Polyethylene glycol-polylysine-curcumin polymicelle, preparation method and application

Abstract

The present invention belongs to the field of compound technology, and discloses a polyethylene glycol-polylysine-curcumin polymer, a preparation method and an application thereof, wherein the structural formula thereof is shown in formula (I): wherein m represents 114 to 227, x represents 5 to 10, and y represents 4 to 8. The present invention grafts curcumin onto a polyethylene glycol-polylysine material as a hydrophobic group to help form micelles, thereby forming a new dosage form of curcumin, and serving as a drug for other hydrophobic periodontitis treatments. The polyethylene glycol-polylysine-curcumin micelle is a new dosage form of curcumin, which can be used as a drug for other hydrophobic periodontitis treatments to achieve controlled release of the drug. The micelles also have good biocompatibility.

Description

Technical Field

[0001] The invention belongs to the technical field of compounds and relates to a nano preparation, in particular to a polyethylene glycol-polylysine-curcumin polymicelle, a preparation method and an application thereof. Background Art

[0002] Periodontitis is a chronic inflammatory disease that affects the supporting structures of the teeth. It is a complex, bacterial-induced immune response that often leads to bacterial overgrowth, primarily caused by the Gram-negative anaerobic bacterium Porphyromonas gingivalis. This leads to progressive and irreversible destruction of tooth-supporting tissues, ultimately resulting in alveolar bone resorption and tooth loss. It not only affects dental aesthetics and masticatory function but is also closely associated with systemic diseases such as diabetes, cardiovascular and cerebrovascular disease, lung function, and Alzheimer's disease. Therefore, effective prevention and treatment of periodontitis are crucial for maintaining human health. In addition to basic treatments such as oral hygiene, tartar removal, and cavity filling, mechanical debridement combined with topical antibiotic therapy remains the mainstay of clinical treatment for periodontitis. However, this treatment approach has drawbacks. It is not only expensive but also can cause patient anxiety and postoperative pain. Furthermore, frequent or indiscriminate use of supplemental antibiotics can lead to the development of drug-resistant strains, and prolonged use of antimicrobial agents can cause bacterial imbalance. Therefore, the development of more effective and non-invasive methods is very important for the treatment of periodontitis (Xin Y, Guo Z, Ma A, et al. A robust ROS generation nanoplatform combating periodontitis via sonodynamic / chemodynamic combination therapy [J]. Chemical Engineering Journal, 2023, 451.). Currently, photodynamic therapy (PDT) has been used for bacterial infections. They can exert broad-spectrum antibacterial or selective anti-anaerobic effects, but they still have major drawbacks, such as low tissue penetration depth and severe phototoxicity after systemic administration of photosensitizers. Therefore, to combat deep periodontitis bacteria, sonodynamic therapy (SDT) induced by ultrasound (US) and sonosensitizers is considered. This is a treatment method that uses ultrasound to stimulate sonosensitizers to produce active substances to damage cells (Mchale AP, Callan JF, Nomikou N, et al. Sonodynamic therapy: concept, mechanism and application to cancer treatment [J]. Adv Exp Med Biol, 2016, 880: 429-450).The mechanism is mainly due to the generation of reactive oxygen species (ROS) or reactive nitrogen species (RNS) by sonosensitizers under low-intensity periodic mechanical vibrations. In addition, the energy of ultrasound causes temperature rise and other non-thermal effects, which together lead to irreversible damage and apoptosis of bacteria (Qian XQ, Zheng YY, Chen Y, et al. Micro / nanoparticle augmented sonodynamic therapy (SDT): breaking the depth shallow of photoactivation [J]. Adv Mater, 2016, 28 (37): 8097-8129). SDT not only has deeper tissue penetration (> 10 cm), but also has no bacterial resistance, which makes it show great advantages over traditional photodynamic therapy (Rosenthal I, Sostaric JZ, Riesz P, et al. Sonodynamic therapy: a review of the synergistic effects of drugs and ultrasound [J]. Ultrason Sonochem, 2004, 11 (6): 349-363). SDT is composed of three main components: sonosensitizer, ultrasound, and oxygen. Sonosensitizers can be organic or inorganic, but traditional sonosensitizers are limited by phototoxicity and skin sensitivity. Therefore, the development of effective sonosensitizers is very important for sonodynamics.

[0003] Curcumin (Cur) is a symmetrical natural polyphenol found in the plants Curcuma aromatica, Acorus calamus, Turmeric, and Curcuma zedoaria. Reports indicate that Cur exhibits a variety of pharmacological activities, including antioxidant, anti-inflammatory, and anti-tumor properties. It also has hepatoprotective and renal functions, antithrombotic effects, myocardial infarction prevention, hypoglycemic, and anti-rheumatic effects. However, Cur is an acidic polyphenol insoluble in ether and water, unable to effectively penetrate cell membranes. Oral administration of Cur results in ineffective therapeutic concentrations and low bioavailability. Therefore, increasing the apparent solubility and dissolution rate of Cur in water is a primary approach to improving its oral absorption. To enhance the efficacy of drug delivery systems and reduce side effects, the construction of nanoscale controlled-release carriers has become a focus of research. Conjugated micelles are excellent nanoscale self-immolating intracellular drug delivery vehicles. As nanomaterials, they offer advantages such as enhanced skin permeability, high drug loading capacity, controlled release of the cargo, and the ability to encapsulate diverse drug types. Chinese and foreign scholars have tried to adopt many composite modification methods, such as cyclodextrin-curcumin, liposome-curcumin, phospholipid-curcumin, etc. (Wu Lisha, Yu Hongying, Zeng Qingbing. Preparation and in vitro drug release of curcumin mPEG_(114)-PCL_(36) nanomicelles [J]. Chinese Journal of Experimental Traditional Chinese Medicine, 2013, 19(12): 53-58.). Although novel, the effective load content of traditional physical encapsulation nanocarriers is low, and the actual mass of nanocarriers reaching the entity is extremely limited, only 1% of the administered dose. Therefore, high drug loading is of great significance for improving the drug delivery efficiency of drug carriers, facilitating drug delivery, and preventing toxicity caused by carrier materials. Summary of the Invention

[0004] The purpose of the present invention is to overcome the deficiencies in the prior art and provide a polyethylene glycol-polylysine-curcumin polymer, a preparation method and an application thereof.

[0005] The technical solution adopted by the present invention to solve its technical problem is:

[0006] A polyethylene glycol-polylysine-curcumin polymicelle, the structural formula of which is shown in formula (I):

[0007]

[0008] Here, m represents 114 to 227, x represents 5 to 10, and y represents 4 to 8.

[0009] Furthermore, the average particle size of the polyethylene glycol-polylysine-curcumin polymicelles is 147.6 nm, and the average Zeta potential is 20.5 mV.

