CN117085127B - Antitumor active material with simulated lactate activity and antitumor drug - Google Patents
Antitumor active material with simulated lactate activity and antitumor drug Download PDFInfo
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- CN117085127B CN117085127B CN202311066550.9A CN202311066550A CN117085127B CN 117085127 B CN117085127 B CN 117085127B CN 202311066550 A CN202311066550 A CN 202311066550A CN 117085127 B CN117085127 B CN 117085127B
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- 230000000259 anti-tumor effect Effects 0.000 title claims description 19
- 239000011149 active material Substances 0.000 title claims description 14
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 title claims description 13
- 239000002246 antineoplastic agent Substances 0.000 title claims description 11
- 229940041181 antineoplastic drug Drugs 0.000 title claims description 11
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims abstract description 52
- 239000002086 nanomaterial Substances 0.000 claims abstract description 33
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- 239000012921 cobalt-based metal-organic framework Substances 0.000 claims description 8
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0047—Sonopheresis, i.e. ultrasonically-enhanced transdermal delivery, electroporation of a pharmacologically active agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Biophysics (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of catalytic materials, and in particular relates to Co 4 Application of N/C NE nano material adopts Co 4 The N/C NE nano material is used as a catalyst and is used for catalyzing the alpha-hydroxy acid compound with the structure shown in the formula 1 to be converted into the alpha-keto acid shown in the formula 2; said Co 4 The N/C NE nano material comprises a nitrogen-doped carbon substrate and Co compounded on the nitrogen-doped carbon substrate 4 N nano-active particles. The invention also relates to the use of Co 4 The principle of catalyzing lactic acid by the N/C NE nano material is used for catalyzing tumor cell lactic acid, so that the application of inhibiting tumor is realized.
Description
Technical Field
The invention belongs to the field of nano materials, in particular to Co 4 Brand new application field of N/C NE nano materials.
Background
The continual quest for biological environmental regulation platforms and instability of enzyme properties has driven the search for suitable alternatives to long-term biological activity. In 2007, fe 3 O 4 NanoparticlesThe son has triggered an interest in designing nanomaterials with artificial enzyme mimetic capabilities. Artificial mimic enzymes have the potential to enhance the therapeutic effect of cancer, and nanomaterials with enzymatic mimicking activity on small metabolic molecules have been developed, including glucose, glutathione, NADH and H 2 O 2 Etc. Thus, nanoezymes are considered to be advantageous candidates for enhancing tumor therapy. However, the preparation of nanoezymes for the catalytic conversion of physiological molecules, in particular key metabolic molecules, remains a great challenge.
The flavin enzyme family is widely present in prokaryotes and eukaryotes and is capable of catalyzing the oxidation of alpha-hydroxy acid substrates to keto acids via the homologous Flavin Mononucleotide (FMN) dependent pathway. Lactate Oxidase (LOX) as one of its members, can specifically oxidize lactate, which is produced by tumor glycolysis and is highly correlated with Tumor Microenvironment (TME) acidosis, immunosuppression, and malignant progression, resulting in neutralization of tumor acidity and reprogramming of immunosuppressive TME. Rational design of nanomaterials with LOX mimetic activity would replace current enzymatic methods, but there are significant challenges in mimicking LOX structure and catalytic activity.
Disclosure of Invention
Aiming at the problem that the prior alpha-hydroxy acid compound is difficult to be mildly converted into alpha-ketoacidolysis, the first aim of the invention is to provide a method for preparing alpha-ketoacidolysis by using Co 4 The method for catalyzing alpha-hydroxy acid to be converted into corresponding keto acid by using the N/C NE nano material aims at realizing effective conversion of the alpha-hydroxy acid based on mild conditions.
A second object of the present invention is to provide a pharmaceutical application that utilizes alpha-hydroxy acid compounds to gently catalyze the conversion of alpha-hydroxy acids in cells.
A third object of the present invention is to provide a composition comprising Co 4 An antitumor drug of N/C NE nanometer material and its active component.
The existing alpha-hydroxy acid compounds have harsh catalytic conversion conditions, unsatisfactory conversion yield and selectivity under mild conditions, and are difficult to meet the requirements of special biological applications. In view of this problem, the present invention provides the following solutions:
co (cobalt) 4 N/C NE nanomaterialsUses Co 4 The N/C NE nano material is used as a catalyst and is used for catalyzing the alpha-hydroxy acid compound with the structure shown in the formula 1 to be converted into the alpha-keto acid shown in the formula 2;
said R is 1 、R 2 H, C alone 1 ～C 6 The substituted alkyl is alkyl with at least one substituent of hydroxyl, ether, nitro, halogen, phenyl, trifluoromethyl and nitro;
said Co 4 The N/C NE nano material comprises a nitrogen-doped carbon substrate and Co compounded on the nitrogen-doped carbon substrate 4 N nano-active particles.
