CN116603081B - Biodegradable radioactivity 90 Y microsphere and preparation method thereof - Google Patents
Biodegradable radioactivity 90 Y microsphere and preparation method thereof Download PDFInfo
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- QCWXUUIWCKQGHC-BJUDXGSMSA-N zirconium-90 Chemical compound [90Zr] QCWXUUIWCKQGHC-BJUDXGSMSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/06—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
- A61K51/1213—Semi-solid forms, gels, hydrogels, ointments, fats and waxes that are solid at room temperature
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
- A61K51/1241—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
- A61K51/1244—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles
- A61K51/1251—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles micro- or nanospheres, micro- or nanobeads, micro- or nanocapsules
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Optics & Photonics (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Physics & Mathematics (AREA)
- Public Health (AREA)
- Dispersion Chemistry (AREA)
- Engineering & Computer Science (AREA)
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- Proteomics, Peptides & Aminoacids (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to the field of radioactive interventional therapy, in particular to a biodegradable radioactivity 90 Y microsphere and its preparation method are provided. The biodegradable radioactivity 90 The Y microspheres are alginate radioactive gel which is formed by crosslinking alginate sol and polyvalent metal ions, wherein the polyvalent metal ions comprise 90 Y 3+ Ions and non-radioactive multivalent metal ions. The invention provides biodegradable radioactivity 90 The Y microsphere has the advantages of degradability, low radionuclide dissolution rate, good embolism effect and the like.
Description
Technical Field
The invention relates to the field of radioactive interventional therapy, in particular to a biodegradable radioactivity 90 Y microsphere and its preparation method are provided.
Background
Radiation therapy is a conventional treatment method for malignant tumors, and is divided into two ways of external irradiation and internal irradiation treatment. The internal irradiation treatment utilizes the specific affinity of tumor tissue and radioactive nuclide and its labeled medicine or introduces radioactive nuclide into tumor tissue in vivo by means of blood vessel, lymphatic vessel and cavity, etc. to attain the goal of treating or controlling tumor. The internal irradiation treatment can break through the limitation of the external irradiation treatment, treat the tumor tissue with higher radiation dose and more targeting, and simultaneously reduce the damage to the normal tissue. Hepatocellular carcinoma (HCC) is the predominant pathological type of primary liver cancer, accounting for 85-90%. HCC is hidden, about 85% of patients are already in middle and late stages at the time of diagnosis, and the time of surgical excision is lost, so that the progress of the disease can be controlled and the survival time can be prolonged only by means of local minimally invasive treatment or systemic treatment and the like. It was found that 80% of liver tumors were supplied by bloodFrom the hepatic artery, only one third or less of the blood supply to the normal liver comes from the hepatic artery, and the rest comes from the portal vein, so that the liver cancer can be treated by local internal tumor irradiation by utilizing the characteristics. Compared to external irradiation, yttrium-90 (ytrium-90, 90 y) microsphere selective internal radiation therapy (selective internal radiation therapy, SIRT) is effective to increase the dose administered to tumor tissue and substantially reduce the dose received by normal tissue. 90 The SIRT of the Y microsphere is loaded with the radionuclide emitting beta rays 90 The Y microsphere is injected into tumor tissue through hepatic artery, the radioactive microsphere can not be aggregated in the tumor tissue by capillary bed of tumor, and the amount of the ionizing radiation received by local area of tumor is up to 100-150 Gy, so that the deoxyribonucleic acid in tumor cells is damaged to generate strong tumor cell killing effect, and meanwhile, the aggregation of the microsphere can also form embolism on the tumor tissue to cut off or reduce blood supply of the tumor tissue. Because of 90 The range of Y in liver tissue is only 2.50 and mm, so that the damage to normal liver tissue is very small to achieve the target tumor cell killing effect. In contrast to the other species of the species, 90 y emits pure beta rays, has short penetration distance in the body and simple and convenient protection, thus 90 Y microsphere therapy has found wide application. 90 The half-life of Y is 64.2 hours, the energy is released to 87% in 8 days, 95% in 2 weeks, and the effective radiation lasts for 7 half-lives, namely about 18 days. 90 Y decays to stable and nontoxic zirconium-90% 90 Zr）。 90 Research on Y microsphere SIRT began in the 50 s of the 20 th century, and so far, several studies have demonstrated its safety and effectiveness, and the united states food and drug administration has approved multiple cousins 90 The Y microsphere product was used for SIRT.
