Tissue high-adhesion poly-beta urethane, drug-loaded nanoparticles and preparation method and application of drug-loaded nanoparticles

Abstract

The invention relates to high-tissue-adhesion poly-beta urethane, drug-loaded nanoparticles and a preparation method and application of the high-tissue-adhesion poly-beta urethane and the drug-loaded nanoparticles. The poly beta urethane is formed by copolymerizing a diacrylate compound and an amino-containing compound; the diacrylate compounds are selected from one or more of compounds as shown in formulas (I-1) and (I-2) or stereoisomers thereof, and at least one diacrylate compound is selected from the compound as shown in the formula (I-2); the amino-containing compound is selected from one or more of compounds shown in a formula (II). The poly-beta urethane can deliver a drug for treating gastrointestinal oxidative stress related diseases (such as gastric ulcer) to a diseased region in a targeted manner, can release the therapeutic drug in a responsive manner at the diseased region, has good gastric mucosa adhesion ability, can improve local drug concentration, and can improve the curative effect of the drug. Therefore, the treatment targeting and the curative effect persistence of the medicine are enhanced, and the treatment effect is enhanced. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceuticals, relates to a drug delivery carrier, and particularly relates to a tissue highly adhesive poly-β-urethane, a drug-loaded nanoparticle, and a preparation method and application thereof. Background Art

[0002] Gastric ulcer, as a common digestive system disease, is easily triggered once the balance between gastric acid, reactive oxygen species, etc. and the defenses such as gastric mucus, bicarbonate secretion, and nitric oxide is disrupted. Currently, traditional drugs for treating gastric ulcers include histamine receptor antagonists (such as ranitidine), proton pump inhibitors (such as omeprazole), antacids, and gastric mucosal protectants, etc. However, these drugs all have unavoidable side effects. To reduce their side effects, researchers have explored various drug delivery nanoplatforms to control the pharmacokinetics of these low-molecular-weight drugs and reduce their unwanted dispersion by targeting specific factors in the gastric region (including low pH environment, gastric mucosal adhesion, and reactive oxygen species response, etc.). Materials such as hollow mesoporous silica, chitosan oligosaccharide, and β-cyclodextrin are widely used as nanocarriers, and novel delivery systems are constructed through structural modification and performance optimization. For example, the amino-functionalized hollow mesoporous silica gastric retention raft formulation developed by Huang et al. requires multiple complex processes such as the synthesis of nanoscale rod-shaped hollow mesoporous silica and surface amino-functionalization. Although the process is complex, this formulation can improve the water solubility of patchouli alcohol and shows significant therapeutic effects in animal model experiments of alcoholic acute gastric ulcer and drug-induced chronic gastric ulcer (Chen H, Pan L, Zhang C, et al. Gastroretentive Raft Forming System for Enhancing Therapeutic Effect of Drug-Loaded Hollow Mesoporous Silica on Gastric Ulcers [J]. Advanced Healthcare Materials, 2024, 13(22). DOI: 10.1002 / adhm.202400566.). The chitosan oligosaccharide nanoparticle-loaded apocynin delivery system reported by Meshali et al. is prepared by the ion gel method, and the obtained nanoparticles show good anti-ulcer activity in the treatment of gastric ulcers (Anter H M, Hashim I I A, Awadin W, et al. Novel chitosan oligosaccharide-based nanoparticles for gastric mucosal administration of the phytochemical "apocynin" [J]. International Journal of Nanomedicine, 2019, Volume 14: 4911 - 4929. DOI: 10.2147 / IJN.S209987.).

[0003] Although these nano-delivery systems have made some progress in disease treatment, there are still obvious deficiencies in the persistence of targeted adhesion. In the complex environment of gastrointestinal peristalsis, digestive fluid flushing, and the dynamic renewal of the mucus layer, they are extremely prone to desorption, resulting in the inability of the nano-carriers to continuously play their roles at the lesion site. Summary of the Invention

[0004] Based on this, the object of the present invention is to provide a novel nano-delivery system, which can target and deliver drugs for treating gastrointestinal oxidative stress-related diseases (such as gastric ulcers) to the lesion site, and can responsively release therapeutic drugs at the lesion site. At the same time, it has good gastric mucosa adhesion ability, can increase the local drug concentration, thereby enhancing the therapeutic targeting and efficacy persistence of the drug, and enhancing the therapeutic effect.

[0005] The technical solutions to achieve the above object are as follows.

[0006] In the first aspect, the present invention provides a poly-β-urethane, which is copolymerized from a diacrylate compound and an amino-containing compound; the diacrylate compound is selected from one or more of the compounds shown in formula (I-1) and (I-2) or their stereoisomers, and at least one diacrylate compound is selected from the compound shown in formula (I-2);

[0007] The amino-containing compound is selected from one or more of the compounds shown in formula (II);

[0008]

[0009] Among them, X is selected from: C1-C 16 alkylene, a saturated hydrocarbon group containing one or more oxygen atoms with a chain length of 1-16 atoms;

[0010] X1 and X2 may be the same or different, and are each independently selected from: R3-substituted or unsubstituted C1-C 16 alkylene, R3-substituted or unsubstituted saturated hydrocarbon groups containing one or more oxygen atoms with a chain length of 1-16 atoms;

[0011] R1 is selected from: hydrogen, C1-C6 alkyl, hydroxyl, carboxyl;

[0012] R2 is selected from: hydrogen, C1-C6 alkyl, hydroxyl, carboxyl;

[0013] R3 is selected from: hydrogen, C1-C6 alkyl, hydroxyl, amino, C1-C6 alkylamino, (C1-C6 alkyl)2amino.

[0014] For example, the poly-β-urethane has the structures shown in the following formula (A) and formula (B):

[0015]

[0016] Among them, X, X1, X2, R1, and R2 are as described above, n≥1, preferably an integer between 1 and 10,000, and more preferably an integer between 1 and 10.

[0017] In a second aspect, the present invention provides a method for preparing the poly-β-urethane, comprising the following steps:

[0018] In an organic solvent, the diacrylate compound and the amino-containing compound are reacted under heating conditions to obtain the poly-β-urethane.

[0019] Among them, the preparation method of the compound shown in formula (I-2) comprises the following steps:

[0020] (1) Compound 1-1 and compound 1-2 are reacted with acetone to obtain compound 2;

[0021] (2) Compound 2 is reacted with a reducing agent to reduce the carboxyl group to obtain compound 3;

[0022] (3) Compound 3 is reacted with acryloyl chloride under the action of a base to obtain the compound shown in formula (I-2); the reaction formula is as follows:

[0023]

[0024] Among them, X1 and X2 are as described above.

[0025] In a third aspect, the present invention provides a drug-loaded nanoparticle, which is prepared by self-assembly of the poly-β-urethane and a small molecule drug described in the present invention in an aqueous medium;

[0026] The small molecule drug is selected from one or more of small molecule drugs with anti-inflammatory functions and small molecule drugs with acid suppression functions.

