CN115429905B - Degradable monodisperse radiotherapy embolism microsphere with stable nuclide label and preparation method and application thereof - Google Patents
Degradable monodisperse radiotherapy embolism microsphere with stable nuclide label and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a degradable monodisperse radiotherapy embolism microsphere with stable nuclide labeling, a preparation method and application thereof, belonging to the technical field of biological medicine, and comprising monodisperse polymer microspheres with particle diameters of 20-200 mu m, wherein the monodisperse polymer microspheres contain radioactive metal nano particles, and the particle diameter variation coefficient is less than 10%; the radioactive metal nano-particles are formed by reducing radionuclide ions Lu-177, Y-90, ho-166, pb-212, re-186 and Re-188 and dopamine nano-particles; the radioactivity of the degradable monodisperse radiotherapy embolism microsphere is 10-1000Bq. The dopamine nano-particles are solidified in the microspheres, the dopamine particles reduce the radioactive metal nuclide ions into metal nano-particles and form quinone groups with phenolic hydroxyl groups on the surfaces of the dopamine nano-particles, and the radioactive metal nano-particles in the microspheres are not easy to free due to the wrapping of the microspheres and the formation of chemical bonds.
Description
Technical Field
The invention relates to the technical field of biological medicine, in particular to a degradable monodisperse radiotherapy embolism microsphere with stable nuclide labeling, a preparation method and application thereof.
Background
Tumor, a killer of human health. The currently common methods for treating tumors include surgical excision, radiotherapy, chemotherapy, radio frequency ablation and the like, and surgical excision is one of the most effective methods for treating early solid tumors. However, most of early tumor patients have no obvious symptoms, most of the patients are in middle and late stages when diagnosis is confirmed, and only 10% -20% of the patients have the opportunity of surgical excision; the traditional radiotherapy and chemotherapy treatment method has the problems of large systemic toxicity, poor patient compliance and the like, and limits the use of the method. The crazy growth of tumor is based on the premise of taking a large amount of human nutrition, no blood supply and no nutrition supply, and the arterial embolism of tumor is realized through a catheter under the guidance of special equipment due to the blood difference of tumor cells and normal tissues, so as to achieve the purpose of 'starving' the tumor, synchronously develop and accurately release medicine (chemoembolization) or locally accurately perform internal radiotherapy (radiotherapy embolization), and accelerate the death of tumor. The embolism intervention treatment has the advantages of small trauma, quick recovery and small toxic and side effects of the whole body, and becomes an important treatment scheme for middle and late stage tumors, and the embolic agent of the treatment method is mainly microspheres. However, the chemotherapeutic medicine via the catheter arterial chemoembolization (TACE) can circulate to the whole body along with blood, so that the systemic toxic and side effects of the medicine are large, and normal cells are easy to damage; in the aspect of chemotherapy drug selection, the current drugs are loaded through ion exchange, so that only drugs containing cations such as doxorubicin and the like can be loaded; meanwhile, the sensitivity of the tumor to the medicine gradually decreases along with the increase of the using times, and the use of the tumor is limited. The Transcatheter Arterial Radiotherapy Embolism (TARE) is grafted onto microsphere by utilizing radionuclide label, and under the guidance of microsphere the radionuclide can be introduced into peripheral microvessel, and on the basis of vascular embolism the radiation produced by nuclide can kill tumor cell. Tumor cells are in the division stage due to rapid growth, cell DNA in the rapid division stage is very sensitive to rays, cancer cells can die due to irradiation of certain energy rays, and the more malignant tumor is, the higher the sensitivity to rays is. The method is considered to be a tumor treatment mode which has less influence on normal tissues and has the best effect of killing tumor cells by radioactive rays.
