CN112791225A - Nano robot for tumor treatment and preparation method thereof - Google Patents
Nano robot for tumor treatment and preparation method thereof Download PDFInfo
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- CN112791225A CN112791225A CN202011249265.7A CN202011249265A CN112791225A CN 112791225 A CN112791225 A CN 112791225A CN 202011249265 A CN202011249265 A CN 202011249265A CN 112791225 A CN112791225 A CN 112791225A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0042—Materials resorbable by the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/02—Surgical adhesives or cements; Adhesives for colostomy devices containing inorganic materials
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05D7/00—Processes, other than flocking, specially adapted for applying liquids or other fluent materials to particular surfaces or for applying particular liquids or other fluent materials
- B05D7/24—Processes, other than flocking, specially adapted for applying liquids or other fluent materials to particular surfaces or for applying particular liquids or other fluent materials for applying particular liquids or other fluent materials
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- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B32/00—Carbon; Compounds thereof
- C01B32/15—Nano-sized carbon materials
- C01B32/152—Fullerenes
- C01B32/154—Preparation
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- C—CHEMISTRY; METALLURGY
- C23—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
- C23C—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
- C23C16/00—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes
- C23C16/22—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes characterised by the deposition of inorganic material, other than metallic material
- C23C16/26—Deposition of carbon only
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- C—CHEMISTRY; METALLURGY
- C23—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
- C23C—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
- C23C16/00—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes
- C23C16/44—Chemical coating by decomposition of gaseous compounds, without leaving reaction products of surface material in the coating, i.e. chemical vapour deposition [CVD] processes characterised by the method of coating
- C23C16/4417—Methods specially adapted for coating powder
Abstract
The invention belongs to the field of nano materials, and particularly relates to a nano robot for tumor treatment and a preparation method thereof. The preparation method provided by the invention comprises the following steps: placing a paramagnetic metal target material in a sputtering chamber, introducing argon and oxygen into the sputtering chamber, and starting a power supply of the sputtering chamber to perform magnetron sputtering; after the magnetron sputtering is finished, introducing acetylene gas into the sputtering chamber; after the acetylene gas is introduced, introducing protective gas into the sputtering chamber, and rapidly cooling the sputtering chamber to obtain paramagnetic metal fullerene; mixing paramagnetic metal fullerene and a cross-linking agent in a solvent, then coating the mixed solution on the surface of a substrate, curing and cutting to obtain the nano robot. The preparation method provided by the invention has a stable production process, the size of the nano-robot to be prepared can be freely adjusted according to clinical requirements, and the nano-robot prepared by the method has good size uniformity and paramagnetism, and has a wide application prospect in the field of tumor treatment.
Description
The present application claims priority of chinese patent application with the title "nano robot for tumor treatment and method for preparing the same" filed by chinese patent office on 2019, 11, 14, and application No. 201911114761.9, the entire contents of which are incorporated herein by reference.
Technical Field
The invention belongs to the field of nano materials, and particularly relates to a nano robot for tumor treatment and a preparation method thereof.
Background
Tumor tissue is actually a complete ecosystem formed by tumor cells and tumor blood vessels, and contains not only tumor cells but also abundant tumor blood vessels inside. Modern biomedical research has demonstrated that tumor vessels are structurally very different from normal vessels. In general, normal blood vessels take a year to grow and are three-layer compact structures consisting of intima, media and adventitia, whereas tumor vessels can be formed in only 4 days and are structurally single-layer thin films consisting of endothelial cells. However, because the endothelial cells constituting the tumor vessels have large gaps and incomplete structures, the tumor vessels usually contain a large number of small pores with nanometer scale, so that small molecules and some nanoparticles can pass through the pores.
When the size of the nanoparticles is a proper size (for example, 50-200 nm), it takes several minutes or even several tens of minutes to pass through the gaps of the tumor vessels, and in this process, the nanoparticles are tightly surrounded by the endothelial cells of the tumor vessels, so that the tumor vessels can be specifically destroyed by proper design. Researchers in the chemical institute firstly use magnetic metal fullerene to design water-soluble nanoparticles with the size of about 150 nanometers, and the nanoparticles can improve internal energy through absorbing radio frequency, and have phase change due to the rise of the internal energy after several minutes to dozens of minutes, and the internal energy is accompanied with the violent expansion of the volume by about 50 percent. Then the magnetic metal fullerene nano-particles are injected into the body of the mouse intravenously, and after a few minutes, the nano-particles reach the tumor position and are stuck on the vessel wall for a long time. The mice were then subjected to radio frequency to "detonate" the nanoparticles. Research results show that the magnetic metal fullerene nano-particles embedded on the wall of the tumor vessel are exploded to effectively destroy the tumor vessel, then the nutrition supply to the tumor is rapidly blocked, and the tumor cells can be completely starved within a few hours.
At present, most reported methods for preparing magnetic metal fullerene still stay in the experimental stage, and have the problems of poor stability of the preparation process, difficult adjustment of the size of the product, poor size uniformity of the product and the like, thereby seriously influencing the application of the magnetic metal fullerene in the field of tumor treatment.
Disclosure of Invention
In view of the above, the present invention is directed to a nano-robot for tumor therapy and a method for manufacturing the same, wherein the method for manufacturing the nano-robot for tumor therapy has a stable production process, and the size of the nano-robot to be manufactured can be freely adjusted according to clinical requirements.
