Background
The main method for non-surgical treatment of primary liver cancer mainly comprises hepatic artery chemoembolization (TACE). Most of the existing TACE operations are that the mixed emulsion of the chemotherapeutic drug and the iodized oil is directly injected into blood supply vessels of tumors through a catheter, so that the chemotherapeutic drug in the embolic agent is slowly released while the blood supply of the tumors is blocked and the tumor necrosis is induced, and the tumors are continuously killed. With the continuous improvement of the technology of tumor targeted therapy, the technology of drug microsphere embolization gradually enters clinical practice, after the drug microspheres are injected into tumor blood supply arteries through arterial cannulas, embolization of tumor capillary vascular networks is complete, collateral circulation is not easy to form compared with a conventional embolization agent, necrosis of cancer tissues is complete, embolization effect can be generated, and the embolization agent can be used as a carrier of an anti-cancer drug, so that the drug in a tumor area can be maintained at a high concentration level for a long time. But only rely on the intervention method to "the medicine microsphere" guide, the operation is complicated, it is unchanged to master, in recent years, propose intervene cooperate with magnetic guide increase medicine target treatment scheme of performance, namely inject the magnetic nanoparticle that is small in size, with superparamagnetism into the tumor area through intervening, then under the guidance of external magnetic field (such as nuclear magnetic resonance), guide and limit the magnetic nanoparticle with medicine or without medicine to the capillary vessel network of the tumor area, can further realize magnetic thermotherapy, targeted chemotherapy, radiotherapy and thermochemotherapy, heat radiotherapy, etc., give play to the greatest efficacy and reduce the minus effect of treatment.
The research on ferromagnetic materials among many magnetic materials is more extensive, and nano ferroferric oxide (Fe) is used as the ferromagnetic material3O4) The research is most common, the characteristics of good biocompatibility, no hemolytic activity, genetic toxicity, superparamagnetism and the like are the good guiding drug carrier for interventional therapy. However, in practical applications, magnetic nanoparticles generally need to be uniform in size, stable in chemical properties, and good in biocompatibility and dispersibility. Because the special structure of the magnetic ferroferric oxide nano particles determines that the magnetic ferroferric oxide nano particles have poor self-dispersing capacity, are easy to agglomerate, are difficult to stably suspend in a solution for a long time, and have the defect that the magnetic ferroferric oxide nano particles cannot be stably suspended in the air, in recent years, a plurality of main sheets are coated. Carbon is stable in chemical property, and the carbon-coated nanoparticles have biocompatibility and unique spectral characteristics and are recognized as ideal coating materials. Because the carbon shell can confine metal substances in a very small space, the influence of the environment on the nano material can be avoided, and the interaction among particles is reduced, thereby solving the problems that the magnetic ferroferric oxide nano particles are easy to agglomerate and can not be stable in the airThere are problems. In addition, due to the existence of the carbon coating layer, the compatibility between the magnetic ferroferric oxide and organisms is improved, so that the carbon-coated magnetic ferroferric oxide nano material has wide application prospect in the aspect of medicine. Carbon-coated Fe reported in domestic and foreign literature3O4The synthesis method of the magnetic microspheres basically adopts a two-step or multi-step method, and basically comprises the following two steps: namely, the magnetic microspheres are synthesized first and then coated with carbon. And in Fe3O4In the preparation process of the magnetic microspheres, in order to control the size of the microspheres, a simple direct synthesis method has to be abandoned, and methods such as a pyrolysis method, a reverse coprecipitation method and the like are adopted, for example, as disclosed in "preparation method of carbon-coated ferroferric oxide magnetic nanocomposite" (application number: 201110303081.9): the particle size is controlled by adjusting the reaction temperature and adding a surfactant. The mechanism of adding the Surfactant (SAA) is to utilize the amphipathy of the SAA component at the interface (surface) to form bridges with CNTs, CNTs particle surfaces and CNTs particles and other materials by the adsorption or reaction of one end functional group, so as to play the roles of coupling and compatibilization. CNTs exhibit excellent dispersibility and processability after SAA surface modification treatment, but in the gene therapy field, it is necessary to combine drugs with high molecular materials and use SAA-modified Fe3O4The magnetic microspheres have negative effects on the viscosity of the polymer and are not beneficial to the combination and attachment of the medicine; ② repeatedly verifying whether SAA conflicts with the activity of the medicine, and the same SAA modified Fe3O4Magnetic microspheres are not used in all drug carriers; thirdly, careful selection is made to fully evaluate the in vivo toxicity of the surfactant; and fourthly, the SAA modification cost is higher. In conclusion, the method has the most defects of the existing synthetic method that the steps are multiple and the particle agglomeration in the synthetic process cannot be safely reduced.