The invention innovatively discovers that the Co 4 The special phase and structure of the N/C NE nano material are controlled in a combined way, so that the excellent catalytic activity and catalytic selectivity of the alpha-hydroxy acid compound can be endowed in a synergistic way, and the effective conversion of the alpha-hydroxy acid compound can be realized under mild conditions.
Co of the catalyst in the invention 4 The N phase and structure are key to synergistically improving the catalytic ability of the alpha-hydroxy acid compounds.
In the invention, the Co 4 The N/C NE nano material is prepared by pyrolysis, ammoniation and baking of Co-MOF material.
In the invention, the Co-MOF material is prepared by a coordination reaction of a cobalt source and a ligand;
preferably, the cobalt source is Co 2+ Is a water-soluble salt of (2);
preferably, the ligand is water-soluble Co (CN) 6 3- A salt;
preferably, the molar ratio of cobalt source to ligand can be adjusted as desired, for example, the molar ratio of the two is 1:0.1-1; further preferably 1:0.4 to 0.6.
Preferably, the complexation stage is added with a surfactant, preferably PVP;
preferably, the weight ratio of the cobalt source to the surfactant is 1:10-20.
Preferably, the temperature of the coordination reaction is 5-45 ℃;
preferably, the time of the complexation reaction is from 6 to 48 hours, preferably from 20 to 30 hours.
In the invention, the pyrolysis process is carried out under a protective atmosphere;
preferably, the pyrolysis temperature is 300 to 800 ℃, preferably 400 to 500 ℃;
preferably, the pyrolysis time is 0.5 to 4 hours, preferably 1 to 2 hours.
In the invention, the atmosphere in the ammoniation roasting stage is an ammonia-containing atmosphere;
in the present invention, the volume content and flow rate of the ammonia gas in the ammonia-containing gas atmosphere may be adjusted as required, for example, may be 1% by volume or more, for example, may be pure ammonia gas;
in the calcination stage, the flow rate of the ammonia-containing gas atmosphere may be adjusted as required, and may be, for example, 100ml/min or more, and further may be 100 to 300ml/min.
Preferably, the temperature of ammoniation roasting is 300-800 ℃, and more preferably 400-500 ℃;
preferably, the ammoniation calcination time is 0.5 to 5H, preferably 1 to 3H.
Preferably, the Co 4 The particle size of the N/C NE nano material is 80-320nm.
In the invention, R is 1 Is H; said R is 2 Is C 1 ～C 3 Preferably methyl; further, lactic acid is also possible.
Preferably, the reaction stage is carried out with the aid of ultrasound. The invention has found that in the Co 4 Under the catalysis of the N/CNE nano material, the ultrasonic assistance is further matched, so that the synergy is further realized, and the catalytic activity and selectivity of the alpha-hydroxy acid can be further improved.
In the present invention, the ultrasonic power is not particularly required, and may be, for example, 0.1 to 100W;
preferably, the temperature of the reaction stage is 15 to 45 ℃, preferably 20 to 40 ℃; the catalyst can be used for the efficient conversion of alpha-hydroxy acid under mild conditions, particularly under the temperature tolerated by a human body, so that the catalyst can be used for chemical synthesis and can also be used for realizing biological simulated enzyme catalysis application by utilizing the principle.
In the present invention, the reaction time may be controlled based on the monitoring means, for example, 0.1 to 30 hours.
The invention also provides a Co 4 Application of N/C NE nano material in pharmacy, co is synthesized by using the synthesis application method of the invention 4 The N/C NE nano material is used for preparing medicines for catalyzing lactic acid in cells to be converted into pyruvic acid.
In the present invention, the Co is beneficial to 4 The N/C NE nano material has excellent catalytic effect of alpha-hydroxy acid under mild condition, and can be used for mild catalysis of alpha-hydroxy acid such as lactic acid in cells by utilizing the thought, so that corresponding pharmaceutical effect can be shown. In the invention, the Co can be based on 4 The N/C NE nano material simulates the activity of the lactic acid enzyme and is used for catalyzing the conversion of lactic acid in cells, so that the corresponding pharmacodynamic effect brought by lactic acid conversion is obtained.
Preferably, it is used for preparing antitumor drugs catalyzing lactic acid oxidation. The method of the invention is universal to the type of tumor, which can act on different types of benign and/or malignant tumors.