The invention provides a preparation method of a nano robot for tumor treatment, which comprises the following steps:
a) placing a paramagnetic metal target material in a sputtering chamber, introducing argon and oxygen into the sputtering chamber, and starting a power supply of the sputtering chamber to perform magnetron sputtering; in the magnetron sputtering process, the temperature of a cavity of the sputtering chamber is 800-1200 ℃;
b) after the magnetron sputtering is finished, maintaining the temperature of a cavity of the sputtering chamber at 800-1200 ℃, and introducing acetylene gas into the sputtering chamber;
c) after the acetylene gas is introduced, introducing a protective gas into the sputtering chamber, and reducing the temperature of the cavity of the sputtering chamber to 100-300 ℃ within 5-15 min to obtain paramagnetic metal fullerene;
d) mixing the paramagnetic metal fullerene and a cross-linking agent in a solvent to obtain a paramagnetic metal fullerene solution; then coating the paramagnetic metal fullerene solution on the surface of a substrate, and curing to obtain a paramagnetic metal fullerene film;
e) and cutting the paramagnetic metal fullerene film according to a preset shape to obtain the nano robot for treating the tumor.
Preferably, in step a), the paramagnetic metal target includes one or more of iron oxide, titanium oxide, and zirconium oxide.
Preferably, in the step a), the power supply is a direct current power supply; the voltage of the power supply is 330-420V; the power of the power supply is 2400-3600W.
Preferably, in the step a), the vacuum degree of the sputtering chamber is 10-30 Pa in the magnetron sputtering process; the gas inflow rate of the argon is 40-50 sccm; the air inflow rate of the oxygen is 10-15 sccm.
Preferably, in the step a), the magnetron sputtering time is 5-8 min.
Preferably, in the step b), the vacuum degree of the sputtering chamber is 10-30 Pa; the gas inflow rate of the acetylene gas is 100-120 sccm.
Preferably, in the step b), the aeration time of the acetylene gas is 10-15 min.
Preferably, in step d), the paramagnetic metal fullerene solution further comprises one or more of graphene oxide, chitosan and folic acid.
Preferably, the mass ratio of the paramagnetic metal fullerene, the graphene oxide, the chitosan, the folic acid and the cross-linking agent is (35-40): (5-10): (10-15): (5-15): (6-12).
The invention provides a nano robot for tumor treatment prepared by the preparation method according to the technical scheme.
Compared with the prior art, the invention provides a nano robot for treating tumors and a preparation method thereof. The preparation method provided by the invention comprises the following steps: a) placing a paramagnetic metal target material in a sputtering chamber, introducing argon and oxygen into the sputtering chamber, and starting a power supply of the sputtering chamber to perform magnetron sputtering; in the magnetron sputtering process, the temperature of a cavity of the sputtering chamber is 800-1200 ℃; b) after the magnetron sputtering is finished, maintaining the temperature of a cavity of the sputtering chamber at 800-1200 ℃, and introducing acetylene gas into the sputtering chamber; c) after the acetylene gas is introduced, introducing a protective gas into the sputtering chamber, and reducing the temperature of the cavity of the sputtering chamber to 100-300 ℃ within 5-15 min to obtain paramagnetic metal fullerene; d) mixing the paramagnetic metal fullerene and a cross-linking agent in a solvent to obtain a paramagnetic metal fullerene solution; then coating the paramagnetic metal fullerene solution on the surface of a substrate, and curing to obtain a paramagnetic metal fullerene film; e) and cutting the paramagnetic metal fullerene film according to a preset shape to obtain the nano robot for treating the tumor. The invention firstly utilizes magnetron sputtering equipment to prepare the small-size paramagnetic metal fullerene with good paramagnetism and particle size uniformity under specific process conditions, then the paramagnetic metal fullerene is prepared into coating liquid, and then coating and film cutting are carried out, thus obtaining the nano robot with good paramagnetism for tumor treatment. The preparation method provided by the invention has stable production process, can freely adjust the size of the nano robot to be cut and prepared according to clinical requirements, and has good size uniformity of products. The nano robot for tumor treatment prepared by the method provided by the invention has good size uniformity and paramagnetism, can efficiently block tumor blood vessels in a targeted manner under the assistance of radio frequency, kills tumor cells, and is completely degraded or absorbed by a human body within 3-5 weeks after the tumor cells are killed without any side effect, so that the preparation method provided by the invention has a wide application prospect in the field of tumor treatment.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides a preparation method of a nano robot for tumor treatment, which comprises the following steps:
a) placing a paramagnetic metal target material in a sputtering chamber, introducing argon and oxygen into the sputtering chamber, and starting a power supply of the sputtering chamber to perform magnetron sputtering; in the magnetron sputtering process, the temperature of a cavity of the sputtering chamber is 800-1200 ℃;
b) after the magnetron sputtering is finished, maintaining the temperature of a cavity of the sputtering chamber at 800-1200 ℃, and introducing acetylene gas into the sputtering chamber;
c) after the acetylene gas is introduced, introducing a protective gas into the sputtering chamber, and reducing the temperature of the cavity of the sputtering chamber to 100-300 ℃ within 5-15 min to obtain paramagnetic metal fullerene;
d) mixing the paramagnetic metal fullerene and a cross-linking agent in a solvent to obtain a paramagnetic metal fullerene solution; then coating the paramagnetic metal fullerene solution on the surface of a substrate, and curing to obtain a paramagnetic metal fullerene film;
e) and cutting the paramagnetic metal fullerene film according to a preset shape to obtain the nano robot for treating the tumor.
