CN116970109A - Sulfoxide group-containing acrylate polymer, preparation method thereof and application thereof in resisting tissue adhesion - Google Patents
Sulfoxide group-containing acrylate polymer, preparation method thereof and application thereof in resisting tissue adhesion Download PDFInfo
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- CN116970109A CN116970109A CN202310925107.6A CN202310925107A CN116970109A CN 116970109 A CN116970109 A CN 116970109A CN 202310925107 A CN202310925107 A CN 202310925107A CN 116970109 A CN116970109 A CN 116970109A
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- sulfoxide
- formula
- acrylate polymer
- thioether
- adhesion
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Classifications
-
- 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
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/048—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F120/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
- C08F120/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F120/10—Esters
- C08F120/38—Esters containing sulfur
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F120/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
- C08F120/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F120/52—Amides or imides
- C08F120/54—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
- C08F120/58—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide containing oxygen in addition to the carbonamido oxygen, e.g. N-methylolacrylamide, N-acryloyl morpholine
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F2/00—Processes of polymerisation
- C08F2/38—Polymerisation using regulators, e.g. chain terminating agents, e.g. telomerisation
-
- 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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F2438/00—Living radical polymerisation
- C08F2438/03—Use of a di- or tri-thiocarbonylthio compound, e.g. di- or tri-thioester, di- or tri-thiocarbamate, or a xanthate as chain transfer agent, e.g . Reversible Addition Fragmentation chain Transfer [RAFT] or Macromolecular Design via Interchange of Xanthates [MADIX]
Abstract
The invention relates to the technical field of biomedical materials, and discloses an acrylic ester polymer containing sulfoxide groups, a preparation method thereof and application thereof in resisting tissue adhesion, wherein the acrylic ester polymer has any one of the following structures, wherein R is as follows 1 Is a C1-C6 methylene group, R 2 Is a C1-C6 linear or branched alkyl radical, R 3 Methyl or hydrogen; n is a natural number from 10 to 1000. The polymer has similar protein resistance and cell resistance as zwitterionic polymer, has excellent postoperative tissue adhesion resistance effect, good flowability, no obvious immunological rejection reaction, good clinical transformation prospect and large applicationThe application value.
Description
Technical Field
The invention relates to the technical field of biomedical materials, in particular to an acrylic ester polymer containing sulfoxide groups, a preparation method thereof and application thereof in resisting tissue adhesion.
Background
The postoperative tissue adhesion refers to the process of forming fibrous bands between postoperative tissues and organs under the conditions of wound, infection and the like, and is the most common cause of long-term complications of clinical operations, especially abdominal operations, and various problems such as intestinal obstruction, infertility, pain and the like can be caused. Taking postoperative abdominal adhesion as an example, the clinical occurrence rate is statistically up to 66% (Benefits and harms of adhesion barriers for abdominal surgery: asystematic review and meta-analysis.Lancet 383,48-59,2014), and 4.3% of the re-hospitalization rate of open surgery is directly related to abdominal adhesion and 16% is indirectly related to abdominal adhesion; for laparoscopic surgery, however, 1.7% of the readmission rate is directly related to the abdominal adhesions and 18.2% is indirectly related (Adhesion-related readmissions after open and laparoscopic surgery: a retrospective cohort study (SCAR update). Lancet 395,33-41, doi:10.1016/S0140-6736 (19) 32636-4 (2020)). The problems caused by the abdominal adhesions seriously affect the quality of life of the patient.
Several approaches and methods for reducing adhesion generation are indicated in the literature, such as at the level of surgical procedures by doctors, using drugs including interventions with related anti-inflammatory, anticoagulant, fibrinolytic drugs, etc. In addition, some commercial products such as anti-blocking films may also play a role, for example(sodium hyaluronate and carboxymethylcellulose flakes), -a. About.>(oxidized regenerated cellulose flakes) and +.>(polyethylene glycol spray gel), and the like. However, these anti-blocking films have their own limitations, such as wound surfacesThe wound cannot be well attached due to the need of strict hemostasis, and is not suitable for minimally invasive surgery such as laparoscopy and the like (Lancet 383,48-59,2014). There is a need to study new materials to further prevent post-operative adhesions from occurring.
The process of tissue adhesion can be subdivided into four steps (Sterile Injury Repair and Adhesion Formation at Serosal surfaces. Front Immunol 12,2021) of macrophage aggregation, fibrin clot formation, fibrosis transition and adhesion formation. Abnormal adsorption of fibronectin and macrophages, fibroblasts in wounds play an important role therein. Some Zwitterionic materials with anti-protein and anti-cell adsorption are therefore expected to be resistant to post-operative tissue adhesion (Zwitterionic biomaterials. Chem Rev 122,17073-17154,2022).
Sulfoxides are a special sulfur-containing chemical that can be oxidized from sulfides and further oxidized to sulfones. The properties of sulfoxides are mainly derived from the strong polarity of the sulfoxide bond, which enables the sulfoxide to form strong interactions between itself or other organic polar molecules or water, thus conferring on it a strong hydrophilic nature (Influence of sulfoxide group placement on polypeptide conformational stability j Am Chem Soc 141,14530-14533 (2019). Whether atypical zwitterionic polymers based on sulfoxide structures can have excellent tissue adhesion preventing effects or not has been studied and explored to solve the problems caused by abdominal adhesion.
