG-Fe particles over time under the condition of pH=5.0+10 mM GSH. (A) Transmission electron micrograph of degradation of SiO ₂ -EGCG-Fe particles; (B) Optical photograph of degradation of SiO ₂ -EGCG-Fe nanoparticles; (C) Element release diagram of SiO ₂ -EGCG-Fe nanoparticles after degradation ; The abscissa is time, and the ordinate is the element release percentage;

Figure 5 is a diagram of the element release of SiO ₂ -TA-M ⁿ⁺ nanoparticles after degradation under different conditions using ICP-AES. The abscissa is time, and the ordinate is the percentage of element release. (A) SiO ₂ -TA-Fe; (B) SiO ₂ -TA-Gd; (C) SiO ₂ -TA-Mn;

Figure 6 shows the biological compatibility of composite nanoparticles doped with different metals and polyphenols: the abscissa is the concentration of composite nanoparticles, and the ordinate is the cell survival rate; (A) SiO ₂ -EGCG-M ⁿ⁺ ; (B) SiO ₂ -TA-M ⁿ⁺ .

detailed description

The technical solution of the present invention will be further described below with specific implementation examples, but the scope of the present invention cannot be limited by this.

Example 1

A method for preparing degradable silica nanoparticles internally doped with a polyphenol-metal complex network structure, comprising the steps of:

SiO ₂ -EGCG-Fe

a) Add 430 μL TEOS and 8.66 mg EGCG (8.66% doped mass ratio) into ethanol-water solution with a volume ratio of 60:1, stir for 10 min to mix well; add 0.5 mL ammonia water dropwise, React at 25°C for 0.5 h to obtain primary SiO ₂ containing polyphenol oligomers.

b) Then add 1.01mg FeCl _{3 ·} 6H ₂ O (the molar ratio is EGCG:Fe=5:1), and continue to react in a water bath at 25°C for 5.5 h, after the reaction is completed. The reaction solution was taken out and placed in a centrifuge tube, centrifuged at 10,000 rpm for 10 min, the supernatant was taken out, the precipitate was washed twice with absolute ethanol, and then washed twice with ultrapure water, and the precipitate was dispersed in 10 mL twice distilled water to obtain the mixed Degradable silica nanoparticles mixed with EGCG-Fe.

The SiO _{2 -TA-Fe nanoparticles can be obtained by replacing the EGCG polyphenol molecules with the corresponding molar ratio of TA according to the above steps, and the SiO 2 -GA} -Fe nanoparticles can be obtained by replacing the polyphenol molecules with the corresponding molar ratio of GA.

Example 2

Taking TA as doped polyphenol molecules and Fe ³⁺ as metal ions, the effect of polyphenol doping ratio on the morphology and monodispersity of composite particles was investigated.

More specifically: SiO ₂ -TA-Fe

a) Add 430 μL TEOS and 8.66 mg TA (doping mass ratio is 8.66%) to the ethanol-water solution with a volume ratio of 60:1, stir for 10 min to mix well; add 0.5 mL ammonia water dropwise, and React at 25°C for 0.5 h to obtain primary SiO ₂ containing polyphenol oligomers.

b) Then add 0.27 mg FeCl _{3 ·} 6H ₂ O (the molar ratio is TA:Fe=5:1), and continue to react in a water bath at 25°C for 5.5 h, after the reaction is completed. The reaction solution was taken out and placed in a centrifuge tube, centrifuged at 10,000 rpm for 10 min, the supernatant was taken out, the precipitate was washed twice with absolute ethanol, and then washed twice with ultrapure water, and the precipitate was dispersed in 10 mL double distilled water to obtain Degradable silica nanoparticles doped with TA-Fe.

According to the above steps, the doping mass ratio of TA can be adjusted to 4.33%, 12%, and 17.2%.

Example 3

The polyphenol molecules were fixed to ensure that the molar ratio of polyphenols to metal ions was 5:1, and the effects of different doped metal ions on the composite particles were investigated.

