A biodegradable two-sided loop brush polymer and a method for preparing the same

Abstract

The application discloses a biodegradable two-face ring brush-shaped polymer and a preparation method thereof. The two-face ring brush-shaped polymer has a structure shown in formula I. A biodegradable macromolecule PCL is arranged as a ring inner core, and a POEGMA chain with good biocompatibility is arranged as a hydrophilic chain segment, so that the two-face ring brush-shaped polymer is formed. The polymer can self-assemble to form stable nanomicelles with a hydrophilic outer shell and a hydrophobic inner core in an aqueous solution, and has high drug loading rate and high encapsulation rate.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of high polymers, in particular to a biodegradable two-sided ring brush-shaped polymer and a preparation method thereof. BACKGROUND

[0002] In recent years, polymers with advanced topological structures have become one of the research hotspots in the biomedical field due to their unique properties superior to traditional linear polymers. Among them, ring brush-shaped polymers have attracted widespread attention from researchers due to their nanoscale size, hyperbranched structure, simultaneously functionalized ring core and polymer surface, and simpler preparation method compared to dendrimers. Ring brush-shaped polymers (amphiphilic copolymer) have a hydrophilic / hydrophobic polymer segment, which can self-assemble into unique core-shell structure micelles in aqueous solution. The encapsulated anticancer drugs can prevent off-target behavior, reduce damage to normal tissues and organs in the human body, and protect the drugs from premature degradation in the surrounding sensitive environment.

[0003] As disclosed in Chapter 3 of the Master's Thesis of Lanzhou University in 2018 entitled "Construction of Two-Sided Ring Brush-Shaped Amphiphilic Block Copolymer and Its Performance as a Drug Carrier", a two-sided ring brush-shaped amphiphilic copolymer P(OEGMA) m -b-P(HEMA-g-OCLh) n The copolymer can form self-assembled micelles with a size of about 200 nm in water, and the in vitro drug loading and release behavior experiment results show that the drug loading rate is 8.61%, the encapsulation rate is 86.09%, and the copolymer has excellent potential as a drug carrier. However, the self-assembled micelles formed by the polymer in water have a large particle size, and the micelles have a short circulation time in the blood after loading the drug, which cannot effectively transport the drug to the tumor tissue.

[0004] Polycaprolactone (PCL) is a very important synthetic biologic material. Due to its good biodegradability, excellent biocompatibility, low immunogenicity, and good mechanical properties, PCL is non-toxic and is a biomedicinal material approved by the US Food and Drug Administration (FDA). It has been widely used in surgical sutures, bone fixation, tissue engineering, and drug carrier fields. In view of the above problems, researchers have attempted to introduce PCL into polymers.

[0005] As disclosed in the fourth chapter of the doctoral thesis of Lanzhou University in 2018, "Synthesis, Self-assembly Behavior and in vitro Performance of New Cyclic Brush Polymers as Anti-cancer Drugs", an amphiphilic cyclic brush copolymer P(HEMA-g-PCL-POEGMA) is disclosed, which can form stable core-shell-crown structure micelles in water, and the particle size is small, about 40 nm, and the drug loading rate is 4.20%. However, the drug loading rate of the polymer disclosed in this document is low.

[0006] The journal article "Synthesis and Characterization of Amphiphilic Cyclic Poly (caprolactone-b-vinyl pyrrolidone)" discloses a controllable synthesis method of amphiphilic cyclic poly (caprolactone-b-vinyl pyrrolidone) block copolymer (Cyclic-PCL-b-PVP). Compared with linear poly (caprolactone-b-vinyl pyrrolidone) (Cyclic-PCL-b-PVP), the thermal stability of the corresponding cyclic block copolymer is significantly improved, and the hydrophilicity also changes. However, the polymer disclosed in this scheme only discusses the synthesis of the polymer and the influence of its topological structure on its thermal and hydrophilic properties, and does not conduct in-depth research on drug loading.