[0027] For example, the small molecule drug with anti-inflammatory function is N-acetylcysteine and / or glutathione; the small molecule drug with acid suppression function is selected from one or more of vonoprazan, omeprazole, pantoprazole, rabeprazole, cimetidine, ranitidine, and famotidine; preferably a combination of a small molecule drug with anti-inflammatory function and a small molecule drug with acid suppression function.

[0028] In a fourth aspect, the present invention provides a method for preparing the drug-loaded nanoparticle, comprising the following steps:

[0029] Dissolve the poly-β-urethane and the small molecule drug in an organic solvent to form an organic phase; drop the organic phase into water to promote the self-assembly of the poly-β-urethane and the small molecule drug in water to form nanoparticles, thereby obtaining the drug-loaded nanoparticle.

[0030] In a fifth aspect, the present invention provides the use of the poly-β urethane as a carrier in the preparation of a medicament for preventing and / or treating gastrointestinal oxidative stress-related diseases.

[0031] In a sixth aspect, the present invention provides the use of the drug-loaded nanoparticles in the preparation of a medicament for preventing and / or treating gastrointestinal oxidative stress-related diseases.

[0032] In a seventh aspect, the present invention provides a medicament for preventing and / or treating gastrointestinal oxidative stress-related diseases, which is prepared from the drug-loaded nanoparticles of the present invention and other pharmaceutically acceptable excipients.

[0033] Among them, the gastrointestinal oxidative stress-related diseases can be gastritis, gastric ulcer, inflammatory bowel disease, and so on.

[0034] The present invention has the following beneficial effects:

[0035] By introducing structural units of dopamine and thioacetal bonds into the copolymer main chain of the diacrylate compound, the present invention prepares a novel poly-β urethane, which has good gastric mucosa adhesion and ROS-responsive properties.

[0036] Encapsulating small molecule anti-inflammatory and / or acid-suppressing drugs (such as N-acetylcysteine and vonoprazan) with the poly-β urethane of the present invention can self-assemble in water to obtain drug-loaded nanoparticles with good nano-scale particle size, dispersibility, and stability. Due to the characteristic that there is a large amount of ROS in the inflammatory site of diseases such as gastric ulcer, the thioacetal bonds contained in the poly-β urethane of the present invention are highly sensitive to ROS. When the drug-loaded nanoparticles reach the gastric ulcer inflammatory region, the high concentration of ROS will cause the thioacetal bonds to break, resulting in the destruction of the nano-carrier structure, and then the dopamine is released by cleavage, and at the same time, the small molecule anti-inflammatory and / or acid-suppressing drugs are released. Therefore, encapsulating small molecule anti-inflammatory and / or acid-suppressing drugs with the poly-β urethane of the present invention can achieve ROS concentration-dependent drug release, responsive release in an inflammatory environment rich in reactive oxygen species (ROS), effectively realizing "lesion-specific" drug delivery, reducing the side effects of drugs in non-target areas, improving the drug utilization rate, and being particularly suitable for the treatment of oxidative stress-related gastric diseases (such as gastric ulcer). That is, the poly-β urethane of the present invention can target and deliver drugs for treating gastrointestinal oxidative stress-related diseases (such as gastric ulcer) to the lesion site, and can release the therapeutic drug responsively at the lesion site, which can increase the local drug concentration, thereby enhancing the therapeutic targeting of the drug and enhancing the therapeutic effect.

[0037] The poly-β urethane of the present invention can efficiently load anti-inflammatory drugs (such as N-acetylcysteine) and acid-suppressing drugs (such as vonoprazan) simultaneously. When the drug-loaded nanoparticles reach the inflammatory area of diseases such as gastric ulcer, the released dopamine can regulate the secretion of gastric acid and pepsin, improving the pathological conditions of gastric ulcer from the level of digestive juice secretion; the anti-inflammatory drug (such as N-acetylcysteine) exerts an antioxidant effect, scavenging excessive oxygen free radicals generated at the inflammatory site, protecting gastric mucosal cells, and promoting the repair of gastric mucosa; the acid-suppressing drug (such as vonoprazan) inhibits the H + -K + -ATPase on gastric mucosal parietal cells, rapidly and persistently reducing gastric acid secretion, and reducing the irritation and erosion of gastric acid to the ulcer surface; each drug synergistically acts at the lesion site of gastrointestinal oxidative stress-related diseases (such as gastric ulcer), jointly promoting the healing of ulcers and improving the therapeutic effect.

[0038] The poly-β urethane of the present invention can form a stable bond with the tissue surface through covalent and non-covalent interactions, has good gastric mucosal adhesion ability, can effectively prolong the residence time of nanoparticles at the lesion site, reduce drug loss, increase the local drug concentration, thereby further enhancing the treatment targeting and efficacy persistence, and greatly improving the therapeutic effect on gastrointestinal oxidative stress-related diseases such as gastric ulcer. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 shows the particle size and PDI of the drug-loaded nanoparticles.

[0040] Figure 2 shows the in vitro release curves of N-acetylcysteine and vonoprazan in the drug-loaded nanoparticles.

[0041] Figure 3 shows the test results of the retention ability of the nanoparticles on the gastric mucosa surface.

[0042] Figure 4 shows the in vivo therapeutic effect of the drug-loaded nanoparticles on rabbits with gastric mucosal ulcer models. DETAILED DESCRIPTION OF THE INVENTION

[0043] For the convenience of understanding the present invention, the present invention will be described more comprehensively below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, these embodiments are provided to make the understanding of the disclosed content of the present invention more thorough and comprehensive.

[0044] The experimental methods without specific conditions noted in the following examples are generally in accordance with conventional conditions or in accordance with the conditions recommended by the manufacturers. All kinds of common chemical reagents used in the examples are commercially available products.

[0045] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the technical field to which the present invention belongs. The terms used in the description of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used in the present invention includes any and all combinations of one or more of the related listed items.

[0046] In addition, as used in the present invention, the term "or" is the inclusive "or" symbol and is equivalent to the term "and / or", unless the context clearly dictates otherwise. The term "based on" is not exclusive and allows for other factors not described, unless the context clearly dictates otherwise. Further, throughout the specification, the meanings of "a", "an", and "the" include plural referents. The meaning of "in" includes "in" and "on".

[0047] The present invention focuses on the treatment problem of gastric ulcers and constructs a ROS-responsive multifunctional nanoparticle delivery system. Due to the abnormally active inflammatory reaction in the gastric ulcer lesion area, a large amount of reactive oxygen species are generated, forming a unique ROS-rich inflammatory microenvironment. The nanocarrier prepared in the present invention cleverly utilizes this characteristic. Its structure contains thioacetal bonds that are extremely sensitive to ROS. Once the nanoparticles reach the gastric ulcer inflammatory site and are in a high-concentration ROS environment, the thioacetal bonds rapidly break, causing the nanocarrier structure to disintegrate and release the drug. The released dopamine can precisely regulate the secretion process of gastric acid and pepsin, improving the pathological conditions of gastric ulcers from the source of digestive juice secretion; at the same time, anti-inflammatory drugs such as N-acetylcysteine released together enhance the self-repair ability of the gastric mucosa with their multiple effects of antioxidant, protecting gastric mucosal cells, and promoting gastric mucosal repair; and proton pump inhibitors such as vonoprazan, as novel potent acid suppressants, can rapidly and persistently inhibit gastric acid secretion, creating a good low-acid environment for ulcer healing. Under the action of the nanoparticle delivery system, each drug works synergistically at the lesion site, not only improving the treatment efficiency but also reducing the adverse effects on normal tissues, opening up a new path for the treatment of ulcers. And the drug-loaded nanoparticles of the present invention can effectively prolong the residence time of the nanoparticles at the lesion site, reduce drug loss, and increase the local drug concentration, thereby further enhancing the treatment targeting and efficacy persistence, and can further improve the treatment effect on gastrointestinal oxidative stress-related diseases such as gastric ulcers.