Disclosure of Invention
Aiming at the problem of postoperative tissue adhesion to a patient, the invention provides the sulfoxide group-containing acrylate polymer which has similar protein resistance and cell resistance as a zwitterionic polymer, has excellent postoperative tissue adhesion resistance effect, has better clinical transformation prospect and has higher application value.
In order to achieve the above purpose, the invention adopts the following technical scheme:
an acrylate polymer containing sulfoxide groups, the acrylate polymer having any one of the following structures:
wherein R is 1 Is a C1-C6 methylene group, R 2 Is a C1-C6 linear or branched alkyl radical, R 3 Methyl or hydrogen; n is a natural number from 10 to 1000.
A series of atypical zwitterionic polymers based on sulfoxide structures are designed and synthesized in the invention, and a strong hydration layer can be formed on the surface of the atypical zwitterionic polymers, the atypical zwitterionic polymers have similar protein resistance and cell resistance as the zwitterionic polymers, and the sulfoxide polymer aqueous solution has excellent postoperative tissue adhesion resistance effect.
Preferably, R 2 Is methyl or ethyl. When R is 2 The longer the chain segment, the weaker the anti-tissue adhesion effect.
The invention also provides a preparation method of the acrylic ester polymer containing sulfoxide groups, which comprises the following steps:
step 1, reacting thioether or thiomorpholine shown in a formula 1 with acryloyl chloride shown in a formula 2 to obtain an acrylate-containing thioether monomer shown in a formula 3 or a formula 4; the reaction formula is as follows:
step 2, reacting the thioether monomer with hydrogen peroxide under the action of molybdenum dichloride to obtain a sulfoxide monomer containing acrylic ester, which is shown as a formula 5 or a formula 6; the reaction formula is as follows:
step 3, free radical polymerization is carried out on the sulfoxide monomer in a solvent through the action of a chain transfer agent, so as to obtain the acrylate polymer containing sulfoxide groups; the reaction formula is as follows:
wherein R is 1 、R 2 、R 3 And n is as defined above.
Preferably, the thioether of formula 1 comprises any one or more of 2- (methylthio) ethanol, 2-hydroxyethyl ethyl sulfide, 2- (propylthio) ethanol, 2- (butylthio) ethanol, 2- (pentylthio) ethanol, 2- (hexylthio) ethanol, 3-methylthio-1-hexanol, 6- (methylthio) -1-hexanol.
Further preferably, the thioether shown in the formula 1 is any one or more of 2- (methylthio) ethanol, 2-hydroxyethyl ethyl sulfide, 3-methylthio-1-hexanol and 6- (methylthio) -1-hexanol, and the obtained polymer has good water solubility.
The dosage of the acryloyl chloride shown in the formula 2 in the step 1 is 1.0-1.5 molar equivalents of thioether or thiomorpholine shown in the formula 1;
the step 1 also comprises an acid binding agent, wherein the dosage of the acid binding agent is 1.0-2.0 molar equivalents of thioether or thiomorpholine shown in the formula 1; preferably, the acid binding agent comprises one or more of triethylamine, N-diisopropylethylamine and pyridine.
The step 1 is to drop the acryloyl chloride shown in the formula 2 into the solution of thioether or thiomorpholine shown in the formula 1, wherein the temperature of the drop process is 0-5 ℃, and the reaction is carried out for 2-24 hours at room temperature after the drop is finished.
The dosage of the dichloro molybdenum dioxide in the step 2 is 0.01 to 0.1 molar equivalent of the thioether monomer;
the hydrogen peroxide is used in the step 2 in an amount of 1 to 1.05 molar equivalents of the thioether monomer;
the oxidation of thioethers to sulfoxides is often difficult to control, often accompanied by the formation of sulfones. Thus, the sulfoxide substance is synthesized in a lower yield and is difficult to separate. In the invention, a small amount of molybdenum dichloride dioxide is added in the thioether oxidation process, and the amount of hydrogen peroxide is accurately controlled, so that the high-efficiency controllable synthesis of sulfoxide monomers is realized, and direct oxidation into sulfone is avoided.
The reaction temperature in the step 2 is room temperature, and the reaction time is 20-60min.
The solvent in the step 1 or the step 2 is selected from any one or more of dichloromethane, chloroform and diethyl ether.
The chain transfer agent in step 3 includes compounds having the structure shown below:
wherein R is 4 Is a C1-C18 linear or branched alkyl group.
As the chain transfer agent, a commercially available chain transfer agent for radical polymerization such as 4-cyano-4- [ (dodecylsulfanylthiocarbonyl) sulfanyl ] pentanoic acid, 2-cyano-2-propyl-4-cyanobenzenedithiocarbonate and the like can be used.
Step 3 also includes a free radical initiator; the free radical initiator comprises azo initiator, organic peroxy initiator or inorganic peroxy initiator, including any one or more of Azobisisobutyronitrile (AIBN), azobisisoheptonitrile (ABVN), persulfate and the like.