[0007] Chinese patent CN103709691A discloses a biodegradable cross-linked polymer, which is a cross-linked polymer network obtained by introducing cross-linkable active groups at the ends of a degradable polymer prepolymer with two or more arms, and then heat polymerization and / or light irradiation treatment. The elastic modulus is between 10 MPa and 1500 MPa, and the degradation rate is between 3 months and 36 months. The reaction is simple and easy to prepare, and is used in the field of medical devices. However, the polymer disclosed in this scheme is a multi-arm cross-linked polymer, which is not suitable for use as a drug sustained-release carrier material.

[0008] The journal article "Synthesis and Self-assembly of Core-shell-crown Structure Amphiphilic Cyclic Brush Copolymer" discloses the preparation of cyclic brush polymer P(HEMA-g-PCL-POEGMA), which is specifically prepared by using PCL and POEGMA as the hydrophobic segment and the hydrophilic segment of the amphiphilic cyclic brush copolymer. Both of them have good biocompatibility, and PCL also has good biodegradability. However, the drug loading rate of the polymer disclosed in this document is low. SUMMARY

[0009] In view of the problems in the prior art and the direction for improvement, the present application provides a biodegradable two-sided ring brush-shaped polymer, which is formed by taking biodegradable macromolecule PCL as a ring-shaped macromolecular core and biocompatible POEGMA chain as a hydrophilic chain segment as a ring-shaped outer core, so as to form a ring-shaped two-sided ring brush-shaped polymer, which can self-assemble to form stable nanomicelles with a hydrophilic outer shell and a hydrophobic inner core in an aqueous solution, so as to solve the technical problems of low drug loading rate of the existing ring brush-shaped polymer or unsuitability of the ring brush-shaped polymer for being used as a drug sustained-release carrier material and the like.

[0010] In order to achieve the above-mentioned purpose, the present application provides a biodegradable two-sided ring brush-shaped polymer, which is characterized by having a structure shown in Formula I:

[0011]

[0012] wherein m is a natural number of 10-50, n is a natural number of 5-20, and p is a natural number of 2-15.

[0013] The present application also provides a preparation method of the biodegradable two-sided ring brush-shaped polymer, which comprises the following steps:

[0014]

[0015] Step 1: propargyl alcohol is subjected to ring-opening polymerization reaction with caprolactone to generate a polymer shown in Formula II;

[0016] Step 2: the polymer shown in Formula II is subjected to substitution reaction with 2-bromoisobutyryl bromide to generate a polymer shown in Formula III;

[0017] Step 3: the polymer shown in Formula III is subjected to atom transfer radical polymerization reaction with 2-hydroxyethyl methacrylate to generate a polymer shown in Formula IV;

[0018] Step 4: the polymer shown in Formula IV is subjected to azidation reaction with sodium azide to generate a polymer shown in Formula V;

[0019] Step 5: the polymer shown in Formula V is subjected to click chemistry reaction to generate a polymer shown in Formula VI;

[0020] Step 6: the polymer shown in Formula VI is subjected to substitution reaction with 2-bromoisobutyryl bromide to generate a polymer shown in Formula VII;

[0021] Step 7: the polymer shown in Formula VII is subjected to atom transfer radical polymerization reaction with oligo(ethylene glycol methoxy methacrylate) to generate the biodegradable two-sided ring brush-shaped polymer shown in Formula I;

[0022] wherein m is a natural number of 10-50, n is a natural number of 5-20, and p is a natural number of 2-15.

[0023] Optionally, in the preparation method of the biodegradable biaxially shaped brush polymer provided by the present invention, in step 1, propynyl alcohol and caprolactone (ε-CL) undergo a ring-opening polymerization reaction under anaerobic conditions in the presence of a catalyst, wherein the molar ratio of propynyl alcohol, caprolactone and the catalyst is 1:15-60:0.02-0.1; preferably, the catalyst is an organometallic compound such as stannous octoate (Sn(Oct)2), stannous isooctanoate or tetraphenyltin.