In the preparation method provided by the invention, a paramagnetic metal target is firstly placed in a sputtering chamber. Wherein, the paramagnetic metal target material preferably comprises one or more of iron oxide, titanium oxide and zirconium oxide. Then, argon and oxygen are introduced into the sputtering chamber, and a power supply of the sputtering chamber is started to carry out magnetron sputtering. Wherein the flow rate of the argon gas is preferably 40-50 sccm, and specifically can be 40sccm, 41sccm, 42sccm, 43sccm, 44sccm, 45sccm, 46sccm, 47sccm, 48sccm, 49sccm or 50 sccm; the aeration time of the argon is consistent with the time of magnetron sputtering; the flow rate of the inlet gas of the oxygen is preferably 10-15 sccm, and specifically 10sccm, 11sccm, 12sccm, 13sccm, 14sccm or 15 sccm; the aeration time of the oxygen is preferably 3-5 min, and specifically can be 3min, 3.5min, 4min, 4.5min or 5 min; the power supply is preferably a Direct Current (DC) power supply; the voltage of the power supply is preferably 330-420V, and specifically can be 330V, 340V, 350V, 360V, 370V, 380V, 390V, 400V, 410V or 420V; the power of the power supply is preferably 2400-3600W, and specifically can be 2400W, 2500W, 2600W, 2700W, 2800W, 2900W, 3000W, 3100W, 3200W, 3300W, 3400W, 3500W or 3600W; in the magnetron sputtering process, the vacuum degree of the sputtering chamber is preferably controlled to be 10-30 Pa, and specifically 10Pa, 15Pa, 20Pa, 25Pa or 30 Pa; in the magnetron sputtering process, the temperature of the cavity of the sputtering chamber is preferably controlled at 800-1200 ℃, and specifically can be 800 ℃, 850 ℃, 900 ℃, 950 ℃, 1000 ℃, 1050 ℃, 1100 ℃, 1150 ℃ or 1200 ℃; the magnetron sputtering time is preferably 5-8 min, and specifically can be 5min, 5.5min, 6min, 6.5min, 7min, 7.5min or 8 min.
In the preparation method provided by the invention, acetylene gas is introduced into the sputtering chamber after the magnetron sputtering is finished. In the process of introducing the acetylene gas, the temperature of the cavity of the sputtering chamber is maintained at 800-1200 ℃, and specifically can be 800 ℃, 850 ℃, 900 ℃, 950 ℃, 1000 ℃, 1050 ℃, 1100 ℃, 1150 ℃ or 1200 ℃; the vacuum degree of the sputtering chamber is preferably controlled to be 10-30 Pa, and specifically can be 10Pa, 15Pa, 20Pa, 25Pa or 30 Pa; the inflow rate of the acetylene gas is preferably 100-120 sccm, and specifically can be 100sccm, 105sccm, 110sccm, 115sccm or 120 sccm; the preferable aeration time of the acetylene gas is 10-15 min, and specifically can be 10min, 10.5min, 11min, 11.5min, 12min, 12.5min, 13min, 13.5min, 14min, 14.5min or 15 min.
In the preparation method provided by the invention, after the acetylene gas is introduced, protective gas is introduced into the sputtering chamber, and the sputtering chamber is rapidly cooled. The vacuum degree of the sputtering chamber is preferably controlled to be 10-30 Pa, and specifically can be 10Pa, 15Pa, 20Pa, 25Pa or 30 Pa; the protective gas is preferably argon and/or nitrogen; the flow rate of the shielding gas is preferably 700 to 1000sccm, and specifically 700sccm, 750sccm, 800sccm, 850sccm, 900sccm, 950sccm or 1000 sccm. In the invention, the process of rapidly cooling is preferably to reduce the temperature of the cavity of the sputtering chamber to 100-300 ℃ within 5-15 min, and the time consumed by rapidly cooling is more preferably 8-10 min, specifically 8min, 8.5min, 9min, 9.5min or 10 min; the temperature of the cavity after the rapid cooling is more preferably 150-250 ℃, and specifically may be 150 ℃, 160 ℃, 170 ℃, 180 ℃, 190 ℃, 200 ℃, 205 ℃, 210 ℃, 220 ℃, 230 ℃, 240 ℃ or 250 ℃. After the rapid cooling is finished, obtaining paramagnetic metal fullerene, wherein the paramagnetic metal fullerene comprises paramagnetic metal particles and carbon spheres coated with the paramagnetic metal particles and having fullerene shapes; the paramagnetic metal particles preferably comprise one or more of Fe, Zr, and Ti; the particle size of the paramagnetic metal fullerene is preferably 1-100 nm, and specifically can be 10nm, 15nm, 20nm, 25nm, 30nm, 35nm, 40nm, 45nm, 50nm, 55nm, 60nm, 65nm, 70nm, 75nm, 80nm, 85nm, 90nm, 95nm or 100 nm.
In an embodiment provided by the present invention, the paramagnetic metal fullerene is prepared in a magnetron sputtering apparatus having a wafer inlet chamber, a sputtering chamber, and a wafer outlet chamber, and a work holder is used to carry the prepared paramagnetic metal fullerene, and the specific process is as follows:
cleaning a workpiece clamp, then installing the workpiece clamp on a moving track of a magnetron sputtering device, enabling the workpiece clamp to enter a wafer inlet chamber along the track, closing a vacuum valve of the wafer inlet chamber, vacuumizing the wafer inlet chamber, opening the vacuum valve of the sputtering chamber after the vacuum degree meets the requirement, and enabling the workpiece clamp to enter the sputtering chamber along the track; the preparation of the paramagnetic metal fullerene is carried out in a sputtering chamber, and the specific process is introduced above and is not described again; paramagnetic metal fullerene generated by rapid cooling is adsorbed around the workpiece clamp; the working clamp moves to the sheet outlet chamber along the operation track and is naturally cooled to room temperature under the protective gas atmosphere; and opening a vacuum valve of the sheet outlet chamber, enabling the working clamp to leave the sheet outlet chamber along the rail, and then collecting the paramagnetic metal fullerene on the working clamp.