The free radical polymerization in the step 3 is carried out for 12-24h at 60-80 ℃ under the anhydrous and anaerobic state.
The solvent for the reaction in the step 3 is selected from any one of common organic solvents such as N, N-Dimethylformamide (DMF), dioxane or dimethyl sulfoxide (DMSO).
The invention also provides application of the acrylate polymer containing sulfoxide groups in preparation of materials for preventing tissue adhesion. The invention uses the human fibrinogen with the highest abundance and highest content in blood as model protein, and successfully determines that the acrylic ester polymer containing sulfoxide groups has excellent protein resistance and cell adsorption capacity by using a commercial ELISA detection kit, thereby verifying the anti-blocking effect in vivo.
The tissue adhesions include any one or more of abdominal adhesions, uterine adhesions, tendon adhesions. The anti-adhesion film (such as INTERCED) used clinically in the prior art is determined by physical characteristics, and is not suitable for minimally invasive surgery such as laparoscope. The sulfoxide polymer developed by the invention has good fluidity and lower viscosity, can be suitable for minimally invasive surgery such as laparoscope and the like, and is suitable for anti-adhesion of various tissues such as abdominal adhesion, uterine adhesion, tendon adhesion and the like.
In addition, the acrylic ester polymer containing sulfoxide groups is different from other zwitterionic polymers, and the sulfoxide polymers have biological activity, such as strong ROS capturing and antioxidation capability, so that the whole abdominal microenvironment can be dynamically regulated, inflammation is avoided, and further tissue adhesion is avoided.
The invention also provides an anti-adhesion material, which comprises the acrylic ester polymer containing sulfoxide groups.
The form of the anti-blocking material comprises an aqueous solution of an acrylate polymer containing sulfoxide groups or a hydrogel containing sulfoxide groups.
The preparation method of the hydrogel containing sulfoxide groups comprises the following steps: polymerizing the sulfoxide monomer, N-methylene bisacrylamide and 2-hydroxy-2-methyl-1-phenyl-1-acetone in water to obtain the hydrogel.
Compared with the prior art, the invention has the following beneficial effects:
(1) The acrylate polymer containing sulfoxide groups has excellent protein adsorption resistance and cell adsorption resistance, can prevent adhesion from occurring from a molecular level, and has long retention time in an abdominal environment, so that the polymer is expected to provide long-acting anti-abdominal adhesion protection. Such as strong ROS capture and antioxidant capacity
(2) The acrylate polymer containing sulfoxide groups has biological activities such as strong ROS capturing and antioxidation capability, and the whole abdominal cavity microenvironment can be dynamically regulated and controlled, so that inflammation is avoided, and further tissue adhesion is generated.
(3) The acrylic ester polymer containing sulfoxide groups has good fluidity and low viscosity, can be suitable for minimally invasive surgery such as laparoscope and the like, has excellent safety performance, does not see obvious immune rejection reaction, and has good clinical transformation prospect.
(4) According to the sulfoxide group-containing acrylate polymer, the generation of sulfone products is avoided through the selection of the catalyst and the control of the hydrogen peroxide dosage in the preparation process, and the sulfoxide polymer is obtained efficiently and controllably.
Drawings
FIG. 1 is a GPC chart and dissolution profile of the series of sulfoxide polymers prepared in examples 1-9.
FIG. 2 is an anti-protein adsorption drawing of the sulfone polymer of application example 1.
FIG. 3 is an anti-cell adsorption drawing of the sulfone polymer of application example 2.
FIG. 4 is a graph of anti-adhesion effect of the series sulfoxide polymers of application example 3 in an abdominal wall-cecum injury adhesion model, a is adhesion score of each group, b is adhesion site photograph at dissection, c is adhesion site H & E and Masson staining chart.
FIG. 5 is a graph showing the anti-adhesion effect of the sulfone polymer PMeSEEA in the model of adhesion of ischemic button in application example 4, wherein a is the adhesion score of each group, b is the weight change before and after the rat test, and c is the physical graph of adhesion site in dissection.
FIG. 6 is an in vitro cytotoxicity evaluation of the sulfone polymer PMeSEEA of application example 5.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention. Modifications and equivalents will occur to those skilled in the art upon understanding the present teachings without departing from the spirit and scope of the present teachings.
The raw materials used in the following embodiments are all commercially available, the chemical raw materials used in the examples are derived from Adamas-beta reagent, other organic reagents are purchased from national medicine chemical company or Michelia, cell lines are all commercially available from ATCC cell banks, and other unexplained raw materials are all commercially available.