[0048] In some embodiments of the present invention, a poly-β-urethane is involved, which is copolymerized from a diacrylate compound and an amino-containing compound; the diacrylate compound is selected from one or more of the compounds shown in formulas (I-1) and (I-2) or their stereoisomers, and at least one diacrylate compound is selected from the compound shown in formula (I-2);

[0049] The amino-containing compound is selected from one or more of the compounds represented by formula (II);

[0050]

[0051] wherein, X is selected from: C1-C 16 alkylene, a saturated hydrocarbon group containing one or more oxygen atoms with a chain length of 1 to 16 atoms;

[0052] X1 and X2 may be the same or different, and are each independently selected from: C1-C 16 alkylene substituted or unsubstituted by R3, a saturated hydrocarbon group containing one or more oxygen atoms with a chain length of 1 to 16 atoms substituted or unsubstituted by R3;

[0053] R1 is selected from: hydrogen, C1-C6 alkyl, hydroxyl, carboxyl;

[0054] R2 is selected from: hydrogen, C1-C6 alkyl, hydroxyl, carboxyl;

[0055] R3 is selected from: hydrogen, C1-C6 alkyl, hydroxyl, amino, C1-C6 alkylamino, (C1-C6 alkyl)2amino.

[0056] As used herein, the term "alkyl" means a branched and straight-chain saturated aliphatic hydrocarbon group having a specific number of carbon atoms. For example, the definition of "C1-C6 alkyl" for "C1-C6" includes groups having 1, 2, 3, 4, 5, or 6 carbon atoms arranged in a straight chain or a branched chain. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl.

[0057] As used herein, the term "saturated hydrocarbon group containing one or more oxygen atoms" refers to a group in which one or more carbon atoms in the alkyl chain are replaced by one or more oxygen atoms, such as: -CH2-O-CH2-, -CH2CH2-O-CH2CH2-O-CH2CH2-, -CH(CH3)CH2-O-CH2CH(CH3)-, -CH2CH2-O-CH2CH2CH2CH2CH2CH2-O-CH2CH2-, -CH(CH3)CH2-O-CH(CH3)CH2-, -CH(CH3)CH2-O-CH(CH3)CH2-O-CH(CH3)CH2-.

[0058] In some preferred embodiments, X is selected from: C1-C 12 alkylene, a saturated hydrocarbon group containing one or more oxygen atoms with a chain length of 1 to 12 atoms.

[0059] In some of the preferred embodiments, X1 and X2 are each independently selected from: C1-C alkyl substituted or unsubstituted with R3 12 alkylene, a saturated hydrocarbon group having 1 to 12 atoms in the chain length substituted or unsubstituted with R3 and containing one or more oxygen atoms.

[0060] In some of the preferred embodiments, R1 is selected from: hydrogen, C1-C3 alkyl, hydroxy, carboxy.

[0061] In some of the preferred embodiments, R2 is selected from: hydrogen, C1-C3 alkyl, hydroxy, carboxy.

[0062] In some of the preferred embodiments, R3 is selected from: hydrogen, C1-C3 alkyl, hydroxy, amino, C1-C3 alkylamino, (C1-C3 alkyl)2amino.

[0063] In some of the preferred embodiments, the compound represented by formula (I-1) is selected from the following compounds:

[0064]

[0065] In some of the preferred embodiments, the compound represented by formula (I-2) is selected from the following compounds:

[0066]

[0067] In some of the preferred embodiments, the amino-containing compound is selected from one or more of the following compounds:

[0068]

[0069] In some of the preferred embodiments, the molar ratio of the diacrylate compound to the amino-containing compound is 1:0.1 to 40, preferably 1:0.5 to 20, more preferably 1:0.8 to 2, more preferably 1:0.9 to 1.5, and even more preferably 1:1 to 1.2.

[0070] In some of the preferred embodiments, the diacrylate compound is selected from one or more of the compounds represented by formula (I-2).

[0071] In some of the preferred embodiments, the diacrylate compound is selected from a combination of the compound represented by formula (I-2) and triethylene glycol diacrylate, and the molar ratio thereof is preferably 1:0.8 to 1.2.

[0072] In some preferred embodiments, the poly-β urethane is copolymerized from TKA, triethylene glycol diacrylate and dopamine, and the molar ratio of TKA, triethylene glycol diacrylate and dopamine is preferably 1:0.5-20:0.5-20, more preferably 1:0.8-1.2:1-3, and even more preferably 1:0.8-1.2:1.8-2.2.

[0073] In some preferred embodiments, the poly-β urethane is copolymerized from TKA and dopamine, and the molar ratio of TKA and dopamine is preferably 1:0.5-20, more preferably 1:0.8-2, and even more preferably 1:0.9-1.5, and even more preferably 1:1-1.2.

[0074] Among them, the structural formula of the TKA is

[0075] In some preferred embodiments, the poly-β urethane has the structures shown in the following formulas (A) and (B):

[0076]

[0077] Among them, X, X1, X2, R1, R2 are as described above, n≧1, preferably an integer between 1 and 10,000, more preferably an integer between 1 and 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.

[0078] In some preferred embodiments, the poly-β urethane has the following structure:

[0079]

[0080]

[0081] Among them, n≧1, preferably an integer between 1 and 10,000, more preferably an integer between 1 and 10, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.

[0082] The end of the poly-β urethane of the present invention can be vinyl or capped with the amino-containing compound described in the present invention, and only its repeating structural unit is drawn in the structural formula.

[0083] In some preferred embodiments, the number-average molecular weight of the poly-β urethane is 2100 Da to 5000 Da, preferably 3000 Da to 4000 Da.

[0084] In some embodiments of the present invention, there is also provided a method for preparing the poly-β urethane as described above, comprising the following steps:

[0085] In an organic solvent, the poly-β-urethane is obtained by reacting the diacrylate compound with the amino-containing compound under heating conditions.

[0086] In some preferred embodiments, the organic solvent is selected from at least one of dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), acetonitrile, and tetrahydrofuran (THF).

[0087] In some preferred embodiments, the reaction is carried out in the presence or absence of an acid-binding agent, and the acid-binding agent is selected from at least one of triethylamine, diisopropylethylamine, pyridine, tetramethylethylenediamine, and piperidine.

[0088] In some preferred embodiments, the molar ratio of the acid-binding agent to the diacrylate compound is 1-2:1.

[0089] In some preferred embodiments, the reaction temperature is 50°C to 120°C, more preferably 85°C to 95°C.