In the invention, taking paramagnetic metal as Fe as an example, the physical and chemical processes involved in the preparation process of the paramagnetic metal fullerene are as follows: after a power supply of the sputtering chamber is started, positive argon ions generated by ionization bombard the iron target to sputter Fe particles from the target, and the sputtered Fe particles are in an oxygen atmosphere, so that 2P of iron can be obtained due to the fact that the oxygen atoms are atoms with larger electronegativity1And 2P3The characteristic peak moves to the direction with higher binding energy, so that Fe particles exist in the form of iron oxide; then the acetylene gas introduced into the sputtering chamber surrounds and coats the Fe particlesAnd reacting at high temperature to generate carbon tube prototypes; and finally, splitting the carbon tube prototype through rapid cooling to form carbon spheres coating Fe particles and generate fullerene morphology, namely the paramagnetic metal fullerene (Fe @ fullerene) prepared by the invention.
In the preparation method provided by the invention, after the paramagnetic metal fullerene is obtained, the paramagnetic metal fullerene and the cross-linking agent are mixed in the solvent to obtain a paramagnetic metal fullerene solution. Wherein, the cross-linking agent includes but is not limited to gelatin, the number average molecular weight of the gelatin is preferably 15000-250000 Da, specifically 15000Da, 20000Da, 50000Da, 100000Da, 150000Da, 200000Da or 250000Da, the mass ratio of the paramagnetic metal fullerene to the cross-linking agent is preferably (35-40): (6-12), specifically (35-40): 6. (35-40): 7.5, (35-40): 9. (35-40): 10.5, (35-40): 12. 35: (6-12) and 36: (6-12) and 37: (6-12) and 38: (6-12) and 39: (6-12) or 40: (6-12); the solvent is preferably water, and the amount of the water is preferably 20-40 wt% of the total mass of the crosslinking agent and the water, and specifically can be 20 wt%, 25 wt%, 30 wt%, 35 wt% or 40 wt%. In the present invention, the paramagnetic metal fullerene solution preferably further contains one or more of graphene oxide, chitosan, and folic acid. The graphene oxide has good biocompatibility and can be functionalized, ordered adsorption effect on paramagnetic metal fullerene can be realized, the porosity of the graphene oxide is preferably 85-95%, specifically 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% or 95%, and the specific surface area of the graphene oxide is preferably 2300-3000 m2A specific value of 2300m2/g、2350m2/g、2400m2/g、2450m2/g、2500m2/g、2550m2/g、2600m2/g、2650m2/g、2700m2/g、2750m2/g、2800m2/g、2850m2/g、2900m2/g、2950m2G or 3000m2The thickness of the graphene oxide is preferably 10-20 nm, and specifically 10nm, 11nm, 12nm, 13nm, 14nm, 15nm, 16nm, 17nm, 18nm,19nm or 20nm, wherein the mass ratio of the paramagnetic metal fullerene to the graphene oxide is preferably (35-40): (5-10), specifically (35-40): 5. (35-40): 6. (35-40): 7. (35-40): 8. (35-40): 9. (35-40): 10. 35: (5-10) and 36: (5-10) and 37: (5-10) and 38: (5-10) and 39: (5-10) or 40: (5-10); the chitosan is cation basic aminopolysaccharide in natural polysaccharide, has good biocompatibility, no toxicity, no antigenicity and biodegradability, can encapsulate compounds with different polarities, is an excellent drug carrier, can also be used as an active agent, the deacetylation degree of the chitosan is preferably more than or equal to 90%, the viscosity of the chitosan at room temperature (25 ℃) is preferably 50-200 mpa.s, particularly 50mpa.s, 100mpa.s, 150mpa.s or 200mpa.s, and the mass ratio of the paramagnetic metal fullerene to the chitosan is preferably (35-40): (10-15), specifically (35-40): 10. (35-40): 11. (35-40): 12. (35-40): 13. (35-40): 14. (35-40): 15. 35: (10-15) and 36: (10-15) and 37: (10-15) and 38: (10-15) and 39: (10-15) or 40: (10-15); the folic acid can specifically react with a folic acid receptor on the cell surface to form a compound, the binding force of the folic acid and the folic acid receptor is very strong, the folic acid has high selectivity on tumors, and the folic acid can be used as a modified compound of a tumor-targeted drug, wherein the mass ratio of the paramagnetic metal fullerene to the folic acid is preferably (35-40): (5-15), specifically (40-50): 5. (40-50): 6. (40-50): 7. (40-50): 8. (40-50): 9. (40-50): 10. (40-50): 11. (40-50): 12. (40-50): 13. (40-50): 14. (40-50): 15. 35: (5-15) and 36: (5-15) and 37: (5-15) and 38: (5-15) and 39: (5-15) or 40: (5-15).
In the preparation method provided by the invention, after the paramagnetic metal fullerene solution is obtained, the paramagnetic metal fullerene solution is coated on the surface of the substrate. Wherein, the coating mode is preferably wire bar coating; the coating speed of the wire rod is preferably 0.3-0.6 m/min, and specifically can be 0.3m/min, 0.35m/min, 0.4m/min, 0.45m/min, 0.5m/min or 0.6 m/min; the weight of the wire bar coated by the wire bar is preferably 0.6-0.8 kg, and specifically can be 0.6kg, 0.65kg, 0.7kg, 0.75kg or 0.8 kg; the coating uniformity of the wire bar coating is preferably controlled to within ± 3%. After the coating is finished, the liquid film formed by coating is cured. Wherein, the curing mode is preferably baking; the baking temperature is preferably 40-60 ℃, and specifically can be 40 ℃, 45 ℃, 50 ℃, 55 ℃ or 60 ℃; the baking time is preferably 40-60 min, and specifically can be 40min, 45min, 50min, 55min or 60 min. After the solidification, a paramagnetic metal fullerene film is formed on the surface of the substrate, wherein the thickness of the paramagnetic metal fullerene film is preferably 100-200 nm, and specifically can be 100nm, 105nm, 110nm, 115nm, 120nm, 125nm, 130nm, 135nm, 140nm, 145nm, 150nm, 155nm, 160nm, 165nm, 170nm, 175nm, 180nm, 185nm, 190nm, 195nm or 200 nm.
