CN109876008B - Medicine for treating tumor and preparation method and application thereof - Google Patents
Medicine for treating tumor and preparation method and application thereof Download PDFInfo
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- CN109876008B CN109876008B CN201910188542.9A CN201910188542A CN109876008B CN 109876008 B CN109876008 B CN 109876008B CN 201910188542 A CN201910188542 A CN 201910188542A CN 109876008 B CN109876008 B CN 109876008B
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Abstract
The invention relates to a medicament, and aims to solve the problems in targeted delivery and controllable release of hydrogen, and aims to provide an application of a metal boride in tumor treatment and a medicament for tumor treatment, wherein the medicament comprises a nano metal boride and a surface modification protective agent. The novel two-dimensional nanosheet material prepared by the invention has the following advantages: 1) the MBNs two-dimensional nano material obtained by the invention has good biological safety; 2) the MBNs two-dimensional nano material obtained by the invention has better acid responsiveness; 3) can be used in combination with chemoradiotherapy for treating gastric cancer. 4) Normal cells and tissues are not affected; 5) the hydrogen released by the MBNs @ PVP in the acidic environment of the stomach has the effects of attenuation and synergy on radiotherapy and chemotherapy.
Description
Technical Field
The invention relates to a medicament, in particular to a medicament for treating tumors and a preparation method and application thereof.
Background
Radiotherapy and chemotherapy are the main methods for clinically treating cancers, particularly middle and late-stage cancers, and are effective systemic treatment means. However, the traditional chemoradiotherapy medicine and administration mode have the defects that the chemoradiotherapy medicine has no specific recognition, is easy to damage normal cells and tissues, even causes systemic poisoning, has low medicine intake efficiency of tumor cells, is easy to cause drug resistance of the tumor cells by repeated administration, and the like.
Gas therapy, an emerging tumor therapy technology, mainly utilizes therapeutic gases (hydrogen H)2Nitrogen monoxide NO, carbon monoxide CO, hydrogen sulfide H2S, etc.) to replace or assist the traditional radiotherapy and chemotherapy and reduce the toxic and side effect of the radiotherapy and chemotherapy drugs. The hydrogen is colorless, tasteless and nontoxic, and hydrogen molecules are effective antioxidant substances and can selectively neutralize strong toxic active oxygen with strong oxidizability, such as hydroxyl radical and nitrite anion, but have no obvious effect on active oxygen with weak oxidizability. Research shows that the hydrogen-rich water intake has obvious protection effect on ischemia reperfusion injury of heart, brain, kidney, small intestine and other organs, and has obvious treatment effect on aging, diabetes, Parkinson's disease and other chronic oxidative stress diseases. The hydrogen can promote the apoptosis of colon cancer cells, has synergistic effect when used in combination with chemotherapeutic drug 5-fluorouracil, and can also relieve the toxicity of kidney without affecting the anti-tumor effect. The hydrogen can relieve the adverse reaction of the liver cancer patient in radiotherapy, remarkably improve the life quality of the tumor patient and not influence the radiotherapy effect.
At present, the administration modes of hydrogen mainly comprise hydrogen absorption, hydrogen drinking, physiological saline for hydrogen injection and the like, and the methods are difficult to reach a deep focus area or have low controllable release efficiency of the gas, so that the targeted delivery and the controllable release of the hydrogen are the main challenges of the current hydrogen treatment.
Disclosure of Invention
Aiming at the problems in the prior art, based on the current severe cancer situation and the future development trend of nano biomedicine, the invention provides a good prospect of utilizing hydrogen as a novel nontoxic and harmless medical gas, and the invention provides a method for preparing a metal boride nanosheet capable of releasing hydrogen with acid responsiveness by utilizing a liquid phase ultrasonic stripping method as a hydrogen release medicament, wherein the metal boride nanosheet is composed of a metal boride with a two-dimensional nanosheet structure and a surface-modified protective agent, and the hydrogen is released in response to an acid environment. Meanwhile, the invention combines the nano-drug with proper pharmaceutical excipients to design an oral dosage form for combined treatment with chemoradiotherapy drugs, thereby realizing the attenuation and synergism of hydrogen on the chemoradiotherapy drugs.