Disclosure of Invention
The technical task of the invention is to provide a preparation process of the carbon-coated magnetic guiding drug carrier, which is simple to operate and low in production cost, aiming at the defects of the prior art.
The technical scheme for solving the technical problem is as follows: (1) weighing 8 moles of NaOH, dissolving the NaOH in deoxidized pure water to form 1.2mol/L solution, adding 80g of pregelatinized starch at 40 ℃, and stirring until the pregelatinized starch is completely dissolved; mixing by ultrasonic at 200 Hz; adding the mixed solution into a reaction kettle, sealing the reaction kettle, purging the reaction kettle through an air inlet valve by using high-purity nitrogen, and discharging internal air;
(2) 1.5 moles of FeCl were weighed3·6H2O, 1 mol FeCl2·4H2Dissolving O in deoxidized pure water to form a mixed solution; the concentration of which is 1.5mol Fe per liter solution3+And 1.0mol Fe2+;
(3) Dropwise adding the mixed solution obtained in the step (2) into the sodium hydroxide starch gelatinization mixed solution obtained in the step (1) through a feed valve; and (3) heating the reaction kettle to 240 ℃, preserving heat for 6 hours, naturally cooling, washing and drying to obtain the carbon-coated nano magnetic ferroferric oxide.
Compared with the prior art, the invention has the following outstanding beneficial effects:
1. production of carbon-coated nano Fe by using the method of the invention3O4Material integrating a carbon coating process into Fe3O4During the formation of (2), not in Fe3O4After the generation process, the process flow is simplified, and the time and the cost are saved.
2. Firstly, the mixed solution of NaOH and starch is gelatinized to increase the viscosity of the solution, then the solution of ferric ions and ferrous ions is added, the ferric ions and the ferrous ions are wrapped by the environment of the gelatinized solution, and OH—The reaction with iron ions and ferrous ions is slowed down, the particle size (less than 100nm) and the agglomeration of the generated ferroferric oxide are finally inhibited, the dispersibility of the final product is improved, the particle size of the final product is reduced, and the performance of the material is improved.
3. Impurity Fe2O3The content is small, and the final product has stable quality and good effect.
4. The carbon coating temperature is low, and the production cost is greatly reduced.
Detailed Description
The invention is described below with reference to the drawings and the detailed description.
Comparative example:
(1) firstly, 0.2 mol of FeCl is respectively weighed3·6H2O, 0.1 mol FeCl2·4H2O is dissolved in 0.3L of deoxygenated pure water, and the mixture is stirred and mixed to form a mixed solution.
(2) Adding the solution prepared in the step (1) into a reaction kettle, sealing the reaction kettle, purging the reaction kettle through an air inlet valve by using high-purity nitrogen, and discharging the air in the reaction kettle.
(3) Then 0.8 mol of NaOH is weighed and dissolved in deoxidized pure water to form 1.0mol/L solution, the solution is stirred and dissolved, and sodium hydroxide solution is dripped into the iron-containing solution through a feed valve. Wherein the proportion of the added substances is the mol ratio Fe3+:Fe2+:OH—2.0: 1.0: 8.0, heating the reaction kettle to 150 ℃, preserving heat for 6 hours, naturally cooling, washing and drying to obtain an initial product.
(4) And then uniformly mixing the initial product with 23g of glucose, and keeping the temperature of 500 ℃ for 6 hours under the protection of nitrogen to obtain the carbon-coated ferroferric oxide.