[0010] The preparation method of the polyethylene glycol-polylysine-curcumin polymicelles as described above comprises the following steps:

[0011] Acylation of 3,3'-thiodipropionic acid with oxalyl chloride to generate 3,3'-thiodipropionic acid chloride;

[0012] mixing the curcumin solution with pyridine used as an acid binding agent to obtain a curcumin mixed solution;

[0013] The mixed solution of 3,3'-thiodipropionic acid chloride and curcumin is stirred and mixed at below 0°C, reacted at room temperature for 3 to 5 hours, and purified to obtain a curcumin derivative containing a monosulfide bond;

[0014] Deprotecting polylysine modified with N-[4-(2,5-dioxo-4-oxazolidinyl)butyl]-2,2,2-trifluoroacetamide to obtain deprotected modified polylysine;

[0015] The modified polylysine is subjected to a condensation reaction with N,N-diisopropylethylamine, and then mixed with a curcumin derivative containing a single sulfide bond activated by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole carboxyl group, and stirred in the dark for 24 to 48 hours for an amidation reaction; the mixture is precipitated with ice ether, dialyzed and freeze-dried to obtain a polyethylene glycol-polylysine-curcumin polymer.

[0016] Furthermore, the step of reacting 3,3'-thiodipropionic acid with oxalyl chloride to generate 3,3'-thiodipropionic acid chloride is specifically as follows:

[0017] Dissolve 3,3'-thiodipropionic acid in anhydrous tetrahydrofuran, add cosolvent N,N-dimethylformamide, slowly add oxalyl chloride under stirring below 0°C, and then stir at room temperature for 2-3 hours to obtain 3,3'-thiodipropionic acid chloride;

[0018] Alternatively, the step of mixing the curcumin solution with pyridine used as an acid binding agent is specifically:

[0019] Dissolve curcumin in anhydrous tetrahydrofuran, add pyridine and stir to obtain a curcumin mixed solution;

[0020] Alternatively, the preparation steps of the curcumin derivative containing a single sulfide bond are specifically as follows:

[0021] Under conditions below 0°C, 3,3'-thiodipropionic acid chloride is slowly added dropwise to the curcumin mixed solution and stirred while being protected from light. The mixture is transferred to room temperature and stirred for 3 to 5 hours. After the reaction is completed, anhydrous tetrahydrofuran is removed by rotary evaporation, the mixture is dissolved with dichloromethane, extracted and washed with hydrochloric acid, and the organic phase is collected and dried to obtain a curcumin derivative containing a monosulfide bond.

[0022] The obtained curcumin derivative containing a monosulfide bond is dissolved in dichloromethane, and a mixed solution of dichloromethane and methanol is used as an eluent and a developing agent. The target product is confirmed by continuous plate spotting until it is completely discharged from the column. The product is collected, spin-dried, and then dried to obtain a purified curcumin derivative containing a monosulfide bond.

[0023] Alternatively, the specific preparation steps of the N-[4-(2,5-dioxo-4-oxazolidinyl)butyl]-2,2,2-trifluoroacetamide modified polylysine are:

[0024] Methoxypolyethylene glycol amine and N-[4-(2,5-dioxo-4-oxazolidinyl)butyl]-2,2,2-trifluoroacetamide were placed in a round-bottom flask, and N,N-dimethylformamide (DMF) was added to dissolve the mixture, and chloroform was added as a cosolvent to assist the dissolution. The mixture was vacuumed and stirred at 40-50°C under inert gas protection. After 3 days, the reaction was treated, and the reaction solution was concentrated by rotary evaporation under reduced pressure, and then added dropwise to icy ether to precipitate a white flocculent precipitate. The precipitate was filtered using a Buchner funnel and dried under vacuum to obtain modified polylysine.

[0025] The modified polylysine was dissolved in 0.5N sodium hydroxide aqueous solution and stirred at room temperature for 2 to 5 hours. After the reaction, the reaction solution was placed in a dialysis bag with a molecular weight cutoff (MWCO) of 1000Da and dialyzed with water. Ultrapure water was replaced every 2 hours. After 24 hours, the sample in the dialysis bag was taken out and placed in a freeze dryer for freeze drying to obtain the deprotected modified polylysine.

[0026] Furthermore, the molar ratio of the 3,3'-thiodipropionic acid to oxalyl chloride is 1:1.2;

[0027] Alternatively, the molar ratio of curcumin to pyridine is 1:10;

[0028] Alternatively, the molar ratio of the chlorinated 3,3'-thiodipropionic acid to curcumin is 1:1;

[0029] Alternatively, when the dichloromethane and methanol mixture is used as the eluent, the volume ratio of dichloromethane:methanol is 400:3; when the dichloromethane and methanol mixture is used as the developing solvent, the volume ratio of dichloromethane:methanol is 100:3;

[0030] Alternatively, the molar ratio of the methoxypolyethylene glycol amine to N-[4-(2,5-dioxo-4-oxazolidinyl)butyl]-2,2,2-trifluoroacetamide is 1:15;

[0031] Alternatively, the methoxypolyethylene glycol amine is mPEG4000-mPEG12000.

[0032] Furthermore, the method further comprises the step of preparing polyethylene glycol-polylysine-curcumin nanomicelles from the polyethylene glycol-polylysine-curcumin polymer, specifically:

[0033] The polyethylene glycol-polylysine-curcumin polymer was dissolved in N,N-dimethylformamide and added to a dialysis bag with a molecular weight cutoff (MWCO) of 2000Da. Ultrapure water was selected as the medium and dialyzed in the dark for 24 hours. The ultrapure water was replaced every 2 hours for the first 12 hours and every 6 hours for the next 12 hours. After 24 hours, the dialysis was stopped, the solution was centrifuged, and the supernatant was filtered with a 0.45μm microporous water filter membrane. The filtrate was placed in a freeze dryer and freeze-dried to obtain polyethylene glycol-polylysine-curcumin nanomicelles.

[0034] Furthermore, the specific steps of the polyethylene glycol-polylysine-curcumin polymer are:

[0035] The purified curcumin derivative containing a monosulfide bond is dissolved in dichloromethane, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole are added for activation, and the mixture is kept in the dark at room temperature for 3 to 4 hours to obtain the activated curcumin derivative containing a monosulfide bond;

[0036] N, N-diisopropylethylamine was added dropwise to the modified polylysine with deprotected groups, and then dichloromethane was added to completely dissolve it for condensation reaction;

[0037] The modified polylysine with the deprotected group after the condensation reaction is added to the activated curcumin derivative containing a single sulfide bond, and the reaction is carried out at 20-30° C. in the dark for 24-48 hours. After the reaction is completed, the reaction solution is concentrated by vacuum rotary evaporation and dropped into icy ether to produce a yellow precipitate. The precipitate is collected by suction filtration using a Buchner funnel, dissolved in ethanol, and then placed in a dialysis bag with a molecular weight cutoff (MWCO) of 2000 Da for dialysis, with ethanol being selected as the dialysis medium. The dialysis solution is replaced every 2 hours. After dialysis in the dark for 24 hours, the material in the dialysis bag is removed by vacuum rotary evaporation to remove the solvent, and vacuum dried to obtain a polyethylene glycol-polylysine-curcumin polymer.

