CN115252876B - Monodisperse luminous development medicine-carrying four-in-one embolism microsphere and preparation method thereof - Google Patents
Monodisperse luminous development medicine-carrying four-in-one embolism microsphere and preparation method thereof Download PDFInfo
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- 239000004005 microsphere Substances 0.000 title claims abstract description 123
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 208000005189 Embolism Diseases 0.000 title claims abstract description 17
- 239000002245 particle Substances 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 11
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 44
- 125000004386 diacrylate group Chemical group 0.000 claims description 44
- 229920001223 polyethylene glycol Polymers 0.000 claims description 44
- 239000011259 mixed solution Substances 0.000 claims description 41
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 30
- 230000003073 embolic effect Effects 0.000 claims description 30
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 claims description 25
- 239000007788 liquid Substances 0.000 claims description 23
- 229960004679 doxorubicin Drugs 0.000 claims description 15
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- 230000009471 action Effects 0.000 claims description 13
- PGWMQVQLSMAHHO-UHFFFAOYSA-N sulfanylidenesilver Chemical class [Ag]=S PGWMQVQLSMAHHO-UHFFFAOYSA-N 0.000 claims description 12
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- 239000003814 drug Substances 0.000 claims description 11
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- 238000004132 cross linking Methods 0.000 claims description 10
- 238000004020 luminiscence type Methods 0.000 claims description 10
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- 229940079593 drug Drugs 0.000 claims description 9
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 claims description 9
- 230000006378 damage Effects 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
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- 238000001723 curing Methods 0.000 claims description 2
- 230000000977 initiatory effect Effects 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000011858 nanopowder Substances 0.000 claims description 2
- 238000004062 sedimentation Methods 0.000 claims description 2
- XUARKZBEFFVFRG-UHFFFAOYSA-N silver sulfide Chemical compound [S-2].[Ag+].[Ag+] XUARKZBEFFVFRG-UHFFFAOYSA-N 0.000 claims description 2
- 229940056910 silver sulfide Drugs 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims description 2
- 229920000671 polyethylene glycol diacrylate Polymers 0.000 claims 5
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 229920002545 silicone oil Polymers 0.000 claims 1
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- 238000009210 therapy by ultrasound Methods 0.000 description 8
- XMLYCEVDHLAQEL-UHFFFAOYSA-N 2-hydroxy-2-methyl-1-phenylpropan-1-one Chemical compound CC(C)(O)C(=O)C1=CC=CC=C1 XMLYCEVDHLAQEL-UHFFFAOYSA-N 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 description 7
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- 201000011510 cancer Diseases 0.000 description 4
- KUDUQBURMYMBIJ-UHFFFAOYSA-N 2-prop-2-enoyloxyethyl prop-2-enoate Chemical compound C=CC(=O)OCCOC(=O)C=C KUDUQBURMYMBIJ-UHFFFAOYSA-N 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 206010014513 Embolism arterial Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
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- 229940044683 chemotherapy drug Drugs 0.000 description 1
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Classifications
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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
-
- 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
- A61L24/0015—Medicaments; Biocides
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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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- 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
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/02—Use of particular materials as binders, particle coatings or suspension media therefor
- C09K11/025—Use of particular materials as binders, particle coatings or suspension media therefor non-luminescent particle coatings or suspension media
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/08—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials
- C09K11/58—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials containing copper, silver or gold
- C09K11/582—Chalcogenides
- C09K11/586—Chalcogenides with alkaline earth metals
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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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
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- General Health & Medical Sciences (AREA)
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- Engineering & Computer Science (AREA)
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Abstract
The invention discloses a luminous developing medicine-carrying four-in-one embolism microsphere with a monodisperse particle size and a preparation method thereof. The microsphere integrates embolism, near infrared two-region visible and X-ray development and anti-tumor functions, and can be used for embolism tumor or hemostasis and other diseases. The method has the advantages of simple process flow, low production cost, good repeatability, easy mass production, monodispersion of microsphere particle size and regulation of microsphere particle size by controlling the proportion of a disperse phase to a continuous phase.
Description
Technical Field
The invention relates to a preparation method of four-in-one polyethylene glycol diacrylate embolic microspheres, in particular to monodisperse drug-loaded embolic microspheres capable of emitting light in a near infrared two-region and developing under X rays and a preparation method thereof.
