CN113842503A - Hydrogel of poly beta amino ester loaded with active substance, preparation method and application thereof - Google Patents
Hydrogel of poly beta amino ester loaded with active substance, preparation method and application thereof Download PDFInfo
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- CN113842503A CN113842503A CN202111048316.4A CN202111048316A CN113842503A CN 113842503 A CN113842503 A CN 113842503A CN 202111048316 A CN202111048316 A CN 202111048316A CN 113842503 A CN113842503 A CN 113842503A
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- amino ester
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- 229920001212 Poly(beta amino esters) Polymers 0.000 title claims abstract description 28
- 239000013543 active substance Substances 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title abstract description 14
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- 125000002252 acyl group Chemical group 0.000 claims abstract description 19
- 239000000126 substance Substances 0.000 claims abstract description 19
- 230000000975 bioactive effect Effects 0.000 claims abstract description 17
- 125000003396 thiol group Chemical group [H]S* 0.000 claims abstract description 17
- GRUHSDOCOBLLQH-UHFFFAOYSA-N prop-2-ynehydrazide Chemical compound NNC(=O)C#C GRUHSDOCOBLLQH-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 13
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- 125000004386 diacrylate group Chemical group 0.000 claims abstract description 12
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 claims abstract description 12
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- RLCKHJSFHOZMDR-UHFFFAOYSA-N (3R, 7R, 11R)-1-Phytanoid acid Natural products CC(C)CCCC(C)CCCC(C)CCCC(C)CC(O)=O RLCKHJSFHOZMDR-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/52—Hydrogels or hydrocolloids
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- A—HUMAN NECESSITIES
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
- C08G65/3332—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing carboxamide group
- C08G65/33324—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing carboxamide group acyclic
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
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- 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
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
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- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/32—Materials or treatment for tissue regeneration for nerve reconstruction
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2371/00—Characterised by the use of polyethers obtained by reactions forming an ether link in the main chain; Derivatives of such polymers
- C08J2371/02—Polyalkylene oxides
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2471/00—Characterised by the use of polyethers obtained by reactions forming an ether link in the main chain; Derivatives of such polymers
- C08J2471/02—Polyalkylene oxides
Abstract
The invention discloses an active substance-loaded poly beta amino ester hydrogel and a preparation method and application thereof.A polyethylene glycol diacrylate and propiolic hydrazide generate Michael addition reaction to obtain poly beta amino ester containing propiolic acyl; the hydrogel of the poly-beta-amino ester loaded with the active substance is obtained by coupling reaction of a double-bond or sulfhydryl-containing bioactive substance with the poly-beta-amino ester and multi-arm sulfhydryl PEG or inositol hexa-mercapto propionate. The hydrogel has good biocompatibility and stable chemical property, can be used as a neurotrophic factor carrier and is used for treating nerve injury.
Description
Technical Field
The invention relates to an active substance-loaded poly beta amino ester hydrogel and a preparation method and application thereof, belonging to the technical field of hydrogel preparation.
Background
Spinal nerve injury is a serious disease of central nervous system injury, and can cause serious dysfunction of limbs under injury, such as partial or complete loss of sensory and motor functions. Spinal cord injury can also cause various complications such as deep vein thrombosis, pulmonary embolism, pain and the like, seriously affect the life quality of people and also bring heavy burden to families and society. The reasons of spinal cord injury include traffic accidents, heavy object injuries, high falling and the like, and 20 ten thousand of spinal cord injury cases are newly added in the world according to statistics.
Firstly, after spinal cord injury occurs, trauma at the injury site can cause a series of secondary pathophysiological reactions such as ischemia and hypoxia, inflammatory cell infiltration, free radical release and the like. These physiological processes, not only lead to axonal and myelin breakdown and even nerve cell death, but astrocytes, microglia, etc. are activated and scar around the injury site. After spinal cord injury, the compact glial scar not only serves as a physical barrier to inhibit nerve regeneration, but also astrocytes and microglia in the scar secrete a large amount of proinflammatory factors to participate in forming a regeneration inhibition microenvironment after injury, so that repair of spinal cord injury is hindered. Researchers have used cell transplantation, tissue engineering, and other methods to inhibit glial scarring. Since the hollow area formed after spinal cord injury requires physical filling, tissue engineering methods containing hydrogels to inhibit glial scarring are considered to be one of the most promising approaches. At present, people mainly adopt natural hydrogel materials such as hyaluronic acid, collagen, acellular tissue matrix and the like, self-assembled polypeptide and PEG hydrogel based on polyethylene glycol, and can effectively improve spinal cord injury repair. However, these hydrogels suffer from potential toxicity of natural material cross-linking agents, potential host reactions of acellular matrix, control of mechanical properties of polypeptide hydrogels, and the problems of non-biological activity and difficulty in functional modification of polyethylene glycol gels during use.