Existing ones that have been used clinically 90 The Y microsphere products comprise resin microspheres, glass microspheres, carbon microspheres and the like. However, these microspheres are not degradable and cannot be absorbed by human body, once the microspheres are displaced or spread, a certain risk is brought to the patient, and the microspheres exist in the human body for a long time and can also affect normal functions of normal viscera.
Disclosure of Invention
To solve the aboveThe technical problem is that the invention provides a biodegradable radioactivity 90 Y microsphere and its preparation method are provided.
In a first aspect, the present invention provides a biodegradable radioactivity 90 Y microspheres, said radioactivity 90 The Y microspheres are alginate radioactive gel which is formed by crosslinking alginate sol and polyvalent metal ions, wherein the polyvalent metal ions comprise 90 Y 3+ Ions and non-radioactive multivalent metal ions. In the invention, alginate sol and radioactivity are adopted 90 Y 3+ Biodegradable radioactivity formed by crosslinking ions and non-radioactive multivalent metal ions 90 Y microspheres, which are biodegradable radioactivity 90 The Y microsphere has the advantages of degradability, low radionuclide dissolution rate, good embolism effect and the like.
According to the invention, the alginate is a biodegradable natural polysaccharide polymer, and can be subjected to gelation reaction with multivalent metal ions, and the multivalent metal ions and guluronic acid groups in the molecular chain of the alginate form a stable ion cross-linked network structure, so that gelation of the alginate and immobilization of the multivalent metal ions are realized, and specific functions are realized. In the present invention, the degradation of alginate in tissues is relatively slow (about 6 months), because the human body lacks enzymes that decompose alginate, the degradation of alginate in tissues is mainly accomplished by the hydrolysis of macromolecules, and in addition, the alginate acts as a cross-linking agent 90 The Y trivalent ions and sodium potassium ions in the environment are slowly exchanged to realize corrosion 90 Y trivalent ions decay simultaneously). Loaded with radionuclides 90 The alginate microspheres of Y can be accumulated in tumor tissue after being injected into hepatic artery, and the microspheres are formed by radionuclide 90 While the sustained release dose of Y remains stable, the alginate microspheres will remain in the tumor tissue until complete degradation as the local radiotherapy process ends.
Further preferably, the alginate sol is a monovalent salt of alginic acid sol; preferably, the monovalent salt sol of alginic acid is a sol formed by dissolving at least one of sodium alginate, potassium alginate and ammonium alginate in water.
Preferably, the biodegradable radioactivity 90 The Y microspheres are spherical or ellipsoidal. Further preferred, the biodegradable radioactivity 90 The diameter of the Y microspheres is 10-200. Mu.m, preferably 20-60. Mu.m.
The invention is found by research that when radioactivity 90 The Y microsphere is spherical with the diameter of 10-200 mu m, can be quickly and uniformly suspended in physiological saline and smoothly pass through a puncture needle head, if the diameter of the microsphere exceeds 200 mu m, the needle head is easy to block, and when the microsphere is injected into a focus position, only large blood vessels can be plugged, and the microsphere cannot be diffused into a capillary network, if the diameter of the microsphere is smaller than 10 mu m, the microsphere increases the risk of penetrating the capillary after injection, and when the diameter of the microsphere is 20-60 mu m, the safety and the effectiveness of the microsphere are proved by a plurality of clinical researches.