The radioactive microsphere is made of radionuclide which can release beta, alpha or low-energy gamma rays and is suitable for treatment and a matrix such as glass, resin and the like, and the diameter of the radioactive microsphere is 5-200 mu m. Nuclides that have been found to be suitable for the preparation of radioactive microspheres are Y-90, P-32, I-125, I-131, ho-166, re-188, lu-177, and the like. Among them, Y-90 (T1/2=64 h, β -energy 2.27 MeV) and P-32 (T1/2= 343.2h, β -energy 1.71 MeV) are pure β -emitting radionuclides, which are clinically common therapeutic nuclides due to their half-life and β -energy that are well suited for treatment.
The radioactive microsphere, especially the Y-90 radioactive microsphere, has wide clinical application due to good curative effect. The Y-90 glass microsphere produced by Boston science company in the United states is one of two radioactive microspheres on the market, but the market application of the radioactive glass microsphere is limited because the radioactive glass microsphere needs to be irradiated by a reactor and the half life of the Y-90 glass microsphere is short; in addition, due to the unstable quality of the glass microsphere raw material, gamma rays can be generated after irradiation, the microsphere has high density and is not degradable, and the product is forbidden in the part of the United states.
The radioactive resin microsphere uses resin as a carrier, and the radionuclide is solidified through ion exchange and a precipitator, so that the radionuclide is fixed in the resin. The advantage of such microspheres is that the density is small relative to glass microspheres, so that the infusion therapy can be performed with physiological saline. In addition, the radioactive resin microspheres can be prepared at a place far away from the reactor without reactor irradiation, thereby being beneficial to the transportation and application of products. The SIRTEX company in Australia prepares commercial Y-90 resin microspheres by using cationic resin microspheres as a carrier, uses the cationic resin as an adsorption material, exchanges Y-90 into the cationic resin, and then adds a precipitant to precipitate the Y-90 in the resin, thereby achieving the purpose of fixing the Y-90. But the resin microsphere Y-90 prepared by the method has higher free rate, wide microsphere particle size distribution range and higher density (1.6 g/cm) 3 ) And the injection is non-degradable, is easy to cause radiation damage to other organs of a human body, is difficult to control the distribution of microsphere tumors, and is easy to subside during injection. Zhao Mingjiang et al used anionic resins as the material, exchanged I-125 into the resin, and then attempted to cure I-125 into the resin by coating (research on the preparation of radioactive resin microspheres, national institute of atomic energy science, 2006). The method can not lead the resin microspheres to be uniformly wrapped, so that the free rate of the resin microspheres is high, and the treatment requirement can not be met. And the method of connecting I-125 with anion resin by adopting a chemical connection method has the radionuclide free rate as high as 10-30 percent.
Chinese patent publication No. CN102671219B discloses a radioactive anion resin microsphere, which is characterized in that: the preparation method comprises an anionic resin with a diameter of 5-200 mu m and a crosslinking degree of 1-20%, and a radionuclide solidified in the anionic resin in a precipitation form; the radioactive anion resin microsphere is prepared by exchanging nonradioactive anions into anion resin, then adding radioactive cation metal nuclide solution, and reacting the radioactive cation metal nuclide in the solution with nonradioactive anions in the resin to generate precipitate; the anionic resin is a strong alkaline anionic resin or a weak alkaline anionic resin, and is converted into OH or Cl anionic resin before use. However, the microsphere still has the defects of high density, easiness in sedimentation in blood vessels, uneven microsphere size, uncontrollable and nondegradable vascular distribution, easiness in dissociation of nuclides and the like.
As described above, the glass microspheres and resin microspheres prepared at present cannot be degraded due to the special process of the preparation process, and the persistent embolism is easy to cause cholecystitis and gastritis; the size of the microspheres is different, and the accurate embolism difficulty is high; in addition, the method is difficult to load other nuclides, and has the defects of high microsphere density and the like.