EXAMPLE 1 Synthesis of PMeSEA sulfoxide Polymer
Step 1, 2- (methylthio) ethanol (13.3 g,145 mmol) and triethylamine (22.1 g,218 mmol) were dissolved in 250mL of anhydrous dichloromethane, and a 50mL dichloromethane solution containing 189mmol (17.1 g) of acryloyl chloride was added dropwise thereto under ice-bath conditions to react overnight. The reaction solution was filtered to remove triethylamine salt, and the filtrate was washed three times with saturated sodium bicarbonate solution, 1M HCl and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated to give a crude product of ethyl 2- (methylthio) acrylate (2- (methylthioo) ethyl acrylate, meea). The crude MeTEA product was purified by column chromatography on silica gel (n-hexane: ethyl acetate=10:2) to give a colorless transparent liquid MeTEA (11.6 g, yield 54.7%)
Step 2,20 mmol (2.92 g) of MeTEA was added to a mixed solution of 20mL of water and 30mL of acetone, 60mg of molybdenum dichloride was added, and 21mmol (2.4 g) of a 30% hydrogen peroxide solution was added dropwise under ice bath conditions, and the reaction was continued for one hour until the solution became clear. The reaction mixture was concentrated under reduced pressure, extracted 3 times with 75mL of dichloromethane, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and extracted with dichloromethane: methanol=10:1 flash column to give ethyl 2- (methylsulfinyl) acrylate (2- (methylsulfinyl) ethyl acrylate (musea, 3.1g, 95%) as a colourless liquid.
Step 3,1g MeSEA sulfoxide monomer, RAFT chain transfer agent 0.083mmol (19.8 mg) BCSPA,0.042mmol (6.9 mg) AIBN, dissolved in 2mL DMF, transferred the solution to a polymerization flask, deoxygenated with nitrogen bubbling for 30 min, placed in an oil bath at 65℃for reaction for 24 hours, after which the reaction was quenched with liquid nitrogen to terminate. The product was precipitated with glacial diethyl ether and dried under reduced pressure to give a pale yellow viscous liquid (0.98 g, yield 98.0%). The polymer molecular weight was determined by DMF phase GPC.
The reaction formula is as follows:
EXAMPLE 2 Synthesis of PEtSEA sulfoxide Polymer
According to the preparation process of step 1 and step 2 in example 1, the raw material of 2- (methylthio) ethanol was modified to 2-hydroxyethyl ethyl sulfide, to obtain ethyl 2- (ethylsulfinyl) acrylate (2- (ethylsulfinyl) ethyl acrylate (EthEA)) having the following structure, with a yield of 60.2%.
According to the procedure of example 1, step 3, etSEA polymerization gave PEtSEA of the following structure in 92.6% yield.
EXAMPLE 3 Synthesis of PPrSEA sulfoxide Polymer
According to the preparation process of step 1 and step 2 in example 1, the starting material of 2- (methylthio) ethanol was modified to 2- (propylthio) ethanol, to give ethyl 2- (propylsulfinyl) acrylate (2- (propylsulfonyl) ethyl acrylate (PrSEA)) having the following structure, the yield was 56.2%.
The preparation process of example 1, step 3, was followed using PrSEA polymerization to give PPrSEA of the structure below in 96.8% yield.
Example 4: synthesis of PBuSEA sulfoxide Polymer
According to the preparation process of step 1 and step 2 in example 1, the starting material of 2- (methylthio) ethanol was modified to 2- (butylthio) ethanol, to obtain ethyl 2- (butylsulfinyl) acrylate (2- (butylsulfinyl) ethyl acrylate (BuSEA)) having the following structure, the yield was 59.0%.
The preparation process of example 1, step 3, was followed by modification of the MeSEA starting material to BuSEA to give PBuSEA of the structure below in 96.8% yield.
Example 5: synthesis of PPeSEA sulfoxide polymers
According to the preparation process of step 1 and step 2 in example 1, the starting material of 2- (methylthio) ethanol was modified to 2- (pentylthio) ethanol, to obtain ethyl 2- (pentylsulfinyl) acrylate (2- (pentalsulfinyl) ethyl acrylate (PeSEA)) having the following structure, the yield was 57.1%.
The preparation process of example 1, step 3, was followed by modification of the MeSEA starting material to PeSEA to give PPeEA having the structure below in 91.3% yield.
Example 6: synthesis of phemea sulfoxide polymers
According to the preparation process of step 1 and step 2 in example 1, the starting material of 2- (methylthio) ethanol was modified to 2- (hexylthio) ethanol, to obtain ethyl 2- (hexylsulfinyl) acrylate (2- (hexynyl) ethyl acrylate (HeSEA)) having the following structure, the yield was 60.1%.
The preparation process of example 1, step 3, was followed by modification of the MeSEA starting material to HeSEA to give PHeEA with the following structure in 91.3% yield.
Example 7: synthesis of PLMeSHA sulfoxide Polymer
The procedure of the preparation of step 1 and step 2 in example 1 was followed, and the 2- (methylthio) ethanol starting material was modified to 6- (methylthio) -1-hexanol, to give 6- (methylsulfinyl) hexyl acrylate (LMeHA) having the following structure, in a yield of 48.1%.
The preparation process of example 1, step 3, was followed by modification of the MeSEA starting material to LMeSHA to give PLMeSHA of the following structure in 96.0% yield.