The invention aims to provide an application of a metal boride in treating tumors, wherein the tumors are digestive tract tumors, particularly in situ gastric cancer and intestinal cancer.
A medicament for the treatment of tumours, said medicament comprising a nano metal boride.
Preferably, the metal boride is a two-dimensional nanosheet structure, the thickness of the two-dimensional nanosheet is generally 1-2nm, the diameter of the particle is generally about 200nm, and the safe dose is 2.5 g/kg.
Preferably, the metal boride is MgB2、MnB2、FeB2、CaB6、SrB6、BaB6、TiB2、ZrB2、EuB6、GdB6AgB and homologs thereof.
Furthermore, the medicament also comprises a surface-modified protective agent, the nano medicament can responsively release hydrogen in an acidic environment, the protective agent is a compound capable of complexing with a metal boride, and the compound comprises, but is not limited to, ethylene diamine tetraacetic acid and salts thereof, polyvinylpyrrolidone, polyethylene glycol, hyaluronic acid and derivatives thereof, and the mass ratio of the metal boride to the compound is (1:2) to (1: 10).
In addition, the invention also provides an oral preparation prepared by the nano-drug and combined treatment of tumor by combined radiotherapy and chemotherapy, thereby realizing the attenuation and synergism of hydrogen on radiotherapy and chemotherapy and solving the technical problems of easy diffusion, low loading capacity and difficult control of the existing hydrogen treatment.
The oral preparation is prepared by compressing metal boride and biocompatible adjuvants such as PVP, agarose, etc. at a ratio of (10:1) - (30:1) into tablet, and combining the tablet with chemoradiotherapy medicine such as chemotherapy medicine Dox, doxorubicin or mitomycin, preferably Dox.
The invention also provides a preparation method of the medicine for treating tumors, which comprises the following steps:
(1) dispersing a metal boride powder raw material and a protective agent in water according to the mass ratio of (1:2) - (1:10), and then adding a chemical etching agent (10:1) - (100:1) into the water;
(2) then the mixed solution is subjected to liquid phase stripping by an ultrasonic crusher, and mechanical crushing is carried out for 20-120 min by 100-150W;
(3) centrifuging the crushed solution at 700-1500 rpm to remove unreacted large particles, centrifuging the supernatant at 10000-13000 rpm, washing with deionized water for 2 times and absolute ethyl alcohol for 2 times after the centrifugation is finished, and drying the product in vacuum to obtain the final product.
The chemical etching agent comprises two types of etching agents: the boron etching agent and the metal etching agent respectively play a role in etching the boron layer and the metal layer of the metal boride, and are added according to the volume ratio of (10:1) - (100: 1). Boron etchants are a class of weak oxidants including, but not limited to, hydrogen peroxide, oxygen, ozone. Metal etchants are a class of weak acids including, but not limited to, acetic acid, carbonic acid, hypochlorous acid, citric acid, malic acid.
The novel two-dimensional nanosheet material prepared by the invention has the following advantages:
1) the MBNs two-dimensional nano material obtained by the invention has good biological safety;
2) the MBNs two-dimensional nano material obtained by the invention has better acid responsiveness, can release hydrogen in an acid environment, basically does not release hydrogen in neutral and alkaline environments, and can control the hydrogen release time after being wrapped by a protective agent and pharmaceutical excipients, so that the MBNs two-dimensional nano material is matched with the gastrointestinal metabolism time, and the drug effect is maximized;
3) compared with hydrogen absorption, hydrogen drinking and hydrogen injection, the MBNs @ PVP two-dimensional nanosheet drug prepared by the invention is used for hydrogen treatment, can realize targeted stomach and controllable hydrogen release by oral administration, and can be used for treating gastric cancer together with chemoradiotherapy drugs.
4) The MBNs @ PVP nano-drug prepared by the invention releases hydrogen in a gastric acid environment, is harmful only to tumor cells, hardly influences normal cells and tissues, can treat tumors with combined effect of chemotherapy at an animal level, and prolongs survival time.
5) The MBNs @ PVP nano-drug is orally taken into the stomach to play a combined treatment effect with radiotherapy and chemotherapy, so that the effect of attenuation and synergism of hydrogen released by the MBNs @ PVP in the acidic environment of the stomach on radiotherapy and chemotherapy is reflected, and the attenuation and synergism of the hydrogen on the radiotherapy and chemotherapy is also proved on a cell level.