[0038] Furthermore, the molar ratio of the purified curcumin derivative containing a monosulfide bond, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 1-hydroxybenzotriazole is 1.5:1:1;

[0039] Alternatively, the molar ratio of the deprotected modified polylysine and N, N-diisopropylethylamine is 1:5;

[0040] Alternatively, the molar ratio of the purified curcumin derivative containing a monosulfide bond to the deprotected modified polylysine is 1:2.5.

[0041] The use of the polyethylene glycol-polylysine-curcumin polymer as described above in drug delivery.

[0042] Use of the polyethylene glycol-polylysine-curcumin polymer as described above in the preparation of a drug for treating periodontitis.

[0043] The advantages and positive effects achieved by the present invention are:

[0044] The polyethylene glycol-polylysine-curcumin polymicelles of the present invention utilize chemical encapsulation, enabling higher curcumin loading, reaching 16-20%, and enabling triggerable on-demand payload delivery. This approach not only reduces premature drug release in the bloodstream but also enables stimuli-responsive drug release after triggering.

[0045] 2. The polyethylene glycol-polylysine-curcumin polymicelles of the present invention, wherein curcumin serves as a hydrophobic group and polyethylene glycol-polylysine serves as a hydrophilic shell, can self-assemble to form micelles. The formation of micelles increases the water solubility of curcumin.

[0046] 3. The polyethylene glycol-polylysine-curcumin micelles of the present invention are linked by single sulfur bonds and only break under specific conditions, such as ultrasound and in areas with high reactive oxygen species (ROS). The ROS content in the periodontitis microenvironment is several times higher than under normal conditions. Breaking the single sulfur bonds allows for smooth release of curcumin. Polyethylene glycol-polylysine also exhibits good biocompatibility.

[0047] 4. The polyethylene glycol-polylysine-curcumin polymicelles of the present invention connect curcumin as a hydrophobic group to the framework material of the nanoparticles, helping to form nanoparticles, forming a new dosage form of curcumin, and serving as a carrier for other hydrophobic periodontitis treatments, thereby achieving the purpose of combined medication.

[0048] 5. The present invention utilizes tiny nanoparticles present in the polyethylene glycol-polylysine-curcumin polymicelles. These nanoparticles are then separated to prepare polyethylene glycol-polylysine-curcumin, creating a novel curcumin formulation. This formulation can also serve as a carrier for the controlled release of other hydrophobic drugs for periodontal disease. The polyethylene glycol-polylysine-curcumin composite nanomicelles exhibit long circulation, escape endothelial cell phagocytosis, and possess excellent biocompatibility.

[0049] 6. Redox-responsive polymer-drug conjugate micelles are excellent nanoscale carriers for self-destructive intracellular drug delivery. To covalently link the polymer and drug, a linker with a single sulfide bond, such as 3,3'-thiodipropionic acid, is used. Curcumin was selected as a model drug and conjugated to a multivalent methoxypolyethylene glycol-polylysine copolymer with 3,3'-thiodipropionic acid as a linker. The resulting polymer-curcumin conjugate is amphiphilic and can self-assemble into hydrodynamic micelles. Regardless of the linker type, micelle disassembly was observed due to the collapse of the single sulfide bond in the presence of ultrasound or ROS aggregation.

[0050] 7. The present invention grafts curcumin as a hydrophobic group onto a polyethylene glycol-polylysine material to help form micelles, creating a new dosage form of curcumin that can be used as a hydrophobic drug for treating periodontitis. The polyethylene glycol-polylysine-curcumin micelles are a new dosage form of curcumin that can be used as a controlled release of other hydrophobic drugs for treating periodontitis. The micelles also have good biocompatibility. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 IR spectra of curcumin (a), polyethylene glycol-polylysine polymer (b) and polyethylene glycol-polylysine-curcumin polymicelles (c) in the present invention;

[0052] Figure 2 is the hydrogen nuclear magnetic resonance spectrum of the polyethylene glycol-polylysine-curcumin polymicelles of the present invention;

[0053] Figure 3 is the size distribution diagram of the polyethylene glycol-polylysine-curcumin polymicelles in the present invention;

[0054] Figure 4 is the Zeta potential distribution diagram of the polyethylene glycol-polylysine-curcumin polymicelles in the present invention;

[0055] Figure 5 is a critical micelle concentration diagram of polyethylene glycol-polylysine-curcumin polymicelles in the present invention;

[0056] Figure 6 Graph showing the ROS of polyethylene glycol-polylysine-curcumin micelles in the present invention;

[0057] Figure 7 Graph showing particle size stability analysis of polyethylene glycol-polylysine-curcumin polymicelles of the present invention;

[0058] Figure 8 This is a pathological section diagram showing the in vivo therapeutic ability of polyethylene glycol-polylysine-curcumin polymicelles of the present invention for periodontitis. DETAILED DESCRIPTION

[0059] The present invention will be further described below with reference to the following examples. The following examples are descriptive rather than restrictive, and the scope of protection of the present invention cannot be limited by the following examples.

[0060] The various experimental operations involved in the specific embodiments are all routine techniques in the field. For parts not specifically annotated in this document, ordinary technicians in this field can refer to various commonly used reference books, scientific literature or related instructions, manuals, etc. before the filing date of this invention to implement them.

[0061] A polyethylene glycol-polylysine-curcumin polymer, the structural formula of which is shown in formula (I):

[0062]

[0063] Here, m represents 114 to 227, x represents 5 to 10, and y represents 4 to 8.

[0064] In polyethylene glycol-polylysine-curcumin polymicelles, curcumin is grafted onto the polymer as a hydrophobic group. Curcumin is part of the polymer structure, rather than simply encapsulated within it. This results in a stable structure that is less susceptible to degradation due to partial release in the bloodstream, allowing for better efficacy of curcumin itself. Furthermore, curcumin, as a hydrophobic group, helps the polymer form nanoparticles.

[0065] The above-mentioned polyethylene glycol-polylysine-curcumin polymicelles graft curcumin as a hydrophobic group onto the skeleton material of the nanoparticles to help form nanoparticles, forming a new dosage form of curcumin, and serving as a carrier for other hydrophobic periodontitis treatments to achieve the purpose of combined medication.