Example 1:
(1) weighing 8 moles of NaOH, dissolving the NaOH in deoxidized pure water to form 1.3mol/L solution, adding 110g of water-soluble starch, and stirring at 25 ℃ until the NaOH is completely dissolved; forming a mixed solution; adding the mixed solution into a reaction kettle, sealing the reaction kettle, purging the reaction kettle through an air inlet valve by using high-purity nitrogen, and discharging internal air; as the soluble starch is added into hot NaOH solution to carry out gelatinization reaction, the starch molecules in the granules stretch and diffuse in all directions, and the expanded starch molecules are mutually connected and intertwined outside the dissolved granules to form a reticular hydrous colloid. When starch enters the particle disintegration stage of the gelatinization reaction, the solution viscosity is maximum, so that starch molecules can be coated around NaOH, the reaction speed of the NaOH with ferric ions and ferrous ions is inhibited, and Fe generated by the NaOH and the ferric ions and the ferrous ions is inhibited3O4Particle size and agglomeration to improve dispersion of the final productReducing the particle size of the final product;
(2) 1.8mol FeCl is weighed3·6H2O, 1 mol FeCl2·4H2Dissolving O in deoxidized pure water to form a mixed solution; the concentration of which is 1.8mol Fe per liter solution3+And 1.0mol Fe2+。
(3) And (3) dropwise adding the mixed solution obtained in the step (2) into the sodium hydroxide starch pasting solution obtained in the step (1) through a feeding valve. Wherein the proportion of the added raw materials is the molar ratio OH—:Fe3+:Fe2+When the ratio is 8: 1.8: 1, heating the reaction kettle to 210 ℃, preserving heat for 7 hours, naturally cooling, washing and drying to obtain carbon-coated nano magnetic Fe3O4。
The traditional preparation process mostly adopts OH-:Fe3+:Fe2+When the ratio is 8: 2: 1 equation ideal theoretical ratio, but in real process, Fe2+Unstable in nature and easily oxidized to Fe3+。Fe3+:Fe2+2: at 1, Fe as an impurity tends to be generated2O3Affecting the quality of the final product.
Because the viscosity of the water solution of the soluble starch is high after gelatinization, the generation of Fe generated by NaOH and iron is inhibited3O4Particle size and agglomeration of (1), Fe3O4Is smaller. And gelatinized starch solution in Fe3O4The carbon coating is completed in the generation process, so that the process flow is simplified, the time and the cost are saved, and the energy is saved.
The ferric chloride in the process step (2) may also be other ferric iron solutions, such as ferric nitrate, ferric sulfate, etc., wherein the ferrous chloride may also be other ferrous iron solutions, such as ferrous nitrate, ferrous sulfate, etc.
In this example, water-soluble starch is used, which is distinguished from soluble starch in that the water-soluble starch can be dissolved in cold water and gelatinized, i.e., can be dissolved at a temperature of 15 ℃ to 25 ℃, but in practice, a better gelatinization effect can be obtained at 25 ℃.
Example 2:
(1) weighing 2 moles of NaOH, dissolving the NaOH in deoxidized pure water to form 1.0mol/L solution, heating the solution to 60 ℃, adding 40g of soluble starch, and stirring the solution until the solution is completely gelatinized to form mixed solution; adding the mixed solution into a reaction kettle, sealing the reaction kettle, purging the reaction kettle through an air inlet valve by using high-purity nitrogen, and discharging internal air;
(2) 0.25 mol FeCl is weighed3·6H2O, 0.25 mol FeCl2·4H2Dissolving O in deoxidized pure water to form a mixed solution; the concentration of which is 1.0mol Fe per liter solution3+And 1.0mol Fe2+。
(3) And (3) dropwise adding the mixed solution obtained in the step (2) into the sodium hydroxide starch pasting solution obtained in the step (1) through a feeding valve. Wherein the proportion of the added raw materials is the molar ratio OH—:Fe3+:Fe2+8.0: 1.0: 1.0, heating the reaction kettle to 180 ℃, preserving heat for 10 hours, naturally cooling, washing and drying to obtain the carbon-coated nano magnetic Fe3O4。
In the present example, the soluble starch used was insoluble in water at normal temperature, but when the water temperature reached 53 ℃ or higher, the soluble starch swelled and disintegrated to form a uniform pasty solution. The gelatinization temperature of the water solution is reduced due to the high alkalinity of the soluble starch which is dissolved in 1.0mol/L NaOH solution, and the gelatinization temperature is reduced at 60 ℃, so that the reaction acceleration and the agglutination acceleration caused by overhigh temperature in the subsequent synthesis can be prevented due to overhigh temperature.