Example 8: synthesis of PBMeSHA sulfoxide Polymer
The procedure of the preparation of step 1 and step 2 in example 1 was followed, and the 2- (methylthio) ethanol starting material was modified to 3-methylthio-1-hexanol, to give hexyl 3- (methylsulfinyl) acrylate (BMeSHA) having the following structure, in a yield of 59.1%.
The preparation process of example 1, step 3, was followed by modification of the MeSEA starting material to BMeSHA to give PBMeSHA of the structure below in 93.0% yield.
Example 9: synthesis of POPEO sulfoxide polymers
According to the preparation process of step 1 and step 2 in example 1, the starting material of 2- (methylthio) ethanol was modified to thiomorpholine to give 1- (1-thiomorpholino-oxide) prop-2-en-1-one (1- (1-thiomorpholino) prop-2-en-1-one (OPEO)) having the following structure, the yield was 68.1%.
Following the procedure of example 1, step 3, the MeSEA feedstock was modified to OPEO to give POPEO of the structure below in 97.9% yield.
GPC spectra, molecular weights and water solubility information of the sulfoxide polymers prepared in examples 1-9 are shown in FIG. 1, the GPC peak shapes of the polymers are single distribution, the molecular weight is about 10kDa, and the water solubility test process and the judgment standard of the polymers are judged according to whether the concentration of the polymers can reach 50mg/mL in water. More than 50mg/mL is water soluble at room temperature, less than 50mg/mL is water insoluble, and the temperature can reach the solubility of 50mg/mL which is temperature dependent after the temperature is reduced to 1-4 ℃. The water solubility reflects to some extent the anti-fouling activity of the polymer and only polymers that are water soluble at room temperature can be used for in vivo applications.
Application example 1 sulfoxide polymer in vitro anti-protein adsorption experiment
The evaluation of the anti-protein adsorption capacity of sulfoxide structures in vitro is shown below: firstly, preparing hydrogel solutions containing different sulfoxide structures, wherein the specific method is as follows:
preparing 300mg of sulfoxide-containing monomer MeSEA prepared in step 2 of example 1, 700mg of deionized water, 3mg of N, N' -methylenebisacrylamide and 0.6mg of 2-hydroxy-2-methyl-1-phenyl-1-acetone into a hydrogel solution; 50. Mu.L of the solution was taken and added to a bottom area of 0.32cm 3 And (3) irradiating the gel mold for 30 minutes by an ultraviolet high-pressure mercury lamp to carry out photopolymerization, carefully taking out sulfoxide hydrogel after the polymerization is finished, putting the sulfoxide hydrogel into a 6-well plate, washing the gel mold for more than 20 times to remove unreacted chemical substances, and finally taking out the hydrogel and putting the hydrogel into a 96-well plate to wait for the next experiment.
Hydrogels were prepared separately from the EtSEA of example 2, the PrSEA of example 3, the LMeSHA of example 7, the opo sulfoxide-containing monomers of example 9 and tested according to the same procedure.
The positive control was polyethylene glycol hydrogel, 300mg of polyethylene glycol monomethyl ether methacrylate (average mw=475), 700mg of deionized water, 3mg of n, n' -methylenebisacrylamide, and 0.6mg of 2-hydroxy-2-methyl-1-phenyl-1-propanone were prepared into a hydrogel solution, and then polymerized according to the same procedure to obtain polyethylene glycol hydrogel.
mu.L of 1mg/mL human fibrinogen solution was added to a 96-well plate containing hydrogel to completely exclude the hydrogel, incubated at room temperature for 2 hours, and then the solution was discarded, and washed 5 times with PBS. The hydrogels were carefully placed in a new 96-well plate and protein concentration was determined using a human fibrinogen ELISA kit.
The specific flow of the measuring process is as follows: adding 100 mu L of human fibrinogen antibody coupled with horseradish peroxidase into a 96-well plate, incubating at 37 ℃ for 60 minutes, discarding liquid, cleaning 5 times by using a cleaning solution in a kit, sequentially adding 50 mu L of chromogenic solution A and 50 mu L of chromogenic solution B in the kit, incubating at 37 ℃ in a dark place for 15 minutes, adding 50 mu L of stop solution into each hole to stop chromogenic reaction, immediately measuring the absorbance value of 450nm wavelength of each hole, finally converting to obtain the protein quantity adsorbed by the whole hydrogel, dividing the protein quantity adsorbed by the surface area of the hydrogel, and obtaining the protein quantity adsorbed by unit area, wherein each group of data is from 4 parallel samples. The polystyrene plane is used as a positive control, the experimental method is consistent, and the description is not repeated.
The results are shown in FIG. 2, wherein PMeSEA has the strongest protein adsorption resistance, which is only 8.26% of the polystyrene plane and 48.3% of the polyethylene glycol hydrogel plane, and the super-hydrophilic structure of sulfoxide can effectively prevent protein adsorption. It can be seen from PMESEA, PEtSEA and pprssea that as the carbon chain grows, the protein adsorption resistance is reduced, the protein adsorption capacity of PMeSEA is 72.9% of PEtSEA, whereas the protein adsorption resistance of PPRSEA, which is derived 3 carbon chain lengths outwards, is drastically reduced and already weaker than that of polyethylene glycol hydrogels.