Background
Cancer is one of the most difficult diseases to cure at present, and along with the gradual acceleration of the life rhythm, irregular life habits gradually occupy the lives of people. The main treatments for cancer mainly include surgical excision, chemotherapy, etc. However, these methods can cause intuitive irreversible damage to the body, and corresponding side effects can also jeopardize body safety. Direct excision is not only likely to cause massive hemorrhage, but also is easy to cause postoperative focus metastasis, and the same treatment completely depends on chemotherapy to kill cancer cells, but also has a non-trivial damage to normal cells, which is known as injury of one thousand years from eight hundred years. The arterial embolism operation via catheter is mainly to inject the embolic agent into the supply vessel of the lesion target organ via arterial or intravenous catheter, so as to occlude the vessel, interrupt the blood supply and starve the target cells, thus finally achieving the treatment purpose.
In addition to blocking blood vessels, the embolic emulsion is mixed with chemotherapeutic drugs, so that the drugs are released to the tumor while the necessary nutrient delivery to the tumor is blocked, and the tumor is killed to achieve the double-tube effect. Compared with the traditional method, the tumor interventional therapy has the advantages of minimally invasive, low cost, safety, good curative effect and the like, and has more important significance for patients with tumors which cannot be operated. For patients with middle and advanced cancer or those who cannot remove tumors using surgery, this is not a palliative therapy; secondly, for the crowd who is too large for operation, the operation excision can be implemented after the tumor is reduced through the catheter arterial embolism operation; in addition, the method can also be used for intra-arterial perfusion chemotherapy for preventing recurrence after tumor resection.
At present, no monodisperse embolic agent with near infrared two-region visible and X-ray developing, drug carrying and embolic functions is available, which provides guarantee for accurate positioning in the embolic process and reflux avoidance and support for avoiding postoperative massive hemorrhage and focus metastasis.
Disclosure of Invention
The invention aims to provide a preparation method of a luminous developing medicine-carrying four-in-one polyethylene glycol diacrylate embolism microsphere with monodisperse particle size and good biocompatibility.
The technical scheme of the invention is as follows:
a preparation method of a luminous development medicine-carrying four-in-one polyethylene glycol diacrylate embolic microsphere comprises the following steps:
s1, adding a photoinitiator 2-hydroxy-2-methyl-1-phenyl-1-acetone into polyethylene glycol diacrylate to obtain a mixed solution;
s2, dispersing doxorubicin, barium sulfate nano powder and silver sulfide quantum dots in the mixed solution, and uniformly mixing the mixed solution by ultrasonic treatment for 30 min;
s3, sucking the obtained mixed solution into an injector, placing the injector on a microfluidic pump as a disperse phase, placing the injector into another microfluidic pump as a continuous phase, generating liquid drops by utilizing shearing action, initiating polymerization reaction by ultraviolet light action, solidifying the liquid drops, and washing the liquid drops with demulsifier and distilled water for multiple times to obtain the monodisperse luminous developing drug-loaded embolism microsphere.
In the preparation method, in the step S1, a photoinitiator is dissolved in polyethylene glycol diacrylate at room temperature to obtain a polyethylene glycol diacrylate solution with the concentration of 90-95% (wt%).
In the preparation method, in the step S1, the added photoinitiator absorbs the energy of light after being irradiated by ultraviolet light and splits into 2 active free radicals to trigger PEG-DA to carry out chain polymerization crosslinking curing, and the preparation method is characterized by rapidness, environmental protection and energy conservation
In the preparation method, in the step S2, according to the different solubility and the different luminescence degree of the silver sulfide and the barium sulfate, the dosage and the mass ratio of the barium sulfate powder to the silver sulfide quantum dots are preferably controlled to be 30:1-10:1.
In the preparation method, in the step S2, the dosage mass ratio of the barium sulfate powder to the PEG-DA is controlled to be preferably 1:10-1:30 according to the sedimentation speed of the barium sulfate.
In the preparation method, in the step S2, the dosage and mass ratio of the doxorubicin to the PEG-DA is controlled to be 1:2000 optimally according to the microsphere drug release rate and the damage degree of the doxorubicin to normal cells.