Preferably, the compound is used for preparing antitumor drugs which catalyze lactic acid oxidation and have ultrasonic sensitization.
The invention also provides an anti-tumor active material with simulated lactate activity, which has a core-shell structure, wherein the core is the Co 4 The shell is a hydrophilic polymer.
The active pharmaceutical particles have excellent stability and cytophagy capacity, are favorable for exerting the catalytic conversion effect of intracellular lactic acid, and further are favorable for improving the anti-tumor effect.
Preferably, the hydrophilic polymer is PEG.
Preferably, the core-shell weight ratio is 1:0.1 to 10; further preferably 1:1 to 4.
The invention also provides an anti-tumor drug, which comprises the Co 4 N/CNE nanomaterial;
preferably, the antitumor drug comprises the antitumor active material.
Preferably, the Co 4 The N/C NE nano material is not less than a pharmaceutically effective amount.
Preferably, the composition further comprises pharmaceutically acceptable auxiliary materials.
Preferably, it is any pharmaceutically acceptable dosage form.
Preferably, a pharmaceutically acceptable injectable formulation; further preferred are pharmaceutically acceptable topical injectable formulations.
The beneficial effects are that:
(1) The invention develops Co 4 The N/C NE material is a brand new synthetic application for mild catalysis of alpha-hydroxy acid conversion, and further finds that with ultrasound assistance, it helps to further improve the alpha-hydroxy acid conversion effect.
(2) The invention can be based on Co 4 The N/C NE material can be applied to antitumor drugs based on lactic acid conversion by mild catalysis of the mechanism of alpha-hydroxy acid conversion. In addition, it is further combined with ultrasound to achieve sensitization.
Furthermore, the material provided by the invention has excellent tumor cell inhibition selectivity, excellent biosafety and suitability.
Drawings
FIG. 1 is a hollow nitrogen-doped carbon nanoparticle Co prepared in example 1 4 A transmission electron microscope image (TEM image), an X-ray diffraction image (XRD image), a high resolution transmission electron microscope image (HRTEM image) and a ray energy spectrum distribution diagram of the N/C NE nano material; wherein (a) is a TEM image; (b) is an XRD pattern; (c) is an HRTEM image; (d) is an EDS profile.
FIG. 2 shows the results of the lactic acid conversion measurements of examples 3 and 4;
(a) The results of the detection of the different catalytic materials in example 3; (b) the test result of example 4;
FIG. 3 is a graph showing the effect of lactic acid conversion in cells of example 5;
FIG. 4 is an anti-tumor effect study of example 6;
(a) Co of different cell types 4 Incubating for 24 hours under N/CNE treatment to obtain a cell viability map; (b) cell viability maps incubated for 24h after the different treatments; (1) Control, (2) US, (3) Co 4 N/C NEs,(4)Co 4 N/C NEs+US。
FIG. 5 is a study of tumor treatment effect in vivo at the animal level;
(a) Is a weight chart of mice under different conditions and at different time; (b) is a graph of survival rate of mice at different times under different conditions. (c) tumor ablation patterns for differently treated animals;
FIG. 6 is a serological test chart of example 8;
detailed description of the preferred embodiments
The invention will be further illustrated with reference to specific examples. These examples should be construed as merely illustrative of the present invention and not limiting the scope of the present invention. Various changes or modifications to the invention based on the principles of the invention will also fall within the scope of the appended claims after reading the description of the invention.
Co according to the invention 4 The preparation method of the N/C NE nano material comprises the following steps:
co (CH) 3 COO) 2 ·4H 2 O solution (A solution) and K 3 [Co(CN) 6 ]Mixing the solution (B solution), stirring, and then centrifugally washing and drying to obtain Co-MOF; then the Co-MOF is pyrolyzed in argon, and then ammoniated and roasted in ammonia gas, thus obtaining the catalyst;
the Co (CH) 3 COO) 2 ·4H 2 The preferred concentration of the O solution is 1-3mg/mL, and the preferred volume is 100-200mL;
the K is 3 [Co(CN) 6 ]The solution preferably has a concentration of 0.5-2.5mg/mL, preferably a volume of 100-200mL;
the volume ratio of the mixed solution A to the mixed solution B is preferably 0.5-2;
the pyrolysis and ammoniation roasting temperatures are respectively 300-800 ℃, and the temperature rising speed is preferably 2.5-10 ℃ for min -1 The preferred time is 0.5-4 hours, respectively.
In the following cases, the room temperature means 20 to 40 ℃.