[0066] The tiny nanoparticles present in the PEG-polylysine-curcumin polymer can be separated to form PEG-polylysine-curcumin, creating a new dosage form of curcumin. This new formulation can also serve as a carrier for other hydrophobic periodontitis drugs, enabling controlled release. The PEG-polylysine-curcumin nanomicelles exhibit excellent biocompatibility, long circulation, and the ability to evade phagocytosis by the reticuloendothelial system.

[0067] A method for preparing polyethylene glycol-polylysine-curcumin polymicelles comprises the following steps:

[0068] Acylation of 3,3'-thiodipropionic acid with oxalyl chloride to generate 3,3'-thiodipropionic acid chloride;

[0069] The curcumin solution was mixed with pyridine as an acid-binding agent;

[0070] The mixed solution of 3,3'-thiodipropionic acid chloride and curcumin is stirred and mixed at sub-zero temperature, reacted at room temperature for 3 to 5 hours, and purified to obtain a curcumin derivative containing a single sulfur bond;

[0071] The polylysine modified with N-[4-(2,5-dioxo-4-oxazolidinyl)butyl]-2,2,2-trifluoroacetamide was subjected to a deprotection group treatment;

[0072] The modified polylysine is subjected to a condensation reaction with N,N-diisopropylethylamine, and then mixed with a curcumin derivative containing a single sulfide bond activated by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole carboxyl group, and stirred in the dark for 24 to 48 hours for an amidation reaction; the mixture is precipitated with ice ether, dialyzed and freeze-dried to obtain a polyethylene glycol-polylysine-curcumin polymer.

[0073] The aforementioned polyethylene glycol-polylysine-curcumin nanomicelles are made from polyethylene glycol, polylysine, curcumin, and 3,3'-thiodipropionic acid. Curcumin and 3,3'-thiodipropionic acid react at a molar ratio of 1:1 to form curcumin containing a monosulfide bond. The polyethylene glycol then reacts with N,N-dimethylformamide to form carboxylated polyethylene glycol (mPEGS). In the presence of a catalyst, the carboxylated polyethylene glycol then reacts with polylysine to form a polyethylene glycol-polylysine polymer. In the presence of a catalyst, the monosulfide bonded curcumin reacts with the polyethylene glycol-polylysine polymer to form a polyethylene glycol-polylysine-curcumin polymer, mPEG-Plys(Cur). PCC is an amphiphilic polymer that can self-assemble in water to form polymer micelle nanoparticles.

[0074] (1) Synthesis of carboxylated curcumin (Cur-S-COOH): 3,3'-thiodipropionic acid was dissolved in anhydrous tetrahydrofuran (THF), and N,N-dimethylformamide (DMF) was added dropwise to the solution. The solution was placed in cold hydrazine, stirred below 0°C, and oxalyl chloride was slowly added dropwise thereto. The solution was stirred at room temperature for 2 to 3 hours. The reaction solution was referred to as solution 1.

[0075] Dissolve curcumin in anhydrous tetrahydrofuran, then add pyridine dropwise to the solution while stirring. This solution is referred to as Solution 2. Place Solution 2 in cold hydrazine, stir below 0°C, and slowly add Solution 1 dropwise. Stir at room temperature for 3-5 hours in the dark. After the reaction is complete, remove the tetrahydrofuran using a rotary evaporator. Add dichloromethane to dissolve the solution. Once completely dissolved, transfer the solution to a separatory funnel and wash with hydrochloric acid. Repeat this washing three times, then collect the organic phase and spin dry.

[0076] Separate by column chromatography using dichloromethane:methanol = 400:3 (V / V, volume ratio) as the eluent. Dissolve the dried sample in dichloromethane and slowly add the sample dropwise to the chromatography column using a rubber-tipped pipette. Elution is performed using dichloromethane:methanol = 100:1 (V / V, volume ratio) as the developing solvent. Continuously apply the plate until the target product exits the column. Collect the target product, spin dry the solvent, and then vacuum dry it for 24 hours to obtain Cur-S-COOH.

[0077] (2) Synthesis of mPEG-PLys(TFA): Methoxypolyethylene glycolamine and Lys(TFA)-NCA were placed in a round-bottom flask and dissolved in N,N-dimethylformamide (DMF). The mixture was stirred at 40-50°C under argon protection and concentrated by rotary evaporation. The reaction solution was then added dropwise to glacial ether. A white flocculent precipitate was immediately formed. The precipitate was collected by filtration using a Buchner funnel and dried under vacuum to obtain the target product, mPEG-PLys(TFA).

[0078] (3) Synthesis of mPEG-PLys: mPEG-PLys (TFA) was placed in a glass bottle, and sodium hydroxide aqueous solution was added and stirred for 2-5 hours. After the reaction, the reaction solution was placed in a dialysis bag with a molecular weight cut-off (MWCO) of 1000 Da and dialyzed with water. The ultrapure water was replaced every two hours. After 24 hours, a sample from the dialysis bag was taken and lyophilized in a freeze dryer to obtain the target product.

[0079] (4) Synthesis of mPEG-PLys(Cur): Place Cur-S-COOH in a round-bottom flask, add dichloromethane and stir to dissolve, then add EDCI and HoBt and activate at room temperature in the dark for 2 hours. This reaction yields solution 3.

[0080] mPEG-Plys was placed in a 25 mL round-bottom flask, and DIPEA was added followed by dichloromethane to completely dissolve it. This solution was called Solution 4.

[0081] Solution 4 was slowly added dropwise to solution 3, plugged with a rubber stopper, and allowed to react in the dark at 20-30°C for 24-48 hours. During this process, the solution gradually changed from orange-red to red. After 24 hours, the reaction was stopped and the reaction solution was concentrated by vacuum rotary evaporation. When the liquid volume was concentrated to 5 mL, it was added dropwise to icy ether, producing a large amount of yellow precipitate. The precipitate was filtered using a Buchner funnel and collected in a small beaker. After dissolving it in alcohol, it was placed in a dialysis bag with a molecular weight cutoff (MWCO) of 2000 Da and dialyzed with ethanol as the dialysis medium. The dialysate was replaced every 2 hours. After 24 hours of dialysis, the contents of the dialysis bag were removed by vacuum rotary evaporation to remove the solvent and vacuum dried to obtain the final product, mPEG-PLys(Cur).

