CN114652819A - Degradable multifunctional nano material for targeting tumor microenvironment and preparation method thereof - Google Patents
Degradable multifunctional nano material for targeting tumor microenvironment and preparation method thereof Download PDFInfo
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- CN114652819A CN114652819A CN202210281691.1A CN202210281691A CN114652819A CN 114652819 A CN114652819 A CN 114652819A CN 202210281691 A CN202210281691 A CN 202210281691A CN 114652819 A CN114652819 A CN 114652819A
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a degradable multifunctional nano material for a targeted tumor microenvironment and a preparation method thereof, and the preparation method comprises the steps of (1) synthesis of a super-small hydrophobic FePt nano particle, (2) synthesis of organic mesoporous silicon wrapping the super-small FePt nano particle, (3) loading of tamoxifen drug, and (4) wrapping of PDGFB polypeptide and a phospholipid membrane of GOx. The nano material prepared by the invention can target a tumor part by PDGF and respond to GSH (glutathione) with high expression of a tumor microenvironment to release a medicamentIncluding ultra-small FePt nanoparticles, GOx, and tamoxifen, where GOx consumes glucose, starves cells, and can produce H2O2And reducing pH within the cancer cell; FePt has strong Fenton catalytic performance and can efficiently catalyze H in a weakly acidic tumor microenvironment2O2Generates cytotoxic hydroxyl free radicals, and finally realizes the effect of chemo-dynamic and chemotherapy synergistic treatment of the tumor.
Description
Technical Field
The invention belongs to the technical field of biomedical materials, and particularly relates to a degradable multifunctional nano material for a targeted tumor microenvironment and a preparation method thereof.
Background
In recent years, cancer treatment strategies based on Reactive Oxygen Species (ROS) have become one of the hot spots of current research, especially the application of chemo-dynamic therapy (CDT) in the field of tumor therapy. The mechanism of action of CDT is the catalytic Fenton/Fenton-like reaction of hydrogen peroxide (H) by the CDT agent2O2) The high level of hydroxyl radicals, which are converted to cytotoxic hydroxyl radicals (. OH), can cause irreversible oxidative damage to cellular biomolecules and accelerate cancer cell death. In addition, the mechanism of CDT is independent of external excitation or local O2The goal of inhibiting the growth of cancer cells is achieved at this level, and efforts are therefore being made to develop strategies for the efficient treatment of CDT with various CDT agents. It is well known that an acidic environment is a necessary condition for the fenton/fenton-like reaction to occur. However, the tumor microenvironment is weakly acidic, which can trigger the slow occurrence of fenton/fenton-like reaction, but cannot improve the reaction efficiency, resulting in low ROS generation in tumor tissues and insignificant tumor treatment effect. In addition, since most CDT agents are not selective for catalytic activity, they do irreversible damage to normal tissue cells. Therefore, it is urgent and challenging to develop new strategies to achieve efficient and specific catalytic reaction of CDT in tumors.
Disclosure of Invention
The invention aims to provide a degradable multifunctional nano material targeting a tumor microenvironment and a preparation method thereof, wherein the surface of the nano material is covalently modified with a human platelet derived factor (PDGF) targeting molecule and a mesoporous organic silicon structure, and can release ultra-small FePt particles, Tamoxifen (TAM) and glucose oxidase (glucose oxidase)GOx). Wherein GOx can produce gluconic acid and H by consuming glucose from the tumor microenvironment2O2(ii) a FePt has strong Fenton catalytic performance and can catalyze H2O2Generates cytotoxic hydroxyl free radicals, and finally realizes the effect of the chemodynamics of the tumor and the tamoxifen-mediated chemotherapy synergistic treatment.