Disclosure of Invention
The invention aims to solve the problems in the prior art and provides a degradable monodisperse radiotherapy embolism microsphere with stable nuclide labeling, a preparation method and application thereof, wherein an emulsion containing dopamine nanoparticles is prepared by adopting a microfluidic technology, the emulsion is crosslinked and solidified or a solvent volatilizes to form a microsphere, and meanwhile, the dopamine nanoparticles are solidified in the microsphere; the dopamine particles dispersed in the microspheres are utilized to reduce radioactive metal nuclide ions into metal nanoparticles, meanwhile, the metal nanoparticles and phenolic hydroxyl groups on the surfaces of the dopamine nanoparticles form quinone groups, and the radioactive metal nanoparticles inside the microspheres are not easy to free due to the wrapping of the microspheres and the formation of chemical bonds.
The invention aims at realizing the following technical scheme:
a nuclide-labeled stable degradable monodisperse radiotherapy embolism microsphere, which comprises monodisperse polymer microspheres with the particle size of 20-200 mu m, wherein the monodisperse polymer microspheres contain radioactive metal nano particles;
the radioactive metal nano-particles are formed by reducing radionuclide ions Lu-177, Y-90, ho-166, pb-212, re-186 and Re-188 and dopamine nano-particles;
the radioactivity of the degradable monodisperse radiotherapy embolism microsphere is 10-1000Bq.
Preferably, the monodisperse polymer microsphere base material is any one or more of gelatin, collagen, silk fibroin, PLLA, PLGA, PDLA, PLA, PCL, chitosan and alginic acid.
Preferably, the density of the degradable monodisperse radiotherapy embolism microsphere is 1.05-1.6g/mL.
Preferably, the monodisperse polymer microsphere has uniform particle size and a particle size variation coefficient of less than 10%.
The application of the degradable monodisperse radio-therapy embolism microsphere with stable combination of nuclides in preparing solid tumor therapeutic drugs or devices, wherein the radioactivity in the solid tumor therapeutic drugs is 5-500mCi.
A preparation method of degradable monodisperse radiotherapy embolism microsphere with stable nuclide label comprises the preparation of monodisperse polymer microsphere and radionuclide label;
the preparation of the monodisperse polymer microsphere comprises the following steps:
step A1, preparing an inner phase fluid, an outer phase fluid and a collecting liquid
Preparing an internal phase fluid: dispersing dopamine nano particles in any one or more solutions containing gelatin, collagen, chitosan, alginic acid and PLLA, PLGA, PLA, PDLA, PCL to obtain an internal phase fluid;
preparing an external phase fluid: dissolving an oil-soluble surfactant in any one or more of soybean oil, n-octanol and liquid paraffin or dissolving a water-soluble surfactant in water to obtain an external phase fluid;
preparing a collection liquid: dissolving a cross-linking agent and an oil-soluble surfactant in one or more of soybean oil, n-octanol and liquid paraffin or dissolving a water-soluble surfactant in water to obtain a collecting liquid;
step A2, preparing monodisperse polymer microspheres
Inputting an internal phase fluid into an injection tube of a microfluidic device, inputting an external phase fluid into a collecting tube of the microfluidic device, wherein the flow rate ratio of the internal phase fluid to the external phase fluid is 1:2-50, forming a monodisperse emulsion in the collecting tube, collecting the emulsion by adopting a container containing a collecting liquid, and reacting the emulsion with the external phase fluid and a cross-linking agent in the collecting liquid or volatilizing a solvent in the emulsion to obtain the monodisperse polymer microsphere;
step A3, washing
Washing with a solvent to remove a collection liquid on the surfaces of the monodisperse polymer microspheres, and then washing with a detergent to remove the solvent on the surfaces of the monodisperse polymer microspheres;
the radionuclide label comprises the following steps:
step B1, soaking the monodisperse polymer microspheres in a solution containing Lu-177, Y-90, ho-166, pb-212, re-186 and Re-188 ions, and stirring or oscillating for 2-48h;
and step B2, washing the degradable monodisperse radiotherapy embolic microspheres by purified water to remove free nuclides.
Preferably, in the step A1, the mass fraction of the gelatin, collagen, silk fibroin, PLLA, PLGA, PLA, PDLA, PCL, chitosan and alginic acid is 1% -30%, and the content of the dopamine particles is 0.5-10mg/mL.
