CN117695431A - Embolic microsphere loaded with radiotherapy nuclide and preparation method thereof - Google Patents
Embolic microsphere loaded with radiotherapy nuclide and preparation method thereof Download PDFInfo
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- CN117695431A CN117695431A CN202311700042.1A CN202311700042A CN117695431A CN 117695431 A CN117695431 A CN 117695431A CN 202311700042 A CN202311700042 A CN 202311700042A CN 117695431 A CN117695431 A CN 117695431A
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- microsphere
- embolic
- chelating agent
- radionuclide
- radiotherapy
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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
- A61L24/02—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
- A61L24/001—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
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
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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
- A61L2300/44—Radioisotopes, radionuclides
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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
- A61L2430/00—Materials or treatment for tissue regeneration
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Surgery (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Materials Engineering (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses an embolism microsphere loaded with a radiotherapy nuclide, which is characterized in that a chelating agent is covalently coupled on the surface of the embolism microsphere through an isocyanate group, and then coordination chelation is carried out between the chelating agent and the radionuclide. Its preparing process is also disclosed. The radionuclide microsphere capable of loading radiotherapy provided by the invention has a broad-spectrum radionuclide chelating function, and can be used for preparing radiotherapy embolism microspheres.
Description
Technical Field
The invention relates to an embolism microsphere loaded with radiotherapy nuclide and a preparation method thereof, belonging to the technical field of medical appliances.
Background
For most HCC patients which can not receive radical treatment, selective hepatic artery chemoembolization (transarterial chemoembolization, TACE) is the first treatment method, namely, under the monitoring of imaging equipment, the embolic material loaded with the chemotherapeutic drugs is injected into blood supply arterial blood vessels of tumor tissues through a catheter, so that the 'hunger' tumors are blocked by blood supply, the growth of the tumors is inhibited, the tumors can be killed by locally releasing the high-concentration chemotherapeutic drugs, and the method has the advantages of minimally invasive, safe and targeted treatment, and the like, thereby improving the treatment efficiency and reducing the systemic toxicity. However, TACE is affected by serious liver dysfunction, portal arterial embolism, chemotherapy drug resistance, distant metastasis of tumor, renal dysfunction, etc., so that radiotherapy in combination with TACE has attracted extensive attention in the academic and market.
The combination of external radiation therapy with TACE has significant efficacy on HCC-complicated portal cancer suppositories, but has limited clinical use due to the risk of liver and adjacent organ dysfunction. Internal radiation therapy is the injection of a radionuclide drug into the hepatic artery, so that the radionuclide is selectively retained in liver tumor tissue, while the dose in normal liver tissue is lower than the tolerance dose. In recent years, internal irradiation therapy has been rapidly developed, and hepatic arterial radiotherapy embolism (transarterial radioembolization, TARE) has become a hot spot for intravascular liver cancer therapy in recent 10 years. Researchers in the last 60 th century utilize colloids 90 Y success in tumor treatment by local and intra-arterial injection was reported by researchers in the 90 s 90 Use of Y glass microspheres in HCC experiments and in clinic. 90 Y emits pure beta rays with a half-life of 64.2h and a maximum penetration depth in soft tissue of 11mm. Currently, there are 2 main types of radiotherapy microspheres approved for use, one of which is produced by Nordion, canada 90 Y glass microspheres, marketed in 1999 under the trade name TheraSphere, FDA, approved palliative treatment for HCC patients who were unable to undergo surgical resection, were 20-300 μm in diameter with isotopes located within the microspheres. The other is resin microsphere produced by Sirtex Medical company in Australia, which is marketed in 2002 under the trade name Sir-Spheres, and is suitable for liver metastasis of colorectal cancer and needs to be combined with chemotherapy, the diameter of the microsphere is 20-60 mu m, and the isotope is marked on the surface of the microsphere. The main difference between the two is that the glass microspheres are more stable, the radioactivity is high, the required quantity of the microspheres is small, the embolism effect is weak, and the permanent embolism is easy to form; the resin microspheres are easy to prepare, radioactive elements are easy to free, so that the number of microspheres required in treatment is large, the effect on hepatic arterial embolism is relatively obvious, but the incidence rate of radioactive injury to non-target tissues is high, and ectopic embolism is easy to form. The microsphere is an embolic agent which is relatively common at present and has relatively ideal curative effect, and has the functions of local radiation and embolism, and the two are 90 Y carrier. The world is being researched 166 Ho sum 188 Re, etc. has not only therapeutic value, but also nuclide imaging, is convenient for follow-up study after treatment, and has higher practical value in clinic.