1. Implementation and comparative material preparation
Example 1
Co 4 Preparation of N/CNE:
co (CH) 3 COO) 2 ·4H 2 O (280.5 mg) was dissolved in 150mL of water and stirred for 10min to give solution A. Will K 3 [Co(CN) 6 ](199.5 mg) and PVP (4.5 g) were dissolved in 150mL of water, and stirred for 30min to obtain solution B. Slowly dropwise adding A into B, reacting at room temperature for 24h, centrifuging the product Co-MOF, washing with water for 3 times, and drying at 60 ℃. Co-MOF at 5℃for min under nitrogen –1 Is reacted for 1h at 450 ℃ to obtain an oxidized roasting product (Co 3 O 4 ). Then, at 1℃for a minute –1 Raising the temperature to 500 ℃, introducing ammonia gas, and reacting for 2 hours to obtain Co 4 N/CNE。
Example 2
Co prepared in example 1 4 N/C NE and NH 2 -PEG-NH 2 Aqueous solution (Co) 4 N/CNE and NH 2 -PEG-NH 2 (molecular weight: 5000) in a weight ratio of 1: 1) Mixing, ultrasonic treating for 30min, and centrifugal washing to obtain Co 4 N/C NE@PEG-NH 2 。
Comparative example 1
Co 2 N/C、Co 3 N/C was prepared according to Cobalt-Based Nitride-Core Oxide-Shell Oxygen Reduction Electrocatalysts, J.Am.chem.Soc.2019,141, 19241-19245;
2. lactic acid conversion study
Example 3
To an aqueous solution of lactic acid (concentration of lactic acid: 5 mM) was added a catalyst (50. Mu.g mL) -1 ) Catalytic reaction was carried out at normal pressure and normal temperature for 10min, and lactic acid decomposition efficiency was measured with a lactic acid kit.
The catalysts are respectively as follows:
a: co of example 1 4 N/C NE；
B: oxidative calcination of the product(Co 3 O 4 /C)；
C：Co 2 N/C；
D：Co 3 N/C。
The results of the test are shown in FIG. 2a:
example 4
The difference compared to group A of example 3 is only that the reaction phase is carried out with the aid of ultrasound, where the power of the ultrasound is 1.75W/cm 2 。
The results of the test are shown in FIG. 2b:
as can be seen from fig. 2, the catalyst of the present invention has unexpected effects at room temperature under the catalysis of lactic acid, and can further improve the conversion rate of lactic acid with the assistance of ultrasound.
3. Intracellular lactic acid conversion assay
Example 5
4T1 cells and Co 4 N/C NEs (50. Mu.g mL-1) were incubated and cultured in DMEM cell culture medium for 4h. Subsequently, the cells were treated separately with (1) control, (2) US (1.75W cm) -2 ,3min)，(3)Co 4 N/C NEs，(4)Co 4 N/C NEs+US(1.75W cm -2 3 min). After a further 12h incubation, the lactic acid content of the cell suspension was detected with a lactic acid detection kit. The results are shown in FIG. 3.
Example 6
Hollow Co 4 N/C NE@PEG-NH 2 Detection of toxicity at the cellular level of nanomaterials (prepared in example 1):
experiments were divided into two subgroups based on different variable parameters:
(1) Different cells are incubated for the same time under different cell environments, and cell activity is detected
The inventors have varied concentrations of Co 4 N/C NE@PEG-NH 2 Nanomaterial (0,25,50,75,100,125 μg mL) -1 ) And cancer cells (mouse breast cancer cells 4T1; human non-small cell lung cancer cell a 549) and normal cells (mouse embryonic fibroblast 3T3; human umbilical vein endothelial cell HUEVC) (10 per well) 4 Individual cells, cell purchase Yu Xiangya medical college) for 24h.
As can be seen from FIG. 4 (a)Co of different concentrations 4 N/C NE@PEG-NH 2 After 24h incubation of the nanomaterial and different normal cells, the cell activity is not obviously changed, and after 24h incubation with cancer cells, the cell survival rate is reduced to a certain extent, which indicates Co 4 N/C NE@PEG-NH 2 The nano material has no obvious cytotoxicity to normal cells, has good biocompatibility and has certain killing capacity to cancer cells.