[0082] Preferably, the molar ratio of 3,3'-thiodipropionic acid to oxalyl chloride is 1:1.2;

[0083] Alternatively, the molar ratio of curcumin to pyridine is 1:10;

[0084] Alternatively, the molar ratio of the chlorinated 3,3'-thiodipropionic acid to curcumin is 1:1;

[0085] Alternatively, when the dichloromethane and methanol mixture is used as the eluent, the volume ratio of dichloromethane:methanol is 400:3; when the dichloromethane and methanol mixture is used as the developing solvent, the volume ratio of dichloromethane:methanol is 100:3;

[0086] Alternatively, the molar ratio of the methoxypolyethylene glycol amine to N-[4-(2,5-dioxo-4-oxazolidinyl)butyl]-2,2,2-trifluoroacetamide is 1:15;

[0087] Alternatively, the methoxypolyethylene glycol amine is mPEG4000-mPEG12000.

[0088] Preferably, the molar ratio of the purified curcumin derivative containing a monosulfide bond, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 1-hydroxybenzotriazole is 1.5:1:1;

[0089] Alternatively, the molar ratio of the deprotected modified polylysine and N, N-diisopropylethylamine is 1:5;

[0090] Alternatively, the molar ratio of the purified curcumin derivative containing a monosulfide bond to the deprotected modified polylysine is 1:2.5.

[0091] A method for preparing drug-loaded polyethylene glycol-polylysine-curcumin nanoparticles comprises the following steps:

[0092] The periodontitis treatment drug is dissolved in N,N-dimethylformamide, added to a dialysis bag with a molecular weight cutoff (MWCO) of 2000Da, and dialyzed for 24 hours in the dark. The solution is centrifuged, the supernatant is filtered with a 0.45μm microporous water filter membrane, and the filtrate is placed in a freeze dryer and freeze-dried to obtain polyethylene glycol-polylysine-curcumin nanomicelles. Preferably, the dialysis process is: ultrapure water is changed every 2 hours for the first 12 hours, and ultrapure water is changed every 6 hours for the next 12 hours.

[0093] Specifically, the relevant preparation and detection are as follows:

[0094] Example 1: Chemical Synthesis of Polyethylene Glycol-Polylysine-Curcumin Polymer (PCC)

[0095] (1) Synthesis of carboxylated curcumin (Cur-S-COOH): 0.36 g of 3,3'-thiodipropionic acid was accurately weighed and placed in a 100 mL round-bottom flask. 20 mL of anhydrous tetrahydrofuran (THF) was added to dissolve the mixture. 100 μL of N,N-dimethylformamide (DMF) was added dropwise to the solution. The mixture was placed in cold hydrazine and stirred below 0°C. 210 μL of oxalyl chloride was slowly added dropwise to the mixture. The mixture was stirred at room temperature for 2 to 3 h. This reaction solution was referred to as solution 1.

[0096] Accurately weigh 0.74g of curcumin into a 100mL round-bottom flask, add 20mL of anhydrous tetrahydrofuran to dissolve it, and then add 1.6mL of pyridine dropwise to the solution while stirring. This solution is called Solution 2. Place Solution 2 in cold hydrazine, stir below 0°C, and slowly add Solution 1 dropwise to it. Protect from light and stir at room temperature for 3-5 hours. After the reaction is completed, remove the tetrahydrofuran by rotary evaporation, then add dichloromethane to dissolve it. After complete dissolution, transfer the solution to a separatory funnel and wash it with 0.1N hydrochloric acid solution. Repeat the washing three times, then collect the organic phase and spin dry it.

[0097] Separate by column chromatography using dichloromethane:methanol = 400:3 (V / V, volume ratio) as the eluent. Dissolve the dried sample in dichloromethane and slowly add the sample dropwise to the chromatography column using a rubber-tipped pipette. Elution is performed using dichloromethane:methanol = 100:1 (V / V, volume ratio) as the developing solvent. Continuously apply the plate until the target product exits the column. Collect the target product, spin dry the solvent, and then vacuum dry it for 24 hours to obtain Cur-S-COOH.

[0098] (2) Synthesis of mPEG-PLys(TFA): Accurately weigh 0.5 g of methoxypolyethylene glycol amine and 0.4 g of Lys(TFA)-NCA (i.e., N-[4-(2,5-dioxo-4-oxazolidinyl)butyl]-2,2,2-trifluoroacetamide) in a 25 mL round-bottom flask and dissolve them in 8 mL of N,N-dimethylformamide (DMF). Vacuum the flask under argon protection and stir the reaction at 40-50°C. The reaction solution was concentrated by rotary evaporation under reduced pressure and then added dropwise to 100 mL of icy ether. A white flocculent precipitate immediately formed. The precipitate was filtered off with a Buchner funnel and dried under vacuum to obtain the target product, mPEG-PLys(TFA).

[0099] (3) Synthesis of polyethylene glycol-polylysine polymer (mPEG-PLys): Accurately weigh 0.8 g of mPEG-PLys (TFA) into a 20 mL glass bottle, add 10 mL of 0.5 N sodium hydroxide aqueous solution and stir to dissolve, cover the bottle, and stir at room temperature for 5 hours. After the reaction, the reaction solution is placed in a dialysis bag with a molecular weight cutoff (MWCO) of 1000 Da and dialyzed with water. The ultrapure water is replaced every two hours. After 24 hours, a sample from the dialysis bag is taken and placed in a freeze dryer for lyophilization to obtain polyethylene glycol-polylysine polymer.

[0100] (4) Synthesis of polyethylene glycol-polylysine-curcumin polymer: Accurately weigh 0.5 g of Cur-S-COOH and place it in a 25 mL round-bottom flask. Add 10 mL of dichloromethane and stir to dissolve. Continue to add 1.0 g of EDCI and 0.09 g of HoBt. Activate at room temperature in the dark for 2 hours. This reaction yields Solution 3.

[0101] Accurately weigh 0.2 g of mPEG-PLys in step (3) into a 25 mL round-bottom flask, add 0.2 mL of DIPEA and then add 10 mL of dichloromethane to completely dissolve it. This solution is called solution 4.

[0102] Solution 4 was slowly added dropwise to solution 3, plugged with a rubber stopper, and allowed to react at 30°C in the dark for 36 hours, during which the solution gradually changed from orange-red to red. After 24 hours, the reaction was stopped and the reaction solution was concentrated by vacuum rotary evaporation. When the liquid volume was concentrated to 5 mL, it was added dropwise to icy ether, producing a large amount of yellow precipitate. The precipitate was filtered using a Buchner funnel and collected in a small beaker. After dissolving it in 5 mL of ethanol, it was placed in a dialysis bag with a molecular weight cutoff (MWCO) of 2000 Da and dialysis was performed using ethanol as the dialysis medium. The dialysate was replaced every 2 hours. After 24 hours of dialysis, the contents of the dialysis bag were removed by vacuum rotary evaporation to remove the solvent and vacuum dried to obtain the final product, mPEG-PLys(Cur).