[0090] In some preferred embodiments, the reaction time is 4h to 84h, more preferably 66h to 76h.

[0091] The compound represented by formula (I-2) in the present invention can be prepared by the following method:

[0092] (1) Compound 1-1 and Compound 1-2 react with acetone to obtain Compound 2;

[0093] (2) Compound 2 reacts with a reducing agent to reduce the carboxyl group to obtain Compound 3;

[0094] (3) Compound 3 reacts with acryloyl chloride under the action of a base to obtain the compound represented by formula (I-2);

[0095] The reaction formula is as follows:

[0096]

[0097] Among them, X1 and X2 are as described above.

[0098] Among them, Compound 1-1 and Compound 1-2 may be the same or different, and they may be independently selected from the following compounds:

[0099]

[0100] In some preferred embodiments, the total molar ratio of Compound 1-1 and Compound 1-2 to acetone in step (1) is 2 to 4:1.

[0101] In some of the preferred embodiments, the reaction solvent in step (1) is selected from at least one of water, acetonitrile, and tetrahydrofuran.

[0102] In some of the preferred embodiments, the reaction temperature in step (1) is 40°C to 90°C, preferably 45°C to 60°C.

[0103] In some of the preferred embodiments, the reaction time in step (1) is 24 h to 72 h, preferably 40 h to 56 h.

[0104] In some of the preferred embodiments, the reducing agent in step (2) is LiAlH4 or BH3, or a combination of sodium borohydride and boron trifluoride.

[0105] In some of the preferred embodiments, the molar ratio of compound 2 to the reducing agent in step (2) is 1:1 to 4.

[0106] In some of the preferred embodiments, the reaction solvent in step (2) is selected from at least one of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, and tetrahydrofuran.

[0107] In some of the preferred embodiments, the reaction temperature in step (2) is 70°C to 120°C, preferably 85°C to 95°C.

[0108] In some of the preferred embodiments, the reaction time in step (2) is 1 h to 24 h, preferably 2 h to 3 h.

[0109] In some of the preferred embodiments, the molar ratio of compound 3 to acryloyl chloride in step (3) is 1:2 to 5.

[0110] In some of the preferred embodiments, the reaction solvent in step (3) is selected from at least one of dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, and tetrahydrofuran.

[0111] In some of the preferred embodiments, the base in step (3) is selected from at least one of triethylamine, diisopropylethylamine, pyridine, tetramethylethylenediamine, and piperidine.

[0112] In some of the preferred embodiments, the molar ratio of the base to compound 3 in step (3) is 2 to 4:1.

[0113] In some of the preferred embodiments, the reaction temperature in step (3) is 15°C to 40°C, preferably 20°C to 30°C.

[0114] In some of the preferred embodiments, the reaction time in step (3) is 12 h to 72 h, preferably 20 h to 28 h.

[0115] In some embodiments of the present invention, there is also involved a drug-loaded nanoparticle, which is prepared by self-assembly of the poly-β-urethane described in the present invention and a small molecule drug in an aqueous medium;

[0116] The small molecule drug is selected from one or more of small molecule drugs with anti-inflammatory functions and small molecule drugs with acid-suppressing functions.

[0117] In some preferred embodiments thereof, the molar ratio of the poly-β-urethane to the small molecule drug is preferably 0.5 - 8:1, more preferably 1 - 6:1, still more preferably 1 - 4:1 or 2 - 5:1, and most preferably 2 - 3:1.

[0118] In some preferred embodiments thereof, the small molecule drug with anti-inflammatory function is selected from N-acetylcysteine and / or glutathione.

[0119] In some preferred embodiments thereof, the small molecule drug with acid-suppressing function is selected from one or more of vonoprazan, omeprazole, pantoprazole, rabeprazole, cimetidine, ranitidine, and famotidine.

[0120] In some preferred embodiments thereof, the small molecule drug is a combination of a small molecule drug with anti-inflammatory function and a small molecule drug with acid-suppressing function.

[0121] In some preferred embodiments thereof, the molar ratio of the small molecule drug with anti-inflammatory function to the small molecule drug with acid-suppressing function is 0.5 - 1.5:1, more preferably 0.8 - 1.2:1, still more preferably 1:0.9 - 1.1.

[0122] In some preferred embodiments thereof, the small molecule drug is a combination of N-acetylcysteine and vonoprazan, and the molar ratio thereof is preferably 1:0.9 - 1.1.

[0123] In some preferred embodiments thereof, the molar ratio of the poly-β-urethane, the small molecule drug with anti-inflammatory function, and the small molecule drug with acid-suppressing function is preferably 1 - 15:0.5 - 1.5:1, more preferably 2 - 10:0.8 - 1.2:1, still more preferably 2 - 8:0.9 - 1.1:1, yet more preferably 3 - 6:0.9 - 1.1:1, and most preferably 4 - 6:1:1.

[0124] In some preferred embodiments thereof, the particle size of the drug-loaded nanoparticle is 70 nm - 200 nm, preferably 90 nm - 150 nm.

[0125] In some embodiments of the present invention, there is also involved a preparation method of the drug-loaded nanoparticle, including the following steps:

[0126] Dissolve the poly-β-urethane and the small molecule drug in an organic solvent to form an organic phase; drop the organic phase into water to promote the self-assembly of the poly-β-urethane and the small molecule drug in water to form nanoparticles, thus obtaining the drug-loaded nanoparticles.

[0127] In some preferred embodiments, the organic solvent is dimethyl sulfoxide and / or N,N-dimethylformamide.

[0128] In some preferred embodiments, the total concentration of the poly-β-urethane and the small molecule drug in the organic phase is 10 mg / mL to 30 mg / mL, preferably 20 mg / mL to 30 mg / mL.

[0129] In some preferred embodiments, the volume ratio of the organic phase to the aqueous phase is 1:8 to 12.

[0130] In some preferred embodiments, the dropping temperature is 15°C to 37°C.

[0131] In some preferred embodiments, the dropping rate is 0.1 mL / min to 1 mL / min, preferably 0.1 mL / min to 0.2 mL / min.

[0132] In some preferred embodiments, during the dropping process, maintain a gentle stirring at a rotation speed of 300 rpm to 800 rpm or an ultrasonic assistance with a power of 40 kHz to 60 kHz to promote the self-assembly of the poly-β-urethane and the small molecule drug in the aqueous phase to form nanoparticles.

[0133] In some preferred embodiments, during the dropping process, maintain a gentle stirring at a rotation speed of 350 rpm - 450 rpm to promote the self-assembly of the poly-β-urethane and the small molecule drug in the aqueous phase to form nanoparticles.

[0134] In some embodiments of the present invention, it also relates to the application of the drug-loaded nanoparticles of the present invention in the treatment of gastrointestinal oxidative stress-related diseases (such as gastric ulcer).

[0135] The following further describes the present invention in detail with specific embodiments.