The hydrogel is a highly interpenetrating three-dimensional network structure and is suitable for exchanging substances such as nutrients, oxygen, wastes and the like. The ideal hydrogel should be easily enzymatically hydrolyzed/hydrolyzed and eventually replaced with new tissue to meet the needs of biomaterials in tissue engineering. Hydrogels can provide cells/tissues with adjustable physicochemical properties and structures, similar to extracellular matrix structures, facilitating the growth and proliferation of cells. Because the synthesized polymer hydrogel has good biocompatibility, the application in the biomedical fields of tissue engineering, medicine/gene transmission and the like is very wide. In particular, poly (. beta. -amino ester) polymer hydrogels have degradability and excellent biocompatibility, and hydrogels of poly (. beta. -amino ester) (PAE) and other polyesters have been developed for tissue engineering. PAEs are prepared from diacrylates and primary/secondary alkylamines by the michael addition reaction without introducing any by-products. In addition, the ester groups in the PAE backbone are susceptible to degradation to small molecules (amino acids and diols). The PAE-based in-situ crosslinked hydrogel is simple and convenient to prepare, and can easily fill tissue defects through minimally invasive implantation to form a research object which is concerned in bioactive molecule conveying and tissue engineering systems.
Disclosure of Invention
The invention aims to provide an active substance-loaded poly beta amino ester hydrogel and a preparation method and application thereof.
The invention adopts the following technical scheme for solving the technical problems:
an active substance-loaded poly beta amino ester hydrogel is prepared by carrying out Michael addition reaction on polyethylene glycol diacrylate and propiolic hydrazide to obtain poly beta amino ester containing propiolic acyl; the hydrogel of the poly-beta-amino ester loaded with the active substance is obtained by coupling reaction of a double-bond or sulfhydryl-containing bioactive substance with the poly-beta-amino ester and multi-arm sulfhydryl PEG or inositol hexa-mercapto propionate.
A preparation method of hydrogel of poly beta amino ester loaded with active substances comprises the following steps:
s1, preparing poly beta amino ester containing propinyl acyl;
s2, uniformly mixing the bioactive substance and the poly beta amino ester containing propiolic acyl at room temperature, dissolving the mixture in distilled water, adding multi-arm sulfhydryl PEG or inositol hexamercapto propionate, and standing for 24 hours to obtain the hydrogel of the poly beta amino ester carrying the active substance.
Further, the step S1 specifically includes:
the propiolic hydrazide and the polyethylene glycol diacrylate are stirred and reacted for 12 to 72 hours at the temperature of between 50 and 90 ℃, unreacted micromolecules are removed through dialysis by a dialysis bag with the molecular weight cutoff of 1000, and the poly-beta-amino ester containing the propiolic acyl is obtained through freeze drying.
Further, the molar ratio of the propiolic hydrazide to the polyethylene glycol diacrylate is 1: 0.8-1.2: 1.
Further, in step S2, the bioactive substance is one or more of nerve growth factor, brain-derived neurotrophic factor, and methylprednisolone.
Further, in the step S2, the molar ratio of the propiolic acyl poly-beta-amino ester to the multi-arm sulfhydryl-containing PEG or the inositol hexakismercaptopropionate is 1: 0.4-0.4: 1.
Furthermore, in step S2, the bioactive substance accounts for 1-30 mol% of the total raw materials, wherein the total raw materials refer to the bioactive substance, the poly-beta-amino ester containing propiolic acyl group and the multi-arm sulfhydryl PEG or inositol hexa-mercapto propionate.
The application of hydrogel of poly beta amino ester loaded with active substance can be used as carrier of factor or medicine.
Further, it can be used for treating spinal nerve injury.
Advantageous effects
The hydrogel prepared by the preparation method disclosed by the invention is good in uniformity and consistency.
The hydrogel loaded with the active substance can be used as a carrier of factors or medicaments and used for treating spinal nerve injury.
The hydrogel loaded with active substances has strong drug slow-release function.