Preferably, in the step A1, the mass ratio of the surfactant in the external phase fluid is 0.01-0.2; the mass fraction of the cross-linking agent is 1% -20%.
Preferably, in the step A1, the oil-soluble surfactant is any one or more of polyglyceryl ricinoleate, diethanolamide oleate, span20, span40, span60, span80 and Tween 85; the cross-linking agent adopts glutaraldehyde, formaldehyde, carbodiimide, diisocyanate, riboflavin, genipin, terephthalaldehyde and CaCl 2 Any one or more of F127, SDS, tween80 and PVA are adopted as the water-soluble surfactant.
Preferably, in the step A3, any one or more of acetone, ethanol, isopropanol and pure water is used as the solvent and the detergent.
The beneficial effects of this technical scheme are as follows:
1. according to the preparation method of the degradable monodisperse radiotherapy embolism microsphere with stable nuclide labeling, dopamine nanoparticles are dispersed in an internal phase fluid, uniform emulsion is prepared through a microfluidic method, the dopamine nanoparticles are simultaneously solidified in the microsphere in the crosslinking solidification process of the emulsion, the microsphere containing the dopamine nanoparticles formed by solidification is soaked in a solution containing radioactive metal nuclide ions, the radioactive metal nuclide is reduced into metal nanoparticles by using the dopamine to form a quinone group with phenolic hydroxyl groups on the surfaces of the dopamine nanoparticles, and the radioactive metal nanoparticles in the microsphere are not easy to free due to encapsulation of the microsphere and formation of chemical bonds.
2. The degradable monodisperse radiotherapy embolism microsphere with stable nuclide labeling has the advantages of uniform size, particle diameter variation coefficient (CV value) less than 10%, moderate density, simple nuclide labeling method and stable labeling compared with other radioactive microspheres.
Drawings
The accompanying drawings, which are included to provide a further understanding of embodiments of the invention and are incorporated in and constitute a part of this application, illustrate embodiments of the invention. In the drawings:
FIG. 1 is a schematic illustration of the preparation of degradable radioactive microspheres of the present invention;
Detailed Description
For the purpose of making apparent the objects, technical solutions and advantages of the present invention, the present invention will be further described in detail with reference to the following examples and the accompanying drawings, wherein the exemplary embodiments of the present invention and the descriptions thereof are for illustrating the present invention only and are not to be construed as limiting the present invention.
In the following embodiments, the adopted microfluidic device is a primary capillary microfluidic device, and the structure of the device comprises an injection tube, a connecting tube and a collecting tube. The injection tube is made of cylindrical glass capillary, the tail of the cylindrical glass capillary with the outer diameter of 960 mu m and the inner diameter of 500 mu m is drawn into a cone shape by a needle drawing instrument, and the cone is polished to a flat mouth with the inner diameter of 40 mu m on abrasive paper; the collecting pipe is made of cylindrical glass capillary with the outer diameter of 960 mu m and the inner diameter of 200 mu m, and two ends of the cylindrical glass capillary are polished and flattened; the connecting pipe is a square glass pipe, two ends of the square glass pipe are polished smoothly and flatly, a square through hole is formed in the center of the square glass pipe, and the size of the through hole is 1.0x1. mm. The tail of the injection tube is inserted into the head of the collecting tube and connected with the head of the collecting tube through a connecting tube. The injection tube, the connecting tube and the collecting tube are coaxially arranged and fixed on the glass slide through AB glue.
Example 1
As shown in fig. 1, in this example, the preparation method is as follows:
step A1, preparing an inner phase fluid, an outer phase fluid and a collecting liquid
Preparing an internal phase fluid: stirring and dissolving chitosan with molecular weight of 70-200 kDa and deacetylation degree of 75-95% in dilute acid to obtain 0.04 g/mL chitosan solution, and adding dopamine nano particles to obtain chitosan solution with dopamine content of 4 mg/mL;
preparing an external phase fluid: adding a surfactant Span80 into n-octanol to obtain a Span80 solution with a mass ratio of 0.1;
preparing a collection liquid: the cross-linking agent glutaraldehyde and the surfactant Span80 are dissolved in n-octanol to obtain glutaraldehyde collecting liquid with the mass fraction of 0.5 percent, and the mass ratio of the surfactant is 0.1.
