CN108785276B - Application of radiotherapy sensitization nano material - Google Patents

Application of radiotherapy sensitization nano material Download PDF

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CN108785276B
CN108785276B CN201811082334.2A CN201811082334A CN108785276B CN 108785276 B CN108785276 B CN 108785276B CN 201811082334 A CN201811082334 A CN 201811082334A CN 108785276 B CN108785276 B CN 108785276B
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CN108785276A (en
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郝永强
符静珂
贺超
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Ninth Peoples Hospital Shanghai Jiaotong University School of Medicine
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Abstract

The invention discloses an application of a radiotherapy sensitization nanometer material, wherein the radiotherapy sensitization nanometer material is a silicon oxide composite material loaded with sodium percarbonate and ferric oxide nanoparticles, and is marked as H-HMS-Fe, and the H-HMS-Fe can be used for radiotherapy sensitization. The H-HMS-Fe prepared by the invention realizes passive targeting on the tumor tissue by utilizing the EPR effect of the nano material, and then improves the oxygenation state of the tumor tissue by generating oxygen around the solid tumor tissue, thereby achieving the purpose of radiotherapy sensitization and having better application prospect.

Description

Application of radiotherapy sensitization nano material
Technical Field
The invention belongs to the field of medical materials, and particularly relates to an application of a radiotherapy sensitization nanometer material.
Background
Hypoxic microenvironments are important features of solid tumors. Under hypoxic conditions, tumor cells secrete a variety of angiogenic growth factors to promote the formation of abnormal blood vessels. Meanwhile, in order to find a better suitable soil, the invasion and metastasis capacities of tumor cells are further improved. In addition, hypoxic microenvironments further increase the malignancy of tumors, rendering tumor cells insensitive to chemotherapeutic drugs or radiation therapy. Hypoxic microenvironment is an important factor in the poor prognosis of tumors. Tumor growth, metastasis and resistance to drug and radiation therapy are greatly enhanced in this microenvironment.
Therefore, the improvement of tumor hypoxia microenvironment is expected to be a new method for improving the curative effect of solid tumors.
Disclosure of Invention
The invention aims to provide application of a radiotherapy sensitization nanometer material, which can achieve the purposes of accurately attacking tumor cells, inhibiting the activity of the tumor cells and improving the curative effect of solid tumors by selectively enriching oxygen and active free radicals released in the microenvironment of the tumor cells.
In order to achieve the purpose, the invention provides an application of a radiotherapy sensitization nano material, wherein the radiotherapy sensitization nano material is a silicon oxide composite material loaded with sodium percarbonate and iron oxide nano particles, and is marked as H-HMS-Fe, and the H-HMS-Fe can be used for radiotherapy sensitization.
Preferably, the H-HMS-Fe comprises a hierarchical HMS (Hollow mesoporous nano silicon spheres) having an inner mesoporous structure and an outer mesoporous structure, wherein the inner mesoporous structure is loaded with Na2CO3•H2O2And iron oxide nano particles are loaded in the outer layer mesoporous structure.
Preferably, the pore diameter of the inner mesoporous structure is 2-4 nm.
Preferably, the pore diameter of the outer mesoporous structure is 4-10 nm.
Preferably, the preparation method of H-HMS-Fe comprises the following steps:
step 1, preparing H @ HMS comprising:
step 1.1, adding Na2CO3Dissolving in deionized water, adding a stabilizer, stirring uniformly, adding HMS, and stirring to uniformly disperse the HMS;
step 1.2, adding aminotrimethylene methylene phosphonic acid (used for providing a weakly acidic environment) into the hydrogen peroxide aqueous solution, uniformly stirring, slowly adding into the solution with uniformly dispersed HMS obtained in the step 1.1, and stirring for 1.5-3h to ensure that hydrogen peroxide enters the mesopores as much as possible; standing for a period of time (e.g., 40min-60 min), centrifuging, washing with water, and drying to obtain Na-loaded2CO3•H2O2The HMS powder is marked as H @ HMS;
step 2, preparing H-HMS-Fe: dispersing the H @ HMS into n-hexane, wherein the concentration of the n-hexane solution of the H @ HMS is about 1mg/mL-5mg/mL, adding the iron oxide nanoparticles, magnetically stirring the mixed solution for 12H-24H, centrifuging, washing with n-hexane to obtain the silicon oxide composite material loaded with sodium percarbonate and iron oxide nanoparticles, and marking as H-HMS-Fe.