In the present invention, the alginate 90 Y microsphere and existing SIRT application 90 Y microspheres have great advantages compared with the prior art, alginate 90 The Y microsphere has degradability, can be completely degraded in vivo after the function of radiotherapy is completed, and degradation products are mannuronic acid and guluronic acid, do not participate in metabolism in vivo, are discharged along with urine, do not influence the normal physiological function of organs, and do not cause microsphere displacement or diffusion. At the same time, alginate 90 Y microsphere loaded radionuclide 90 Y is present throughout the microsphere and is a radionuclide in a stable, ionically crosslinked form 90 Y being immobilized therein, not just the surface of the microspheres, as resin microspheres adsorb radionuclides 90 Y, so that alginate 90 Y microspheres have a lower radionuclide dissolution rate. Furthermore, alginate 90 The Y microsphere has proper specific gravity, hydrophilic surface, easy dispersion and suspension during injection and good compatibility with human tissues and blood. In addition, the sodium alginate microsphere is a common vascular embolic agent, has certain plasticity and expansibility, and clinical reports show that the sodium alginate microsphere has good embolic effect, does not cause vascular occlusion, and recovers organ functions after treatment is finishedAnd (5) repeating the process. In addition, alginate 90 The Y microspheres can also be loaded with other active drugs, and the drugs are slowly released into local tissues along with the degradation of the microspheres in the microspheres, so that the therapeutic effect of multiple modes is realized.
Further preferably, radioactivity 90 In the Y microspheres 90 Y 3+ The ions are cross-linked with alginate ions, 90 Y 3+ ions are not easily eluted or ion exchange is performed to dissolve out, and the radioactivity is high 90 The Y microspheres are crosslinked by further non-radioactive polyvalent metal ions, i.e. surface 90 Y 3+ The ions further increase the crosslink density under high concentrations of non-radioactive multivalent metal ions and a small amount of surface occurs 90 Y 3+ Ion exchange of ions with non-radioactive multivalent metal ions results in microspheres with high surface cross-linking density and surface 90 Y 3+ The present invention provides radioactivity with less ion distribution 90 The dissolution rate of the radionuclide in the Y microspheres is low.
Further preferably, the radioactivity 90 Y microsphere is within 64.2 hours 90 Y half-life) the radionuclide dissolution rate in physiological saline is less than 1%, preferably less than 0.2%, to ensure safety and effectiveness for clinical use.
Further preferably, the non-radioactive multivalent metal ion comprises Ca 2+ 、Fe 2+ 、Fe 3+ 、Ba 2+ 、Al 3+ 、Zn 2+ And Cu 2+ One or more of the following.
In a second aspect, the present invention provides a biodegradable radioactivity 90 The preparation method of the Y microsphere comprises the following steps:
1) Preparing particles: dispersing an aqueous solution of monovalent salt of alginic acid into an oily liquid under stirring to obtain a microparticle emulsion;
2） 90 Y 3+ ion primary crosslinking; will be under stirring 90 Y 3+ Adding the ionic water solution into the microparticle emulsion, and performing crosslinking and curing to obtain crosslinked microspheres; the said 90 Y 3+ Ion water-solubleThe liquid contains or does not contain non-radioactive multivalent metal ions;
3) Non-radioactive multivalent metal ions resolidify; immersing the crosslinked microsphere into non-radioactive multivalent metal ion aqueous solution, and performing resolidification molding.
The invention is characterized in that 90 Y 3+ Preliminary ion crosslinking, low concentration under stirring 90 Y 3+ Adding ion water solution into the particle emulsion, and performing crosslinking curing to obtain crosslinked microsphere, if 90 Y 3+ Too low an ion concentration (mass concentration below 0.1%) can supplement low concentrations of non-radioactive multivalent metal ions; the non-radioactive multivalent metal ions of the invention are resolidified, the crosslinked microspheres are obtained by separation after demulsification and washing in the step 2), and then the crosslinked microspheres are soaked in the non-radioactive multivalent metal ion aqueous solution for no less than 1 hour to be resolidified and molded, thus forming 90 Y microspheres are stored in an aqueous multivalent metal ion solution until the aqueous multivalent metal ion solution is replaced with physiological saline before use.