In the preparation method, in the step S3, the flow rate of the water phase is 2 mu L/min-20 mu L/min and the flow rate of the oil phase is 50 mu L/min-200 mu L/min.
In the preparation method, in the step S3, a 365nm ultraviolet light source is selected.
In the preparation method, in step S3, the washing is as follows: washed 3 times with 1% Triton (Triton X-100) aqueous solution, rinsed thoroughly with distilled water, and dried under vacuum.
The luminous development medicine-carrying four-in-one polyethylene glycol diacrylate embolic microsphere prepared by any one of the preparation methods has four functions of embolism, anti-tumor, luminescence and development, wherein the polyethylene glycol diacrylate wraps the anti-tumor medicine, the near infrared two-region luminous material and the development material under X rays form a microsphere structure.
The particle size distribution of the four-in-one polyethylene glycol diacrylate embolic microsphere for carrying medicine through luminescence development is within any narrow range of 100-1200 mu m, and the microsphere has monodispersity.
Compared with the prior art, the invention has the advantages that:
(1) According to the method, firstly, an anti-tumor drug, a near infrared two-region luminescent material and an X-ray developer are loaded into polyethylene glycol diacrylate, drops with the required particle size are rapidly and accurately formed through shearing action, and cross-linking and solidification are rapidly initiated through ultraviolet light, so that the four-in-one embolic microsphere is directly obtained.
(2) The four-in-one embolism microsphere prepared by the method can emit light and be visible in a near infrared two-region due to the action of the silver sulfide quantum dots, and can be developed under X rays due to the existence of the barium sulfate, so that the application of the four-in-one embolism microsphere is wider due to the cooperation of the two components, and the four-in-one embolism microsphere can be positioned better and accurately;
(3) The four-in-one embolism microsphere prepared by the invention has better biocompatibility, wider controllable range of particle size, monodisperse particle size and better embolism; better biocompatibility and more favorable clinical application.
Drawings
FIG. 1 is a microscopic view of the four-in-one polyethylene glycol diacrylate embolic microsphere obtained in example 1;
FIG. 2 is a near infrared two-region luminescence of the four-in-one polyethylene glycol diacrylate embolic microsphere obtained in example 1;
FIG. 3 is an X-ray image of the four-in-one polyethylene glycol diacrylate embolic microsphere obtained in example 1.
FIG. 4 is a graph showing the cell viability of the four-in-one polyethylene glycol diacrylate embolic microspheres obtained in example 1.
FIG. 5 is a chart showing the living and death of cells in the case where the four-in-one polyethylene glycol diacrylate embolic microsphere obtained in example 1 was incubated with normal cells.
Detailed Description
The present invention will be described in detail with reference to specific examples.
The microsphere morphology photograph was measured by an OLYMPU SCKX53 inverted fluorescence microscope.
Near infrared two-zone luminescence data were measured by a UniNano-NIR II near infrared two-zone imager.
The X-ray development data were measured by IVIS Lumina XRMS type small animal living body imaging instrument.
Cytotoxicity data were measured by SpectraMax M3 enzyme-labeled instrument.
Cell viability data were measured by OLYMPU SCKX53 inverted fluorescence microscopy.
Example 1
Microsphere preparation
0.3g of 2-hydroxy-2-methyl-1-phenyl-1-propanone as a photoinitiator was mixed into 10g of polyethylene glycol diacrylate (Mw=575) at room temperature to obtain a polyethylene glycol diacrylate mixed solution, 5mg of doxorubicin was dispersed in the mixed solution, 1g of nano-sized barium sulfate powder was dispersed in the mixed solution, 0.1g of silver sulfide quantum dots was dispersed in the mixed solution, and a uniform mixed solution was formed by ultrasonic treatment for 30 min. The resulting mixed droplets were then drawn into a syringe and placed on a microfluidic pump as the aqueous phase (dispersed phase). Then, the simethicone is sucked by a syringe with the same specification and is arranged on a microfluidic pump with the same specification as an oil phase (continuous phase), a transparent hose is used for connecting a channel with a syringe needle, the flow rate of the disperse phase is set to be 2 mu L/min-5 mu L/min, the flow rate of the continuous phase is set to be 200 mu L/min, liquid drops are formed through shearing action, the particle size of the obtained microsphere is in direct proportion to the flow rate of the disperse phase and in inverse proportion to the flow rate of the continuous phase, and the microsphere with different particle sizes is obtained by adjusting the flow rate proportion of the disperse phase to the continuous phase. And (3) applying 365nm ultraviolet light above the collecting channel, and crosslinking within 5 seconds to obtain the embolic microsphere. Washing with 1% Triton (Triton X-100) aqueous solution for 3 times, thoroughly rinsing with distilled water, and vacuum drying.