In order to achieve the aim, the invention provides a preparation method of a degradable multifunctional nano material for targeting a tumor microenvironment, which comprises the following steps:
(1) synthesis of FePt nanoparticles
Dissolving hexadecanediol and platinum acetylacetonate in dibenzyl ether, heating in an inert gas atmosphere, adding a mixed stabilizer and dinonylcarbonyl iron, heating and refluxing, cooling to room temperature to obtain FePt nanoparticles, and transferring the FePt nanoparticles to a water phase;
(2) synthesis of FePt @ MONs
Adding triethanolamine and hexadecyl trimethyl p-toluenesulfonamide into the FePt nanoparticle aqueous solution prepared in the step (1), dropwise adding the FePt nanoparticle aqueous solution after oil bath, dropwise adding a mixed solution of tetraethoxysilane and bis- [ gamma- (triethoxy silicon) propyl ] -tetrasulfide, heating and recovering to obtain FePt @ MONs particles;
(3) loading of tamoxifen
Mixing an aqueous solution of 9-12 mg/mL FePt @ MONs particles with a methanol solution of tamoxifen with the same concentration, incubating for 24h at 30-40 ℃ and 170rpm in a shaking table, centrifuging for 8-12 min at 7500-8500 rpm, drying and collecting powder to obtain FePt-TAM @ MONs;
(4) preparation of phospholipid membranes
Mixing a PDGF-PEG chloroform solution with a hydrogenated soybean phospholipid chloroform solution, a cholesterol chloroform solution and a distearoyl phosphatidyl ethanolamine chloroform solution, and performing rotary evaporation for 15-25 min at 35-40 ℃ in a container to obtain a phospholipid membrane;
(5) synthesis of nanomaterials
And (3) adding a glucose oxidase aqueous solution into the container obtained in the step (4), performing ultrasonic treatment after rotational hydration, dropwise adding the FePt-TAM @ MONs aqueous solution obtained in the step (3), continuing ultrasonic treatment and performing centrifugal dispersion to obtain the multifunctional nano material, and dispersing the multifunctional nano material in water to obtain the multifunctional nano material named FePt-TAM @ MONs-GOx-PDGF-Liposome.
Further, the mass ratio of the hexadecanediol, the platinum acetylacetonate and the dinonyl carbonyl iron in the step (1) is 2:1: 3-4, and the concentration of the hexadecanediol dissolved in the dibenzyl ether is 0.01-0.02 g/mL; the mixed stabilizer is prepared by mixing oleylamine and oleic acid according to the volume ratio of 1: 1.
Further, the volume ratio of the mixed stabilizer to the dibenzyl ether is 0.5-1.0: 20.
Further, the heating temperature in the inert gas atmosphere in the step (1) is 90-120 ℃, the heating temperature of reflux is 290-300 ℃, and the time of reflux is 2-4 h.
Further, the mass ratio of the triethanolamine to the hexadecyl trimethyl-p-toluenesulfonyl ammonium in the step (2) is 0.3-0.4: 2-3, and the concentration of the triethanolamine dissolved in the FePt nano particle solution is 2.5 multiplied by 10-3～3.0×10-3g/mL。
Further, the size of the FePt nano particles is 2-3 nm, wherein the Fe/Pt ratio is 1: 6.
further, the volume ratio of the FePt nanoparticle solution, the ethyl orthosilicate and the bis- [ gamma- (triethoxy silicon) propyl ] -tetrasulfide dropwise added in the step (2) is 1:1: 0.8-0.9.
Furthermore, the oil bath and heating temperature in the step (2) are both 70-90 ℃, and the oil bath and heating time is 25-35 min and 15-17 h respectively.
Further, the specific process after heating in the step (2) is as follows: and (3) cooling the mixed solution, magnetically recovering, centrifuging for 3-5 times, dispersing in a methanol solution of sodium chloride, heating, refluxing, centrifuging for 3-5 times, and dispersing in water.
Further, the concentration of the PDGF-PEG chloroform solution and the hydrogenated soybean phospholipid chloroform solution, the concentration of the cholesterol chloroform solution and the concentration of the distearoyl phosphatidyl ethanolamine chloroform solution in the step (3) are respectively 9-12 mg/mL, and the volume ratio of the PDGF-PEG chloroform solution to the hydrogenated soybean phospholipid chloroform solution, the concentration of the cholesterol chloroform solution and the concentration of the distearoyl phosphatidyl ethanolamine chloroform solution is 50:500: 0.02-0.04: 0.1.
Further, the concentration of the glucose oxidase aqueous solution in the step (5) is 0.05-0.15 mg/mL, the time of spin hydration is 25-35 min, the rotation speed of centrifugation is 8000rpm, and the time of centrifugation is 8-12 min.
Further, the multifunctional nano material is prepared by adopting a preparation method of the degradable multifunctional nano material targeting the tumor microenvironment.
Further, the core amino acid sequence of platelet-derived factor (PDGF) in the present invention is ASSVGNVADSTEPTKR, and may be a derivative of PDGF having a core amino acid sequence.