Step A2, preparing monodisperse polymer microspheres
At room temperature, injecting an inner phase fluid into an injection tube through an injection pump, injecting an outer phase fluid into a receiving tube, adjusting the flow rate of the inner phase solution and the outer phase solution (the flow rate of the inner phase fluid is 200 uL/h, the flow rate of the outer phase fluid is 500 uL/h), shearing to obtain a monodisperse W/O emulsion, and carrying out a crosslinking reaction in a collecting liquid to obtain the monodisperse chitosan microspheres.
Step A3, washing
Washing chitosan microsphere with purified water, and storing in purified water solution.
Step B1, 10mg of monodisperse chitosan microspheres were soaked in 2mCi of 177-LuCl 3 Stirring for 2h;
and step B2, washing the degradable monodisperse radiotherapy embolic microspheres by purified water to remove free nuclides.
Example 2
In this example, the preparation method is as follows:
step A1, preparing an inner phase fluid, an outer phase fluid and a collecting liquid
Preparing an internal phase fluid: dissolving gelatin in pure water at 50 ℃ to obtain gelatin solution with the mass ratio of 5%, adding dopamine nano particles after complete dissolution, and stirring to obtain gelatin solution with the dopamine content of 4 mg/mL;
preparing an external phase fluid: adding surfactant polyricinoleic acid glyceride (PGPR) into soybean oil to obtain PGPR solution with the mass ratio of 0.1;
preparing a collection liquid: the cross-linking agent formaldehyde and the surfactant polyricinoleic acid glyceride (PGPR) are dissolved in soybean oil to obtain a formaldehyde collection liquid with the mass fraction of 5%, and the mass fraction of the PGPR is 10%.
Step A2, preparing monodisperse polymer microspheres
In an environment of 60 ℃, injecting an inner phase fluid into an injection tube through an injection pump, injecting an outer phase fluid into a receiving tube, adjusting the flow rate of the inner phase solution and the outer phase solution (the flow rate of the inner phase fluid is 100 uL/h, the flow rate of the outer phase fluid is 1000 uL/h), shearing to obtain a monodisperse W/O emulsion, and carrying out a crosslinking reaction in a collecting liquid to obtain the monodisperse gelatin microspheres containing dopamine nano particles.
Step A3, washing
After washing the gelatin microspheres with isopropanol, drying and preserving the gelatin microspheres in a vacuum drying oven at 40 ℃.
Step B1, 10mg of monodisperse gelatin microspheres were swelled and then immersed in 1mCi of 177-LuCl 3 Oscillating for 4 hours;
and step B2, washing the degradable monodisperse radiotherapy embolic microspheres with purified water, and centrifuging to remove free nuclides in the solution.
Example 3
In this example, the preparation method is as follows:
step A1, preparing an inner phase fluid, an outer phase fluid and a collecting liquid
Preparing an internal phase fluid: dissolving silk fibroin in deionized water at 40 ℃ to obtain silk fibroin solution with the mass fraction of 1%, adding dopamine nano particles after complete dissolution, and stirring to obtain silk fibroin solution with the dopamine content of 0.5 mg/mL;
preparing an external phase fluid: adding a surfactant Span80 into liquid paraffin to obtain Span80 solution with the mass ratio of 0.1;
preparing a collection liquid: the cross-linking agent glutaraldehyde and the surfactant Span80 are dissolved in liquid paraffin to obtain glutaraldehyde collecting liquid with the mass fraction of 1 percent, and the mass fraction of the surfactant is 0.1.