The flow rates of the liquid of the disperse phase and the continuous phase are regulated, so that the microspheres with different particle diameters can be obtained.
Microsphere microscope
The microspheres prepared in this example were dried and sieved and observed under an inverted fluorescence microscope. The result shows that the microsphere prepared by the embodiment has monodispersity and good sphericity, and is round and smooth in surface and distributed on the microsphere with 100-300 mu m.
Near infrared two-zone visible luminous effect
The microspheres prepared in the embodiment and the common polyethylene glycol diacrylate microspheres are respectively filled in an EP tube, and the light-emitting condition is observed under a near infrared two-region small animal imaging instrument. The results show that the microspheres prepared in the embodiment have obvious light emission in the near infrared two regions, and the common polyethylene glycol diacrylate microspheres do not emit light.
Luminous effect under X-ray
The microspheres prepared in the embodiment and the common polyethylene glycol diacrylate microspheres are respectively filled in an EP tube, and the light-emitting condition is observed under an X-ray small animal imaging instrument. The results show that the microspheres prepared in the example can be developed under X-rays, and the common polyethylene glycol diacrylate microspheres are not developed under X-rays.
Cytotoxicity of cells
The microsphere prepared in the example is used for detecting cytotoxicity by using an MTT method, the microsphere is incubated in cells for 24 hours, 48 hours and 72 hours respectively, the survival rate of the cells is measured by using an enzyme-labeled instrument, and then the cells are stained by AM/PI, and the living and dead conditions of the cells are observed under an inverted fluorescence microscope. The result shows that the microsphere prepared by the example has almost no cytotoxicity except the cytotoxicity of the doxorubicin itself, and has higher cell survival rate, which indicates that the microsphere has better biocompatibility.
FIG. 1 is a microscopic view of the four-in-one polyethylene glycol diacrylate embolic microsphere obtained in example 1, showing that the microsphere particle size has monodispersity, good sphericity and smoother and uniform sphere itself;
FIG. 2 is a near infrared two-region luminescence diagram of the four-in-one polyethylene glycol diacrylate embolic microsphere obtained in example 1, and as can be seen from the figure, the four-in-one polyethylene glycol diacrylate embolic microsphere has stronger luminescence and stronger visibility in the near infrared two-region than the common polyethylene glycol diacrylate microsphere;
FIG. 3 is an X-ray image of the four-in-one polyethylene glycol diacrylate embolic microsphere obtained in example 1, showing that the four-in-one polyethylene glycol diacrylate embolic microsphere is easier to develop and more visible under X-rays than the conventional polyethylene glycol diacrylate microsphere;
FIGS. 4 and 5 are cytotoxicity data of the four-in-one polyethylene glycol diacrylate embolic microsphere obtained in example 1, and cell viability data of FIG. 4; FIG. 5 shows the cell viability and staining data, and shows that the microspheres incubated with doxorubicin had good cell viability and little cytotoxicity.