[0103] The final product mPEG-PLys (Cur) has the structural formula:

[0104]

[0105] Among them, m=114, x=6, y=7.

[0106] The detection object mPEG-PLys(Cur) in each of the following examples is the final product mPEG-PLys(Cur) prepared in Example 1.

[0107] Example 2 Fourier transform infrared spectroscopy

[0108] The infrared absorption spectrum of the samples was measured and analyzed using a Fourier transform infrared spectrometer to observe the relationship between the characteristic peaks of each sample. Accurately weigh 1.0 mg each of curcumin Cur, mPEG-PLys, and mPEG-PLys (Cur), and take 150 mg of kBr. If it is crystalline, it needs to be ground. The mass ratio is (sample: KBr = 1:150). After sufficient grinding, pour it into the tableting mold and press it into tablets. The pressure is about 5 Pa and wait for 30 seconds. Then continue to pressurize until the pressure reaches about 8 Pa for 0.5-1 min. The tablets are transparent or translucent and put into the machine. The samples are analyzed according to the relevant characteristic absorption peaks. The results are as follows Figure 1 shown.

[0109] The infrared absorption peaks of each sample were measured by Fourier transform infrared spectrometer. According to current research, the infrared characteristic absorption peaks of Cur are 3357cm -1 Stretching of -OH group on benzene ring, 1586cm -1 Stretching vibration of benzene ring, 1513cm -1 Vibration of CC and CO groups, 1282 cm -1 The aromatic stretching vibration of the CO group; the infrared characteristic absorption peaks of mPEG-PLys are 1750-1680 cm -1 C=O carbonyl, 1680-1630cm -1 R-NH-R' tertiary amide, 1275-1020cm - 1 CO ether bond, 3500-3400cm -1 NH2, 3000-2850cm -1 CH. Comparing MCur with the above characteristic peaks, the sample was successfully synthesized.

[0110] Example 3 H NMR spectrum of nanomicelles

[0111] The nuclear magnetic resonance (NMR) spectrum of the sample was measured and analyzed using a nuclear magnetic resonance spectrometer to observe the number, position, and integral of the corresponding hydrogen atoms to confirm the successful synthesis of the sample. Accurately weigh 1.0 mg of mPEG-PLys(Cur), dissolve it in 1.0 mL of dmso-d6, measure it using a nuclear magnetic resonance spectrometer, and analyze it using Mestrenova. The results are as follows: Figure 2 shown.

[0112] In this experiment, nuclear magnetic resonance hydrogen spectroscopy (1H NMR) was used to characterize the structure of mPEG-PLys(Cur). The NMR spectrum results are as follows: 1H NMR(DMSO-d6,400MHz,ppm): δ7.60(m,16H,ArCH=CH),7.53-7.09(m,48H,Ar),6.82(m,16H,COCH=CH),6.17(t,16H,COCH2CO),4.08(s,13H,CH),3.85(s,48H, CH3),3.51(m,420H,OCH2CH2O),3.24(s,3H,CH3),3.15(s,26H,CH2CH2NH),2. 93-2.90(m,32H,CH2),2.70-2.65(m,32H,COCH2CH2),1.95-1.05(m,78H,CH2).

[0113] The determination of hydrogen nuclear magnetic resonance spectrum proved the successful synthesis of mPEG-PLys(Cur), providing structurally correct and pure raw materials for subsequent experiments.

[0114] Example 4 Particle size of nanomicelles

[0115] The samples were analyzed using a Malvern particle size analyzer to determine the nanoparticle size and stability of the nanomicelles. 2.0 mg of each mPEG-PLys(Cur) was accurately weighed and ultrasonically dispersed in 1 mL of ultrapure water. The solution was then filtered through a 0.45 μm microporous filter to remove large particles. To ensure a stable micellar solution, the samples were allowed to stand for 2 hours after preparation. Three parallel experiments (n=3) were performed, each using a Malvern particle size analyzer, using water as the dispersant.

[0116] The particle size and distribution of the sample in aqueous solution were measured using a Malvern particle size analyzer. Figure 3 The average particle size of MCur was 147.6 nm (PDI = 0.111). The nanomicelle size measurement showed that all samples exhibited a relatively uniform particle size distribution range, with the micelle size being less than 200 nm, meeting the particle size requirements for passive targeting of nanoparticles in drug delivery systems.

[0117] Example 5 Zeta potential of nanomicelles

[0118] The samples were analyzed using a Malvern particle size analyzer to determine the charge of the nanoparticles. 2.0 mg of each mPEG-PLys(Cur) was accurately weighed and ultrasonically dispersed in 2 mL of 0.1 mmol / L KCl solution. The solution was then filtered through a 0.45 μm microporous water filter to remove large particles. To ensure a stable micellar solution, the samples were allowed to stand for 2 hours after preparation. Three parallel experiments (n=3) were performed, each using a Malvern particle size analyzer, using water as the dispersant.

[0119] The Zeta potential of each sample was measured by Malvern particle size analyzer. Figure 4 The nanomicelles are positively charged, with an average potential of 20.5 mV. Because the surface of the P. gingivalis membrane is negatively charged, this allows the drug to better interact electrostatically with the bacterial membrane, leading to the leakage of proteins and other bacterial components, further enhancing its penetration into the bacteria.

[0120] Example 6 Critical Micelle Concentration Analysis (CMC) of Nanomicelles

[0121] The concentration of stable micelles formed by the stimuli-responsive nanoparticles in aqueous solution was analyzed using a fluorescence spectrophotometer. 25.0 mg of mPEG-PLys(Cur) was accurately weighed and placed in a 50 mL beaker. Ultrapure water was added to dissolve the solution, which was then transferred to a 10 mL volumetric flask and brought to volume with ultrapure water to prepare a 2500 μg / mL stock solution. The stock solution was then diluted to concentrations of 100, 50, 25, 12.5, 10, 8, 5, 2.5, 1.25, 1, 0.8, and 0.5 μg / mL. Each sample was sonicated for 5 minutes to ensure uniform dispersion and then filtered through a 0.45 μm aqueous microporous filter to remove aggregated macromolecules. The entire preparation and handling process was performed in the dark. Measure the fluorescence intensity of each sample (fluorescence measurement conditions: excitation wavelength λex = 480nm, receiving range λem = 500-700nm, Ex and Em slit widths are both 5nm, sample cell thickness 1cm), and record the fluorescence absorbance value of the sample at 484nm. Draw a graph and calculate the critical micelle concentration of the sample. Figure 5 As shown, the critical micelle concentration (CMC), an indicator of micelle stability, was determined using a probe-free method because curcumin is inherently fluorescent. The corresponding CMC was 13.86 ± 1.18 μg / mL. The low CMC value indicates that the nanomicelles have good stability, making them more suitable for in vivo application.