POPEO having a cyclic structure also has good resistance to protein adsorption, comparable to PEtSEA, possibly due to structural exposure to sulfoxide groups, and the six-membered ring imparts some rigidity to the polymer structure. These results are expected to be somewhat predictive of the fact that the increase in carbon number is accompanied by a concomitant decrease in anti-fouling capacity, and it is not readily understood why PMeEA has the best anti-protein adsorption capacity. Interestingly, the carbon chain length of PLMeSHA was much greater than PPrSEA, but its resistance to protein adsorption was greater than PPrSEA, indicating that the position of the sulfoxide group greatly affected the properties of the polymer, with better resistance to fouling when exposed.
Application example 2 sulfoxide polymer in vitro anti-cell adsorption experiment
The characterization method of the sulfoxide structure in vitro anti-cell adsorption capacity comprises the following steps of firstly preparing 25% sulfoxide polymer aqueous solution (12 kDa, taking PEG 10kDa as a reference), mixing the polymer aqueous solution with Matrigel matrigel=1:9 to obtain Matrigel containing 2.5% polymer concentration, adding 50 mu L of Matrigel solution into a 96-well plate, incubating at 37 ℃ for 1 hour to solidify the Matrigel, adding 8000A 549-EGFP cells into each well, culturing at 37 ℃ for 12 hours, and observing the adherence condition of the cells on the surface of the Matrigel by using a laser confocal microscope, wherein the Matrigel can be gradually digested by cell hydrolysis, and the culturing time can not be too long. Since it is difficult to digest the matrigel with pancreatin, the number of matrigel surface-attached cells was obtained by counting EGFP fluorescence.
As a result, as shown in FIG. 3, PMeSEA had the strongest cell adsorption resistance, and the cell attachment amount was 31.6% of that of the plain polystyrene, 54.9% of that of the PEG group, and 69.4% of that of PEtSEA. The PPrSEA showed the worst anti-cell adsorption effect, which is consistent with the trend of the previous anti-protein adsorption result, but PEtSEA, PLMeSHA and POPEO have little difference in anti-cell adsorption capability, probably at the living cell level, and various proteins are involved in the cell adhesion process, so that the difference in anti-cell adsorption capability of the polymer is diluted.
Application example 3 evaluation of in vivo anti-blocking Effect of sulfoxide Polymer
Establishing a mouse abdominal wall-cecum injury model:
ICR mice of 6-8 weeks of age were fasted for 12 hours, anesthetized with isoflurane, and an opening of 2-3cm was cut in the abdomen with surgical scissors in the middle of the abdomen, the skin was cut in sequence, the abdominal wall was carefully removed from the cecum. The side of the cecum, which is opposite to the abdominal wall, is taken as the front side, a surgical knife is used for lightly scratching the front side of the cecum until the cecum bleeds, the abdominal wall adjacent to the cecum is also lightly scratched to bleed by the surgical knife, the cecum is put back to the original position, the tie film at the tail end of the cecum is sutured with the abdominal wall by a surgical thread, the condition that the cecum is clung to the abdominal wall is caused, and finally, the surgical opening is sutured by the surgical thread.
The intervention procedure for sulfoxide polymers was as follows, each sulfoxide polymer (50 kDa) was formulated with sterile PBS as a 25wt% solution (control was PEG 20kDa, and application of an equivalent dose of PEG 50kDa in this model resulted in massive death of the mice, so 20kDa was used as control), and 200. Mu.L of polymer solution was spread evenly over the wound in the abdominal wall-cecum injury model.
PBS-treated mice were used as a control group, anti-adhesion membrane-inserted control group: the sheet with slightly larger area than the wound was removed with surgical scissors for later use, the wound was cleaned of wound bleeding with surgical gauze and sterile PBS, and the interleaved sheet was placed over the wound to ensure complete coverage of the wound. Mice were sacrificed 7 days later and adhesion status was assessed anatomically.
Experimental grouping conditions: the experiment was divided into 6 groups, 6 of the interleaved groups, and 10 of each of the remaining groups. Wherein the experimental group: about 200 μl of various aqueous sulfoxide-containing polymer solutions were uniformly applied to the cecum surface and the injured side of the abdominal wall, covering the wound, while the experimental control group used negative control and positive control. The negative control was not treated and the positive control was an anti-adhesion membrane (interleaved) for clinical use.
Scoring criteria: reference (Adhesions and Healing of Intestinal Anastomoses: the Effect of Anti-joining Barriers. Surg Innov 23,266-276,2016) score. 0: the adhesive is not adhered; 1, the method comprises the following steps: slightly adhering; 2, the method comprises the following steps: moderate blocking requires application of a certain force to allow for passive detachment; 3, the method comprises the following steps: heavier adhesion, incapability of passive separation and need sharp separation; 4, the following steps: other tissue organs are involved in adhesion formation. And finally, recording the scoring results of each group, and carrying out statistical analysis.
Histological evaluation: cecal and abdominal wall tissues associated with lesions and/or adhesions were collected and histologically assessed under an OLYMPUSBX51 optical microscope for H & E and Masson staining.