The invention provides a preparation method of hydrogel capable of loading a bioactive substance poly-beta-amino ester in a covalent grafting/embedding manner. The hydrogel has good biocompatibility and stable chemical property. The hydrogel of the invention can be used as a neurotrophic factor carrier for treating nerve injury.
Detailed Description
The following detailed description of embodiments of the invention is intended to be illustrative, and is not to be construed as limiting the invention.
The invention adopts the following technical scheme for solving the technical problems:
an active substance-loaded poly beta amino ester hydrogel is characterized in that poly beta amino ester containing propiolic acyl is obtained by the Michael addition reaction of polyethylene glycol diacrylate and propiolic hydrazide; the hydrogel of the poly-beta-amino ester loaded with the active substance is obtained by coupling reaction of a double-bond or sulfhydryl-containing bioactive substance with the poly-beta-amino ester and multi-arm sulfhydryl PEG or inositol hexa-mercapto propionate.
A preparation method of hydrogel of poly beta amino ester loaded with active substances comprises the following steps:
s1, preparing poly beta amino ester containing propinyl acyl; stirring and reacting propiolic hydrazide and polyethylene glycol diacrylate for 12-72 hours at 50-90 ℃, dialyzing by a dialysis bag with molecular weight cutoff of 1000 to remove unreacted micromolecules, and freeze-drying to obtain the poly-beta-amino ester containing propiolic acyl; the molar ratio of the propiolic hydrazide to the polyethylene glycol diacrylate is 1: 0.8-1.2: 1.
S2, uniformly mixing the bioactive substance and the poly beta amino ester containing propiolic acyl at room temperature, dissolving the mixture in distilled water, adding multi-arm sulfhydryl PEG or inositol hexamercapto propionate, and standing for 24 hours to obtain the hydrogel of the poly beta amino ester carrying the active substance. The bioactive substances are one or more of nerve growth factor, brain-derived neurotrophic factor and methylprednisolone; the molar percentage of the bioactive substances in the total raw materials is 1-30%; the total raw materials refer to bioactive substances, poly beta amino ester containing propinyl acyl and PEG or inositol hexamercapto propionate of multi-arm mercapto; the molar ratio of the poly-beta-amino ester containing propinyl acyl to PEG or inositol hexakismercapto propionate containing multi-arm mercapto is 1: 0.4-0.4: 1.
Example 1
Synthesis of poly (beta-amino ester) containing propinyl acyl
Propiolic hydrazide (0.1mmol) and polyethylene glycol diacrylate (0.1mmol, Mw600) are stirred and reacted for 24 hours at 70 ℃, unreacted small molecules are removed through dialysis by a dialysis bag with the molecular weight cut-off of 1000, and the poly (beta-amino ester) containing the propiolic hydrazide is obtained through freeze drying.
Example 2
Preparation of hydrogel of poly (beta-amino ester)
Poly (. beta. -amino ester) containing propiolic hydrazide (68.4mg) was dissolved in 6mL of a distilled water solution, and phytanic acid ester (26.1mg) was added thereto and mixed well. Standing for 24 hours to obtain the hydrogel of the poly (beta-amino ester), wherein the hydrogel has self-repairing performance.
Example 3
Preparation of hydrogel of poly (beta-amino ester)
Poly (. beta. -amino ester) containing propiohydrazide (68.4mg) was dissolved in 6mL of distilled water, and multi-arm PEG thiol (100mg) was added thereto and mixed well. Standing for 24 hours to obtain the hydrogel of the poly (beta-amino ester), and the hydrogel also has self-repairing performance.
Example 4
Preparation of hydrogel containing poly (beta-amino ester) of nerve growth factor
Nerve growth factor (1mg) was added to poly (. beta. -amino ester) containing propiohydrazide (68.4mg) and dissolved in 6mL of distilled water solution, and multi-arm PEG thiol (100mg) was added and mixed well. Standing for 24 hours to obtain the hydrogel of the nerve growth factor-loaded poly (beta-amino ester), and the hydrogel also has self-repairing performance.
Example 5
Preparation of Methylprednisolone-containing poly (beta-amino ester) hydrogel
Methylprednisolone (1mg) is added to poly (beta-amino ester) containing propiolic hydrazide (68.4mg), dissolved in 6mL of distilled water solution, multi-arm PEG sulfhydryl (100mg) is added, and the mixture is uniformly mixed. Standing for 24 hours to obtain the hydrogel of the nerve growth factor-loaded poly (beta-amino ester), and the hydrogel also has self-repairing performance.