Drawings
FIG. 1 shows TEM, SEM images of acid-responsive hydrogen-releasing two-dimensional magnesium boride nano-drugs of the present invention;
FIG. 2 shows XRD, Mapping images of acid-responsive hydrogen-releasing two-dimensional magnesium boride nano-drugs of the present invention;
FIG. 3 shows the ultraviolet absorption spectrum and the infrared spectrum of the two-dimensional magnesium boride nano-drug with acid-response hydrogen release of the invention.
FIG. 4 shows the responsive release of H of the acid-responsive hydrogen-releasing two-dimensional magnesium boride nano-drug of the invention to PBS of different pH values2A behavior;
FIG. 5 shows the behavior of the acid-responsive hydrogen-releasing two-dimensional magnesium boride nano-drug of the present invention and its responsive release H2 in a simulated gastric acid environment after being coated with PVP;
FIG. 6 is a graph showing the results of the toxicity attenuation and efficacy test of hydrogen on chemoradiotherapy at the level of normal cells and tumor cells, respectively, in the study of the present invention;
FIG. 7 shows the variation of ATP production at different times for normal cells and tumor cells, respectively, studied in the present invention with hydrogen in combination with chemoradiotherapy;
FIG. 8 is a graph showing the effect of acid-responsive hydrogen-releasing two-dimensional magnesium boride nano-drug in combination with chemoradiotherapy on animal level treatment in accordance with the present invention;
FIG. 9 shows the evaluation of the attenuation effect of the acid-responsive hydrogen-releasing magnesium boride nano-drug in combination with radiotherapy and chemotherapy on myocardial tissues in mice according to the present invention;
FIG. 10 shows the tissue slice images of the major organs (liver, spleen, lung, kidney) of mice treated with the acid-responsive hydrogen-releasing two-dimensional magnesium boride nano-drug in combination with chemoradiotherapy.
Detailed Description
The present invention will be described in more detail and fully with reference to the following examples, which are not intended to limit the scope of the invention.
Example 1
Preparation of the material: firstly, H is put in2O(120ml)、MgB2(90mg) and PEG (4000) (450mg) were mixed well in a vessel, placed on an ice bath, and H was added sequentially2O2(9ml) and HAc (180ul), followed by glass breaking with a sonicator, set to the sonicator parameters: the amplitude transformer is 6, (intermittent time) 2.2 s/(working time) 6.6s, and total ultrasonic treatment is carried out for 60 min. After completion of ultrasonication, the resulting precipitate was immediately dispensed into 50ml centrifuge tubes and centrifuged (12500r/s, 25min), and the resulting precipitate was washed twice with water (12500r/s, 25min) and twice with absolute ethanol (12500r/s, 10 min). And (4) drying the final precipitate for 5h in vacuum to obtain the novel two-dimensional magnesium boride nanosheets MBNs.
FIG. 1 is a Transmission Electron Microscope (TEM) and Scanning Electron Microscope (SEM) image of the material, which shows that the prepared MBNs material is a two-dimensional nano-sheet stacked net structure, FIG. 2 is an XRD and Mapping image of the novel two-dimensional nano-material, and the prepared two-dimensional nano-material containing MgB can be obtained from the image A2、MgB4Two crystal phases, and the Mapping image of fig. B shows that the elements contained in the material are mainly Mg, B, O. FIG. 3 shows the UV absorption spectra of MBNs and their near infrared spectra from which it can be seen that O should come from a coating of PEG which forms borate (B-O-PEG) and HO-B on the surface of MBN, e.g. at 2470 and 1165cm-1The newly appearing peak reflects the result.
Fig. 4 shows that the probe of MB + Pt used in the novel two-position nanosheets produced in example 1 detects the release of hydrogen in PBS with different pH values in vitro (the produced hydrogen discolors the MB + Pt probe), which indicates that the release of hydrogen in PBS with pH values of 7.4, 6.8, 5.0 and 1.2 respectively is not released in PBS with pH value of 7.4, and as the pH value is reduced, the release time of hydrogen is shorter and shorter, and the release time of hydrogen in simulated gastric acid environment of MBNs is only about 2 h.