Step A2, preparing monodisperse polymer microspheres
In an environment of 40 ℃, injecting an inner phase fluid into an injection tube through an injection pump, injecting an outer phase fluid into a receiving tube, adjusting the flow rate of the inner phase solution and the outer phase solution (the flow rate of the inner phase fluid is 200 uL/h, the flow rate of the outer phase fluid is 400 uL/h), shearing to obtain a monodisperse W/O emulsion, and carrying out a crosslinking reaction in a collecting liquid to obtain the monodisperse silk fibroin microsphere containing dopamine nano particles.
Step A3, washing
The silk fibroin microspheres are washed by isopropanol and then dried and stored in a vacuum drying oven at 40 ℃.
Step B1, swelling 10mg of monodisperse silk fibroin microspheres, and soaking in 1mCi of 90-YCl 3 Oscillating for 2 hours;
and step B2, washing the degradable monodisperse radiotherapy embolic microspheres with purified water, and centrifuging to remove free nuclides in the solution.
Example 4
Step A1, preparing an inner phase fluid, an outer phase fluid and a collecting liquid
Preparing an internal phase fluid: dissolving PLGA, PLLA and PDLA in dichloromethane to obtain PLGA-PLLA-PDLA solution with the mass fraction of 30%, adding dopamine nano particles after complete dissolution, and dispersing the dopamine nano particles in the solution by ultrasound to obtain PLGA-PLLA-PDLA solution with the dopamine content of 10 mg/mL;
preparing an external phase fluid: adding surfactant PVA into pure water to obtain PVA solution with the mass ratio of 0.02;
preparing a collection liquid: the surfactant PVA is dissolved in water to obtain a collecting liquid with the mass fraction of 2%.
Step A2, preparing monodisperse polymer microspheres
At room temperature, injecting an inner phase fluid into an injection tube through an injection pump, injecting an outer phase fluid into a receiving tube, adjusting the flow rate of the inner phase solution and the outer phase solution (the flow rate of the inner phase fluid is 200 uL/h, the flow rate of the outer phase fluid is 4000 uL/h), shearing to obtain a monodisperse O/W emulsion, and volatilizing the solvent in the inner phase to obtain the monodisperse PLGA-PLLA-PDLA microspheres containing dopamine nano particles.
Step A3, washing
And washing the PLGA-PLLA-PDLA microspheres with pure water, and naturally air-drying.
Step B1, swelling 5mg of monodisperse PLGA-PLLA-PDLA microspheres and soaking in 1mCi of 90-YCl 3 Shaking for 48 hours;
and step B2, washing the degradable monodisperse radiotherapy embolic microspheres with purified water, and centrifuging to remove free nuclides in the solution.
Example 5
Step A1, preparing an inner phase fluid, an outer phase fluid and a collecting liquid
Preparing an internal phase fluid: dissolving collagen and chitosan in acetic acid with the pH value of 3.5, adding 8% sodium alginate to obtain sodium alginate-collagen-chitosan solution with the mass fraction of 15%, adding dopamine nano particles after complete dissolution, and stirring to obtain sodium alginate-collagen-chitosan solution with the dopamine content of 4 mg/mL;
preparing an external phase fluid: adding a surfactant oleic acid diethanolamide into n-octanol to obtain oleic acid diethanolamide solution with the mass ratio of 0.1;
preparing a collection liquid: the cross-linking agent genipin, terephthalaldehyde and surfactant oleic acid diethanolamide are dissolved in n-octanol to obtain genipin-terephthalaldehyde collecting liquid with the mass fraction of 1%, and the mass fraction of the surfactant is 0.1.
Step A2, preparing monodisperse polymer microspheres
In an environment of 4 ℃, injecting an inner phase fluid into an injection tube through an injection pump, injecting an outer phase fluid into a receiving tube, adjusting the flow rate of the inner phase solution and the outer phase solution (the flow rate of the inner phase fluid is 100 uL/h, the flow rate of the outer phase fluid is 5000 uL/h), shearing to obtain a monodisperse W/O emulsion, and performing a crosslinking reaction in a collecting liquid to obtain the monodisperse sodium alginate-collagen-chitosan microsphere containing dopamine nano particles.