[0136] The test method for the number average molecular weight of the poly-β-urethane in the following examples is as follows:

[0137] Prepare a solution with a concentration of about 5 mg / mL of the poly-β-urethane sample using deuterated chloroform as the solvent. Use a 400 MHz nuclear magnetic resonance spectrometer for 1 1H NMR test. In the obtained 1In the \(^1H\) NMR spectrum, the characteristic peaks of the polymer end groups and the main chain were selected for integration. According to the number of hydrogen atoms in the end groups and the number of hydrogen atoms in the main chain repeating unit, the average number of repeating units (DPn) of poly-β-urethane was calculated. Finally, the number-average molecular weight (Mn) was calculated according to the following formula:

[0138] Mn = DPn × Mrepeat + Mend groups. Where Mrepeat is the molar mass of the repeating unit and Mendgroups is the total molar mass of the two end groups.

[0139] DPn = (Imain / Hrepeat) / (Iend / Hend), where Imain, Hrepeat, Iend, and Hend represent the main chain peak area, the number of main chain repeating units, the end group peak area, and the number of hydrogen atoms in the end group, respectively.

[0140] Synthesis of poly-β-urethane in Example 1

[0141] (1) Synthesis of TK-COOH:

[0142]

[0143] Under N2 protection, 25 mL of acetone (0.34 mol) and 54 mL of mercaptoacetic acid (0.78 mol) were measured into 80 mL of water, and the reaction was heated at 50 °C for 48 h. The reaction mixture was concentrated and then precipitated with ethyl acetate in an ice bath and washed 3 times to obtain TK-COOH, with a yield of 14.27 g and a yield of 16.32%; 1 HNMR (400 MHz, DMSO-d6) δ 12.61 (s, 1.76H), 3.37 (s, 4.21H), 1.54 (s, 6H).

[0144] (2) Synthesis of TK-OH:

[0145]

[0146] Under N2 protection, 9 g of TK-COOH (0.04 mol) was dissolved in 300 mL of THF, and 6 g of LiAlH4 (0.16 mol) was slowly added in portions. The mixture was refluxed under condensation at 90 °C for 2.5 h. After the reaction solution was cooled to room temperature, 15% aqueous NaOH solution was slowly added dropwise to the stirred reaction mixture until no further change occurred. The mixture was filtered, and the filtrate was dried with anhydrous MgSO4, filtered, rotary evaporated and concentrated, and purified by a silica gel column chromatography to obtain TK-OH, with a yield of 6.98 g and a yield of 88.58%; 11H NMR (400 MHz, DMSO-d6) δ 4.81 (t, J = 5.5 Hz, 1.93H), 3.52 (td, J = 7.0, 5.4 Hz, 3.95H), 2.66 (t, J = 7.1 Hz, 3.93H), 1.53 (s, 6H).

[0147] (3) Synthesis of TKA:

[0148]

[0149] Under an ice bath, 7 g of TK-OH (0.036 mol) was dissolved in 100 mL of dichloromethane (DCM), 10.9 mL of triethylamine (0.078 mol) was added, and 6.6 mL of acryloyl chloride (0.078 mol) was added dropwise. The reaction was carried out at room temperature for 24 h, and the product was purified by a silica gel column chromatography to obtain TKA with a yield of 8.26 g and a yield of 76.12%; 1 1H NMR (400 MHz, Chloroform-d) δ 6.43 (dd, J = 17.4, 1.4 Hz, 1.97H), 6.13 (dd, J = 17.3, 10.5 Hz, 1.76H), 5.85 (dd, J = 10.4, 1.4 Hz, 1.93H), 4.32 (t, J = 7.0 Hz, 3.81H), 2.92 (t, J = 7.0 Hz, 3.76H), 1.63 (s, 6H).

[0150] (4) Synthesis of poly-β urethane dT:

[0151]

[0152] Under N2 protection, 100 mg of TKA (0.33 mmol) and 68 mg of dopamine (0.33 mol) were dissolved in DMF, and the reaction was carried out at 90 °C for 72 h. Then, the obtained reaction mixture was dialyzed in pure water using a 2000 Da dialysis bag for 3 days, and the water was changed every 4 h. After dialysis, the product was freeze-dried to obtain dT with a yield of 158.36 mg and a yield of 96.8%. The number-average molecular weight was measured to be approximately 3100 Da 。 1 1HNMR (400 MHz, DMSO-d6) δ 6.66 - 6.55 (m, 3H), 6.48 - 6.40 (m, 1.42H), 6.35 (d, J = 17.3 Hz, 0.77H), 6.24 - 6.09 (m, 0.66H), 5.96 (d, J = 9.8 Hz, 0.53H), 4.32 - 4.07 (m, 8.11H), 3.36 (s, 4.23H), 2.94 - 2.62 (m, 8.29H), 1.56 (d, J = 3.5 Hz, 12.35H).

[0153] (4) Synthesis of poly-β-urethane d2T:

[0154]

[0155] Under N2 protection, 100 mg of TKA (0.33 mmol), 127 mg of dopamine (0.66 mmol) and 82 μL of triethylene glycol diacrylate (0.33 mmol) were dissolved in DMF, and the reaction was carried out at 90 °C for 72 h. Then, the obtained reaction mixture was dialyzed in pure water using a dialysis bag with a molecular weight cut-off of 2000 Da for 3 days, and the water was changed every 4 h. After dialysis, the product was freeze-dried to obtain d2T with a yield of 294.97 mg and a yield rate of 93.19%. The number-average molecular weight was measured to be approximately 3200 Da. 1 H NMR (400 MHz, DMSO-d6) δ 6.64 - 6.55 (m, 2.68H), 6.43 (d, J = 8.0 Hz, 1.3H), 6.35 (d, J = 16.9 Hz, 1.11H), 6.25 - 6.10 (m, 0.95H), 5.97 (t, J = 8.8 Hz, 0.85H), 4.32 - 4.08 (m, 8.29H), 3.68 - 3.47 (m, 7.76H), 3.35 (s, 4.29H), 2.93 - 2.65 (m, 8.12H), 1.57 (t, J = 3.0 Hz, 6.33H).

[0156] Example 2 Preparation of drug-loaded nanoparticles

[0157] (1) Weigh 25 mg of poly-β-urethane dT, 25 mg of vonoprazan (VNP) and 25 mg of N-acetylcysteine (NAC) respectively, and dissolve them in DMF to prepare poly-β-urethane dT solution, VNP solution and NAC solution with a concentration of 25 mg / mL respectively; mix the poly-β-urethane dT solution, VNP solution and NAC solution together according to the molar ratio of dT:VNP:NAC = 5:1:1 as the organic phase; drop the organic phase into 10 times the volume of the aqueous phase (pure water) at room temperature (the dropping rate is 0.12 mL / min). During the dropping process, the system is maintained under gentle stirring (400 rpm) to promote the self-assembly of the three components in the aqueous phase to form nanoparticles, denoted as dT NPs.

[0158] (2) Using d2T as the carrier, drug-loaded nanoparticles d2TNPs were prepared by the same method and ratio as in (1).

[0159] (3) Using sodium acetate buffer solution (pH 5.2, 25 mM), pure water and PBS solution with pH 7.4 as the aqueous phase respectively, and at the same time mixing the three components in the organic phase in different ratios, drug-loaded nanoparticles were prepared by the method in (1).