Further preferably, in the step 1), the mass concentration of the monovalent salt of alginic acid is 0.5-5%, the stirring speed is 500-3000 rpm, and the volume ratio of the oily liquid to the monovalent salt solution of alginic acid is 1:0.1-1; and/or, step 2) said 90 Y 3+ In the ion water solution, the ion water solution is mixed, 90 Y 3+ the mass concentration of the ion and/or non-radioactive multivalent metal ion is 0.1% -1%, and the adding volume is not more than the volume of the monovalent salt water solution of the alginic acid; and/or, in step 3), the mass concentration of the non-radioactive multivalent metal ion aqueous solution is 5% -20%.
Further preferably, a water-in-oil surfactant is added to the oily liquid; the oily liquid is a liquid which is not dissolved with the aqueous solution of the monovalent salt of alginic acid; and/or the oily liquid comprises one or more of edible oil, liquid paraffin, mineral oil, kerosene, gasoline and silicone oil; the water-in-oil surfactant comprises a lipophilic surfactant having an HLB of less than 10; and/or the water-in-oil surfactant comprises span series surfactant and/or glyceryl monostearate.
In the invention, when preparing particles, step 1) under the action of shearing force of oily liquid, the monovalent salt alginate solution (water phase) forms emulsified particles wrapped by oily liquid (oil phase), namely water-in-oil emulsion, the mass concentration of monovalent salt alginate is preferably 0.5-5%, the stirring speed is preferably 500-3000 rpm, the shearing force of the preparation method under the preferred stirring speed can more effectively shear the monovalent salt alginate solution to form particles, and the particle size and shape of the particles are better, and the volume ratio of the oily liquid to the monovalent salt alginate solution is preferably 1:0.1-1, the preparation efficiency is low due to the fact that the water phase volume is too small, and the stability of the water-in-oil emulsion is affected due to the fact that the water phase volume is too large. The oily liquid can be added with a water-in-oil type surfactant, so that emulsion with higher stability and smaller particle size of emulsion particles can be obtained. The stirring time at the time of the microparticle preparation is not less than 30 minutes to ensure the stability of the microparticles.
Step 2) is carried out 90 Y 3+ Low concentration of ions during preliminary crosslinking 90 Y 3+ Ions (or non-radioactive multivalent metal ion-supplemented) diffuse inward from the outside of the emulsion particles, wherein 90 Y 3+ The sum of the mass concentrations of the ions (or of the non-radioactive multivalent metal ions) is preferably 0.1-1%. When the concentration is too low, the emulsion particles are not crosslinked and solidified or the crosslinking process is too low, the particles are adhered or even fused after stirring is stopped, and when the concentration is too high, ions can form a relatively compact crosslinking layer on the surfaces of the particles, so that the ions are influenced to diffuse into the particles, the crosslinking degree of the particles is low, and the crosslinking ions (especially 90 Y 3+ Ions) are mainly distributed on the surface of the microsphere. 90 Y 3+ The ionic primary crosslinking is maintained for at least 1 hour, so that uniform crosslinking can be formed, 90 Y 3+ stable microspheres with uniform ion distribution. Low concentration of 90 Y 3+ The added volume of ions (or non-radioactive multivalent metal ions) does not exceed the volume of monovalent salt water solution of alginic acid.
Step 3) non-radioactive multivalent metal ion resolidification is performed by high concentrations of non-radioactive multivalent metalThe solution resolidifies the microspheres, increases the ion crosslinking density of the surfaces of the microspheres, and the microspheres obtain stronger mechanical property and stability, and simultaneously, the microspheres have a small amount of surfaces 90 Y 3+ The ions are partially ion exchanged with a high concentration of non-radioactive multivalent metal, such that the microsphere surface 90 Y 3+ Ions are reduced and dissolution rate after preservation and injection is lower. The demulsification method comprises the steps of standing for layering, centrifuging, adding ethanol and the like to separate microspheres, wherein the separated microspheres are soaked in a high-concentration non-radioactive multivalent metal solution for at least 1 hour, and the mass concentration of the high-concentration non-radioactive multivalent metal solution is preferably 5-20%.