Materials which can be used for preparing the embolic microsphere are a lot, gelatin sponge, iodized oil and the like in the early stage, along with the development and progress of the materials, common materials comprise polyvinyl alcohol (PVA), polylactic acid-glycolic acid copolymer (PLGA), calcium alginate, chitosan and the like, and the materials have good biocompatibility, are nontoxic, low in price and rich in sources, so that the materials are widely applied in the field of biomedicine. There are many embolic microspheres in the market such as blank microspheres, drug-loaded microspheres, radioactive microspheres, degradable microspheres, etc. The radiotherapy embolism treatment has wide application in treating malignant tumors such as livers, has small wounds, low risks and few complications, and can obviously improve the survival time and the survival quality of patients with or without portal vein cancer embolism in middle and late stages. The technology can also be used for treating tumor residues or recrudescence after liver cancer operation, transitional treatment before liver transplantation or liver cancer excision, intrahepatic duct cancer, liver metastasis cancer and the like, and can also replace TACE, radiofrequency ablation and chemotherapy. Therefore, the development and preparation of the embolic microsphere capable of loading the radionuclide have important research significance and market value.
The Chinese patent No. 1288755A discloses a safe microsphere carrying pure beta rays and a preparation method thereof, which is formed by compounding glass microsphere carrying pure beta rays and a corrosion-resistant coating coated on the outer surface of the glass microsphere by adopting a sol-gel method, and can be widely used for treating cancers by internal radiotherapy. Chinese patent No. 115120749A discloses a method for preparing radiotherapy microsphere and radiotherapy microsphere, which comprises polymerizing organic macromolecules and ionic acrylic acid monomer to obtain organic macromolecule hydrogel microsphere, immersing in 90 In the Y ion solution, the radiotherapy microsphere is obtained by dehydration after treatment by alkaline solution 90 The Y load rate is high, the falling off is not easy, and the like; the invention of China patent CN103120640A discloses an embolic agent and a preparation method thereof and a using method thereof, wherein the embolic agent comprises a liposome, 131I iodized oil and magnetic nano particles are wrapped on the liposome, and the outer surface of the liposome is connected with an anti-tumor agentTumor medicine. The technology develops a treatment technology combining radiotherapy, thermotherapy and embolism treatment; chinese patent No. 114522256A discloses a polyhydroxyalkanoate drug-loaded radiotherapy microsphere, its preparation method and application, the microsphere is composed of polyhydroxyalkanoate microsphere and radionuclide, the radionuclide is radioactive 125 I or 131 I. The microsphere is prepared by a double-cavity electrospray method, has adjustable particle size, good biocompatibility and safety, and can be used for tumor interventional embolism and intratumoral radiotherapy; chinese patent No. 115944753A discloses an organic-inorganic composite radiotherapy microsphere and a preparation method thereof. The microsphere is inlaid 90 The hydrogel microsphere of the Y inorganic particles, wherein the particle size of the 90Y inorganic particles is 5-50 microns, and the particle size of the hydrogel microsphere is 30-300 microns. The composite microsphere has the following characteristics that 90 High Y load and 90 the Y element can not fall off, etc. The above-mentioned patent technology is physical encapsulation and loading of radionuclides, and does not involve chemical bonding and chelation of radionuclides and carriers.
Chinese patent No. 115590824A discloses a polyvinyl alcohol embolism microsphere with developer, its preparation method and application, firstly, diethyl triamine pentaacetic anhydride and methacrylic acid-2-amino ethyl ester are mixed to produce amidation, the reaction is carried out to produce DTPA connected with two methacrylic acid-2-amino ethyl esters, then chelating reaction is carried out with gadolinium salt, crosslinking agent with developing element is prepared, then emulsion polymerization method or microfluidic method is used to prepare polyvinyl alcohol microsphere, and the crosslinking agent is used to crosslink, thus preparing polyvinyl alcohol embolism microsphere with developing effect and drug carrying capability under MRI. The technique is magnetic resonance imaging and does not belong to radiotherapy embolism technology.