The PDGF-PEG of the invention is PDGF through carboxyl terminal and polyethylene glycol (PEG-NH)2) The amino terminal of (a) is linked by an amide covalent bond.
GOx, in the present invention, is glucose oxidase, derived from Aspergillus niger, a dimer consisting of 2 identical subunits, each having a molecular weight of about 80 kDa. Each subunit contains one Flavin Adenine Dinucleotide (FAD) and one iron ion. Contains about 16% neutral sugars and 2% amino sugars, with 3 cysteine residues and 8 potential sites for N-linked glycosylation.
The chemotherapy medicament Tamoxifen (TAM) is mainly used for treating tumors through the synergy with chemokinetics, and can also be other chemotherapy medicaments.
In summary, the invention has the following advantages:
1. the FePt-TAM @ MONs-GOx-PDGF-FITC-Liposome material prepared by the invention can be applied to tumor treatment, and has the main advantages that the PDGF can be used for targeting a tumor part, and drugs including ultra-small FePt nanoparticles, GOx and tamoxifen can be released in response to GSH with high tumor microenvironment expression; in which GOx consumes glucose, starves cells, and produces H2O2(ii) a FePt has strong Fenton catalytic performance and can catalyze H2O2Generates cytotoxic hydroxyl free radicals, and finally realizes the effect of chemodynamics and chemotherapy synergistic treatment of the tumor.
2. The preparation method of the FePt nano-particles is simple and convenient, the preparation method is suitable for mass production, the prepared multifunctional nano-particles can realize the responsive degradation of a tumor microenvironment, and the FePt nano-particles have good biological safety.
Drawings
FIG. 1 is a TEM image of ultra-small FePt nanoparticles prepared in example 1;
FIG. 2 is a TEM image of FePt @ MONs prepared in example 2;
FIG. 3 is a TEM image of FePt-TAM @ MONs-GOx-PDGF-Liposome prepared in example 3;
FIG. 4 is a chart of the infrared absorption spectrum of FePt-TAM @ MONs-GOx-PDGF-Liposome prepared in example 3;
FIG. 5 shows the uptake of two nanoparticles FePt-TAM @ MONs-FITC-Liposome, FePt-TAM @ MONs-GOx-PDGF-FITC-Liposome by tumor cells;
FIG. 6 is a TEM image of FePt-TAM @ MONs-GOx-PDGF-Liposome incubated for 12h under different pH conditions;
FIG. 7 is a graph of the relative cell viability of 4T1 cancer cells treated with different concentrations of FePt-TAM @ MSN-GOx-PDGF-Liposome for 24 h.
Detailed Description
The principles and features of this invention are described below in conjunction with embodiments, which are included to explain the invention and not to limit the scope of the invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Example 1
The embodiment provides a method for synthesizing ultra-small FePt nano particles and transferring the ultra-small FePt nano particles into a water phase, which comprises the following steps:
(1) 0.2g of hexadecanediol, 0.1g of platinum acetylacetonate and benzyl ether (20mL) were uniformly mixed in a three-necked flask.
(2) Heated to 100 ℃ under nitrogen atmosphere and added 170. mu.L oleic acid and 170. mu.L oleylamine.
(3) After 30min, 500. mu.L of oleic acid and 500. mu.L of oleylamine were added, followed by addition of 0.3653g of dinonylcarbonyl iron, the temperature was set at 291.2 ℃ and heating reflux was carried out for 3 h.
(4) After the reaction is finished, cooling the reaction system to room temperature in the nitrogen atmosphere, and collecting the ultra-small FePt nanoparticles.
(5) Taking 10mL of FePt N-hexane solution, adding 3mL of N, N dimethyl amide (DMF) solution of 0.1mM of tetrafluoroboronose, layering the liquid surface, and removing the supernatant, wherein the upper layer is clear N-hexane.
(6) Adding 0.01g of dimercaptobutyric acid (DMSA) into the lower layer solution, incubating for 50min at 170rpm in a shaking table, washing once each for 10min with deionized water and ethanol at 14000rpm, dispersing the nanoparticles with N, N-dimethylformamide, repeating the washing process for three times, and finally dispersing in water to obtain FePt aqueous solution, wherein the concentration of FePt is 500 mug/mL.