In the preparation method provided by the invention, after the paramagnetic metal fullerene film is obtained, the paramagnetic metal fullerene film is cut according to a preset shape. Wherein the cutting shape can be cylindrical, rectangular, spherical, ellipsoidal or irregular; the cutting size can be determined according to clinical requirements, for example, the size of the nano robot for cardiovascular diagnosis and treatment is in the sub-millimeter order, and the size of the nano robot for gastrointestinal tract and solid tumor diagnosis and treatment is in the millimeter to centimeter order. In the invention, the cutting mode is preferably laser cutting; the scanning step of the laser cutting is preferably 10-200 nm/s, and specifically can be 10nm/s, 20nm/s, 30nm/s, 40nm/s, 50nm/s, 60nm/s, 70nm/s, 80nm/s, 90nm/s, 100nm/s, 110nm/s, 120nm/s, 130nm/s, 140nm/s, 150nm/s, 160nm/s, 170nm/s, 180nm/s, 190nm/s or 200 nm/s; the laser spot of the laser cutting is preferably 0.05-0.1 μm, and specifically can be 0.05 μm, 0.06 μm, 0.07 μm, 0.08 μm, 0.09 μm or 0.1 μm; the electron beam energy of the laser cutting is preferably 10-100 mJ, and specifically can be 10mJ, 20mJ, 30mJ, 40mJ, 50mJ, 60mJ, 70mJ, 80mJ, 90mJ or 100 mJ; the cutting precision of the laser cutting is preferably less than 100 nm. And after the cutting is finished, obtaining the nano robot for treating the tumor.
The invention firstly utilizes magnetron sputtering equipment to prepare the small-size paramagnetic metal fullerene with good paramagnetism and particle size uniformity under specific process conditions, then the paramagnetic metal fullerene is prepared into coating liquid, and then coating and film cutting are carried out, thus obtaining the nano robot with good paramagnetism for tumor treatment. The preparation method provided by the invention has stable production process, can freely adjust the size of the nano robot to be cut and prepared according to clinical requirements, and has good size uniformity of products. The nano robot for tumor treatment prepared by the method provided by the invention has good size uniformity and paramagnetism, can efficiently block tumor blood vessels in a targeted manner under the assistance of radio frequency, kills tumor cells, and is completely degraded or absorbed by a human body within 3-5 weeks after the tumor cells are killed without any side effect, so that the preparation method provided by the invention has a wide application prospect in the field of tumor treatment.
The invention also provides a nano robot for treating tumors, which is prepared by adopting the method of the technical scheme. The nano robot for treating the tumor has good size uniformity and paramagnetism, and can efficiently block tumor blood vessels in a targeted manner under the assistance of radio frequency to kill tumor cells; moreover, after the nano robot for tumor treatment provided by the invention kills tumor cells, the nano robot is completely degraded or absorbed by a human body within 3-5 weeks without any side effect, so that the nano robot for tumor treatment provided by the invention has a wide application prospect in the field of tumor treatment. In addition, the metal fullerene has excellent free radical scavenging effect and has the function of resisting oxidation damage and repairing various cells, so the nano robot for treating the tumor provided by the invention can also be used as a medicine and has good treatment effect on various diseases.
For the sake of clarity, the following examples are given in detail.
Example 1
The preparation method of the paramagnetic metal fullerene comprises the following steps:
1) cleaning: firstly, wiping a glass workpiece clamp with alcohol, then putting the workpiece clamp into an ultrasonic cleaning machine, carrying out deionized water ultra-cleaning and alcohol ultra-cleaning, and finally putting the workpiece clamp into alcohol steam for drying;
2) pasting a protective film: sticking a polyethylene film on the cleaned workpiece clamp, protecting the cleanliness of the workpiece clamp and protecting the workpiece clamp from being damaged;
3) installing the workpiece clamp pasted with the film on a running track of a magnetron sputtering device, and tearing off the protective film before entering a film inlet chamber;
4) the working clamp moves to a film feeding chamber of the magnetron sputtering device, then a vacuum gate valve is closed, and a vacuum pump is started to keep the vacuum degree at 15 Pa;
5) opening a vacuum gate valve of a sputtering chamber of the magnetron sputtering device, and enabling the workpiece clamp to enter the fixed position of the sputtering chamber through a track;
6) introducing argon and oxygen into the sputtering chamber, starting a DC power supply (380V and 3000W) of the sputtering chamber, bombarding an iron target (ferric oxide) for magnetron sputtering, and keeping for 5 min; wherein the argon flow is 45sccm, and the ventilation time is consistent with the time for performing magnetron sputtering; the oxygen flow is 10sccm, and the ventilation time is 3 min; during magnetron sputtering, the temperature of the cavity of the sputtering chamber is maintained at 1000 ℃;
7) after the magnetron sputtering is finished, maintaining the temperature of a cavity of the sputtering chamber to be 1000 ℃, and introducing acetylene gas into the sputtering chamber, wherein the flow rate of the acetylene gas is 100sccm, and the introduction time is 10 min;
8) after the acetylene gas is introduced, introducing argon as a protective gas, introducing the amount of 800sccm, and simultaneously starting a cooling device to ensure that the temperature of the cavity of the sputtering chamber is up to 200 ℃ within 10min to obtain carbon sphere particles adsorbed around the working clamp, namely the paramagnetic metal fullerene prepared by the embodiment;
9) then, the working clamp moves to a film discharging chamber of the magnetron sputtering device along the operation track, protective gas argon is introduced into the film discharging chamber, the introduction amount is 300sccm, and the film discharging chamber is naturally cooled to 25 ℃;
10) and opening a vacuum valve of the sheet outlet chamber, enabling the working clamp to leave the sheet outlet chamber along the rail, and then collecting the paramagnetic metal fullerene on the working clamp to obtain paramagnetic metal fullerene particles.