Preferably, the stabilizer is used for improving the stability of sodium percarbonate and consists of magnesium sulfate and sodium metasilicate, wherein the ratio of the magnesium sulfate: the mass ratio of the sodium metasilicate is 5:1-10: 1.
Preferably, in step 1.1, the concentration of sodium carbonate ranges from 1mg/mL to 5mg/mL, and the mass ratio of sodium carbonate to HMS is 2% -20%.
Preferably, in step 1.2, the molar ratio of hydrogen peroxide to sodium carbonate is 0.5:1 to 2: 1.
Preferably, in the step 2, the molar ratio of H @ HMS to the iron oxide nanoparticles is 10:1 to 20: 1.
The invention uses the organic mesoporous silicon oxide material as a carrier, and constructs the oxygen-releasing nano transmission material by using the action of oxygen generated by sodium percarbonate under the catalytic action (pH 7.4) of iron oxide nanoparticles through a method of loading sodium percarbonate and magnetic iron oxide nanoparticles in the carrier material and on the surface of the carrier material respectively.
According to the invention, the nano material for releasing oxygen is constructed, the passive targeting of the tumor tissue is realized by utilizing the EPR effect (namely the high permeability and retention effect of the solid tumor) of the nano material, and then the oxygenation state of the tumor tissue is improved by generating oxygen around the solid tumor tissue, the radiotherapy curative effect of the tumor tissue is improved, and the nano material has a good application prospect.
Drawings
FIG. 1 is a schematic diagram of the preparation process of the H-HMS-Fe composite material of the present invention.
FIG. 2 is a graph showing the in vitro oxygen release profile of the nanocomposite (H-HMS-Fe) provided by the present invention, wherein the PBS solution of H-HMS (pH 7.4) is used as a control group, and the PBS solution of H-HMS-Fe (pH 7.4) is used as an experimental group.
FIG. 3 is a graph showing the relationship between the survival rate of cloned cells and the radiation dose in the research experiment of the radiosensitization performance of the nanocomposite.
Detailed Description
The technical solution of the present invention is further described below with reference to the accompanying drawings and examples.
Example 1
The invention provides Na2CO3•H2O2@HMS-Fe3O4The preparation method of the composite material comprises the following steps:
1. preparing composite mesoporous silica nanoparticles (HMS):
2g of cetyltrimethylammonium chloride and 0.08g of triethanolamine were dissolved in 20mL of deionized water, heated and stirred to 95 ℃. Thereafter, 1g of ethyl orthosilicate was added dropwise to the above solution, and stirring was continued for 1 h. Then, a mixed solution of 1g of ethyl orthosilicate and 2g of bis- [3- (triethoxysilyl) propyl ] -tetrasulfide was added to the above solution, and stirring was continued for 4 hours. And then centrifuging, washing with water, washing with alcohol, and removing the surfactant in the mesopores by using an acidic ethanol solution to obtain the composite mesoporous silica nano-particle HMS.
The method firstly uses cetyl trimethyl ammonium chloride CTAC as a surfactant, forms micelles by using CTAC self-assembly, hydrolyzes tetraethoxysilane TEOS in an alkaline aqueous solution, and forms an inner-layer mesoporous structure (the aperture is 2-4 nm) by using the micelles as templates. Adding bis- [3- (triethoxysilyl) propyl ] -tetrasulfide as a pore-enlarging agent, continuously self-assembling the pore-enlarging agent to form micelles, and assembling the hydrolysate of the tetraethoxysilane by using the micelles as templates to form an outer layer mesoporous structure (the pore diameter is 4-10 nm).
2. Preparation of magnetic iron oxide nanoparticles (Fe)3O4 NPs）
2mmol of Fe (acac)310mmol1, 2-hexadecanediol, 6mmol oleic acid, 6mmol oleylamine, 20mL diphenyl ether were mixed well and stirred magnetically for 1h under nitrogen protection. The solution temperature was slowly raised to 200 ℃ and reacted at this temperature for 30min, after which the solution temperature was raised to 265 ℃ and the reaction was continued for 30 min. After the reaction is finished, the temperature is reduced to room temperature, 40mL of ethanol solution is added into the solution, the reactant is dispersed into n-hexane solution containing 0.05mL of oleic acid and 0.05mL of oleylamine after centrifugation, unreacted residual substances are removed through centrifugation, and then the obtained magnetic iron oxide nanoparticles are dispersed into n-hexane.
3. Preparation of H-HMS-Fe, as shown in FIG. 1:
step 1 (S1), adding 0.5g of Na2CO3Dissolved in 25mL of deionized water, and then a stabilizer (0.02 g) composed of magnesium sulfate and sodium metasilicate was added to the above solution to disperse the prepared HMS (1.0 g) into the above solutionThen, the mixture was magnetically stirred for 6 hours to obtain a solution A. 0.0016g of aminotrimethylenephosphonic acid was added to 0.8g of a 50% aqueous hydrogen peroxide solution by mass and stirred uniformly, and the solution was slowly added to solution A and stirred for 2 hours. Stopping stirring, standing the solution for 50 min, centrifuging, washing with water, and vacuum freeze drying to obtain Na-loaded carrier2CO3•H2O2And (3) HMS, denoted as H @ HMS.
Step 2 (S2), dispersing 20mg of the H @ HMS powder obtained in the step 1 into 20mL of n-hexane solution, and then adding 2mL of iron oxide nanoparticle n-hexane solution (Fe)3O4The concentration of NPs is 5 mg/mL), magnetically stirring the mixed solution for 12H, centrifuging the product, and washing the product with n-hexane to obtain the target product, namely the silicon oxide composite material loaded with sodium percarbonate and iron oxide nanoparticles, which is marked as H-HMS-Fe.
The H-HMS-Fe composite material prepared in example 1 is subjected to an in vitro oxygen release experiment, and the experiment method comprises the following steps: the experimental group and the control group were dispersed in PBS (phosphate buffer saline) having a pH of 7.4, respectively, and then the oxygen content in the solutions was measured with a dissolved oxygen meter, respectively. As shown in fig. 2, the oxygen solubility of the PBS solution of H-HMS as the experimental group was greatly increased compared to that of the PBS solution of H-HMS as the control group under the same condition of pH =7.4, indicating that H-HMS-Fe generates more oxygen per unit time than that of H-HMS as the control group under the neutral condition.
Research on radiotherapy sensitization of nano composite material
The results of the experiment on the survival rate of the cloned cells are shown in fig. 3 by respectively carrying out the experiment on a blank control group (directly carrying out X-ray irradiation on the cloned cells), an experiment control group (adding H-HMS into the cloned cells and then carrying out X-ray irradiation) and an experiment group in the embodiment of the invention (adding H-HMS-Fe into the cloned cells and then carrying out X-ray irradiation), and the survival rate of the cloned cells is obviously reduced compared with that of the control group along with the increase of the radiation dose in the experiment group in the embodiment.
Experiments prove that the H-HMS-Fe composite material provided by the invention slowly releases oxygen in a neutral environment (including a blood circulation system, extracellular matrix, cytoplasm and the like) with the pH of about 7.4, so that the hypoxic microenvironment of malignant solid tumors is improved. Under the weak acid microenvironment (lysosome organelle in the cell) with pH value of about 5, hydroxyl free radical (active oxygen free radical) is released, so that oxidative damage to tumor cells is realized, apoptosis and necrosis are induced, and the nano-particles can be used for targeted therapy and improving the curative effect of solid tumors.
In summary, the H-HMS-Fe composite material provided by the present invention uses composite mesoporous silica nanoparticles (HMS) as carriers, the nanomaterial has a hierarchical mesoporous structure, the pore diameter of the inner layer mesoporous structure is about 2-4nm, the pore diameter of the outer layer mesoporous structure is about 4-10nm, and sodium percarbonate (Na) is loaded in the inner layer mesoporous structure2CO3•H2O2) And magnetic iron oxide nano particles (Fe) with the size of about 4nm are loaded in the outer-layer dielectric pores3O4NPs), construction of a biological Environment responsive Na2CO3•H2O2@HMS-Fe3O4Abbreviated as H-HMS-Fe. The EPR effect of the nano material is utilized to realize passive targeting on the tumor tissue, and then oxygen is generated around the solid tumor tissue to improve the oxygenation state of the tumor tissue, so that the purpose of radiotherapy sensitization is achieved, and the nano material has a good application prospect.
While the present invention has been described in detail with reference to the preferred embodiments, it should be understood that the above description should not be taken as limiting the invention. Various modifications and alterations to this invention will become apparent to those skilled in the art upon reading the foregoing description. Accordingly, the scope of the invention should be determined from the following claims.