The ultra-small FePt nanoparticles prepared in step (4) of example 1 were morphologically characterized by Transmission Electron Microscopy (TEM), as shown in fig. 1. TEM results show that the nano-material synthesized under the conditions has uniform morphology, is ultra-small alloy nano-particles and has good dispersibility.
Example 2
The embodiment provides a synthesis method of organic mesoporous silicon (FePt @ MONs) wrapping ultra-small FePt nanoparticles, which comprises the following steps:
(1) 0.034g triethanolamine and 0.24g cetyltrimethyl-p-toluenesulfonyl ammonium (CTAT) were added to 11.5mL FePt aqueous solution, the mixture was subjected to oil bath at 80 ℃ and stirred for 30min, 1mL FePt solution was added dropwise, and then 1mL mixed solution of tetraethyl orthosilicate (TEOS) and 800. mu.L of bis- [ gamma- (triethoxysilyl) propyl ] -tetrasulfide (BTES) was added dropwise, and the mixture was heated at 80 ℃ for 16 hours.
(2) Cooling, magnetically recovering, dispersing in mixed solution of ethanol and water, centrifuging at 8000rpm for 3 times, dispersing in 1% NaCl methanol solution, and heating and refluxing at 60 deg.C for 16 hr.
(3) And dispersing in a mixed solution of ethanol and water, centrifuging at 8000rpm for 3 times, and dispersing in water to obtain FePt @ MONs.
The FePt @ MONs prepared in example 2 was topographically characterized by Transmission Electron Microscopy (TEM) as shown in fig. 2. TEM results show that the nano material synthesized under the conditions has uniform morphology and obvious pores, and the ultra-small FePt nano is wrapped.
Example 3
The embodiment provides a preparation method of a FePt-TAM @ MONs-GOx-PDGF-Liposome material, which comprises the following steps:
(1) loading of tamoxifen
10mg/mL FePt @ MONs in water was mixed with 10mg/mL tamoxifen in methanol and incubated at 37 ℃ and 170rpm for 24h in a shaker. And centrifuging at 8000rpm for 10min, drying and collecting powder to obtain FePt-TAM @ MONs.
(2) PDGF-PEG Synthesis
5mg of PDGF, 50mg of EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), 50mg of NHS (N-hydroxysuccinimide) were added to 5mL of dimethyl sulfoxide, magnetically stirred for 2h, and 10mg of PEG-NH were added2Stirring was continued for 6 h. Dialyzing in deionized water for 3 times after 6h, and collecting the product, namely PDGF-PEG.
(3) Preparation of FePt-TAM @ MONs-GOx-PDGF-Liposome
Spin-drying PDGF-PEG solution containing 500mg PEG at 37 deg.C, adding chloroform, and dispersing again;
adding 500mL of chloroform solution of Hydrogenated Soybean Phospholipid (HSPC) (10mg/mL), 30 μ L of chloroform solution of cholesterol (10mg/mL) and 100 μ L of chloroform solution of Distearoylphosphatidylethanolamine (DSPE) (10mg/mL) to mix;
the mixed solution is steamed for 20min in a single-mouth bottle at 37 ℃ and 100rpm to form a phospholipid membrane;
adding 1mL of GOx solution with the concentration of 100 mu g/mL into 10mL of water, uniformly mixing, adding into a film-forming single-mouth bottle, and rotationally hydrating for 30 min;
after 30min, the solution is subjected to ultrasonic treatment, 1mL of FePt-TAM @ MONs solution (wherein the concentration of Fe is 100 mu g/mL) is added dropwise, and the ultrasonic treatment is continued for 10 min. Centrifuging at 8000rpm for 10min, and dispersing in water to obtain FePt-TAM @ MONs-GOx-PDGF-Liposome.
The FePt-TAM @ MONs-GOx-PDGF-Liposome prepared in example 3 was topographically characterized by Transmission Electron Microscopy (TEM) as shown in FIG. 3. TEM results show that the prepared nano material has gaps which are compared with the structure shown in figure 2, the observable degree of the pore structure of the material is reduced, and the surface phospholipid layer is obviously coated. Structural characterization is carried out on FePt-TAM @ MONs-GOx-PDGF-Liposome prepared in example 3 by means of an infrared spectrometer, and as shown in figure 4, after the structure and the compound are modified, corresponding characteristic absorption peak changes are finally reflected in the absorption spectrogram of FePt-TAM @ MONs-GOx-PDGF-Liposome, and the successful preparation of FePt-TAM @ MONs-GOx-PDGF-Liposome is proved.