The Chinese patent No. 115429905A discloses a degradable monodisperse radiotherapy embolism microsphere with stable nuclide labeling, a preparation method and application thereof, wherein the microsphere comprises monodisperse polymer microsphere with the particle diameter of 20-200 mu m, radioactive metal nano particles are contained, and radionuclide ions are used for preparing the microsphere 177 Lu、 90 Y、 166 Ho、 188 Re and the like are formed by reduction with dopamine nano particles. Inside the microsphere, the radioactive metal nano-particles are generated by the microsphereThe ball is not easy to be dissociated due to the wrapping and chemical bond formation; the Chinese patent No. 115671321A discloses a surface phosphonated silica microsphere, a preparation method thereof and application thereof in radiopharmaceuticals, wherein the surface of the silica microsphere is phosphonated and modified by taking the silica microsphere with better biological safety as a carrier, so as to prepare the surface phosphonated silica microsphere, and the surface phosphate radical of the surface of the silica microsphere is utilized to chelate the radionuclide so as to obtain the radioactive surface phosphonated silica microsphere. In the above patent, the embolic microsphere and the radioactive metal are combined by the action of static electricity and the like, and the problems of undefined ligand chemical structure, unbalanced radionuclide loading, and the like may exist.
Unlike available patent technology, the present invention provides one simple and efficient method for the coupling modification of radionuclide chelating agent in embolic microsphere. Specifically, the surface of the embolic microsphere is modified by diisocyanate reagents, the surface of the embolic microsphere is covalently coupled with a chelating agent group with a definite structure, and the chelating agent group is further coordinated and chelated with radionuclide to prepare the embolic microsphere loaded with radionuclide, and meanwhile, the risks of dissolution and falling of the radionuclide of the embolic microsphere in the using process are avoided or reduced. More particularly, a method and related process for covalently coupling radionuclide chelators to embolic microspheres is provided.
Disclosure of Invention
The invention aims to realize the embolic microsphere loaded with the radiotherapy nuclide by covalently coupling a chelating agent group on the surface of the embolic microsphere and further carrying out coordination chelation with the radionuclide.
The aim of the invention is achieved by the following technical scheme:
an embolism microsphere loaded with radiotherapy nuclide is prepared through covalent coupling of chelating agent with isocyanate group, and coordination chelating between chelating agent and radionuclide.
Preferably, the isocyanate groups are chemically coupled to hydroxyl or imino groups on the chelating agent.
Preferably, the isocyanate groups are derived from toluene-2, 4-diisocyanate, m-xylylene diisocyanate or 1, 3-xylylene diisocyanate.
Preferably, the chelating agent is selected from ethylene triamine pentaacetic acid, diethylene triamine tetraacetic acid or N-hydroxyethyl ethylene diamine triacetic acid.
Preferably, the radionuclide is selected from 177 Lu、 90 Y、 166 Ho、 188 Re、 64 Cu is selected.
Preferably, the embolic microspheres are made of polylactic acid, polycaprolactone, polyglycolic acid, polyethylene glycol, polyacrylate, polyvinyl alcohol, cellulose, alginic acid and salts thereof, hyaluronic acid and salts thereof, chitosan, dextran or gelatin.
The invention also discloses a preparation method of the embolism microsphere loaded with the radiotherapy nuclide, which comprises the following steps:
(1) Immersing the embolic microspheres in an organic solution of diisocyanate reagents, and performing grafting reaction under the action of a catalyst to obtain embolic microspheres modified with isocyanate groups;
(2) Immersing the embolic microsphere modified with isocyanate groups in an aqueous solution of a chelating agent, and performing grafting reaction under the action of a catalyst to obtain the embolic microsphere with the surface covalently modified with the chelating agent;
(3) And uniformly mixing the radionuclide with the embolic microsphere modified with the chelating agent, and reacting for a period of time to enable the radionuclide to be loaded on the embolic microsphere through coordination of the chelating agent.
Preferably, the catalyst in steps (1) and (2) is triethylamine.
Preferably, the organic solvent in step (1) is selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, toluene and chloroform.
Preferably, the reaction temperature in the step (1) is 40-90 ℃ and the reaction time is 0.5-4 h; the reaction temperature of the step (2) is 40-90 ℃ and the reaction time is 0.5-4 h.
Preferably, the radionuclide in step (3) is 90 YCl 3 。
The beneficial effects are that: the radionuclide microsphere capable of loading radiotherapy provided by the invention has a broad-spectrum radionuclide chelating function, and can be used for preparing radiotherapy embolism microspheres.
Drawings
FIG. 1 is a chemical structure of N-hydroxyethyl ethylenediamine triacetic acid (NHEDTA).
FIG. 2 is a schematic diagram of a process for preparing embolic microspheres loaded with radiotherapeutic nuclides.
FIG. 3 is a schematic diagram of the structure of embolic microspheres loaded with radiotherapeutic nuclides.
FIG. 4 is a schematic diagram of the loading process of a radionuclide for radiotherapy (in order to 90 Y is an example).
The specific implementation method comprises the following steps:
the present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention in any way.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, and the terms used herein in this description of this invention are for the purpose of describing particular embodiments only and are not intended to be limiting of this invention.