In the present invention, the biodegradable radioactivity 90 The preparation method of the Y microsphere has the advantages of simple preparation method, low cost and high preparation efficiency, and the microsphere obtained by the method is stable and radioactive 90 Y is mainly distributed in the microsphere, the surface of the microsphere is mainly crosslinked by non-radioactive multivalent metal ions, and the dissolution rate of the radionuclide is small when the radionuclide is stored and used. Moreover, the method can be operated in a closed environment, is easy to realize automatic production, does not cause radioactive pollution, and has small radiation dose for operators.
Preferably, in step 1), the particle diameter in the fine particle emulsion is 20 to 60. Mu.m.
In a third aspect, the present invention provides a microsphere selective endo-radiotherapeutic agent comprising said biodegradable radioactivity 90 And Y microspheres.
In a fourth aspect, the present invention also provides the biodegradable radioactivity 90 Use of Y microspheres in the preparation of a microsphere selective endoradiotherapy.
The invention has the advantages that: alginate provided by the invention 90 The Y microspheres can be completely degraded in the body after the function of radiotherapy is completed, do not participate in metabolism in the body, are discharged along with urine, do not influence the normal physiological functions of organs, and do not generate microsphere displacement or diffusion. Furthermore, alginate 90 Y microsphere loaded radionuclide 90 Y is in the whole microsphere(more radionuclides) 90 Y is supported inside the microsphere) and the radionuclide is delivered in a stable, ionically crosslinked form 90 Y being immobilized therein, not just the surface of the microspheres, as resin microspheres adsorb radionuclides 90 Y, so that alginate 90 Y microspheres have a lower radionuclide dissolution rate. Alginate 90 The Y microsphere has proper specific gravity, hydrophilic surface, easy dispersion and suspension during injection and good compatibility with human tissues and blood. The sodium alginate microsphere is a common vascular embolic agent, has certain plasticity and expansibility, and clinical reports show that the sodium alginate microsphere has good embolic effect, does not cause vascular occlusion, and can quickly recover organ functions after treatment is finished. Alginate 90 The Y microspheres can also be loaded with other active drugs, and the drugs are slowly released into local tissues along with the degradation of the microspheres in the microspheres, so that the therapeutic effect of multiple modes is realized. The biodegradable radioactivity of the invention 90 The preparation method of the Y microsphere is simple, low in cost and high in preparation efficiency. The obtained microsphere is stable and radioactive 90 Y is mainly distributed in the microsphere, the surface of the microsphere is mainly crosslinked by non-radioactive multivalent metal ions, and the dissolution rate of the radionuclide is small when the radionuclide is stored and used. And the method can be operated in a closed environment, is easy to realize automatic production, does not cause radioactive pollution, and has small radiation dose for operators.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention are clearly and completely described below. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods. The examples are not intended to identify the particular technology or conditions, and are either conventional or are carried out according to the technology or conditions described in the literature in this field or are carried out according to the product specifications. The reagents and instruments used, etc. are not identified to the manufacturer and are conventional products available for purchase by regular vendors.
In the embodiment of the invention, used 90 Y 3+ The ion is German Eckert&Ziegler Radiopharma GmbH company product, is 90 YCl 3 Preserving in 0.04M hydrochloric acid solution, purifying>99% radioactivity specific activity was 2pmol/3KBq (0.207 Ci/mg), sodium alginate and potassium alginate were all from Qingdao Mingya seaweed group Co.
The invention will be further illustrated with reference to examples.
Example 1
This example provides a biodegradable radioactivity 90 The preparation method of the Y microsphere comprises the following steps:
1) Preparing particles: 0.1g of sodium alginate (high viscosity specification) is dissolved in 9.9g of deionized water to obtain sodium alginate solution with the mass concentration of 1%, the sodium alginate solution is slowly added into 20mL of liquid paraffin under stirring, 0.1g of span 80 is dissolved in the liquid paraffin, the stirring speed is 1000 revolutions per minute, and stirring is continued for 1 hour after the sodium alginate solution is added.