The paramagnetic metal fullerene particles prepared in this example were measured for particle size, uniformity of particle size, purity, degree of graphitization, saturation magnetization, residual magnetization, and coercive force.
The particle size and the particle size uniformity are obtained by analyzing the morphology and the crystallization morphology of the prepared paramagnetic metal fullerene particles by using a JEM-2010 high-resolution transmission electron microscope, and the calculation formula of the particle size uniformity is as follows: (D)Big (a)-DSmall)/(DBig (a)+DSmall)×100％，DBig (a)Denotes the maximum diameter value, D, measured from the granules preparedSmallRepresents the smallest diameter measured from the prepared particles;
the purity and graphitization degree are obtained by performing water solubility analysis on the prepared paramagnetic metal fullerene particles by using an FES165 Fourier infrared spectrometer (FT-IR) and a cary-300VARIAN ultraviolet visible spectrum analyzer;
the magnetization and coercive force were obtained by performing magnetic property analysis on the prepared paramagnetic metal fullerene particles using a Lakeshore 7410 vibrating sample magnetometer.
The measurement results are as follows: the grain size is 80-90 nm, the uniformity of the grain size is less than 5.8%, the purity is more than 99.9%, the graphitization degree is more than 94%, the saturation magnetization is 19.655emu/G, the residual magnetization is 4.4944emu/G, and the coercive force is 567.86G.
Comparative example 1
The preparation of fullerene comprises the following steps:
the method adopts a thermal evaporation method, uses natural graphite as a raw material, and synthesizes fullerene from evaporated carbon atoms in a non-oxidizing atmosphere at a very high temperature.
The saturation magnetization, residual magnetization and coercive force of the fullerene prepared in the comparative example were measured, and the results were: saturation magnetization of 40X 10-3emu/g, remanent magnetization 8.5862X 10-3emu/G and coercive force 162.8G.
Example 2
The preparation of the nano robot for treating the tumor comprises the following steps:
1) mixing all the materialsMixing the paramagnetic metal fullerene particles (40 parts by mass), graphene oxide (5 parts by mass), chitosan (15 parts by mass), folic acid (10 parts by mass), and a gelatin aqueous solution (30 parts by mass, gelatin content 30 wt%) prepared in example 1 to obtain a paramagnetic metal fullerene solution; wherein the number average molecular weight of the gelatin is 20000 Da; graphene oxide having a porosity of 90% and a specific surface area of 2800m2G, thickness 15 nm; the chitosan is provided by Qingdao Honghai biotechnology limited, the deacetylation degree is 90%, and the room temperature viscosity is 100 mpa.s.
2) Extruding the paramagnetic metal fullerene solution prepared in the step 1) to the surface of a substrate in a wire bar coating mode, wherein the wire bar coating speed is 0.4m/mim, the wire bar weight is 0.7kg, and the coating uniformity is controlled within +/-3%; then placing in an oven at 50 deg.C for 50min to obtain 150 nm-thick paramagnetic metal fullerene film.
3) Performing laser cutting on the paramagnetic metal fullerene film, wherein the scanning step is 100nm/s, the laser spot is 0.05 mu m, the energy of an electron beam is 50mJ, and the cutting precision is less than 100 nm; after the laser cutting is finished, the cylindrical nano robot (with the height of 150nm and the diameter of 100nm) for treating the tumor is obtained.
Example 3
The preparation of the nano robot for treating the tumor comprises the following steps:
1) mixing the paramagnetic metal fullerene particles (35 parts by mass), graphene oxide (6 parts by mass), chitosan (15 parts by mass), folic acid (12 parts by mass), and a gelatin aqueous solution (32 parts by mass, gelatin content 30 wt%) prepared in example 1 to obtain a paramagnetic metal fullerene solution; wherein the number average molecular weight of the gelatin is 20000 Da; graphene oxide having a porosity of 90% and a specific surface area of 2800m2G, thickness 15 nm; the chitosan is provided by Qingdao Honghai biotechnology limited, the deacetylation degree is 90%, and the room temperature viscosity is 100 mpa.s.
2) Extruding the paramagnetic metal fullerene solution prepared in the step 1) to the surface of a substrate in a wire bar coating mode, wherein the wire bar coating speed is 0.5m/mim, the wire bar weight is 0.8kg, and the coating uniformity is controlled within +/-3%; then placing in an oven at 53 deg.C for 45min to obtain paramagnetic metal fullerene film with thickness of 160 nm.
3) Performing laser cutting on the paramagnetic metal fullerene film, wherein the scanning step is 100nm/s, the laser spot is 0.05 mu m, the energy of an electron beam is 50mJ, and the cutting precision is less than 100 nm; after the laser cutting is finished, a cylindrical nano robot (with the height of 160nm and the diameter of 110nm) for treating tumors is obtained.