[0024] The reaction conditions recommended in step 1 of this invention are as follows: Propylene alcohol, ε-CL, and Sn(Oct)₂ are mixed uniformly at a molar ratio of 1:15–60:0.02–0.1, deoxygenated, and stirred at 40–150°C for 1–6 hours. After vacuum drying, the polymer (alkynyl-PCL-OH) shown in Formula II is obtained, with the following reaction formula:

[0025]

[0026] Optionally, in the preparation method of the biodegradable biaxially shaped brush polymer provided by the present invention, in step 2, the polymer shown in Formula II is reacted with 2-bromoisobutyryl bromide (abbreviated as...) i BuBr) undergoes a substitution reaction under alkaline conditions, wherein the molar ratio of the polymer, the base, and 2-bromoisobutyryl bromide shown in Formula II is 1:4 to 16:3 to 12; preferably, the base is a weak organic base such as triethylamine or pyridine.

[0027] The reaction conditions recommended in step 2 of this invention are as follows: the polymer shown in Formula II, triethylamine, and... are reacted in a molar ratio of 1:4 to 16:3 to 12. i BuBr was added to DCM (dichloromethane), and the mixture was stirred at room temperature for 36–48 hours. After vacuum drying, the polymer (alkynyl-PCL-) shown in Formula III was obtained. i BuBr), the reaction formula is as follows:

[0028]

[0029] Optionally, in the preparation method of the biodegradable biaxially shaped brush polymer provided by the present invention, in step 3, under anaerobic conditions, the polymer shown in Formula III and 2-hydroxyethyl methacrylate (HEMA) undergo an atom transfer radical polymerization reaction in the presence of a catalyst; preferably, the catalyst includes CuBr and a ligand, wherein the ligand is selected from 2,2′-bipyridine (bpy) or tris(2-dimethylaminoethylamine) (Me6TREN); more preferably, the molar ratio of the polymer shown in Formula III, HEMA, bpy and CuBr is 1:8 to 25:2:1, and the molar ratio of the polymer shown in Formula III, HEMA, tris(2-dimethylaminoethylamine) and CuBr is 1:8 to 25:1:1.

[0030] The reaction condition in step 3 is as follows: the polymer of formula III (alkynyl-PCL-b-PHEMA) is dissolved in a mixed solution of isopropyl alcohol and DMF in a molar ratio of 1:8-25:2:1, oxygen is removed, and the reaction is stirred at 50-70°C for 2-4h, and then dialysis and freeze-drying are performed to obtain the polymer of formula IV (alkynyl-PCL-b-PHEMA). i After BuBr, HEMA, bpy, and CuBr are uniformly mixed in a mixed solution of isopropyl alcohol and DMF, oxygen is removed, and the reaction is stirred at 50-70°C for 2-4h, and then dialysis and freeze-drying are performed to obtain the polymer of formula IV (alkynyl-PCL-b-PHEMA).

[0031]

[0032] Optionally, in the preparation method of the biodegradable two-sided loop brush-shaped polymer provided by the application, in step 4, the molar ratio of the polymer of formula IV to sodium azide is 1:10-50.

[0033] The reaction condition in step 4 is as follows: the polymer of formula IV and NaN3 are dissolved in a mixed solution of a small amount of DMF and water in a molar ratio of 1:10-50, and the reaction is stirred at 40-60°C for 24-48h, and then dialysis and freeze-drying are performed to obtain the polymer of formula V (alkynyl-PCL-b-PHEMA-N3).

[0034]

[0035] Optionally, in the preparation method of the biodegradable two-sided loop brush-shaped polymer provided by the application, in step 5, the polymer of formula V is subjected to a click chemistry reaction under anaerobic conditions and in the presence of N', N', N', N', N'-pentamethyldiethylenetriamine (PMDETA) and CuBr, and preferably, the molar ratio of the polymer of formula V, PMDETA, and CuBr is 1:10-50:10-50.

[0036] The reaction condition in step 5 is as follows: the polymer of formula V, PMDETA, and CuBr are dissolved in a large amount of DMF solution in a molar ratio of 1:10-50:10-50, uniformly mixed, oxygen is removed, and the reaction is stirred at 80-120°C for 24-48h, and then dialysis and freeze-drying are performed to obtain the polymer of formula VI.