2） 90 Y 3+ Ion primary crosslinking: 414mCi (containing 2 mg) 90 YCl 3 ) A kind of electronic device 90 Adding deionized water into the Y feed liquid to form 2mL of solution, and keeping the stirring state of the step 1) to obtain 90 Y 3+ Slowly adding the ionic solution into the microparticle emulsion, performing crosslinking and curing, and maintaining the stirring state for 1 hour after the addition is finished to obtain crosslinked microspheres;
3) Non-radioactive multivalent metal ion resolidification: stopping stirring the microsphere emulsion obtained in the step 2), adding ethanol, standing, demulsifying and layering, collecting microspheres in the lower water phase, washing with deionized water, and soaking the crosslinked microspheres in 5% CaCl 2 In solution (5 gCaCl) 2 Dissolving in 95g deionized water), soaking for at least 1 hr, sterilizing under wet heat, sealing, and replacing Ca with normal saline before use 2+ An aqueous ionic solution.
Example 2
1) Preparing particles: 0.05g of sodium alginate (high viscosity specification) was dissolved in 9.95g of deionized water to obtain a sodium alginate solution having a mass concentration of 0.5%, and the remainder was the same as in example 1.
2） 90 Y 3+ Ion primary crosslinking: 103mCi (containing 0.5 mg) 90 YCl 3 ) A kind of electronic device 90 Feed liquid Y and 1.5mg CaCl 2 Deionized water was added to form 2mL of a solution, and the remainder was the same as in example 1.
3) Non-radioactive multivalent metal ion resolidification: the same as in example 1.
Example 3
1) Preparing particles: 0.5g of sodium alginate (medium viscosity specification) was dissolved in 9.5g of deionized water to obtain a sodium alginate solution having a mass concentration of 5%, and the remainder was the same as in example 1.
2） 90 Y 3+ Ion primary crosslinking: 207mCi (containing 1 mg) 90 YCl 3 ) A kind of electronic device 90 Y feed liquid and 19mg CaCl 2 Deionized water was added to form 2mL of a solution, and the remainder was the same as in example 1.
3) Non-radioactive multivalent metal ion resolidification: the same as in example 1.
Example 4
1) Preparing particles: potassium alginate was used instead of sodium alginate, the remainder being the same as in example 1.
2） 90 Y 3+ Ion primary crosslinking: the same as in example 1.
3) Non-radioactive multivalent metal ion resolidification: the same as in example 1.
Example 5
1) Preparing particles: the procedure of example 1 was repeated except that the stirring speed was 3000 rpm.
2） 90 Y 3+ Ion primary crosslinking: the same as in example 1.
3) Non-radioactive multivalent metal ion resolidification: the same as in example 1.
Example 6
1) Preparing particles: the procedure of example 1 was repeated except that the stirring speed was 500 rpm.
2） 90 Y 3+ Ion primary crosslinking: the same as in example 1.
3) Non-radioactive multivalent metal ion resolidification: the same as in example 1.
Example 7
1) Preparing particles: 0.1g of sodium alginate (high viscosity specification) was dissolved in 9.9g of deionized water to obtain a sodium alginate solution having a mass concentration of 1%, 2mL of the prepared 1% sodium alginate solution was used, and the rest was the same as in example 1.
2） 90 Y 3+ Ion primary crosslinking: the same as in example 1.
3) Non-radioactive multivalent metal ion resolidification: the same as in example 1.
Example 8
1) Preparing particles: 0.2g of sodium alginate (high viscosity specification) was dissolved in 19.8g of deionized water to obtain a sodium alginate solution having a mass concentration of 1%, and the remainder was the same as in example 1.
2） 90 Y 3+ Ion primary crosslinking: the same as in example 1.
3) Non-radioactive multivalent metal ion resolidification: the same as in example 1.
Example 9
1) Preparing particles: the procedure of example 1 was repeated except that the liquid paraffin was not subjected to span 80.
2） 90 Y 3+ Ion primary crosslinking: the same as in example 1.