More specifically: SiO ₂ -TA-Mn

a) Add 430 μL TEOS and 12 mg TA (12% doping ratio) into ethanol-water solution with a volume ratio of 60:1, stir for 10 min to mix well; add 0.5 mL of ammonia water dropwise, at 25 The reaction was carried out at ℃ for 0.5 h to obtain primary SiO ₂ containing polyphenol oligomers.

b) Then add 0.28 mg MnCl _{2 ·} 4H ₂ O (the molar ratio is TA:Mn=5:1), and continue to react in a water bath at 25°C for 5.5 h, after the reaction is completed. The reaction solution was taken out and placed in a centrifuge tube, centrifuged at 10,000 rpm for 10 min, the supernatant was taken out, the precipitate was washed twice with absolute ethanol, and then washed twice with ultrapure water, and the precipitate was dispersed in 10 mL double distilled water to obtain Degradable silica nanoparticles doped with TA-Mn.

According to the above steps, Mn ²⁺ can be replaced by Fe ³⁺ , Gd ³⁺ , Zn ²⁺ , Cd ²⁺ etc. in the corresponding molar ratio to obtain SiO ₂ -TA-Fe, SiO ₂ -TA-Gd, SiO ₂ - TA-Zn, SiO ₂ -TA-Cd and other composite particles.

More specifically: SiO ₂ -EGCG-Mn

a) Add 430 μL TEOS and 12 mg EGCG (12% doping ratio) into ethanol-water solution with a volume ratio of 60:1, stir for 10 min to mix well; add 0.5 mL of ammonia water dropwise, at 25 The reaction was carried out at ℃ for 0.5 h to obtain primary SiO ₂ containing polyphenol oligomers.

b) Then add 1.03 mg MnCl _{2 ·} 4H ₂ O (the molar ratio is EGCG:Mn=5:1), and continue to react in a water bath at 25°C for 5.5 h, after the reaction is completed. The reaction solution was taken out and placed in a centrifuge tube, centrifuged at 10,000 rpm for 10 min, the supernatant was taken out, the precipitate was washed twice with absolute ethanol, and then washed twice with ultrapure water, and the precipitate was dispersed in 10 mL double distilled water to obtain Degradable silica nanoparticles doped with EGCG-Mn.

According to the above steps, Mn ²⁺ can be replaced by Fe ³⁺ , Gd ³⁺ , Zn ²⁺ , Cd ²⁺ etc. in the corresponding molar ratio to obtain SiO ₂ -EGCG-Fe, SiO ₂ -EGCG-Gd, SiO ₂ - EGCG -Zn, SiO ₂ - EGCG-Cd and other composite particles

Example 4

The SiO ₂ -EGCG-Fe nanoparticles prepared in Example 1 were placed under the condition of pH=5.0+10 mM GSH, and their degradation in an in vitro simulated environment was investigated. When the degradation time was 1 day, 3 days, 5 days, and 7 days, the entire degradation system was centrifuged, and the precipitate was taken for TEM characterization. The supernatant was nitrated with 2% HNO ₃ and analyzed by ICP-AES.

Performance testing:

1. Drop the nanoparticle aqueous solution prepared in Example 1 on the copper grid, and perform TEM characterization after drying. The results are shown in Figure 1. It can be seen from A in Figure 1 that the SiO ₂ -GA-Fe particles are monodisperse and solid Porous and spherical, with an average particle size of about 85±5 nm; from Figure 1B, it can be seen that the SiO ₂ -EGCG-Fe particles are spherical in structure, uniform in size, with an average particle size of about 100±10 nm. Both of the above two particle structures are solid porous spherical, and there are obviously more pores inside; it can be seen from C in Figure 1 that the SiO ₂ -TA-Fe nanoparticles are obviously hollow and eccentric structures, and the pore distribution is larger than that of the former two. This is mainly due to the large molecular weight of TA and the large polyphenol metal structure built.