The materials or instruments used in the following examples, if not specifically described, were available from conventional commercial sources.
Example 1
Taking 10mL of embolic microspheres, namely polyvinyl alcohol (PVA), repeatedly ultrasonically cleaning the embolic microspheres by ethanol and deionized water for three times, taking out the embolic microspheres, immersing the embolic microspheres into 20mL of toluene solution of toluene-2, 4-diisocyanate (TDI) (volume concentration is 10%), adding triethylamine as a catalyst (volume concentration is 5%), treating for 1h at 60 ℃ for grafting reaction, then taking out the embolic microspheres, repeatedly flushing the embolic microspheres by toluene for 3 times, and then placing the embolic microspheres in 20mL of N-hydroxyethyl ethylenediamine triacetic acid water solution with the concentration of 10wt% and the concentration of 5% (v./v.) by using triethylamine as a catalyst, and treating for 2h at 40 ℃. Taking out the embolism microsphere after the reaction is finished, washing the embolism microsphere for 3 times by pure water, and soaking the embolism microsphere in the pure water or drying and preserving the embolism microsphere; 1mL of the embolic microspheres modified with the chelating agent groups were immersed in 10mL of sodium acetate-acetic acid buffer solution (0.2 mol/L, pH=4.5 0.1mL of radionuclide is added 90 YCl 3 The aqueous solution (concentration 0.1 mg/L) was reacted at 80℃for 20 minutes, and the embolic microspheres were removed and rinsed 3 times with pure water to obtain radionuclide-loaded embolic microspheres.
The embolic microsphere with the radionuclide chelating agent on the surface can be loaded with various radionuclides, can realize the radiotherapy combined treatment of the embolic microsphere in the using process, can also be used for positron emission imaging (PET/CT) contrast, and is beneficial to tracking the degree and the range of embolism after the embolic treatment.
The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the present invention and to implement the same, but are not intended to limit the scope of the present invention, and all equivalent changes or modifications made according to the spirit of the present invention should be included in the scope of the present invention.
Claims (10)
1. An embolism microsphere loaded with radiotherapy nuclide is characterized in that a chelating agent is covalently coupled on the surface of the embolism microsphere through an isocyanate group, and then coordination chelation is carried out between the chelating agent and radionuclide.
2. Embolic microsphere according to claim 1, characterized in that the isocyanate groups are chemically coupled with hydroxyl or imino groups on the chelating agent.
3. Embolic microsphere according to claim 1, characterized in that the isocyanate groups are derived from toluene-2, 4-diisocyanate, m-xylylene diisocyanate or 1, 3-xylylene diisocyanate.
4. Embolic microsphere according to claim 1, characterized in that the chelating agent is selected from ethylene triamine pentaacetic acid, diethylene triamine tetraacetic acid or N-hydroxyethyl ethylene diamine triacetic acid.
5. Embolic microsphere according to claim 1, characterized in that the radionuclide is derived from 177 Lu、 90 Y、 166 Ho、 188 Re、 64 Cu is selected.
6. The embolic microsphere according to claim 1, wherein the embolic microsphere is made of polylactic acid, polycaprolactone, polyglycolic acid, polyethylene glycol, polyacrylate, polyvinyl alcohol, cellulose, alginic acid and salts thereof, hyaluronic acid and salts thereof, chitosan, dextran, or gelatin.
7. A method for preparing embolic microspheres loaded with a radiotherapeutic radionuclide according to any one of claims 1 to 6, characterised in that it comprises the steps of:
(1) Immersing the embolic microspheres in an organic solution of diisocyanate reagents, and performing grafting reaction under the action of a catalyst to obtain embolic microspheres modified with isocyanate groups;
(2) Immersing the embolic microsphere modified with isocyanate groups in an aqueous solution of a chelating agent, and performing grafting reaction under the action of a catalyst to obtain the embolic microsphere with the surface covalently modified with the chelating agent;
(3) And uniformly mixing the radionuclide with the embolic microsphere modified with the chelating agent, and reacting for a period of time to enable the radionuclide to be loaded on the embolic microsphere through coordination of the chelating agent.
8. The process according to claim 7, wherein the catalyst in each of the steps (1) and (2) is triethylamine.
9. The process according to claim 7, wherein the organic solvent in the step (1) is selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, toluene and chloroform.
10. The preparation method according to claim 7, wherein the reaction temperature in the step (1) is 40-90 ℃ and the reaction time is 0.5-4 hours; the reaction temperature of the step (2) is 40-90 ℃ and the reaction time is 0.5-4 h.
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