(2) Mouse breast cancer cell 4T1 and mouse embryo fibroblast 3T3 in Co 4 Incubation for the same time under different treatment groups of N/CNE, and detection of cell activity
The inventors have identified different treatment groups at the same concentration as mouse breast cancer cells 4T1 (10 per well) 4 Individual cells, cell purchase Yu Xiangya medical college) for 24h. The different treatment groups are respectively: (1) Control, (2) US, (3) Co 4 N/C NEs,(4)Co 4 N/C NEs+US。
From fig. 4 (b), it can be seen that after the nanomaterial and mouse breast cancer cells and mouse embryo fibroblasts of different treatment groups are incubated for 24 hours, the cell activity is obviously changed, and after the nanomaterial and mouse breast cancer cells are incubated for 24 hours, the cell survival rate is reduced to a certain extent, which indicates that the killing capacity of chemical kinetics on cancer cells is very strong.
Example 7
Hollow Co 4 N/C NE@PEG-NH 2 Detection of antitumor ability of nanomaterial (prepared in example 1) at animal level:
taking 4T1 cells as model cells, taking BALB/C female mice as model mice, constructing a mouse subcutaneous tumor model, and adopting Co provided by the invention 4 N/C NE@PEG-NH 2 As an antitumor material. The experiment set up 4 experimental groups (5 mice per group): (1) Saline, (2) US, (3) Co 4 N/C NEs and (4) Co 4 N/C NEs+US, the material was injected into mice (10 mg kg) -1 ) The monitoring was continued for 14 days. (body weight of mice was recorded every two days during this period)
From FIG. 5 (a), it is evident that there is no significant change in the body weight of the mice, indicating Co 4 N/C NE@PEG-NH 2 No obvious toxicity; as can be seen from FIG. 5 (b), saline, US, and Co 4 The survival rate of the N/C NEs group mice is not obviously improved, but Co 4 After 50 days, the survival rate of the mice in the N/CNE+US group is still high, which indicates Co 4 The N/CNE+US group has excellent anti-tumor effect. Figure 5c shows that the tumor can be ablated effectively using the method of the invention.
Example 8
Physiological saline and Co were taken on days 1, 3 and 7 4 N/C NEs (intravenous injection, 15mg kg) -1 ) Blood of mice after injection. Blood was routinely measured on an automated hematology analyzer (HF-3800, hlife, adult, china). The blood was then centrifuged to obtain serum, and the serum was tested on a blood chemistry analyzer (Pointcare V2, MNCHIP, tianjin, china) to obtain blood chemistry index, the results of which are shown in FIG. 6.
Claims (11)
1. An antitumor active material with simulated lactate activity is characterized by having a core-shell structure, wherein the core is Co 4 The shell is a hydrophilic polymer;
said Co 4 The N/C NE nano material is prepared by pyrolysis, ammoniation and baking of Co-MOF material; the Co-MOF material is prepared by a coordination reaction of a cobalt source and a ligand; and the ligand is water-soluble Co (CN) 6 3- A salt;
a surfactant is added in the coordination reaction stage, and the surfactant is PVP; the temperature of the coordination reaction is 5-45 ℃; the time of the coordination reaction is 6-48 h;
the pyrolysis temperature is 300-800 ℃; the pyrolysis time is 0.5-4 h;
the atmosphere in the ammonification roasting stage is an ammonia-containing gas atmosphere; the ammoniation roasting temperature is 300-800 ℃; the ammoniation roasting time is 0.5-5 h;
the tumor is breast cancer or non-small cell lung cancer.
2. The antitumor active material with a simulated lactate activity as claimed in claim 1, wherein said cobalt source is Co 2+ Is a water-soluble salt of (a).
3. The antitumor active material with simulated lactate activity as claimed in claim 1, wherein the pyrolysis process is carried out under a protective atmosphere.
4. The antitumor active material having a simulated lactate activity according to claim 1, wherein the volume content of ammonia gas in the ammonia-containing atmosphere is greater than or equal to 1v%.
5. The antitumor active material with simulated lactate activity as claimed in claim 1, wherein the ammoniation roasting temperature is 400-500 ℃.
6. The antitumor active material having a simulated lactate activity as claimed in claim 1, wherein said Co 4 The particle size of the N/C NE nano material is 80-320nm.
7. The antitumor active material with simulated lactate activity according to any one of claims 1-6, wherein the hydrophilic polymer is PEG.
8. The antitumor active material with simulated lactate activity according to any one of claims 1-6, wherein the core-shell weight ratio is 1:0.1 to 10.
9. Use of an antitumor active material with simulated lactate activity according to any one of claims 1-8 for the preparation of an antitumor drug for catalyzing the conversion of intracellular lactic acid into pyruvic acid.
10. The use according to claim 9 for the preparation of an antitumor drug which catalyzes the oxidation of lactic acid and has an ultrasound sensitization effect.
11. An antitumor drug comprising the antitumor active material according to any one of claims 1 to 8.
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