[0160] The particle size and polydispersity index (PDI) of the obtained drug-loaded nanoparticles were detected and analyzed using a Malvern particle size analyzer.

[0161] The experimental results showed ( Figure 1 ) that the particle size of the particles self-assembled by the nanoparticles in pure water was about 120 nm; in sodium acetate buffer solution, the particle size of the self-assembled nanoparticles increased significantly, reaching about 260 nm; while in PBS solution with pH 7.4, the particle size of the self-assembled nanoparticles was even larger, about 2750 nm. This indicated that the nanoparticles presented relatively ideal particle size and dispersion effect in pure water, and using pure water as the aqueous phase was more conducive to the preparation of drug-loaded nanoparticles.

[0162] In addition, when dT (or d2T):VNP:NAC = 5:1:1 (molar ratio), it had a smaller particle size and polydispersity index, indicating that the structure of its nanoparticles was more stable and uniform, and the excellent particle size and distribution characteristics could significantly improve its tissue penetration and therapeutic effect in vivo.

[0163] Example 3 In vitro release experiment

[0164] In this example, an HCl solution with pH 1.2 was used as the drug release medium and an HCl solution containing 10 mM H2O2 and with pH 1.2 was used as the drug release medium to simulate the normal gastric acid environment and the inflammatory gastric acid environment respectively. The ROS-responsive drug release amount of the prepared drug-loaded nanoparticles within 24 h was tested, the drug release amount of the drug-loaded nanoparticles was calculated through the standard curves of VNP and NAC, and a drug release curve was plotted.

[0165] In addition, PLGA 1500 -PEG 1000 -PLGA 1500 is an ABA-type triblock copolymer composed of polyethylene glycol (PEG 1000 ) and poly(lactic-co-glycolic acid) (PLGA 1000 ). PLGA is a copolymer of poly(lactic acid) (PLA) and poly(glycolic acid) (PGA), and the molar ratio of lactic acid (LA):glycolic acid (GA) = 75:25. This copolymer has been used as a standard material in many studies to construct drug delivery systems. In this example, PLGA 1500 -PEG 1000 -PLGA 1500 was used as the carrier to prepare drug-loaded nanoparticles (abbreviated as PEG-PLGANPs) according to the method in step (1) of Example 2 as a control material.

[0166] Prepare the standard curve:

[0167] Weigh 2 mg of VNP and 2 mg of NAC, mix them and dissolve in 1 mL of HPLC-grade methanol to obtain a mixed solution with a mass concentration of 2 mg / mL of NAC and VNP. Dilute the mixed solution by half to 4 concentrations to obtain NAC and VNP mixed solutions with concentrations of 1 mg / mL, 500 μg / mL, 250 μg / mL, and 125 μg / mL. Analyze and detect the peak area of the mixed solution by HPLC and use Prism software to analyze and draw a standard curve graph.

[0168] Load the drug-loaded nanoparticles dTNPs and d2TNPs and PEG-PLGANPs prepared in steps (1) and (2) of Example 2 into dialysis bags with a molecular weight cut-off of 2000 Da. Each type of drug-loaded nanoparticle is divided into 2 groups for experiments, with 1 mL in each group. Place the dialysis bags into 50 mL conical flasks, which are respectively filled with 20 mL of HCl solution containing 10 mM H2O2 and pH = 1.2 and 20 mL of HCl solution without H2O2 and pH = 1.2 as the drug release media. Place each group of conical flasks into a constant temperature shaker oscillator at 37 °C with a rotation speed of 200 r / min for drug release experiments. Set the sampling time points to 0.5 h, 1 h, 3 h, 6 h, 12 h, and 24 h. At each time point, accurately take out 2 mL of solution from each group of conical flasks with a pipette and place it into a centrifuge tube. To ensure that the total volume remains unchanged, add 2 mL of the corresponding drug release medium each time. After the drug release ends, detect the release amounts of VNP and NAC by HPLC. Calculate the cumulative release rates of VNP and NAC in different drug release media within 24 h.

[0169] Cumulative release rate of VNP = Amount of VNP released from nanoparticles at time t / Initial drug loading amount of VNP in nanoparticles × 100%

[0170] Cumulative release rate of NAC = Amount of NAC released from nanoparticles at time t / Initial drug loading amount of NAC in nanoparticles × 100%

[0171] The results are as Figure 2 shown: Within 24 h, in the HCl solution with pH 1.2, the drug release amounts of dT NPs are approximately 28.5% and 56.6%, and those of d2TNPs are approximately 29.8% and 56.5%. In the HC solution containing 10 mM H2O2 and pH 1.2, a large amount of VNP and NAC are released. The drug release amounts of dTNPs reach 43.1% and 78.4%, and those of d2TNPs reach 41.7% and 76.8%. However, there is no obvious change in the drug release curves of PEG-PLGA NPs in the two media. This shows that the drug-loaded nanoparticles prepared by the present invention have good VNP and NAC release effects in high-concentration ROS, have the characteristics of ROS-responsive release, and can achieve the purpose of targeted therapy. While the commonly used PLGA 1500 -PEG1000 -PLGA 1500 The carrier does not have the characteristic of ROS-responsive release.

[0172] Example 4 Adhesion Experiment

[0173] In this example, nanoparticles encapsulating fluorescent dyes were constructed and an in vitro adhesion experiment was carried out to evaluate the retention ability of the nanoparticles on the gastric mucosa surface.

[0174] Control group: PEG-PLGA was dissolved in DMF to prepare a PEG-PLGA solution with a concentration of 25 mg / mL. The PEG-PLGA solution and 10 μL of a 2 mg / mL lipophilic fluorescent probe DIR (1,1′-dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine iodide) were self-assembled in 10 volumes of water at a molar ratio of PEG-PLGA to DIR of 5:1 to obtain fluorescent signal-bearing PEG-PLGA NPs@DIR.

[0175] Experimental group: dT and d2T were respectively dissolved in DMF to prepare a 25 mg / mL dT solution and a 25 mg / mL d2T solution. The dT solution and the d2T solution and 10 μL of a 2 mg / mL lipophilic fluorescent probe DIR were self-assembled in 10 volumes of water at a molar ratio of dT (or d2T):DIR of 5:1 to obtain fluorescent signal-bearing dTNPs@DIR and d2TNPs@DIR.

[0176] Fresh Babl / c mouse gastric tissues were dissected and used in the experiment. After thoroughly washing the surface residues with phosphate buffer solution (PBS) at pH 7.4, they were co-incubated with the above nanoparticle solutions at 37 °C for 10 minutes. After the incubation, they were thoroughly rinsed with artificial gastric juice (pH 1.2) to remove non-specifically adsorbed nanoparticles, and then left to stand in the dark with 20 μL of artificial gastric juice placed at the bottom to keep it moist. They were rinsed 5 times with artificial gastric juice before each imaging. Imaging was performed using a small animal in vivo imaging system at 30 min, 6 h, 18 h, and 24 h respectively, and the changes in fluorescent signals were recorded to evaluate the retention degree of the nanoparticles on the gastric tissue surface.