Example 2
Microsphere preparation
0.3g of 2-hydroxy-2-methyl-1-phenyl-1-propanone as a photoinitiator was mixed into 10g of polyethylene glycol diacrylate (Mw=575) at room temperature to obtain a polyethylene glycol diacrylate mixed solution, 5mg of doxorubicin was dispersed in the mixed solution, 0.5g of nano-sized barium sulfate powder was dispersed in the mixed solution, 0.1g of silver sulfide quantum dots was dispersed in the mixed solution, and a uniform mixed solution was formed by ultrasonic treatment for 30 min. The resulting mixed droplets were then drawn into a syringe and placed on a microfluidic pump as the aqueous phase (dispersed phase). Then, the simethicone is sucked by a syringe with the same specification and is arranged on a microfluidic pump with the same specification as an oil phase (continuous phase), a transparent hose is used for connecting a channel with a syringe needle, the flow rate of the disperse phase is set to be 2 mu L/min-5 mu L/min, the flow rate of the continuous phase is set to be 200 mu L/min, liquid drops are formed through shearing action, the particle size of the obtained microsphere is in direct proportion to the flow rate of the disperse phase and in inverse proportion to the flow rate of the continuous phase, and the microsphere with different particle sizes is obtained by adjusting the flow rate proportion of the disperse phase to the continuous phase. And (3) applying 365nm ultraviolet light above the collecting channel, and crosslinking within 5 seconds to obtain the embolic microsphere. Washing with 1% Triton (Triton X-100) aqueous solution for 3 times, thoroughly rinsing with distilled water, and vacuum drying.
The flow rates of the liquid of the disperse phase and the continuous phase are regulated, so that the microspheres with different particle diameters can be obtained.
Microsphere microscope
The morphology of the microspheres was measured in the same manner as in example 1, and the result showed that the microspheres were monodisperse in particle size and distributed in a range of 300 to 500 μm in the same particle size as in example 1.
Near infrared two-zone visible luminous effect
The light-emitting effect in the near infrared two region was measured in the same manner as in example 1, and the result showed that the light-emitting effect was good as in example 1.
Luminous effect under X-ray
The development effect under X-rays was measured in the same manner as in example 1, and as a result, it was found that the development effect was good, but the degree of luminescence was slightly lower than in example 1.
Cytotoxicity of cells
Cytotoxicity of the microspheres was measured in the same manner as in example 1, and the result showed that the biocompatibility of the microspheres was good.
Example 3
Microsphere preparation
0.3g of 2-hydroxy-2-methyl-1-phenyl-1-propanone as a photoinitiator was mixed into 10g of polyethylene glycol diacrylate (Mw=575) at room temperature to obtain a polyethylene glycol diacrylate mixed solution, 5mg of doxorubicin was dispersed in the mixed solution, 1g of nano-sized barium sulfate powder was dispersed in the mixed solution, 0.05g of silver sulfide quantum dots was dispersed in the mixed solution, and a uniform mixed solution was formed by ultrasonic treatment for 30 min. The resulting mixed droplets were then drawn into a syringe and placed on a microfluidic pump as the aqueous phase (dispersed phase). Then, the simethicone is sucked by a syringe with the same specification and is arranged on a microfluidic pump with the same specification as an oil phase (continuous phase), a transparent hose is used for connecting a channel with a syringe needle, the flow rate of the disperse phase is set to be 2 mu L/min-5 mu L/min, the flow rate of the continuous phase is set to be 200 mu L/min, liquid drops are formed through shearing action, the particle size of the obtained microsphere is in direct proportion to the flow rate of the disperse phase and in inverse proportion to the flow rate of the continuous phase, and the microsphere with different particle sizes is obtained by adjusting the flow rate proportion of the disperse phase to the continuous phase. And (3) applying 365nm ultraviolet light above the collecting channel, and crosslinking within 5 seconds to obtain the embolic microsphere. Washing with 1% Triton (Triton X-100) aqueous solution for 3 times, thoroughly rinsing with distilled water, and vacuum drying.
The flow rates of the liquid of the disperse phase and the continuous phase are regulated, so that the microspheres with different particle diameters can be obtained.
Microsphere microscope
The morphology of the microspheres was measured in the same manner as in example 1, and the result showed that the microspheres were monodisperse in particle size and distributed in a range of 300 to 500 μm in the same particle size as in example 1.
Near infrared two-zone visible luminous effect
The light-emitting effect in the near infrared two region was measured in the same manner as in example 1, and the result showed that the light-emitting effect was good, but the light-emitting degree was lower than in example 1.
Luminous effect under X-ray
The development effect under X-rays was measured in the same manner as in example 1, and as a result, it was found that the development effect was good, as in example 1.
Cytotoxicity of cells
Cytotoxicity of the microspheres was measured in the same manner as in example 1, and the result showed that the biocompatibility of the microspheres was good.