Example 3:
(1) firstly, weighing 8mol of NaOH, dissolving the NaOH in deoxidized pure water to form 1.2mol/L solution, adding 80g of pregelatinized starch at 40 ℃, and stirring until the pregelatinized starch is completely dissolved; and (2) ultrasonically mixing uniformly at the frequency of 200Hz, wherein the ultrasonic waves enable air bubbles in the mixed solution to vibrate under the action of sound waves, the air bubbles grow and collapse to play a role in cavitation when reaching a certain limit, and the ultrasonic cavitation is utilized to uniformly mix NaOH with starch molecules in the solution and control the size and the distribution of starch particles. Adding the mixed solution into a reaction kettle, sealing the reaction kettle, purging the reaction kettle through an air inlet valve by using high-purity nitrogen, and discharging internal air;
(2) 1.5 moles of FeCl were weighed3·6H2O, 1 mol FeCl2·4H2Dissolving O in deoxidized pure water to form a mixed solution; the concentration of which is 1.5mol Fe per liter solution3+And 1.0mol Fe2+。
(3) And (3) dropwise adding the mixed solution obtained in the step (2) into the sodium hydroxide starch pasting solution obtained in the step (1) through a feeding valve. Wherein the proportion of the added raw materials is the molar ratio OH—:Fe3+:Fe2+When the ratio is 8: 1.5: 1, heating the reaction kettle to 240 ℃, preserving heat for 6 hours, naturally cooling, washing and drying to obtain carbon-coated nano magnetic Fe3O4。
The pregelatinized starch is a modified starch, and can be mixed with cold water to obtain paste, thereby avoiding the trouble of heating for gelatinization. However, in practical exploration, a better gelatinization effect can be obtained at 40 ℃, and the gelatinization effect is better superposed with the ultrasonic effect at the temperature.
The test results of the comparative example, the example 1, the example 2 and the example 3 show that the yield of the products of the comparative example, the example 1, the example 2 and the example 3 is respectively 40.78%, 67.23%, 68.27% and 73.42%, and the yield of the products is obviously higher than that of the comparative example coated with high-temperature carbon after the reverse coprecipitation method; the result of the synchronous thermal analysis at the final temperature of 1000 ℃ shows that: the residue contents of the comparative example, the example 1, the example 2 and the example 3 are respectively 20.25 percent, 28.31 percent, 27.24 percent and 30.12 percent, and the residual product after 1000 ℃ thermal weight loss is Fe2O3Calculating Fe by Fe mass conservation3O4The contents are respectively as follows: comparative example 29.36%; example 1 was 41.05%; example 2 was 39.50%; example 3 was 43.67%; the carbon contents of the comparative examples and examples 1, 2 and 3 were 11.42%, 26.18%, 28.77% and 29.77%, respectively, as calculated from the yields, and it can be seen that examples 1, 2 and 3 had high purities and contained carbonHigh volume and better carbon coating effect than the comparative example.
FIG. 1 is a scanning electron microscope picture of example 2 of the present invention, and it can be seen from the picture that carbon-coated nano-Fe prepared by the example of the present invention3O4The particles have no agglomeration, uniform appearance and uniform particle size distribution<100nm。
It should be noted that while the invention has been described in detail with respect to specific embodiments thereof, it will be apparent to those skilled in the art that various obvious changes can be made therein without departing from the spirit and scope of the invention.