[0177] The results are as Figure 3 shown: The fluorescence intensities of dTNPs@DIR and d2TNPs@DIR at each time point were always significantly higher than those of PEG-PLGA NPs@DIR, and the fluorescence intensities of dT NPs@DIR and d2TNPs@DIR increased significantly with time, showing good tissue enrichment and continuous retention ability.

[0178] Example 5 In Vivo Therapeutic Effect

[0179] In this example, rabbits were used as experimental animals, and a visual gastric mucosal ulcer model was established to test the healing-promoting effect of the drug-loaded nanoparticles of the present invention. Before the experiment, the animals were fasted for 24 hours with free access to water and then anesthetized (intramuscular injection of ketamine-xylazine anesthesia, ketamine concentration 40 mg / kg, xylazine concentration 5 mg / kg) to ensure no pain response during the experiment.

[0180] Under sterile conditions, a wound was created on the anterior wall of the gastric body by mechanical traction using a biopsy forceps through an endoscope, resulting in a focal circular ulcer injury with a diameter of approximately 8-11 mm. Only one ulcer was created in each animal. After successful ulcer induction, the animals were randomly divided into the following groups:

[0181] Control group: gavaged with an equal volume of normal saline.

[0182] Drug administration group: Three experimental groups were respectively gavaged with equal concentrations and equal doses of the following drug-loaded nanoparticles: d2TNPs co-loaded with NAC and VNP prepared in step (2) of Example 2 (d2T:VNP:NAC = 5:1:1 (molar ratio)), denoted as the NAC+VNP group; d2TNPs loaded only with NAC prepared according to the method of step (2) of Example 2 (d2T:NAC = 5:1 (molar ratio)), denoted as the NAC group; d2T NPs loaded only with VNP prepared according to the method of step (2) of Example 2 ((d2T:VNP = 5:1 (molar ratio)), denoted as the VNP group; all were administered through a spraying tube and an endoscope, and the administration dose was 1 mL.

[0183] Ulcer induction started on Day 0, and the drugs were administered on Days 1, 3, and 7 respectively. The animals were given liquid food daily and raised in a constant temperature environment. Body temperature, feeding behavior, and general condition were closely monitored to ensure a stable anesthesia and recovery process. On Days 1, 3, and 7, the animals were anesthetized, and then an animal endoscope was used to observe the ulcer site and calculate its area. The ulcer area at each time point was based on the area on the day of ulcer induction (Day 0) (100%), and the percentage of the remaining area was calculated to reflect the degree of ulcer healing. Finally, a trend graph of the residual rate of ulcer area over time was plotted to evaluate the differences in ulcer repair effects among groups.

[0184] The results are as Figure 4As shown, in the gastric ulcer treatment experiment, the construction of the gastric ulcer animal model was completed on day 0, and the drug administration process was initiated on day 1. The results showed that after drug administration, the ulcer areas of both the control group and each drug administration group gradually decreased. Compared with the control group, the decreasing trend of the ulcer area in each drug administration group was more significant, intuitively demonstrating the therapeutic effect of the drug administration group on gastric ulcer. Among them, the NAC+VNP group showed particularly outstanding performance, and the reduction amplitude of its ulcer area was significantly better than that of other groups, indicating that the combined drug administration regimen of NAC+VNP showed more excellent effects in the treatment of gastric ulcer.

[0185] The above-described embodiments only represent several implementation manners of the present invention. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the present invention patent shall be subject to the appended claims.

Claims

1. A poly-β urethane, characterized in that, It is copolymerized from a diacrylate compound and an amino-containing compound; the diacrylate compound is selected from one or more of the compounds shown in formula (I-1) and (I-2) or their stereoisomers, and at least one diacrylate compound is selected from the compound shown in formula (I-2); The amino-containing compound is selected from one or more of the compounds shown in formula (II); Among them, X is selected from: C1-C 16 an alkylene group, a saturated hydrocarbon group containing one or more oxygen atoms and having a chain length of 1 to 16 atoms; X1 and X2 may be the same or different, and are each independently selected from: C1-C which is substituted or unsubstituted by R3 16 alkylene, a saturated hydrocarbon group having 1 to 16 atoms in chain length and containing one or more oxygen atoms which is substituted or unsubstituted by R3; R1 is selected from: hydrogen, C1-C6 alkyl, hydroxyl, carboxyl; R2 is selected from: hydrogen, C1-C6 alkyl, hydroxyl, carboxyl; R3 is selected from: hydrogen, C1-C6 alkyl, hydroxyl, amino, C1-C6 alkylamino, (C1-C6 alkyl)2amino.

2. The poly-β urethane according to claim 1, characterized in that, X is selected from: C1-C 12 an alkylene group, a saturated hydrocarbon group containing one or more oxygen atoms and having a chain length of 1 to 12 atoms; and / or, X1 and X2 are each independently selected from: C1-C which is substituted or unsubstituted by R3 12 alkylene group, a saturated hydrocarbon group having 1 to 12 atoms in chain length which contains one or more oxygen atoms and is substituted or unsubstituted by R3; And / or, R1 is selected from: hydrogen, C1-C3 alkyl, hydroxyl, carboxyl; And / or, R2 is selected from: hydrogen, C1-C3 alkyl, hydroxyl, carboxyl; And / or, R3 is selected from: hydrogen, C1-C3 alkyl, hydroxyl, amino, C1-C3 alkylamino, (C1-C3 alkyl)2amino.

3. The poly-β-urethane according to claim 1, wherein The compound shown in formula (I-1) is selected from the following compounds: And / or, the compound shown in formula (I-2) is selected from the following compounds: And / or, the amino-containing compound is selected from one or more of the following compounds:

4. The poly-β-urethane according to claim 1, characterized in that, The molar ratio of the diacrylate compound to the amino-containing compound is 1:0.1 to 40, preferably 1:0.5 to 20, more preferably 1:0.8 to 2, more preferably 1:0.9 to 1.5, and more preferably 1:1 to 1.

2.

5. The poly-β-urethane according to claim 1, characterized in that, The diacrylate compound is selected from one or more of the compounds shown in formula (I-2); Or, it is selected from the combination of the compound shown in formula (I-2) and triethylene glycol diacrylate, and the molar ratio is preferably 1:0.8 to 1.

2.

6. The poly-β-urethane according to claim 1, characterized in that, It is copolymerized from TKA, triethylene glycol diacrylate and dopamine, and the molar ratio of TKA, triethylene glycol diacrylate and dopamine is preferably 1:0.5 to 20:0.5 to 20, more preferably 1:0.8 to 1.2:1 to 3, and more preferably 1:0.8 to 1.2:1.8 to 2.2; Or, it is copolymerized from TKA and dopamine, and the molar ratio of TKA and dopamine is preferably 1:0.5 to 20, more preferably 1:0.8 to 2, more preferably 1:0.9 to 1.5, and more preferably 1:1 to 1.2; The structural formula of the TKA is 7. The poly-β urethane according to claim 1, characterized in that, The poly-β urethane has the structures shown in formula (A) and formula (B) as follows: Wherein, X, X1, X2, R1, R2 are as described in any one of claims 1-3, n≧1, preferably an integer between 1 and 10000, and more preferably an integer between 1 and 10.