[0037]

[0038] Optionally, the preparation method of the biodegradable two-faced ring brush-shaped polymer provided by the present application, in step 6, the polymer represented by formula VI is subjected to substitution reaction with 2-bromoisobutyryl bromide under alkaline conditions, wherein the molar ratio of the polymer represented by formula VI, the base and 2-bromoisobutyryl bromide is 1:2-8:2-6; preferably, the base is triethylamine, pyridine and the like weak organic base.

[0039] The reaction condition in step 6 recommended by the present application is as follows: the polymer represented by formula VI, triethylamine and i BuBr is added into dichloromethane, and stirred at room temperature for 36-48 h, and then vacuum dried to obtain the polymer represented by formula VII, and the reaction formula is as follows:

[0040]

[0041] Optionally, the preparation method of the biodegradable two-faced ring brush-shaped polymer provided by the present application, in step 7, the polymer represented by formula VII is subjected to atom transfer radical polymerization with oligo(ethylene glycol methoxy methyl acrylate) (OEGMA) under anaerobic conditions and under the catalysis of 2,2'-bipyridine (bpy) and CuBr, wherein the molar ratio of the polymer represented by formula VII, oligo(ethylene glycol methoxy methyl acrylate), bpy and CuBr is 1:5-30:2:1.

[0042] The reaction condition in step 7 recommended by the present application is as follows: the polymer represented by formula VII, OEGMA, bpy and CuBr are dissolved in DMF solution according to the molar ratio of 1:5-30:2:1, oxygen is removed, and then stirred at 50-70°C for 0.5-1 h, and then dialyzed and freeze-dried to obtain the biodegradable two-faced ring brush-shaped polymer represented by formula I, and the reaction formula is as follows:

[0043]

[0044] Compared with the prior art, the present application has the following beneficial effects:

[0045] 1、The biodegradable two-faced ring brush-shaped polymer provided by the present application is a two-faced structure polymer, wherein the hydrophobic surface is PCL structure and directly located on the ring, and the hydrophilic surface is P(HEMA-g-POEGMA) structure and located on the side chain of the ring. Each polymer fragment in the polymer structure has a relatively high drug loading rate and encapsulation rate in a proper polymerization degree range, and can reach 8.90% and 89.25% respectively, so as to effectively improve the bioavailability of anticancer drugs, and has application prospect as a drug carrier.

[0046] 2. The biodegradable two-faced brush-shaped polymer provided by the application can form self-assembled micelles with a size of about 40 nm in water, and has good stability in a phosphate buffer solution (PBS, pH 7.4, ionic strength 150 mM).

[0047] 3. The biodegradable two-faced brush-shaped polymer provided by the application is prepared by a simple operation and under mild reaction conditions. BRIEF DESCRIPTION OF DRAWINGS

[0048] Figure 1 The nuclear magnetic resonance characterization diagram of the biodegradable two-faced brush-shaped polymer prepared in Example 1 of the application;

[0049] Figure 2 The particle size change diagram of the biodegradable two-faced brush-shaped polymer micelles prepared in Example 1 of the application. DETAILED DESCRIPTION

[0050] The following detailed description of the embodiments of the application is given on the premise of the technical solutions of the application, and detailed implementation modes and processes are given, but the protection scope of the application is not limited to the following examples, and the experimental methods not specified in the following examples are usually performed according to conventional conditions.

[0051] Example 1: Preparation of biodegradable two-faced brush-shaped polymer

[0052] 1) 0.1 g of propargyl alcohol and 6.80 g of ε-CL were placed in a reaction tube, and oxygen was removed by freezing-extraction-thawing for three times, the reaction tube was sealed, and stirring was performed at 110 DEG C in an oil bath for about 8 min to make it homogeneous. After freezing, 28.936 mg of Sn(Oct)2 (stannous octoate) was added under nitrogen protection, and oxygen was removed again by freezing-extraction-thawing for three times, the reaction tube was sealed, and reaction was performed at 110 DEG C for 2 h. After the reaction was completed, the reaction tube was cooled, a small amount of THF was added to dilute the product, excess ice anhydrous methanol was added for precipitation, centrifugation was performed, the crude product was diluted with THF again, ice anhydrous methanol was added for precipitation and centrifugation, and the process was repeated three times, and finally white flocculent solid (the polymer shown in Formula II) was obtained by vacuum drying. The substance was detected by nuclear magnetic hydrogen spectrum, and each characteristic peak in the polymer was found from the corresponding hydrogen spectrum, and then the polymerization degree m of polycaprolactone was calculated to be 28.