Example 4
Microsphere preparation
0.3g of 2-hydroxy-2-methyl-1-phenyl-1-propanone as a photoinitiator was mixed into 10g of polyethylene glycol diacrylate (Mw=575) at room temperature to obtain a polyethylene glycol diacrylate mixed solution, 5mg of doxorubicin was dispersed in the mixed solution, 1g of nano-sized barium sulfate powder was dispersed in the mixed solution, 0.1g of silver sulfide quantum dots was dispersed in the mixed solution, and a uniform mixed solution was formed by ultrasonic treatment for 30 min. The resulting mixed droplets were then drawn into a syringe and placed on a microfluidic pump as the aqueous phase (dispersed phase). Then, the simethicone is sucked by a syringe with the same specification and is arranged on a microfluidic pump with the same specification as an oil phase (continuous phase), a transparent hose is used for connecting a channel with a syringe needle, the flow rate of a disperse phase is set to be 5 mu L/min, the flow rate of the continuous phase is set to be 150 mu L/min-200 mu L/min, liquid drops are formed through shearing action, the particle size of the obtained microsphere is in direct proportion to the flow rate of the disperse phase and in inverse proportion to the flow rate of the continuous phase, and the microsphere with different particle sizes is obtained by adjusting the flow rate proportion of the disperse phase to the continuous phase. And (3) applying 365nm ultraviolet light above the collecting channel, and crosslinking within 5 seconds to obtain the embolic microsphere. Washing with 1% Triton (Triton X-100) aqueous solution for 3 times, thoroughly rinsing with distilled water, and vacuum drying.
The flow rates of the liquid of the disperse phase and the continuous phase are regulated, so that the microspheres with different particle diameters can be obtained.
Microsphere microscope
The morphology of the microspheres was measured in the same manner as in example 1, and the result showed that the particle size of the microspheres was monodisperse and distributed in a range of 300 to 500. Mu.m.
Near infrared two-zone visible luminous effect
The light-emitting effect in the near infrared two region was measured in the same manner as in example 1, and the result showed good light-emitting effect.
Luminous effect under X-ray
The development effect under X-rays was measured in the same manner as in example 1, and it was found that the development effect was good.
Cytotoxicity of cells
Cytotoxicity of the microspheres was measured in the same manner as in example 1, and the result showed that the biocompatibility of the microspheres was good.
Example 5
Microsphere preparation
0.3g of 2-hydroxy-2-methyl-1-phenyl-1-propanone as a photoinitiator was mixed into 10g of polyethylene glycol diacrylate (Mw=575) at room temperature to obtain a polyethylene glycol diacrylate mixed solution, 5mg of doxorubicin was dispersed in the mixed solution, 1g of nano-sized barium sulfate powder was dispersed in the mixed solution, 0.1g of silver sulfide quantum dots was dispersed in the mixed solution, and a uniform mixed solution was formed by ultrasonic treatment for 30 min. The resulting mixed droplets were then drawn into a syringe and placed on a microfluidic pump as the aqueous phase (dispersed phase). Then, the simethicone is sucked by a syringe with the same specification and is arranged on a microfluidic pump with the same specification as an oil phase (continuous phase), a transparent hose is used for connecting a channel with a syringe needle, the flow rate of a disperse phase is set to be 10 mu L/min, the flow rate of the continuous phase is set to be 100 mu L/min-150 mu L/min, liquid drops are formed through shearing action, the particle size of the obtained microsphere is in direct proportion to the flow rate of the disperse phase and in inverse proportion to the flow rate of the continuous phase, and the microsphere with different particle sizes is obtained by adjusting the flow rate proportion of the disperse phase to the continuous phase. And (3) applying 365nm ultraviolet light above the collecting channel, and crosslinking within 5 seconds to obtain the embolic microsphere. Washing with 1% Triton (Triton X-100) aqueous solution for 3 times, thoroughly rinsing with distilled water, and vacuum drying.
The flow rates of the liquid of the disperse phase and the continuous phase are regulated, so that the microspheres with different particle diameters can be obtained.
Microsphere microscope
The morphology of the microspheres was measured in the same manner as in example 1, and the result showed that the particle size distribution was good, and the distribution was in the range of 500 to 700. Mu.m.