Claims (5)

1. The application of the radiotherapy sensitization nanometer material is characterized in that the radiotherapy sensitization nanometer material is loaded with sodium percarbonate and Fe3O4The silicon oxide composite material of the nano particles is marked as H-HMS-Fe, and the H-HMS-Fe is used for preparing radiotherapy sensitizing drugs; the H-HMS-Fe comprises HMS with a hierarchical structure, and the HMS hasHas an inner mesoporous structure and an outer mesoporous structure, wherein the inner mesoporous structure is loaded with Na2CO3•H2O2Fe is loaded in the outer layer mesoporous structure3O4Nanoparticles; the aperture of the inner mesoporous structure is 2-4 nm; the pore diameter of the outer layer mesoporous structure is 4-10 nm.
2. The use of the radiosensitizing nanomaterial of claim 1, wherein the preparation method of H-HMS-Fe comprises the steps of:
step 1, preparing H @ HMS comprising:
step 1.1, adding Na2CO3Dissolving in deionized water, adding a stabilizer, stirring uniformly, adding HMS, and stirring to uniformly disperse the HMS;
step 1.2, adding aminotrimethylene methylene phosphonic acid into the hydrogen peroxide water solution, uniformly stirring, slowly adding into the solution with uniformly dispersed HMS obtained in the step 1.1, and stirring for 1.5-3 h; standing for a period of time, centrifuging, washing with water, and drying to obtain Na-loaded carrier2CO3•H2O2The HMS powder is marked as H @ HMS;
step 2, preparing H-HMS-Fe: dispersing the H @ HMS into n-hexane, and adding Fe3O4Nano particles, magnetically stirring the mixed solution for 12-24 h, centrifuging, and washing with n-hexane to obtain loaded sodium percarbonate and Fe3O4The silicon oxide composite material of the nano particles is marked as H-HMS-Fe.
3. The use of the radiosensitizing nanomaterial of claim 2, wherein the stabilizer consists of magnesium sulfate and sodium metasilicate, wherein the ratio of magnesium sulfate: the mass ratio of the sodium metasilicate is 5:1-10: 1.
4. The use of the radiosensitizing nanomaterial according to claim 2, wherein in step 1.1, the concentration of sodium carbonate ranges from 10mg/mL to 50mg/mL, and the mass ratio of sodium carbonate to HMS ranges from 1% to 100%.
5. The use of the radiosensitizing nanomaterial according to claim 2, wherein in step 1.2, the molar ratio of hydrogen peroxide to sodium carbonate is 0.5:1 to 2: 1.
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CN109481677B (en) * 2018-11-30 2021-06-29 上海交通大学医学院附属第九人民医院 Temperature-responsive oxygen slow-release nanocomposite and preparation method and application thereof
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CN105056848A (en) * 2015-07-14 2015-11-18 南京邮电大学 Mesoporous organosilica nanosphere adopting double-layer yolk-eggshell structure and preparation method
CN107281220A (en) * 2016-03-31 2017-10-24 中国科学院上海硅酸盐研究所 A kind of mesopore silicon oxide base active oxygen (ROS) radiotherapeutic sensitizer and preparation method thereof

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