Claims (9)
1. An active substance-loaded poly beta amino ester hydrogel is characterized in that poly beta amino ester containing propiolic acyl is obtained by the Michael addition reaction of polyethylene glycol diacrylate and propiolic hydrazide; the hydrogel of the poly-beta-amino ester loaded with the active substance is obtained by coupling reaction of a double-bond or sulfhydryl-containing bioactive substance with the poly-beta-amino ester and multi-arm sulfhydryl PEG or inositol hexa-mercapto propionate.
2. The method of claim 1, wherein the hydrogel of poly beta amino ester loaded with active agent is prepared by: the method comprises the following steps:
s1, preparing poly beta amino ester containing propinyl acyl;
s2, uniformly mixing the bioactive substance and the poly beta amino ester containing propiolic acyl at room temperature, dissolving the mixture in distilled water, adding multi-arm sulfhydryl PEG or inositol hexamercapto propionate, and standing for 24 hours to obtain the hydrogel of the poly beta amino ester carrying the active substance.
3. The method of claim 2, wherein: the step S1 specifically includes:
the propiolic hydrazide and the polyethylene glycol diacrylate are stirred and reacted for 12 to 72 hours at the temperature of between 50 and 90 ℃, unreacted micromolecules are removed through dialysis by a dialysis bag with the molecular weight cutoff of 1000, and the poly-beta-amino ester containing the propiolic acyl is obtained through freeze drying.
4. The method of claim 3, wherein: the molar ratio of the propiolic hydrazide to the polyethylene glycol diacrylate is 1: 0.8-1.2: 1.
5. The method of claim 2, wherein: the bioactive substance in step S2 is one or more of nerve growth factor, brain-derived neurotrophic factor, and methylprednisolone.
6. The method of claim 2, wherein: the molar ratio of the propinyl acyl poly-beta-amino ester to the multi-arm sulfhydryl-containing PEG or inositol hexakismercaptopropionate in the step S2 is 1: 0.4-0.4: 1.
7. The method of claim 6, wherein: the molar percentage of the bioactive substances in the total raw materials in the step S2 is 1-30%.
8. Use of an active substance loaded poly beta amino ester hydrogel as claimed in claim 1, which can be used as a carrier for factors or drugs.
9. Use of an active agent loaded poly beta amino ester hydrogel according to claim 1 for the treatment of spinal nerve injury.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104307049A (en) * | 2014-09-29 | 2015-01-28 | 四川大学华西医院 | Imitated extracellular matrix injectable in-situ hydrogel and preparation method and application thereof |
| CN105176080A (en) * | 2015-07-28 | 2015-12-23 | 南京微腾生物科技有限公司 | Injectable hydrogel with good biocompatibility, preparation method and applications |
| CN107987285A (en) * | 2016-10-26 | 2018-05-04 | 天津大学 | A kind of conduction injection aquagel and preparation method thereof |
| WO2019200152A1 (en) * | 2018-04-13 | 2019-10-17 | Thomas Zarembinski | Compositions and methods for the treatment of brain damage |
| CN112480389A (en) * | 2019-09-10 | 2021-03-12 | 天津大学 | Low-oxygen responsive injectable hydrogel and preparation method thereof |
| CN113289068A (en) * | 2021-05-25 | 2021-08-24 | 南通大学 | Preparation method of injectable hydrogel based on poly beta-amino ester/PEGDA |
-
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- 2021-09-08 CN CN202111048316.4A patent/CN113842503A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104307049A (en) * | 2014-09-29 | 2015-01-28 | 四川大学华西医院 | Imitated extracellular matrix injectable in-situ hydrogel and preparation method and application thereof |
| CN105176080A (en) * | 2015-07-28 | 2015-12-23 | 南京微腾生物科技有限公司 | Injectable hydrogel with good biocompatibility, preparation method and applications |
| CN107987285A (en) * | 2016-10-26 | 2018-05-04 | 天津大学 | A kind of conduction injection aquagel and preparation method thereof |
| WO2019200152A1 (en) * | 2018-04-13 | 2019-10-17 | Thomas Zarembinski | Compositions and methods for the treatment of brain damage |
| CN112480389A (en) * | 2019-09-10 | 2021-03-12 | 天津大学 | Low-oxygen responsive injectable hydrogel and preparation method thereof |
| CN113289068A (en) * | 2021-05-25 | 2021-08-24 | 南通大学 | Preparation method of injectable hydrogel based on poly beta-amino ester/PEGDA |
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