Example 2
The toxicity and ATP yield influence of the in vitro hydrogen and chemotherapy drug DOX on cancer cells and normal cells are detected, the cells are respectively selected to be gastric cancer cells (BGC-823) and four normal cells (H9C2, LO2, mMSC, HEK-293cells), and each cell is divided into an air group, an air + DOX (1 mu g/mL, 0.5 mu g/mL, 0.25 mu g/mL, 0.125 mu g/mL), a hydrogen group, and a hydrogen + DOX (1 mu g/mL, 0.5 mu g/mL, 0.25 mu g/mL, 0.125 mu g/mL) group to detect the attenuation and synergy of the hydrogen on the chemotherapy drug, wherein the hydrogen group, the hydrogen + DOX (1 mu g/mL, 0.5 mu g/mL, 0.25 mu g/mL, 0.125 mu g/mL) group are cultured by using a special hydrogen incubator containing 60%. FIG. 6 shows the effect of hydrogen on the attenuation and the synergism of chemotherapeutic drugs at the cellular level, and the results show that the DOX concentration (1. mu.g/mL, 0.5. mu.g/mL, 0.25. mu.g/mL, 0.125. mu.g/mL) on cancer cells increases with the DOX concentration, and the same damage law is applied to normal cells, but the damage to cancer cells is strengthened after hydrogen is applied, and the damage to normal cells is weakened, thus proving that hydrogen has the effect of attenuation and synergism on chemotherapeutic drugs.
Meanwhile, the change of ATP yield of the cells at different culture times (3h, 6h, 12h and 24h) after administration is detected. FIG. 7 is a graph showing the result of detection H2The ATP levels of treated normal cells will fluctuate slightly around normal values, but in most cases are usually slightly above normal levels. DNA damage by DOX also impairs mitochondrial function, so DOX and H2The respiration of cancer cells can be synergistically restricted (panel a), resulting in synergistically enhanced cytotoxicity to cancer cells. On the other hand, H2The activation of normal cell energy effectively overcomes the cell energy loss caused by the damage of DOX to mitochondria, so that the energy of mMSC (mesenchymal stem cell) is kept near the normal level (figure B), and reflects H2The mitochondria protection and damage resistance. H2Protection against mitochondrial damage to hepatocytes and splenocytes was similar to that of mscs cells over a period of time (panel DE). However, it appears that there is little long-term mitochondrial damage to heart, liver and spleen by DOX under current conditionsRecovery (graph CDE) can yield H2The protective effect of (D) is highly correlated with cell type and depends on the cell pair for different concentrations of DOX and H2The sensitivity of (2).
Example 3
In this example, it is verified that the oral dosage form of the novel nano-drug of the present invention can achieve the toxicity reduction and the synergy effect in combination with intravenous Dox injection in an in situ gastric cancer model.
Firstly, the specific preparation steps of the oral preparation are as follows: the MBNs prepared in example 1 and PVP (55000) are ground and mixed uniformly according to the mass ratio of 1:19, and tabletting is carried out (the pressure is 8 × 10)4N or so) to obtain the final oral material MBNs @ PVP. And the hydrogen release condition of the MBNs @ PVP in the simulated gastric acid environment is detected by using the method of the MB + Pt probe in example 1, and fig. five shows that the hydrogen release condition of the MBNs @ PVP in the simulated gastric acid environment (PBS, pH 1.2) is detected by using the method, and the result shows that the MBNs coated by the PVP prolong the hydrogen release time (completely release hydrogen for about 8 hours), so that the purpose of slowly releasing hydrogen is achieved.
Because the mice can not directly swallow the oral preparation, the mouse feed and the nano-drug are prepared into the oral feed by adopting the tabletting method. Specifically, the method comprises the following steps: grinding mouse feed into powder, uniformly mixing the powder with MBNs @ PVP according to the proportion of 5mg/4995mg, pressing the mixture into a feed shape by using a tablet press, and feeding mice, wherein each mouse is fed with 5g of the special feed every day; the specific administration mode of the chemotherapeutic drug is as follows: the chemotherapy drug substance Doxorubicin (DOX) is administered by intravenous injection at a dose of 3mg/kg, once every three days, and continuously injected for a treatment course (three times). The results of treatment of gastric cancer were judged based on the survival and histological evaluation of the mice in each group.