Near infrared two-zone visible luminous effect
The light-emitting effect in the near infrared two region was measured in the same manner as in example 1, and the result showed good light-emitting effect.
Luminous effect under X-ray
The development effect under X-rays was measured in the same manner as in example 1, and it was found that the development effect was good.
Cytotoxicity of cells
Cytotoxicity of the microspheres was measured in the same manner as in example 1, and the result showed that the biocompatibility of the microspheres was good.
Example 6
Microsphere preparation
0.3g of 2-hydroxy-2-methyl-1-phenyl-1-propanone as a photoinitiator was mixed into 10g of polyethylene glycol diacrylate (Mw=575) at room temperature to obtain a polyethylene glycol diacrylate mixed solution, 5mg of doxorubicin was dispersed in the mixed solution, 1g of nano-sized barium sulfate powder was dispersed in the mixed solution, 0.1g of silver sulfide quantum dots was dispersed in the mixed solution, and a uniform mixed solution was formed by ultrasonic treatment for 30 min. The resulting mixed droplets were then drawn into a syringe and placed on a microfluidic pump as the aqueous phase (dispersed phase). Then, the simethicone is sucked by a syringe with the same specification and is arranged on a microfluidic pump with the same specification as an oil phase (continuous phase), a transparent hose is used for connecting a channel with a syringe needle, the flow rate of a disperse phase is set to be 15 mu L/min, the flow rate of the continuous phase is set to be 100 mu L/min-150 mu L/min, liquid drops are formed through shearing action, the particle size of the obtained microsphere is in direct proportion to the flow rate of the disperse phase and in inverse proportion to the flow rate of the continuous phase, and the microsphere with different particle sizes is obtained by adjusting the flow rate proportion of the disperse phase to the continuous phase. And (3) applying 365nm ultraviolet light above the collecting channel, and crosslinking within 5 seconds to obtain the embolic microsphere. Washing with 1% Triton (Triton X-100) aqueous solution for 3 times, thoroughly rinsing with distilled water, and vacuum drying.
The flow rates of the liquid of the disperse phase and the continuous phase are regulated, so that the microspheres with different particle diameters can be obtained.
Microsphere microscope
The morphology of the microspheres was measured in the same manner as in example 1, and the result showed that the particle size distribution was good, and the distribution was in the range of 700 to 900. Mu.m.
Near infrared two-zone visible luminous effect
The light-emitting effect in the near infrared two region was measured in the same manner as in example 1, and the result showed good light-emitting effect.
Luminous effect under X-ray
The development effect under X-rays was measured in the same manner as in example 1, and it was found that the development effect was good.
Cytotoxicity of cells
Cytotoxicity of the microspheres was measured in the same manner as in example 1, and the result showed that the biocompatibility of the microspheres was good.
Example 7
Microsphere preparation
0.3g of 2-hydroxy-2-methyl-1-phenyl-1-propanone as a photoinitiator was mixed into 10g of polyethylene glycol diacrylate (Mw=575) at room temperature to obtain a polyethylene glycol diacrylate mixed solution, 5mg of doxorubicin was dispersed in the mixed solution, 1g of nano-sized barium sulfate powder was dispersed in the mixed solution, 0.1g of silver sulfide quantum dots was dispersed in the mixed solution, and a uniform mixed solution was formed by ultrasonic treatment for 30 min. The resulting mixed droplets were then drawn into a syringe and placed on a microfluidic pump as the aqueous phase (dispersed phase). Then, the simethicone is sucked by a syringe with the same specification and is arranged on a microfluidic pump with the same specification as an oil phase (continuous phase), a transparent hose is used for connecting a channel with a syringe needle, the flow rate of a disperse phase is set to be 20 mu L/min, the flow rate of the continuous phase is set to be 50 mu L/min-100 mu L/min, liquid drops are formed through shearing action, the particle size of the obtained microsphere is in direct proportion to the flow rate of the disperse phase and in inverse proportion to the flow rate of the continuous phase, and the microsphere with different particle sizes is obtained by adjusting the flow rate proportion of the disperse phase to the continuous phase. And (3) applying 365nm ultraviolet light above the collecting channel, and crosslinking within 5 seconds to obtain the embolic microsphere. Washing with 1% Triton (Triton X-100) aqueous solution for 3 times, thoroughly rinsing with distilled water, and vacuum drying.