Statistical analysis: data are expressed as Mean ± standard deviation (Mean ± SD) or as upper and lower limits, upper and lower quartiles and median. The significance difference was calculated by unpaired students t-test. Fig. 4 shows the p-value directly.
The results are shown in FIG. 4, wherein a is the adhesion score of each group, b is the photograph of the adhesion site when dissected, c is the adhesion site H & E and Masson staining chart, AW: abdominal wall; CE: cecum, cecum. PMeSEA exhibits the best anti-abdominal adhesions effect, with no severe adhesions other than the sutures present between the pericecal tie film and the abdominal wall during molding. Among other polymers PEtSEA, PPrSEA and POPEO, PPrSEA had the worst effect, and the other two were similar, with little effect of PEG. At the same time we used commercial interleaved oxidized regenerated cellulose flakes as a control and found that blocking was still very severe.
Application example 4 verification of post-operative adhesion resistance effect of PMeSEA Polymer
To further verify the anti-post-operative adhesion effect of sulfoxide polymers, a rat ischemic button adhesion model was established
Rats 180g-200g in weight are fasted for 12 hours, isoflurane is anesthetized, the skin and the abdominal wall of the rats are cut off from the center in sequence, four knots are respectively tied at equal intervals on the left and right abdominal walls by surgical sutures, and 50 mu L of 25wt% PMeSEA sulfoxide polymer PBS solution (sulfoxide polymer molecular weight 50 kDa) or an INTECEED anti-adhesion sheet is uniformly smeared on each knot. After 7 days, rats were sacrificed and the adhesion was observed by dissection, and the adhesion tissues were fixed with 4% paraformaldehyde and stained with H & E and Masson.
Scoring criteria: reference (Abdominal scar characteristics: do they predict intra-abdominal adhesions with repeat cesarean deliveriesJ Obstet Gynaecol Res.2014; 40:1643-1648) scoring: 0 point: the adhesive is not adhered; 1, the method comprises the following steps: single adhesion exists between viscera or between viscera and abdominal wall; 2, the method comprises the following steps: two adhesions are arranged between viscera or between viscera and abdominal wall; 3, the method comprises the following steps: more than two adhesions are arranged between the viscera or between the viscera and the abdominal wall, or the intestinal loops form a lump without adhesion with the abdominal wall; 4, the following steps: the viscera adhere directly to the abdominal wall, regardless of the number and extent of adhesions. And finally, recording the scoring results of each group, and carrying out statistical analysis.
The results are shown in FIG. 5, where a is the adhesion score of each group, b is the weight change before and after the rat test, and c is the physical map of adhesion sites when dissected. By taking commercial anti-adhesion membrane INTERCED as a Control, the effect of PMeSEA polymer is found to be far better than that of INTERCED, the latter has almost no effect in the model, like a Control group, ischemic nodules are obviously adhered to the membrane, liver, adipose tissues and the like, even organs are directly adhered to the abdominal wall, the number and width of adhesion bands are far greater than those of PMeSEA, and PMeSEA is only slightly adhered to the membrane, can be passively separated, and is not adhered to tissues such as liver and the like. The application of PMeSEA had no significant effect on rat body weight.
Application example 5 safety evaluation of sulfoxide Polymer PMeSEA
Cytotoxicity: the in vitro cytotoxicity of sulfoxide polymers was evaluated by CCK-8 kit, in which the active ingredient WST-8 is a compound similar to MTT, which in the presence of an electron coupling reagent can be reduced by some dehydrogenases in the mitochondria to form formazan in orange color. The more and the faster the cell proliferation, the darker the color; the greater the cytotoxicity, the lighter the color. For the same cells, the shade of color and the number of cells are linear.
Firstly, cells with good growth state are digested, inoculated into a 96-well plate, 100 mu L of cell suspension (4000 cells per well) is added to each well, after 12h of adherence, sulfoxide polymers with various concentrations are added, and after 48h, the test is carried out, and 10 mu L of CCK-8 solution is added to each well. Incubation was continued for 1h at 37℃and absorbance at 450nm was measured for each well using a microplate reader. As a result, as shown in FIG. 6, it was found that all the water-soluble sulfoxide polymers at a concentration of up to 100. Mu.g/mL did not cause significant toxicity to AGS, RAW264.7 and NIH-3T3 cells.
Evaluation of mice blood biochemistry and blood routine by PMeSEA:
ICR mice of 6-8 weeks of age were selected and given 6 times every two days by tail vein injection of PBS, PEG solution or PMeSEA solution (100 mg/kg). And then collecting the blood of the mice into a heparin sodium anticoagulation tube through orbital blood sampling, and analyzing blood biochemical and blood conventional indexes.