Step A3, washing
Washing sodium alginate-collagen-chitosan microsphere with isopropanol and pure water, and naturally air-drying.
Step B1, swelling 5mg of monodisperse sodium alginate-collagen-chitosan microspheres and soaking in 1mCi of 90-YCl 3 Oscillating for 4 hours;
and step B2, washing the degradable monodisperse radiotherapy embolic microspheres with purified water, and centrifuging to remove free nuclides in the solution.
Example 6
Step A1, preparing an inner phase fluid, an outer phase fluid and a collecting liquid
Preparing an internal phase fluid: dissolving PCL and PLA in dichloromethane to obtain a PLA-PCL solution with the mass fraction of 10%, adding dopamine nano particles after complete dissolution, and dispersing the obtained dopamine nano particles in the solution by ultrasound to obtain a PLA-PCL solution with the dopamine content of 10 mg/mL;
preparing an external phase fluid: adding a surfactant F-127 into pure water to obtain an F-127 solution with a mass ratio of 5%;
preparing a collection liquid: the surfactant F-127 was added to pure water to obtain a 5% by mass F-127 solution.
Step A2, preparing monodisperse polymer microspheres
At room temperature, injecting an inner phase fluid into an injection tube through an injection pump, injecting an outer phase fluid into a receiving tube, adjusting the flow rate of the inner phase solution and the outer phase solution (the flow rate of the inner phase fluid is 200 uL/h, the flow rate of the outer phase fluid is 600 uL/h), shearing to obtain a monodisperse O/W emulsion, and volatilizing the solvent in the inner phase to obtain the monodisperse PLA-PCL microsphere containing dopamine nano particles.
Step A3, washing
And washing the PLA-PCL microspheres with pure water, and naturally air-drying.
Step B1, 5mg of monodisperse PLA-PCL microspheres were swelled and then soaked in 1mCi of 90-YCl 3 Shaking for 48 hours;
and step B2, washing the degradable monodisperse radiotherapy embolic microspheres with purified water, and centrifuging to remove free nuclides in the solution.
The foregoing description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any way, and any simple modification, equivalent variation, etc. of the above embodiment according to the technical matter of the present invention fall within the scope of the present invention.
Claims (9)
1. A degradable monodisperse radiotherapy embolism microsphere with stable nuclide labeling is characterized in that: comprises monodisperse polymer microspheres with the particle size of 20-200 mu m, wherein the monodisperse polymer microspheres contain radioactive metal nano particles;
the monodisperse polymer microsphere base material is any one or more of gelatin, collagen, silk fibroin, PLLA, PLGA, PLA, PDLA, PCL, chitosan and alginic acid;
the radioactive metal nano-particles are formed by reducing radionuclide ions Lu-177, Y-90, ho-166, pb-212, re-186 and Re-188 and dopamine nano-particles;
the radioactivity of the degradable monodisperse radiotherapy embolism microsphere is 10-1000Bq.
2. The nuclide-labeled-stable, degradable monodisperse radiation therapy embolic microsphere according to claim 1, wherein: the density of the degradable monodisperse radiotherapy embolism microsphere is 1.05-1.6g/mL.
3. The nuclide-labeled-stable, degradable monodisperse radiation therapy embolic microsphere according to claim 1, wherein: the particle size of the monodisperse polymer microsphere is uniform, and the particle size variation coefficient is less than 10%.
4. Use of a degradable monodisperse radiotherapy embolic microsphere according to any of claims 1-3 in the preparation of a solid tumor therapeutic drug or device, wherein the radioactivity in the solid tumor therapeutic drug is between 5 and 500mCi.