2. The nanoparticle aqueous solution prepared in Example 3 was dropped on the copper grid, and then subjected to TEM characterization after drying. The results are shown in FIG. 2 . It can be seen from Fig. 2 that the SiO ₂ -TA-M ⁿ⁺ particles are all monodisperse hollow eccentric porous spheres with an average particle size of about 100±10 nm. Figure 2 shows that when the doping ratio of polyphenols is fixed and the molar ratio of polyphenols to metal ions is also fixed, the morphology and size of the composite particles are not much different, which also shows that doping with different metal ions will not affect the composite particles. morphology and monodispersity.

3. The nanoparticle aqueous solution obtained in Example 2 was dropped on the copper grid, and then subjected to TEM characterization after drying. The results are shown in FIG. 3 . It can be seen from Figure 3 that the proportion of internal doped polyphenols has an effect on the morphology of composite particles; when the proportion of TA internal doping is 4.33%, some of the particles show a hollow eccentric structure, and a small part is solid porous structure; when the proportion increases to 8.66%, the particle morphology is hollow eccentric porous spherical structure; continue to increase the proportion of internal doped polyphenols, it will be found that the hollow structure of the particles is getting bigger and bigger, and the dispersion of the particles is reduced. The above results indicate that the morphology of composite particles is related to the concentration of polyphenols added.

4. The SiO ₂ -EGCG-Fe precipitate after in vitro simulated degradation in Example 4 was redispersed and dropped on the copper grid, and after drying, the TEM characterization results were shown in A in FIG. 4 . From Figure 4A, it can be seen that after the first day of degradation, the skeleton structure of the particles is still very clear, and only a few particles are slightly blurred on the surface; when the degradation time is 3 days, a small amount of particles cannot maintain the complete particle size, as shown in the TEM photo A large number of particles with a particle size of less than 50 nm appeared; at 5 days and 7 days, it was obvious that a large number of fragments had been produced, and the particles had been completely degraded, indicating that the particles could be well degraded in 10 mM GSH weakly acidic buffer solution. The stimulus response causes the internal skeleton to collapse, disintegrating into pieces. From Figure 4B, it can be found that with the increase of degradation time, the amount of SiO ₂ composite particles becomes less and less, which can also explain that the particles have been degraded with the increase of time. The acidified supernatant in embodiment 4 is carried out ICP-AES elemental analysis, the data of C in Fig. 4 shows that along with the increase of degradation time, the content of Si element and metal element also increases in the degradation solution, this further illustrates that in 10 Under the degradation condition of mM GSH weakly acidic buffer solution, the composite particles can be degraded.

5. The nanoparticles (SiO ₂ -TA-Fe, SiO ₂ -TA-Mn, SiO ₂ -TA-Gd) prepared in Example 3 were subjected to simulated degradation in vitro, and the supernatant was collected for nitrification, and carried out by ICP-AES. Elemental analysis of serum. It can be seen from Figure 5 that as the degradation time increases, the content of silicon and metal elements released in the supernatant increases, indicating that the composite particles are effectively degraded under the dual stimulation of acidity and glutathione.

6. Use HeLa cells as target cells to evaluate the biocompatibility of composite nanoparticles doped with polyphenol-metal complexes: Dilute the digested monodispersed HeLa cell suspension with culture medium, and dilute it with 100 μL/well The density was seeded in a 96-well plate, and the number of cells in each well was controlled to be about 10 ⁵ . The 96-well plate was cultured in an incubator with 5% _CO2 at 37 °C for 24 h, and then the culture medium was removed. In Figure 6, A added polyphenol molecules as EGCG, and the particle concentration was 100 μg/mL SiO ₂ -EGCG-Fe, SiO ₂ -EGCG-Mn, SiO ₂ -EGCG-Gd, SiO ₂ -EGCG-Zn, SiO ₂ - EGCG-Cd composite nanoparticle cell culture fluid. B in Figure 6 is SiO ₂ -TA-Fe, SiO ₂ -TA-Mn, SiO ₂ -TA-Gd, SiO ₂ -TA-Zn, SiO ₂ -TA-Cd composite nano Granule cell culture medium. Set up 4 replicate wells for each group, after continuing to culture for 6 h, remove the culture medium, wash twice with PBS buffer (pH=7.4), add 200 μL of culture medium and continue to culture for 18 h, then add 10 μL of concentration 5 mg/mL of MTT, continue to incubate for 4 h, carefully remove the culture medium, add 150 μL DMSO, incubate at 37 ^o C for 25 min, shake evenly, measure the absorbance at 490 nm on a microplate reader, and calculate the cell survival rate. Figure 6 shows that the cell survival rate of the composite nanoparticles is above 80%, indicating that the composite nanoparticles synthesized by this method have good biological compatibility and are suitable as drug carriers.