FIG. 8 shows the evaluation of the treatment effect of PBS, MBNs @ PVP, DOX, MBNs @ PVP and DOX groups at the animal level, wherein the survival time of each group is shorter, the survival time of the MBNs @ PVP and DOX group is the longest, and the evaluation of the blood cells of the group B and the group C can find that the mouse can automatically regulate the WBC and RBC to the normal level at the later period of the DOX treatment (after 29 or 36 days), but the combined action of the MBN @ PVP and the DOX can obviously accelerate the normal level of white blood cells and red blood cells, which directly proves that the hydrogen released by the MBNs @ PVP in the gastric acid response has the attenuation and the increasing effects on the chemotherapeutic drugs, and the H & E staining and the Masson staining of the heart slices among the groups of FIG. 9 can obtain that the hydrogen released by the MBNs @ PVP in the gastric acid response can reduce the myocardial fibrosis caused by the chemotherapeutic drugs to the heart. Fig. 10 shows a comparison of the histological morphology of the individual tissues, demonstrating that the material itself does not cause significant toxic side effects in mice on normal tissues.
Claims (10)
1. The application of the metal boride in preparing the medicine for treating tumor is characterized in that the metal boride is MgB2The metal boride is in a two-dimensional nanosheet structure, and the tumor is in-situ gastric cancer.
2. The medicine for treating tumor is characterized by comprising nano metal boride and surface-modified protective agent PEG, wherein the metal boride is MgB2The tumor is in-situ gastric cancer, and the metal boride has a two-dimensional nanosheet structure.
3. The drug for use in the treatment of tumors according to claim 2, wherein the mass ratio of the metal boride to the protective agent is (1:2) - (1: 10).
4. The agent according to claim 2, wherein the agent further comprises PVP and/or agarose.
5. The medicament for the treatment of tumors as claimed in claim 4, wherein said medicament is in oral dosage form.
6. The agent for the treatment of tumors as claimed in claim 5, wherein said agent is used in combination with a chemoradiotherapy agent.
7. The drug for treatment of tumors as claimed in claim 6, wherein said chemoradiotherapy drug is chemotherapeutic drug Dox.
8. A process for the preparation of a medicament according to claim 2 for the treatment of tumours, said process comprising the steps of:
(1) dispersing metal boride powder and a protective agent in water according to a mass ratio of (1:2) - (1:10), and then adding a chemical etching agent in the water in a ratio of (10:1) - (100: 1); the chemical etching agent comprises a boron etching agent and a metal etching agent, wherein the boron etching agent is a weak oxidant, and the metal etching agent is a weak acid;
(2) then the mixed solution is subjected to liquid phase stripping by an ultrasonic crusher;
(3) centrifuging the crushed solution to remove unreacted large particles, centrifuging the supernatant at 10000-13000 rpm, washing the particles after centrifugation, and drying the product in vacuum to obtain a final product;
the metal boride is MgB2；
The tumor is in-situ gastric cancer.
9. The method for preparing a medicament for treating tumors according to claim 8, wherein the weak oxidants are hydrogen peroxide, oxygen and ozone.
10. The method for preparing a medicament for treating tumors according to claim 8, wherein the weak acid is acetic acid, carbonic acid, hypochlorous acid, citric acid, malic acid.
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| CN113041353A (en) * | 2021-02-26 | 2021-06-29 | 深圳大学 | Metal organic framework nano-drug, preparation method thereof and application thereof in antitumor therapy |
| CN114053441A (en) * | 2021-10-09 | 2022-02-18 | 中国辐射防护研究院 | Radioactive embolism microball containing nano silicon and its preparing method, composition and use |
| CN114053599B (en) * | 2021-10-09 | 2023-10-24 | 中国辐射防护研究院 | Medicine box for tumor immunotherapy |
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| CN103099780B (en) * | 2012-12-11 | 2015-11-25 | 中国科学院深圳先进技术研究院 | Prepare the method for hydrogen microvesicle aqueous solution, its product and application |
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