8. The poly-β-urethane according to claim 1, characterized in that, The poly-β urethane has the following Wherein, n≧1, preferably an integer between 1 and 10000, and more preferably an integer between 1 and 10.

9. The poly-β urethane according to any one of claims 1-8, characterized in that, Its number average molecular weight is 2100Da to 5000Da, preferably 3000Da to 4000Da.

10. A method for preparing the poly-β-urethane according to any one of claims 1-9, characterized in that, It includes the following steps: In an organic solvent, the diacrylate compound and the amino-containing compound react under heating conditions to obtain the poly-β urethane.

11. The preparation method of the poly-β urethane according to claim 10, characterized in that, The organic solvent is selected from at least one of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile and tetrahydrofuran; And / or, the reaction is carried out in the presence or absence of an acid-binding agent, and the acid-binding agent is preferably at least one selected from triethylamine, diisopropylethylamine, pyridine, tetramethylethylenediamine, and piperidine; And / or, the temperature of the reaction is 50°C to 120°C, preferably 85°C to 95°C; And / or, the reaction time is 4h to 84h, preferably 66h to 76h.

12. The method for preparing poly-β urethane according to claim 10 or 11, characterized in that, The preparation method of the compound shown in formula (I-2) comprises the following steps: (1) Compound 1-1 and compound 1-2 react with acetone to obtain compound 2; (2) Compound 2 reacts with a reducing agent to reduce the carboxyl group to obtain compound 3; (3) Compound 3 reacts with acryloyl chloride under the action of a base to obtain the compound shown in formula (I-2); The reaction formula is as follows: Wherein, X1 and X2 are as described in any one of claims 1-3; Preferably, compound 1-1 and compound 1-2 may be the same or different, and they are each independently selected from the following compounds:

13. The preparation method of the poly-β urethane according to claim 12, characterized in that, In step (1), the total molar ratio of compound 1-1 and compound 1-2 to acetone is 2 to 4:1; And / or, the reaction solvent in step (1) is selected from at least one of water, acetonitrile, and tetrahydrofuran; And / or, the reaction temperature in step (1) is 40°C to 90°C, preferably 45°C to 60°C; And / or, the reaction time in step (1) is 24h to 72h, preferably 40h to 56h; And / or, the reducing agent in step (2) is LiAlH4 or BH3, or a combination of sodium borohydride and boron trifluoride; And / or, the molar ratio of compound 2 to the reducing agent in step (2) is 1:1 to 4; And / or, the reaction solvent in step (2) is selected from at least one of dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, and tetrahydrofuran; And / or, the reaction temperature in step (2) is 70°C to 120°C, preferably 85°C to 95°C; And / or, the reaction time in step (2) is 1h to 24h, preferably 2h to 3h; And / or, the molar ratio of compound 3 to acryloyl chloride in step (3) is 1:2 to 5; And / or, the reaction solvent in step (3) is selected from at least one of dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, and tetrahydrofuran; And / or, the base in step (3) is selected from at least one of triethylamine, diisopropylethylamine, pyridine, tetramethylethylenediamine, and piperidine; And / or, the molar ratio of the base to compound 3 in step (3) is 2 to 4:1; And / or, the reaction temperature in step (3) is 15°C to 40°C, preferably 20°C to 30°C; And / or, the reaction time in step (3) is 12h to 72h, preferably 20h to 28h.

14. A drug-loaded nanoparticle, characterized in that, Prepared by self-assembly of the poly-β urethane and the small molecule drug according to any one of claims 1-9 in an aqueous medium; The small molecule drug is selected from one or more of small molecule drugs with anti-inflammatory functions and small molecule drugs with acid suppression functions; The molar ratio of the poly-β-urethane to the small molecule drug is preferably 0.5 to 8:1, more preferably 1 to 6:1, still more preferably 1 to 4:1 or 2 to 5:1, and most preferably 2 to 3:

1.

15. The drug-loaded nanoparticles according to claim 14, wherein, The small molecule drug with anti-inflammatory function is selected from N-acetylcysteine and / or glutathione; And / or, the small molecule drug with acid suppression function is selected from one or more of vonoprazan, omeprazole, pantoprazole, rabeprazole, cimetidine, ranitidine, and famotidine; Preferably, the small molecule drug is a combination of a small molecule drug with anti-inflammatory function and a small molecule drug with acid suppression function, and the molar ratio is preferably 0.5 to 1.5:1, more preferably 0.8 to 1.2:1, still more preferably 1:0.9 to 1.1, and most preferably a combination of N-acetylcysteine and vonoprazan; Preferably, the molar ratio of the poly-β-urethane, the small molecule drug with anti-inflammatory function, and the small molecule drug with acid suppression function is preferably 1 to 15:0.5 to 1.5:1, more preferably 2 to 10: 0.8 to 1.2:1, still more preferably 2 to 8: 0.9 to 1.1:1, still more preferably 3 to 6: 0.9 to 1.1:1, most preferably 4 to 6:1:

1.

16. The drug-loaded nanoparticles according to claim 14 or 15, characterized in that, The particle size of the drug-loaded nanoparticles is 70 nm to 200 nm, preferably 90 nm to 150 nm.

17. A method for preparing the drug-loaded nanoparticles according to any one of claims 14-16, characterized in that, Comprising the following steps: Dissolve the poly-β-urethane and the small molecule drug in an organic solvent to form an organic phase; drop the organic phase into water to promote the self-assembly of the poly-β-urethane and the small molecule drug in water to form nanoparticles, thus obtaining the drug-loaded nanoparticles.

18. The method for preparing the drug-loaded nanoparticles according to claim 17, wherein The organic solvent is dimethyl sulfoxide and / or N,N-dimethylformamide; And / or, the total concentration of the poly-β-urethane and the small molecule drug in the organic phase is 10 mg / mL to 30 mg / mL; And / or, the volume ratio of the organic phase to the water is 1:8 to 12; And / or, the dropping temperature is 15 °C to 37 °C; And / or, the dropping rate is 0.1 mL / min to 1 mL / min, preferably 0.1 mL / min to 0.2 mL / min; And / or, during the dropping process, maintain a gentle stirring at a rotation speed of 300 rpm to 800 rpm or an ultrasonic assistance with a power of 40 kHz to 60 kHz to promote the self-assembly of the poly-β-urethane and the small molecule drug in the aqueous phase to form nanoparticles.

19. Use of the poly-β-urethane according to any one of claims 1-9 as a carrier in the preparation of a drug for preventing and / or treating gastrointestinal oxidative stress-related diseases.

20. Use of the drug-loaded nanoparticles according to any one of claims 14-16 in the preparation of a drug for preventing and / or treating gastrointestinal oxidative stress-related diseases.

21. The application according to claim 19 or 20, characterized in that, The gastrointestinal oxidative stress-related diseases are gastritis, gastric ulcer, and inflammatory bowel disease.

22. A drug for preventing and / or treating gastrointestinal oxidative stress-related diseases, characterized in that, Prepared from the drug-loaded nanoparticles according to any one of claims 14-16 and other pharmaceutically acceptable excipients.

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