3) Non-radioactive multivalent metal ion resolidification: using FeCl 3 Substituted CaCl 2 The remainder was the same as in example 1.
Comparative example 1
1) Preparing particles: the same as in example 1.
2） 90 Y 3+ Ion primary crosslinking: the same as in example 1.
3) This stepUnlike example 1, the non-radioactive re-solidification of polyvalent metal ions is no longer performed, i.e. deionized water is used instead of CaCl 2 The solution was the same as in example 1.
Comparative example 2
1) Preparing particles: the same as in example 1.
2） 90 Y 3+ Ion primary crosslinking: 207mCi (containing 1 mg) 90 YCl 3 ) A kind of electronic device 90 Deionized water was added to the Y feed solution to form 2mL of a solution, and the remainder was the same as in example 1.
3) Non-radioactive multivalent metal ion resolidification: the same as in example 1.
Comparative example 3
1) Preparing particles: the same as in example 1.
2） 90 Y 3+ Ion primary crosslinking: 207mCi (containing 1 mg) 90 YCl 3 ) A kind of electronic device 90 Y feed liquid and 199mg CaCl 2 Deionized water was added to form 2mL of a solution, and the remainder was the same as in example 1. 2mL of solution was formed, the remainder being the same as in example 1.
3) Non-radioactive multivalent metal ion resolidification: the same as in example 1.
Detecting the microspheres obtained in the above examples and comparative examples, observing the shape and stability of the microspheres under an optical microscope, measuring the diameter, soaking the microspheres in 37 ℃ physiological saline for 64.2 hours, separating the microspheres, and measuring the proportion of the radioactivity in the physiological saline to the total activity of the microspheres to obtain 90 Y dissolution rate. The test results are shown in the following table:
table 1 results of microsphere performance measurements for examples and comparative examples
Experimental example [ ] 90 Y microsphere animal experiment
Establishing rabbit VX2 liver cancer animal model, growing tumor in rabbit liver for 14 days, and dividing 6 experimental rabbits into two groups randomly 90 Y microsphere groups, control group), 3 per groupThe lower limb artery of each rabbit was punctured, a catheter guidewire was introduced from the femoral artery into the hepatic tumor blood supply artery under the guidance of an angiographic interventional therapy system, and then a catheter prepared according to the conditions of example 5 90 Y microsphere [ ] 90 Y microsphere group) or normal saline (control group) is injected into the liver tumor blood supply artery of the rabbit, 90 dispersing the Y microspheres in 5mL of physiological saline before injection, wherein the injection amount is 90 Y microspheres were about 100 mCi/min, physiological saline was 5 mL/min, and after the injection was completed, the mixture was sutured, and gentamicin sulfate (8X 10) 4 U/d) for 3 days, and measuring tumor volume under CT image after continuous feeding for 21 days, wherein the result is 90 The volume of the Y microsphere group is (3.12+/-1.06), and the volume of the control group is (10.03+/-1.56) cm 3 ， 90 The tumor volume of the Y microsphere group was significantly smaller than that of the control group (P<0.05）。
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims (9)
1. Biodegradable radioactivity 90 Y microspheres, characterized in that the biodegradable radioactivity 90 The Y microspheres are alginate radioactive gel which is formed by crosslinking alginate sol and polyvalent metal ions, wherein the polyvalent metal ions comprise 90 Y 3+ Ions and non-radioactive multivalent metal ions;
the biodegradable radioactivity 90 The Y microspheres are spherical; the biodegradable radioactivity 90 The diameter of the Y microsphere is 20-60 mu m; the radioactivity is as follows 90 The radionuclide dissolution rate of the Y microspheres in the physiological saline is less than 0.2% in 64.2 hours;
the can give birth toBiodegradable radioactivity 90 The Y microsphere is prepared by a preparation method comprising the following steps:
1) Preparing particles; dispersing 0.5-5% monovalent salt of alginic acid water solution into oily liquid under stirring of 500-3000 rpm to obtain microparticle emulsion;
2） 90 Y 3+ ion primary crosslinking; will be under stirring 90 Y 3+ Adding the ionic water solution into the microparticle emulsion, and performing crosslinking and curing to obtain crosslinked microspheres; the said 90 Y 3+ With or without non-radioactive multivalent metal ions in the aqueous ionic solution, said 90 Y 3+ In the ion water solution, the ion water solution is mixed, 90 Y 3+ the mass concentration of the ion and/or non-radioactive multivalent metal ion is 0.1% -1%, and the adding volume is not more than the volume of the monovalent salt water solution of the alginic acid;
3) Non-radioactive multivalent metal ions resolidify; immersing the crosslinked microspheres into non-radioactive multivalent metal ion aqueous solution, and performing resolidification molding; the mass concentration of the non-radioactive multivalent metal ion aqueous solution is 5% -20%.