Example 4
1) The preparation method of the paramagnetic metal fullerene comprises the following steps:
1.1) cleaning: firstly, wiping a glass workpiece clamp with alcohol, then putting the workpiece clamp into an ultrasonic cleaning machine, carrying out deionized water ultra-cleaning and alcohol ultra-cleaning, and finally putting the workpiece clamp into alcohol steam for drying;
1.2) pasting a protective film: sticking a polyethylene film on the cleaned workpiece clamp, protecting the cleanliness of the workpiece clamp and protecting the workpiece clamp from being damaged;
1.3) installing the workpiece clamp pasted with the film on a running track of a magnetron sputtering device, and tearing off the protective film before entering a film inlet chamber;
1.4) operating the working clamp to a wafer feeding chamber of a magnetron sputtering device, then closing a vacuum gate valve, and starting a vacuum pump to keep the vacuum degree at 15 Pa;
1.5) opening a vacuum gate valve of a sputtering chamber of the magnetron sputtering device, and enabling a workpiece clamp to enter the fixed position of the sputtering chamber through a track;
1.6) introducing argon and oxygen into the sputtering chamber, starting a DC power supply (420V, 3600W) of the sputtering chamber, bombarding an iron target (ferric oxide) for magnetron sputtering, and keeping for 5 min; wherein the argon flow is 50sccm, and the ventilation time is consistent with the time for performing magnetron sputtering; the oxygen flow is 12sccm, and the ventilation time is 3 min; during magnetron sputtering, the temperature of the cavity of the sputtering chamber is maintained at 1050 ℃;
1.7) after the magnetron sputtering is finished, keeping the cavity temperature of the sputtering chamber at 1050 ℃, and introducing acetylene gas into the sputtering chamber, wherein the flow rate of the acetylene gas is 110sccm, and the introduction time is 10 min;
1.8) after the acetylene gas is introduced, introducing argon as a protective gas with the introduction amount of 900sccm, and simultaneously starting a cooling device to ensure that the temperature of a cavity of a sputtering chamber is reduced to 205 ℃ within 10min to obtain carbon sphere particles adsorbed around a working clamp, namely the paramagnetic metal fullerene prepared by the embodiment;
1.9), moving the working clamp to a film discharging chamber of a magnetron sputtering device along the running track, introducing protective gas argon into the film discharging chamber, introducing the protective gas argon with the amount of 350sccm, and naturally cooling to 25 ℃;
1.10) opening a vacuum valve of the sheet outlet chamber, enabling the working clamp to leave the sheet outlet chamber along a track, and then collecting the paramagnetic metal fullerene on the working clamp to obtain paramagnetic metal fullerene particles.
The paramagnetic metal fullerene particles prepared in this example were measured for particle size, uniformity of particle size, purity, degree of graphitization, saturation magnetization, residual magnetization, and coercive force.
The particle size and the particle size uniformity are obtained by analyzing the morphology and the crystallization morphology of the prepared paramagnetic metal fullerene particles by using a JEM-2010 high-resolution transmission electron microscope, and the calculation formula of the particle size uniformity is as follows: (D)Big (a)-DSmall)/(DBig (a)+DSmall)×100％，DBig (a)Denotes the maximum diameter value, D, measured from the granules preparedSmallRepresents the smallest diameter measured from the prepared particles;
the purity and graphitization degree are obtained by performing water solubility analysis on the prepared paramagnetic metal fullerene particles by using an FES165 Fourier infrared spectrometer (FT-IR) and a cary-300VARIAN ultraviolet visible spectrum analyzer;
the magnetization and coercive force were obtained by performing magnetic property analysis on the prepared paramagnetic metal fullerene particles using a Lakeshore 7410 vibrating sample magnetometer.
The measurement results are as follows: the grain size is 90-10 nm, the uniformity of the grain size is less than 5.3%, the purity is more than 99.9%, the graphitization degree is more than 93%, the saturation magnetization is 19.325emu/G, the residual magnetization is 4.4322emu/G, and the coercive force is 577.26G.
2) The preparation of the nano robot for treating the tumor comprises the following steps:
2.1) mixing the paramagnetic metal fullerene particles (38 parts by mass) prepared in the step 1), graphene oxide (7 parts by mass), chitosan (13 parts by mass), folic acid (12 parts by mass) and a gelatin aqueous solution (30 parts by mass, the gelatin content being 30 wt%) to obtain a paramagnetic metal fullerene solution; wherein the gelatin has a number average molecular weight of 20000 Da; graphene oxide having a porosity of 90% and a specific surface area of 2800m2G, thickness 15 nm; the chitosan is provided by Qingdao Honghai biotechnology limited, the deacetylation degree is 90%, and the room temperature viscosity is 100 mpa.s.
2.2) extruding the paramagnetic metal fullerene solution prepared in the step 1) to the surface of the substrate in a wire bar coating mode, wherein the wire bar coating speed is 0.6m/mim, the wire bar weight is 0.8kg, and the coating uniformity is controlled within +/-3%; then placing in an oven at 48 deg.C for 50min to obtain 145 nm-thick paramagnetic metal fullerene film.
2.3) carrying out laser cutting on the paramagnetic metal fullerene film, wherein the scanning step is 100nm/s, the laser spot is 0.05 mu m, the energy of an electron beam is 50mJ, and the cutting precision is less than 100 nm; after the laser cutting is finished, a cylindrical nano robot (with the height of 145nm and the diameter of 95nm) for treating tumors is obtained.