Blood biochemical indicators include: ALT (alanine aminotransferase), AST (aspartic acid aminotransferase), TBIL (total bilirubin), DBIL (direct bilirubin), BUN (blood urea nitrogen), CR (blood creatinine), UA (uric acid), ALB (albumin), GGT (glutamyl transpeptidase), ALP (alkaline phosphatase), CK (creatine kinase), LDH (lactate dehydrogenase). Blood routine index includes: WBC (white blood cells), LYM% (lymphocyte percentage), MON (monocyte percentage), EOS (eosinophil percentage), BAS (BAS percentage), NEU (neutrophil percentage), lym# (lymphocyte concentration value), mon# (monocyte concentration value), eos# (eosinophil concentration value), bas# (BAS concentration value), neu# (neutrophil concentration value), RBC (red blood cells), HGB (hemoglobin concentration), HCT (hematocrit), MCV (mean red blood cell volume), MCH (mean red blood cell hemoglobin amount), MCHC (mean red blood cell hemoglobin concentration), RDW-CV (red blood cell volume distribution width), RDW-SD (red blood cell volume distribution width), PLT (platelets), MPV (platelet average volume), PCT (platelet volume), PDW (platelet distribution width), P-LCR (large platelet ratio), P-LCC (platelet count).
As shown in Table 1 and Table 2, after 5 continuous administrations (100 mg/kg), the blood biochemistry and blood routine indexes of the mice were measured, and after 5 administrations, the blood routine and blood biochemistry parameters of the PMeSEA and PEG group were not statistically different from those of the Control group, which indicated that the PMeSEA was the same safe material as the PEG and had little influence on the normal physiological activities of the mice.
TABLE 1 Effect of PMeSEA on Biochemical indicators of mouse blood
TABLE 2 Effect of PMeSEA on mouse blood routine index
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Claims (10)
1. An acrylate polymer containing sulfoxide groups, characterized in that the acrylate polymer has any one of the following structures:
wherein R is 1 Is a C1-C6 methylene group, R 2 Is a C1-C6 linear or branched alkyl radical, R 3 Methyl or hydrogen; n is a natural number from 10 to 1000.
2. The sulfoxide group-containing acrylate polymer according to claim 1, wherein R 2 Is methyl or ethyl.
3. The method for producing a sulfoxide group-containing acrylate polymer according to claim 1, comprising the steps of:
step 1, reacting thioether or thiomorpholine shown in a formula 1 with acryloyl chloride shown in a formula 2 to obtain an acrylate-containing thioether monomer shown in a formula 3 or a formula 4;
step 2, reacting the thioether monomer with hydrogen peroxide under the action of molybdenum dichloride to obtain a sulfoxide monomer containing acrylic ester, which is shown as a formula 5 or a formula 6;
step 3, free radical polymerization is carried out on the sulfoxide monomer in a solvent through the action of a chain transfer agent, so as to obtain the acrylate polymer containing sulfoxide groups;
wherein R is 1 、R 2 、R 3 And n is as defined in claim 1.
4. The method for producing a sulfoxide group-containing acrylate polymer according to claim 3, wherein the sulfide represented by formula 1 comprises any one or more of 2- (methylthio) ethanol, 2-hydroxyethyl ethyl sulfide, 2- (propylthio) ethanol, 2- (butylthio) ethanol, 2- (pentylthio) ethanol, 2- (hexylthio) ethanol, 3-methylthio-1-hexanol, 6- (methylthio) -1-hexanol.
5. The method for producing a sulfoxide group-containing acrylate polymer according to claim 3, wherein the amount of the acryloyl chloride represented by formula 2 in step 1 is 1.0 to 1.5 molar equivalents of the thioether or thiomorpholine represented by formula 1;
and/or, the step 1 also comprises an acid-binding agent, wherein the dosage of the acid-binding agent is 1.0-2.0 molar equivalents of thioether or thiomorpholine shown in the formula 1;
and/or, in the reaction process of the step 1, the acryloyl chloride shown in the formula 2 is dropwise added into the solution of the thioether or thiomorpholine shown in the formula 1, the temperature of the dropwise adding process is 0-5 ℃, and the reaction is carried out for 2-24 hours at room temperature after the dropwise adding is finished.
6. The method for producing a sulfoxide group-containing acrylate polymer according to claim 3, wherein the molybdenum dichloride in step 2 is used in an amount of 0.01 to 0.1 molar equivalent to the thioether monomer;
and/or, the hydrogen peroxide is used in the step 2 in an amount of 1 to 1.05 molar equivalents of the thioether monomer;
and/or the reaction temperature in the step 2 is room temperature, and the reaction time is 20-60min.
7. A method for preparing an acrylate polymer containing sulfoxide groups according to claim 3 wherein the chain transfer agent in step 3 comprises a compound having the structure:
wherein R is 4 A linear or branched alkyl group of C1-C18;
and/or, step 3 further comprises a free radical initiator;
and/or, the free radical polymerization in the step 3 is carried out for 12-24 hours at the temperature of 60-80 ℃ under the anhydrous and anaerobic state.
8. Use of an acrylate polymer containing sulfoxide groups according to claim 1 or 2 for the preparation of a material for preventing tissue adhesions.
9. The use of claim 8, wherein the tissue adhesions comprise any one or more of abdominal adhesions, uterine adhesions, tendon adhesions.
10. An antiblocking material comprising the sulfoxide group-containing acrylate polymer of claim 1 or 2.
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