[0053] 2) 2.0 g of the polymer shown in Formula II (m = 28) above was dissolved in 5 mL of anhydrous DCM, and stirring was performed. The mixture was placed in an ice bath, 0.7088 g of triethylamine was added, stirring was performed for about 10 min, and then 1.1209 g of 4-mercapto-2,2'-dimethyl-2'-sulfanyl-2H-1-benzopyran (DMDB) was added, and stirring was performed for 2 h. After the reaction was completed, the reaction tube was cooled, and the product was precipitated with excess ice anhydrous methanol, and centrifugation was performed. The process was repeated three times, and finally white flocculent solid (the polymer shown in Formula III) was obtained by vacuum drying. iBuBr, stirring for 20 min, then stirring at room temperature for 48 h. After the reaction was completed, the solvent was evaporated, the product was dissolved in THF, and the insoluble matter was removed by suction filtration. The filtrate was precipitated in excess ice-free methanol, centrifuged, and the crude product was dissolved in THF again. The solution was precipitated in ice-free methanol and centrifuged. The process was repeated three times, and the final product was dried in vacuum to obtain a light yellow solid, which was the polymer of formula III (m = 28, PCL with bromine as the end group i BuBr).

[0054] 3) 4.4 g of the polymer of formula III, 1.78 g of monomer 2-hydroxyethyl methacrylate, and 0.625 g of bipyridine were weighed into 0.15 mL of DMF and 2.0 mL of isopropyl alcohol, and the mixture was dissolved completely and then placed in a polymerization tube. The tube was subjected to three cycles of freezing, vacuumizing, and thawing to remove oxygen, and 0.287 g of CuBr solid powder was added under nitrogen protection. The tube was subjected to three cycles of freezing, vacuumizing, and thawing, sealed, and reacted at 60°C for 4 h. After the reaction was completed, the product was diluted with a small amount of THF, precipitated in excess ice-free diethyl ether, centrifuged, dissolved in a small amount of DMF, and subjected to water dialysis for 48 h. After freeze-drying, a white powder was obtained, which was the polymer of formula IV (i.e., an amphiphilic polymer with bromine as the end group). The product was subjected to nuclear magnetic hydrogen spectrum detection, and the corresponding characteristic peaks in the polymer were found from the corresponding hydrogen spectrum, and the degree of polymerization n of the hydrophilic segment was calculated to be 8.

[0055] 4) 1.3 g of the polymer of formula IV (n = 8) was dissolved in 5 mL of DMF, and 0.5 g of NaN3 was dissolved in distilled water. The two solutions were mixed in a round-bottom flask, sealed, and stirred at 45°C for 48 h. After dialysis and freeze-drying, a white powder was obtained, which was the polymer of formula V (i.e., an amphiphilic polymer with azide as the end group).

[0056] 5) In a 1 L three-necked flask, 750 mL of DMF was poured in, and the temperature was increased to 100°C under stirring while high-purity nitrogen was introduced to remove oxygen. After about 1 h, 0.3466 g of PMDETA and 0.2844 g of CuBr powder were added into the flask. 0.35 g of the polymer of formula V was dissolved in 10 mL of DMF, and the solution was slowly injected into the three-necked flask after being deoxygenated. The reaction was continued for 24 h after the injection was completed. After the reaction was completed, most of the DMF solvent was removed by rotary evaporation, and the crude product was subjected to water dialysis for 48 h. After freeze-drying, a white powder was obtained, which was the polymer of formula VI.