[0122] Example 7 Ability of Nanomicelles to Generate Active Oxygen Species

[0123] The ability of stimuli-responsive nanoparticles to generate reactive oxygen species was analyzed using a multifunctional microplate reader. 2.0 mg of mPEG-PLys (Cur) was accurately weighed and placed in a small brown bottle. Each solution was dissolved in 4 mL of ultrapure water to prepare a 0.5 mg / mL solution. The samples were divided into groups, including an ultrasound group (MCur+H2O) and a non-ultrasound group (MCur+H2O). Then, 100 μL of DCFH-DA (100 μM) and 100 μL of each sample solution were added to a 96-well black plate, respectively, with a total volume of 200 μL. Parallel groups (n=3) were set up for each group. At the same time, a blank group (including an ultrasound group and a non-ultrasound group) was set up, that is, 100 μL of ultrapure water and 100 μL of DCFH-DA were mixed into a 96-well black plate, and parallel groups (n=3) were set up. The excitation wavelength λex=485 nm, the receiving range λem=530 nm, and the ultrasound selection was 1 MHz, 50% duty cycle, 1 W / cm 2 ,5min, the results are as follows Figure 6 shown.

[0124] A ROS probe was used to measure the ROS production capacity of the nanomicelles under different experimental conditions. Data analysis showed that the ultrasound group (blank group: 1597, MCur+H2O: 1123) produced significantly more ROS than the non-sound group (blank group: 287, MCur+H2O: 4506). Furthermore, under the same conditions, the drug group produced more ROS than the blank group. These results demonstrate that the nanomicelles can have a positive SDT effect.

[0125] Example 8 Nanomicelle Particle Size Stability

[0126] 10.0 mg of mPEG-PLys(Cur) was accurately weighed and dispersed in ultrapure water and buffer solution (acetic acid-sodium acetate solution containing 1 mM H2O2, pH = 5.0) respectively, with a final concentration of 500 μg / mL. The changes in the micelle size were then measured using a Malvern particle size analyzer at 0, 1, 2, 3, 4, 8, 12, 24, and 48 hours. The results are shown in the figure. Figure 7 shown.

[0127] Ultrapure water (UPW) and a slightly acidic aqueous solution containing H2O2 were selected as release media for in vitro particle size change experiments. UPW simulates the normal physiological environment, while the slightly acidic aqueous solution containing H2O2 simulates the environment inside bacteria. As shown in the figure, the particle size of MCur varies slightly in both UPW and slightly acidic aqueous solutions containing H2O2. Under UPW conditions, the particle size of MCur varies slightly within 48 hours, reaching approximately 230 nm at 48 hours. This is due to the aggregation of nanomicelles over time. The particle size of MCur in the slightly acidic aqueous solution containing H2O2 varies more significantly, with the nanocarrier's particle size varying from 165 nm to approximately 490 nm over time. This significant change in the nanocarrier's particle size over time is due to the degradation of MCur in high H2O2 concentrations and slightly acidic environments, which in turn affects the particle size.

[0128] Example 9 Ability of Nanomicelles to Treat Periodontitis in Vivo

[0129] Twenty rats were randomly divided into four groups, including a blank group, a positive control group, an mPEG-PLys(Cur) group, and an mPEG-PLys(Cur) ultrasound group. The blank group consisted of healthy rats without any treatment. The positive control group consisted of rats with periodontitis who were treated with PBS solution. The mPEG-PLys(Cur) group consisted of rats with periodontitis who were treated with medication and ultrasound. The rats with periodontitis were treated with 100 μL of PBS solution and a treatment solution (mPEG-PLys(Cur), solvent: PBS solution) with a concentration of 200 μg / mL, respectively. Five minutes after the administration, ultrasound was performed on the periodontitis lesions in the mPEG-PLys(Cur) ultrasound group. The treatment was repeated every three days for five consecutive times. Three days after the last administration, the rats were euthanized, and the palatal and buccal periodontal tissues were collected for pathological sectioning to observe the therapeutic effect of periodontitis. The ultrasound was performed at 1 MHz, 50% duty cycle, and 1 W / cm 2 ,5min.

[0130] Pathological sections were used to observe immune cell infiltration, tissue disorder, and edema in each group. The positive control group had the highest number of immune cell infiltrations, accompanied by tissue disorder and edema. The treatment group showed significant improvement compared to the positive control group. The results indicate that the nanomicelles have excellent therapeutic capabilities for periodontitis.

[0131] Advantages of the present invention in the field of chemically modified curcumin:

[0132] The article "Curcumin-loaded redox response of self-assembled micelles for enhanced antitumor and anti-inflammation efficacy" reported that the curcumin loading capacity through chemical modification was 7.62 and 8.21 wt%, respectively, while the curcumin loading capacity in the present invention reached 16-20 wt%. The article "A robust ROS generation nanoplatform combating periodontitis via sonodynamic / chemodynamic combination therapy" reported that the drug in this study could generate 2.5×10 3 au, whereas in the present invention, the active oxygen generated is 4.5×10 3 It can be seen that the present invention has certain advantages in application.

[0133] Although the embodiments of the present invention are disclosed for illustrative purposes, those skilled in the art will understand that various substitutions, changes and modifications are possible without departing from the spirit and scope of the present invention and the appended claims. Therefore, the scope of the present invention is not limited to the contents disclosed in the embodiments.

Claims

1. A polyethylene glycol-polylysine-curcumin polymicelle, characterized in that: Its structural formula is shown in formula (I): Here, m represents 114 to 227, x represents 5 to 10, and y represents 4 to 8.

2. The polyethylene glycol-polylysine-curcumin polymicelle according to claim 1, wherein: The average particle size of the polyethylene glycol-polylysine-curcumin polymicelles is 147.6 nm, and the average Zeta potential is 20.5 mV.

3. The method for preparing the polyethylene glycol-polylysine-curcumin polymicelles according to claim 1 or 2, wherein: The following steps are involved: Acylation of 3,3'-thiodipropionic acid with oxalyl chloride to generate 3,3'-thiodipropionic acid chloride; mixing the curcumin solution with pyridine used as an acid binding agent to obtain a curcumin mixed solution; The mixed solution of 3,3'-thiodipropionic acid chloride and curcumin is stirred and mixed at below 0°C, reacted at room temperature for 3 to 5 hours, and purified to obtain a curcumin derivative containing a monosulfide bond; Deprotecting polylysine modified with N-[4-(2,5-dioxo-4-oxazolidinyl)butyl]-2,2,2-trifluoroacetamide to obtain deprotected modified polylysine; The modified polylysine is subjected to a condensation reaction with N,N-diisopropylethylamine, and then mixed with a curcumin derivative containing a single sulfide bond activated by 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole carboxyl group, and stirred in the dark for 24 to 48 hours for an amidation reaction; the mixture is precipitated with ice ether, dialyzed and freeze-dried to obtain a polyethylene glycol-polylysine-curcumin polymer.