Test example 1
Evaluating the tumor targeting ability of FePt-TAM @ MONs-GOx-PDGF-Liposome, and specifically comprising the following steps:
(1) culture of tumor cells
Subjecting MCF-7 cells to a treatment at 1X 105The density of each plate was inoculated in a confocal dish, and cultured for 12 hours in DMEM medium containing 10% Fetal Bovine Serum (FBS) and 1% streptomycin double antibody.
(2) Monitoring of nanoparticle uptake by tumor cells
The prepared FePt-TAM @ MONs-FITC-Liposome, FePt-TAM @ MONs-GOx-PDGF-FITC-Liposome nano-particles loaded with fluorescein isothiocyanate are used for incubating cells at the concentration of FePt @ MONs40 mu g/mL, the cells are stained by a Heochest 33342 live cell nucleus staining reagent after 6h, laser confocal shooting is carried out after staining, and the situation that the cells take in the nano-particles without PDGF protein is monitored.
As shown in FIG. 5, FePt-TAM @ MONs-GOx-PDGF-FITC-Liposome nanoparticles incubated tumor cells showed higher FITC fluorescence signals than FePt-TAM @ MONs-FITC-Liposome incubated cancer cells, indicating that the PDGF-bound nanoparticles were tumor cell-targeted and increased in the number of nanoparticles taken up by the cells.
Test example 2
Evaluating the acidic responsiveness of FePt-TAM @ MONs-GOx-PDGF-Liposome, comprising the incubation of materials under different pH conditions, and specifically comprising the following steps:
FePt-TAM @ MONs-GOx-PDGF-Liposome is respectively dispersed in phosphate buffer solution with pH of 4.5, 5.5, 6.5 and 7.4, and incubated for 12h in a shaker at 37 ℃ and 170 rpm.
As shown in fig. 6, TEM results show that the structural collapse of the nanomaterial is accelerated with the decrease of pH, and the nanomaterial structure is proved to have the characteristic of low pH response collapse.
Test example 3
Evaluating the anti-tumor effect of FePt-TAM @ MONs-GOx-PDGF-Liposom, which comprises the following steps:
(1) culture of tumor cells
Are respectively provided with 104Density per well 4T1 cells were seeded in 96-well plates and cultured in 1640 medium for 12 h. After 12h the cells were incubated with different concentrations of material for 24 h.
(2) MTT (methyl thiazolyl tetrazolium) detection of proliferation inhibition effect of FePt-TAM @ MONs-GOx-PDGF-Liposome on tumor cells
Media was removed from 96-well plates and media was added to each well with MTT as 9: 1, continuously incubating in an incubator for 4h, removing liquid, adding 250 mu L of dimethyl sulfoxide solution into each hole, shaking up gently, and detecting at 490nm with a microplate reader.
As shown in FIG. 7, MTT results indicate that FePt-TAM @ MONs-GOx-PDGF-Liposome has a concentration-dependent growth inhibitory effect on 4T1 tumor cells.
While the present invention has been described in detail with reference to the specific embodiments thereof, it should not be construed as limited by the scope of the present patent. Various modifications and changes may be made by those skilled in the art without inventive step within the scope of the appended claims.