5. A preparation method of a degradable monodisperse radiotherapy embolism microsphere with stable nuclide labeling is characterized by comprising the following steps: including preparation of monodisperse polymer microsphere and radionuclide labeling;
the preparation of the monodisperse polymer microsphere comprises the following steps:
step A1, preparing an inner phase fluid, an outer phase fluid and a collecting liquid
Preparing an internal phase fluid: dispersing dopamine nano particles in any one or more solutions containing gelatin, collagen, silk fibroin, chitosan, alginic acid and PLLA, PLGA, PLA, PDLA, PCL to obtain an internal phase fluid;
preparing an external phase fluid: dissolving an oil-soluble surfactant in any one or more of soybean oil, n-octanol and liquid paraffin or dissolving a water-soluble surfactant in water to obtain an external phase fluid;
preparing a collection liquid: dissolving a cross-linking agent and an oil-soluble surfactant in one or more of soybean oil, n-octanol and liquid paraffin or dissolving a water-soluble surfactant in water to obtain a collecting liquid;
step A2, preparing monodisperse polymer microspheres
Inputting an internal phase fluid into an injection tube of a microfluidic device, inputting an external phase fluid into a collecting tube of the microfluidic device, wherein the flow rate ratio of the internal phase fluid to the external phase fluid is 1:2-50, forming a monodisperse emulsion in the collecting tube, collecting the emulsion by adopting a container containing a collecting liquid, and reacting the emulsion with the external phase fluid and a cross-linking agent in the collecting liquid or volatilizing a solvent in the emulsion to obtain the monodisperse polymer microsphere;
step A3, washing
Washing with a solvent to remove a collection liquid on the surfaces of the monodisperse polymer microspheres, and then washing with a detergent to remove the solvent on the surfaces of the monodisperse polymer microspheres;
the radionuclide label comprises the following steps:
step B1, soaking the monodisperse polymer microspheres in a solution containing Lu-177, Y-90, ho-166, pb-212, re-186 and Re-188 ions, and stirring or oscillating for 2-48h;
and step B2, washing the degradable monodisperse radiotherapy embolic microspheres by purified water to remove free nuclides.
6. The method for preparing the nuclide-labeled-stable degradable monodisperse radiotherapy embolic microsphere according to claim 5, wherein the method comprises the following steps: in the step A1, the mass fraction of the gelatin, the collagen, the silk fibroin, the PLLA, PLGA, PLA, PDLA, PCL, the chitosan and the alginic acid is 1-30%, and the content of the dopamine particles is 0.5-10mg/mL.
7. The method for preparing the nuclide-labeled-stable degradable monodisperse radiotherapy embolic microsphere according to claim 6, wherein the method comprises the following steps: in the step A1, the mass ratio of the surfactant in the external phase fluid is 0.01-0.2; the mass fraction of the cross-linking agent is 1% -20%.
8. The method for preparing the nuclide-labeled-stable degradable monodisperse radiotherapy embolic microsphere according to claim 7, wherein the method comprises the following steps: in the step A1, the oil-soluble surfactant is any one or more of polyglyceryl ricinoleate, diethanolamide oleate, span20, span40, span60, span80 and Tween 85; the cross-linking agent adopts glutaraldehyde, formaldehyde, carbodiimide, diisocyanate, riboflavin, genipin, terephthalaldehyde and CaCl 2 Any one or more of F127, SDS, tween80 and PVA are adopted as the water-soluble surfactant.
9. The method for preparing the nuclide-labeled-stable degradable monodisperse radiotherapy embolic microsphere according to claim 8, wherein the method comprises the following steps: in the step A3, any one or more of acetone, ethanol, isopropanol and pure water is adopted as the solvent and the detergent.
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| CN111603575A (en) * | 2020-02-28 | 2020-09-01 | 彭盛 | Radioactive embolism microsphere with core-shell structure and preparation method and application thereof |
| CN114504661A (en) * | 2022-02-14 | 2022-05-17 | 四川大学华西医院 | 177 Lu-loaded degradable high polymer material microsphere and preparation method and application thereof |
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| CN111603575A (en) * | 2020-02-28 | 2020-09-01 | 彭盛 | Radioactive embolism microsphere with core-shell structure and preparation method and application thereof |
| CN114504661A (en) * | 2022-02-14 | 2022-05-17 | 四川大学华西医院 | 177 Lu-loaded degradable high polymer material microsphere and preparation method and application thereof |
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