The flow rates of the liquid of the disperse phase and the continuous phase are regulated, so that the microspheres with different particle diameters can be obtained.
Microsphere microscope
The morphology of the microspheres was measured in the same manner as in example 1, and the result showed that the particle size distribution was good, and the distribution was in the range of 900 to 1200. Mu.m.
Near infrared two-zone visible luminous effect
The light-emitting effect in the near infrared two region was measured in the same manner as in example 1, and the result showed good light-emitting effect.
Luminous effect under X-ray
The development effect under X-rays was measured in the same manner as in example 1, and it was found that the development effect was good.
Cytotoxicity of cells
Cytotoxicity of the microspheres was measured in the same manner as in example 1, and the result showed that the biocompatibility of the microspheres was good.
It will be understood that modifications and variations will be apparent to those skilled in the art from the foregoing description, and it is intended that all such modifications and variations be included within the scope of the following claims.
Claims (7)
1. The preparation method of the luminous development medicine-carrying four-in-one embolism microsphere with the monodisperse particle size is characterized by comprising the following steps of:
s1, adding a photoinitiator 2-hydroxy-2-methyl-1-phenyl-1-acetone into polyethylene glycol diacrylate (PEG-DA) to obtain a mixed solution; adding a photoinitiator to polyethylene glycol diacrylate with Mw=575 at room temperature according to 3wt% to obtain a PEG-DA solution with 90-95 wt%;
s2, dispersing doxorubicin, barium sulfate nano powder and silver sulfide quantum dots in the mixed solution, and uniformly mixing by ultrasonic; according to the different solubility and the different luminescence degree of the silver sulfide and the barium sulfate, the dosage and mass ratio of the barium sulfate powder to the silver sulfide quantum dots is controlled to be 30:1-10:1; controlling the dosage mass ratio of the barium sulfate powder to the PEG-DA to be 1:10-1:30 according to the sedimentation speed of the barium sulfate;
s3, sucking the obtained mixed liquid drops into a syringe and placing the mixed liquid drops on a microfluidic pump to serve as a water phase, then sucking dimethyl silicone oil by using the syringe with the same specification and placing the mixed liquid drops on the microfluidic pump with the same specification to serve as an oil phase, connecting a channel by using a transparent hose and a syringe needle, generating liquid drops by using a shearing action, initiating a polymerization reaction by using an ultraviolet light action, solidifying the liquid drops, and washing the liquid drops with distilled water for multiple times by using a demulsifier to obtain the monodisperse luminous developing drug-loaded embolism microsphere; the flow rate of the water phase is 2-20 mu L/min and the flow rate of the oil phase is 50-200 mu L/min.
2. The preparation method according to claim 1, wherein in step S1, the added photoinitiator absorbs light energy after being irradiated by ultraviolet light, and splits into 2 active free radicals to initiate PEG-DA to undergo chain polymerization, cross-linking and curing, and the preparation method is characterized by being rapid, environment-friendly and energy-saving.
3. The preparation method according to claim 1, wherein in step S2, the dosage mass ratio of doxorubicin to PEG-DA is controlled to be 1:2000 according to the microsphere drug release rate and the damage degree of doxorubicin to normal cells.
4. The method according to claim 1, wherein in step S3, 365nm ultraviolet light source is selected.
5. The method according to claim 1, wherein in step S3, the washing is: washed 3 times with 1% Triton (Triton X-100) aqueous solution, rinsed thoroughly with distilled water, and dried under vacuum.
6. The monodisperse luminescent development drug-loaded four-in-one embolism microsphere prepared by the preparation method according to any one of claims 1-5 is characterized in that polyethylene glycol diacrylate wraps an anti-tumor drug, a near infrared two-region luminescent material and an X-ray development material to form a microsphere structure, and simultaneously has four functions of embolism, luminescence, development and anti-tumor.
7. The monodisperse luminescent developing drug-loaded four-in-one embolic microsphere according to claim 6, wherein the microsphere has a particle size controllable in any range of 100-1200 μm and a certain flow rate corresponding to the microsphere has a monodisperse property.
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