Claims (10)
1. A preparation method of a degradable multifunctional nano material targeting a tumor microenvironment is characterized by comprising the following steps:
(1) synthesis of FePt nanoparticles
Dissolving hexadecanediol and platinum acetylacetonate in dibenzyl ether, heating in an inert gas atmosphere, adding a mixed stabilizer and dinonylcarbonyl iron, heating and refluxing, cooling to room temperature to obtain FePt nanoparticles, and converting the FePt nanoparticles into a water phase to obtain a FePt nanoparticle aqueous solution;
(2) synthesis of FePt @ MONs
Adding triethanolamine and hexadecyl trimethyl p-toluenesulfonamide into the FePt nanoparticle aqueous solution prepared in the step (1), dropwise adding the FePt nanoparticle aqueous solution after oil bath, dropwise adding a mixed solution of tetraethoxysilane and bis- [ gamma- (triethoxy silicon) propyl ] -tetrasulfide, heating and recovering to obtain FePt @ MONs particles;
(3) loading of tamoxifen
Mixing an aqueous solution of FePt @ MONs particles of 9-12 mg/mL with a methanol solution of tamoxifen of the same concentration, incubating for 24 hours in a shaking table at 30-40 ℃ at 170rpm, centrifuging for 8-12 minutes at 7500-8500 rpm, drying and collecting powder to obtain FePt-TAM @ MONs;
(4) preparation of phospholipid membranes
Mixing PDGF-PEG chloroform solution with hydrogenated soybean phospholipid chloroform solution, cholesterol chloroform solution and distearoyl phosphatidyl ethanolamine chloroform solution, and performing rotary evaporation for 15-25 min at 35-40 ℃ in a container to obtain a phospholipid membrane;
(5) synthesis of nanomaterials
And (3) adding a glucose oxidase aqueous solution into the container obtained in the step (4), performing ultrasonic treatment after rotational hydration, dropwise adding the FePt-TAM @ MONs aqueous solution obtained in the step (3), performing continuous ultrasonic treatment, and performing centrifugal dispersion to obtain the multifunctional nano material.
2. The preparation method of the degradable multifunctional nanomaterial targeted to tumor microenvironment of claim 1, wherein the mass ratio of the hexadecanediol, the platinum acetylacetonate and the dinonylcarbonyl iron in the step (1) is 2:1: 3-4, and the concentration of the hexadecanediol dissolved in the dibenzyl ether is 0.01-0.02 g/mL; the mixed stabilizer is prepared by mixing oleylamine and oleic acid according to the volume ratio of 1: 1.
3. The preparation method of the degradable multifunctional nano material targeting the tumor microenvironment in the step (1), wherein the heating temperature in the inert gas atmosphere in the step (1) is 90-120 ℃, the heating temperature of the reflux is 290-300 ℃, and the time of the reflux is 2-4 h.
4. The preparation method of the degradable multifunctional nano material targeting the tumor microenvironment according to claim 1, wherein the mass ratio of the triethanolamine and the cetyltrimethyl-p-toluenesulfonate in the step (2) is 0.3-0.4: 2-3, and the concentration of the triethanolamine dissolved in the FePt nanoparticle solution is 2.5 x 10-3～3.0×10-3g/mL。
5. The preparation method of the degradable multifunctional nano material targeting the tumor microenvironment according to claim 1, wherein the volume ratio of the FePt nanoparticle solution, the tetraethoxysilane and the bis- [ gamma- (triethoxysilyl) propyl ] -tetrasulfide dropped in the step (2) is 1:1: 0.8-0.9.
6. The preparation method of the degradable multifunctional nanomaterial targeted to tumor microenvironment of claim 1, wherein the oil bath and heating temperature in the step (2) are both 70-90 ℃, and the oil bath and heating time are respectively 25-35 min and 15-17 h.
7. The method for preparing the degradable multifunctional nano material targeting the tumor microenvironment according to claim 1, wherein the specific process after the heating in the step (2) is as follows: and cooling the mixed solution, recovering the magnetic force, centrifuging for 3-5 times, dispersing in a methanol solution of sodium chloride, heating, refluxing, centrifuging for 3-5 times, and dispersing in water.
8. The preparation method of the degradable multifunctional nanomaterial targeted to tumor microenvironment in claim 1, wherein the concentrations of the PDGF-PEG chloroform solution, the hydrogenated soybean phospholipid chloroform solution, the cholesterol chloroform solution and the distearoyl phosphatidyl ethanolamine chloroform solution in the step (4) are 9-12 mg/mL, and the volume ratio of the PDGF-PEG chloroform solution to the hydrogenated soybean phospholipid chloroform solution, the cholesterol chloroform solution and the distearoyl phosphatidyl ethanolamine chloroform solution is 50:500: 0.02-0.04: 0.1.
9. The preparation method of the degradable multifunctional nano material targeting the tumor microenvironment in the step (5), wherein the concentration of the glucose oxidase aqueous solution in the step (5) is 0.05-0.15 mg/mL, the time of the rotational hydration is 25-35 min, the rotation speed of the centrifugation is 8000rpm, and the time of the centrifugation is 8-12 min.
10. The multifunctional nano material prepared by the preparation method of the multifunctional nano material with the degradable targeting tumor microenvironment according to any one of claims 1 to 9.
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