2. The biodegradable radioactivity of claim 1 90 Y microspheres, characterized in that the non-radioactive multivalent metal ions comprise Ca 2+ 、Fe 2+ 、Fe 3+ 、Ba 2+ 、Al 3+ 、Zn 2+ And Cu 2+ One or more of the following.
3. Biodegradable radioactivity as claimed in claim 1 or 2 90 The preparation method of the Y microsphere is characterized by comprising the following steps:
1) Preparing particles; dispersing an aqueous solution of monovalent salt of alginic acid into an oily liquid under stirring to obtain a microparticle emulsion;
2） 90 Y 3+ ion primary crosslinking; will be under stirring 90 Y 3+ Adding the ionic water solution into the microparticle emulsion, and performing crosslinking and curing to obtain crosslinked microspheres; the said 90 Y 3+ The ionic aqueous solution may or may not contain non-radioactive multivalent metal ions;
3) Non-radioactive multivalent metal ions resolidify; immersing the crosslinked microspheres into non-radioactive multivalent metal ion aqueous solution, and performing resolidification molding;
in the step 1), the mass concentration of the monovalent salt of alginic acid is 0.5-5%, and the stirring speed is 500-3000 r/min; in step 2), the 90 Y 3+ In the ion water solution, the ion water solution is mixed, 90 Y 3+ the mass concentration of the ion and/or non-radioactive multivalent metal ion is 0.1% -1%, and the adding volume is not more than the volume of the monovalent salt water solution of the alginic acid; in the step 3), the mass concentration of the non-radioactive multivalent metal ion aqueous solution is 5% -20%.
4. A biodegradable radioactivity according to claim 3 90 The preparation method of the Y microspheres is characterized in that in the step 1), the volume ratio of the oily liquid to the monovalent salt water solution of the alginic acid is 1:0.1-1.
5. The biodegradable radioactivity of claim 4 90 The preparation method of the Y microspheres is characterized in that a water-in-oil surfactant is added into the oily liquid; the oily liquid is a liquid which does not dissolve with an aqueous solution of monovalent salt of alginic acid.
6. The biodegradable radioactivity of claim 5 90 The preparation method of the Y microspheres is characterized in that the oily liquid comprises one or more of edible oil, liquid paraffin, mineral oil, kerosene, gasoline and silicone oil; the water-in-oil surfactant comprises a lipophilic surfactant having an HLB of less than 10.
7. The biodegradable radioactivity of claim 5 90 The preparation method of the Y microsphere is characterized in that the water-in-oil type surfactant comprises span series surfactants and/or glyceryl monostearate.
8. A microsphere selective endo-radiotherapeutic agent comprising a biodegradable radioactivity as claimed in claim 1 or 2 90 And Y microspheres.
9. Biodegradable radioactivity as claimed in claim 1 or 2 90 Use of Y microspheres in the preparation of a microsphere selective endoradiotherapy.
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| WO2023025943A1 (en) * | 2021-08-26 | 2023-03-02 | Norwegian University Of Science And Technology (Ntnu) | Diblock polymer |
| WO2023066994A1 (en) * | 2021-10-21 | 2023-04-27 | Blue Wave Therapeutics Gmbh | Peptide-coupled alginate gels comprising radionuclides |
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