Evaluation of Effect
Tumor treatment
1) Introduction of radio frequency heating technology and heating principle:
1.1) radio frequency heating technology: the tissue to be heated is placed between a pair of capacitance plates (the electrodes are not in contact with the human body), and radio frequency voltage is applied between the electrodes (capacitance field method), so that the tissue body between the capacitance plates absorbs electric field energy and converts the electric field energy into heat energy during thermotherapy, thereby raising the temperature of the tissue. Generally, the radio frequency band is 13.56MHz, and the power is 0-800W.
1.2) heating principle: the nanometer robot for treating tumor absorbs electromagnetic wave energy under the action of the alternating magnetic field to generate vibration motion, paramagnetic metal fullerene particles in the nanometer robot generate heat due to hysteresis loss, and tumor tissues accumulated by the paramagnetic metal fullerene particles can also generate heat due to heat transfer. The tumor tissue has the advantages of distorted and expanded blood vessels, large blood resistance, unhealthy vascular receptors, poor temperature sensitivity, difficult heat dissipation under the action of high temperature, easy heat accumulation, quick temperature rise, formation of a huge heat storage reservoir, 5-10 ℃ temperature difference with normal tissue, and severe volume expansion of about 30-60% of paramagnetic metal fullerene particles contained in the nano robot. If the temperature of the tumor tissue is made to reach 43 ℃ or the tumor blood vessels burst, the tumor cells are overheated or cut off the nutrition to die.
2) And (3) tumor treatment operation:
1mg of the nano-robot for tumor treatment prepared in example 2 was diluted into physiological saline and then intravenously injected into mice. The nano-robots injected into the mouse body can automatically recognize tumor cells through the modified folic acid, and the nano-robots reach the tumor position and are clamped on the blood vessel wall for a long time after 30-60 min (due to the fact that the endothelial cells forming the tumor blood vessel have large gaps and incomplete structures, the tumor blood vessel usually comprises a large number of small holes with nanometer scales, small molecules and some nano-particles can enter through the through holes, and when the nano-robots for tumor treatment pass through the gaps of the tumor blood vessel, the nano-robots can be tightly surrounded by the endothelial cells of the tumor blood vessel). After confirming that the excess nanotubrobots flowed away by CT scanning, the mice were then rf "detonated". After several minutes to dozens of minutes, the internal energy rises to generate phase change, and the volume is expanded by about 30-60% along with the violent expansion, so that the nanometer robots which are embedded on the wall of the tumor vessel and used for treating the tumor explode to effectively destroy the tumor vessel, then quickly block the nutrition supply to the tumor, and completely starve the tumor cells within several hours.
3) Evaluation of biocompatibility and degradation:
the nano robots for tumor therapy prepared in examples 2 to 4 were used as test samples, respectively, the tumor therapy operation of step 1.2) was performed, and then the biocompatibility and degradation condition of each test sample in vivo was identified by CT image, and the results are shown in table 1:
TABLE 1 biocompatibility and degradation of different test samples
As can be seen from the data in Table 1, the nano robot for tumor treatment is completely degraded or absorbed by a human body within 3-5 weeks after killing tumor cells, and has no side effect.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A preparation method of a nano robot for tumor treatment comprises the following steps:
a) placing a paramagnetic metal target material in a sputtering chamber, introducing argon and oxygen into the sputtering chamber, and starting a power supply of the sputtering chamber to perform magnetron sputtering; in the magnetron sputtering process, the temperature of a cavity of the sputtering chamber is 800-1200 ℃;
b) after the magnetron sputtering is finished, maintaining the temperature of a cavity of the sputtering chamber at 800-1200 ℃, and introducing acetylene gas into the sputtering chamber;
c) after the acetylene gas is introduced, introducing a protective gas into the sputtering chamber, and reducing the temperature of the cavity of the sputtering chamber to 100-300 ℃ within 5-15 min to obtain paramagnetic metal fullerene;
d) mixing the paramagnetic metal fullerene and a cross-linking agent in a solvent to obtain a paramagnetic metal fullerene solution; then coating the paramagnetic metal fullerene solution on the surface of a substrate, and curing to obtain a paramagnetic metal fullerene film;
e) and cutting the paramagnetic metal fullerene film according to a preset shape to obtain the nano robot for treating the tumor.
2. The method according to claim 1, wherein in step a), the paramagnetic metal target comprises one or more of iron oxide, titanium oxide and zirconium oxide.
3. The method according to claim 1, wherein in step a), the power supply is a dc power supply; the voltage of the power supply is 330-420V; the power of the power supply is 2400-3600W.
4. The preparation method of claim 1, wherein in the step a), during the magnetron sputtering process, the vacuum degree of the sputtering chamber is 10-30 Pa; the gas inflow rate of the argon is 40-50 sccm; the air inflow rate of the oxygen is 10-15 sccm.
5. The preparation method of claim 4, wherein in the step a), the magnetron sputtering time is 5-8 min.
6. The manufacturing method according to claim 1, wherein in the step b), the degree of vacuum of the sputtering chamber is 10 to 30 Pa; the gas inflow rate of the acetylene gas is 100-120 sccm.
7. The method according to claim 6, wherein the acetylene gas is introduced in the step b) for 10 to 15 min.
8. The method according to claim 1, wherein the paramagnetic metal fullerene solution further comprises one or more of graphene oxide, chitosan and folic acid in step d).
9. The preparation method according to claim 8, wherein the mass ratio of the paramagnetic metal fullerene, the graphene oxide, the chitosan, the folic acid and the cross-linking agent is (35-40): (5-10): (10-15): (5-15): (6-12).
10. The nano robot for treating tumor prepared by the preparation method of any one of claims 1 to 9.
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