4. The preparation method according to claim 3, wherein: The specific step of reacting 3,3'-thiodipropionic acid with oxalyl chloride to generate 3,3'-thiodipropionic acid chloride is: Dissolve 3,3'-thiodipropionic acid in anhydrous tetrahydrofuran, add cosolvent N,N-dimethylformamide, slowly add oxalyl chloride under stirring below 0°C, and then stir at room temperature for 2-3 hours to obtain 3,3'-thiodipropionic acid chloride; Alternatively, the step of mixing the curcumin solution with pyridine used as an acid binding agent is specifically: Dissolve curcumin in anhydrous tetrahydrofuran, add pyridine and stir to obtain a curcumin mixed solution; Alternatively, the preparation steps of the curcumin derivative containing a single sulfide bond are specifically as follows: Under conditions below 0°C, 3,3'-thiodipropionic acid chloride is slowly added dropwise to the curcumin mixed solution and stirred while being protected from light. The mixture is transferred to room temperature and stirred for 3 to 5 hours. After the reaction is completed, anhydrous tetrahydrofuran is removed by rotary evaporation, the mixture is dissolved with dichloromethane, extracted and washed with hydrochloric acid, and the organic phase is collected and dried to obtain a curcumin derivative containing a monosulfide bond. The obtained curcumin derivative containing a monosulfide bond is dissolved in dichloromethane, and a mixed solution of dichloromethane and methanol is used as an eluent and a developing solvent. The target product is confirmed by continuous plate counting until it completely exits the column. The product is collected, spin-dried, and then dried to obtain a purified curcumin derivative containing a monosulfide bond. Alternatively, the specific preparation steps of the N-[4-(2,5-dioxo-4-oxazolidinyl)butyl]-2,2,2-trifluoroacetamide modified polylysine are: Methoxypolyethylene glycol amine and N-[4-(2,5-dioxo-4-oxazolidinyl)butyl]-2,2,2-trifluoroacetamide were placed in a round-bottom flask, and N,N-dimethylformamide (DMF) was added to dissolve the mixture, and chloroform was added as a cosolvent to assist the dissolution. The mixture was vacuumed and stirred at 40-50°C under inert gas protection. After 3 days, the reaction was treated, and the reaction solution was concentrated by rotary evaporation under reduced pressure, and then added dropwise to icy ether to precipitate a white flocculent precipitate. The precipitate was filtered using a Buchner funnel and dried under vacuum to obtain modified polylysine. The modified polylysine was dissolved in 0.5N sodium hydroxide aqueous solution and stirred at room temperature for 2 to 5 hours. After the reaction, the reaction solution was placed in a dialysis bag with a molecular weight cutoff (MWCO) of 1000Da and dialyzed with water. Ultrapure water was replaced every 2 hours. After 24 hours, the sample in the dialysis bag was taken out and placed in a freeze dryer for freeze drying to obtain the deprotected modified polylysine.

5. The preparation method according to claim 4, characterized in that: The molar ratio of 3,3'-thiodipropionic acid to oxalyl chloride is 1:1.2; Alternatively, the molar ratio of curcumin to pyridine is 1:10; Alternatively, the molar ratio of the chlorinated 3,3'-thiodipropionic acid to curcumin is 1:1; Alternatively, when the dichloromethane and methanol mixture is used as the eluent, the volume ratio of dichloromethane:methanol is 400:3; when the dichloromethane and methanol mixture is used as the developing solvent, the volume ratio of dichloromethane:methanol is 100:3; Alternatively, the molar ratio of the methoxypolyethylene glycol amine to N-[4-(2,5-dioxo-4-oxazolidinyl)butyl]-2,2,2-trifluoroacetamide is 1:15; Alternatively, the methoxypolyethylene glycol amine is mPEG4000-mPEG12000.

6. The preparation method according to claim 3, wherein: The method further comprises the step of preparing polyethylene glycol-polylysine-curcumin nanomicelles from the polyethylene glycol-polylysine-curcumin polymer, specifically: The polyethylene glycol-polylysine-curcumin polymer was dissolved in N,N-dimethylformamide and added to a dialysis bag with a molecular weight cutoff (MWCO) of 2000Da. Ultrapure water was selected as the medium and dialyzed in the dark for 24 hours. The ultrapure water was replaced every 2 hours for the first 12 hours and every 6 hours for the next 12 hours. After 24 hours, the dialysis was stopped, the solution was centrifuged, and the supernatant was filtered with a 0.45μm microporous water filter membrane. The filtrate was placed in a freeze dryer and freeze-dried to obtain polyethylene glycol-polylysine-curcumin nanomicelles.

7. The preparation method according to any one of claims 3 to 6, characterized in that: The specific steps of the polyethylene glycol-polylysine-curcumin polymer are: The purified curcumin derivative containing a monosulfide bond is dissolved in dichloromethane, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole are added for activation, and the mixture is kept in the dark at room temperature for 3 to 4 hours to obtain the activated curcumin derivative containing a monosulfide bond; N, N-diisopropylethylamine was added dropwise to the modified polylysine with deprotected groups, and then dichloromethane was added to completely dissolve it for condensation reaction; The modified polylysine with the deprotected group after the condensation reaction is added to the activated curcumin derivative containing a single sulfide bond, and the reaction is carried out at 20-30° C. in the dark for 24-48 hours. After the reaction is completed, the reaction solution is concentrated by vacuum rotary evaporation and dropped into icy ether to produce a yellow precipitate. The precipitate is collected by suction filtration using a Buchner funnel, dissolved in ethanol, and then placed in a dialysis bag with a molecular weight cutoff (MWCO) of 2000 Da for dialysis, with ethanol being selected as the dialysis medium. The dialysis solution is replaced every 2 hours. After dialysis in the dark for 24 hours, the material in the dialysis bag is removed by vacuum rotary evaporation to remove the solvent, and vacuum dried to obtain a polyethylene glycol-polylysine-curcumin polymer.

8. The preparation method according to claim 7, characterized in that: The molar ratio of the purified curcumin derivative containing a monosulfide bond, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 1-hydroxybenzotriazole is 1.5:1:1; Alternatively, the molar ratio of the deprotected modified polylysine and N, N-diisopropylethylamine is 1:5; Alternatively, the molar ratio of the purified curcumin derivative containing a monosulfide bond to the deprotected modified polylysine is 1:2.

5.

9. Use of the polyethylene glycol-polylysine-curcumin polymer according to claim 1 or 2 in preparing a drug for treating periodontitis.

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