The above descriptions are only preferred embodiments of the present invention, and all equivalent changes and modifications made according to the scope of the patent application of the present invention shall fall within the scope of the present invention.

Claims (10)

1. A method for preparing degradable silicon dioxide nanoparticles with internal doping polyphenol-metal mesh, which is characterized in that: polyphenol molecules and silicon sources are first mixed and reacted for a certain period of time in an alkaline solution to obtain internal Synthesis step (1) of primary _SiO2 particles doped with polyphenol oligomers; adding metal ions to the above reaction solution, continuing the reaction for a certain period of time, and centrifuging the reactants to obtain internally doped polyphenol-metal mesh Synthetic steps of silica nanoparticles (2). 2. the preparation method of the silicon dioxide nanoparticle of inner doping polyphenol-metal mesh according to claim 1, is characterized in that: comprise the steps: (1) Add the silicon source TEOS and polyphenol into the ethanol-water solution, stir for 10 min to make it evenly mixed; add ammonia water drop by drop, and react for a certain period of time at 25 °C to obtain the primary polyphenol oligomer internally doped _SiO2 particles; (2) Add metal ions to the above mixed solution, continue to react in a water bath at 25°C for a period of time, centrifuge, wash the precipitate with absolute ethanol and deionized water, and finally obtain a bismuth doped with polyphenol-metal mesh. Silicon oxide nanoparticles. 3. according to claim 2, the preparation method of the silicon dioxide nanoparticles doped with polyphenol-metal mesh, is characterized in that: polyphenol is epigallocatechin gallic acid, tannic acid, gallic acid any of the. 4. The method for preparing silica nanoparticles internally doped with polyphenol-metal mesh according to claim 2, characterized in that: in step (1), the volume ratio of ethanol to water in the ethanol-water solution The ratio is 60:1, the reaction time is 0.5 h, and the reaction temperature is 25°C. 5. the preparation method of the silicon dioxide nanoparticle of inner doping polyphenol-metal network according to claim 2, is characterized in that: the mol ratio of metal ion and polyphenol in the control step (2) is 1: 4～1:10. 6. the preparation method of the silicon dioxide nanoparticle of inner doping polyphenol-metal network according to claim 2, is characterized in that: described metal ion is iron ion, manganese ion, gadolinium ion, europium ion , one or more of copper ions, zinc ions, and cadmium ions. 7. The preparation method of silica nanoparticles internally doped with polyphenol-metal mesh according to claim 2, characterized in that: the reaction time in the control step (2) is 5.5 h, and the reaction temperature is 25°C . 8. A silica nanoparticle of internally doped polyphenol-metal mesh obtained by the preparation method according to any one of claims 1-7, characterized in that: said internally doped polyphenol-metal The particle size of the silica nanoparticles of the network is 80-100nm. 9. according to claim 8, the silicon dioxide nanoparticle of internal doping polyphenol-metal network, is characterized in that: polyphenol is in the silicon dioxide nanoparticle of internal doping polyphenol-metal network Doping mass ratio should be less than 20%. 10. according to claim 8 or 9 described internal doping polyphenol-metallic mesh silica nanoparticles, it is characterized in that: the silicon dioxide nanoparticle of internal doping polyphenol-metal mesh has biological degradable properties, As a drug release carrier, the degradation conditions are pH ≤ 6, the concentration of glutathione is 10 mM, and the degradation time is 3-7 days.