[0057] 6) Weigh 0.5 g of the polymer of Formula VI into 5 mL of anhydrous DCM and stir until uniform. Place the mixture in an ice bath, add 1.212 g of triethylamine and stir for about 10 min, then add 2.07 g of 2-bromoisobutyryl bromide and stir for 20 min. Then, stir the mixture at room temperature for 48 h. After the reaction is complete, spin dry the solvent, dissolve in THF, and filter to remove insoluble material. Precipitate the filtrate into excess anhydrous ice methanol, centrifuge, and repeat the THF dilution, ice anhydrous methanol precipitation, and centrifugation three more times. Finally, dry the product under vacuum to obtain a light yellow solid, which is the polymer of Formula VII (cyclic amphiphilic polymer with bromine end groups).

[0058] 7) Weigh 0.1 g of the polymer of Formula VII into 9 mL of a mixture of anisole and DMF (1:2 by volume), then add 0.267 g of monomer OEGMA and 0.0078 g of bipyridine. After mixing, transfer the mixture into a polymerization tube. After three freeze-thaw-lysis cycles using an oil pump, quickly add 0.5577 g of CuBr powder under nitrogen protection, continue the freeze-thaw-lysis cycles three more times, seal the tube, and place it in a 60 °C oil bath for about 30 min of stirring. After the reaction is complete, quench the reaction with air, precipitate into excess anhydrous ice ether, centrifuge, and dialyze for 48 h to remove the copper catalyst and unreacted monomer. After lyophilization, obtain the biodegradable two-faced cyclodextrin-shaped polymer of Formula I. Perform nuclear magnetic hydrogen spectrum detection on the polymer, as shown in FIG. 1, find the corresponding characteristic peaks in the hydrogen spectrum, and then calculate the polymerization degree of OEGMA to be p = 8. Figure 1

[0059] Example 2-4

[0060] Example 2-4 provides a method for preparing a biodegradable two-faced cyclodextrin-shaped polymer, which is similar to Example 1, except that the amounts of materials used in each step are different. See Table 1 below for details.

[0061] Comparative Example 1-3

[0062] Comparative Example 1-3 provides a method for preparing a biodegradable two-faced cyclodextrin-shaped polymer, which is similar to Example 1, except that the amounts of materials used in each step are different. See Table 1 below for details.

[0063] Comparative Example 4

[0064] This comparative example provides a biodegradable two-faced cyclodextrin-shaped polymer, and the specific reaction formula is as follows:

[0065]

[0066] The preparation method is as follows:

[0067] ​1) 7.2 g propargyl alcohol and 18.1 mL triethylamine were dissolved in 100 mL anhydrous dichloromethane, stirred under nitrogen protection and cooled to 0 °C, then 16.4 mL BuBr was slowly added dropwise into the solution. After the completion of dropwise addition, the reaction was continued at 0 °C for a period of time, and then continued at room temperature for 24 h. The product was vacuum filtered to remove insoluble substances, extracted with saturated sodium chloride three times, then extracted with ultrapure water once, dried with anhydrous magnesium sulfate, and distilled under reduced pressure to obtain a small molecule initiator. i BuBr. After the completion of dropwise addition, the reaction was continued at 0 °C for a period of time, and then continued at room temperature for 24 h. The product was vacuum filtered to remove insoluble substances, extracted with saturated sodium chloride three times, then extracted with ultrapure water once, dried with anhydrous magnesium sulfate, and distilled under reduced pressure to obtain a small molecule initiator.

[0068] 2) 2.45 g HEMA, 0.483 mg of the above small molecule initiator, and 0.74 g bpy were dissolved in a mixed solvent of 0.3 mL DMF and 3.2 mL isopropyl alcohol. After complete dissolution, it was placed in a polymerization tube, and the oxygen was removed by freeze-thaw-lysis three times. 0.34 g CuBr solid powder was added under nitrogen protection, and the freeze-thaw-lysis cycle was continued for three times. The tube was sealed and reacted at 65 °C for 2 h. After the completion of the reaction, it was air quenched, diluted with a small amount of DMF, precipitated with excess ice anhydrous ether, centrifuged, and then dissolved in a small amount of DMF for water dialysis for 48 h. After freeze-drying, a white powder was obtained. The degree of polymerization of PHEMA was calculated by nuclear magnetic resonance to be a = 8.

[0069] 4) 0.2 g of the above white powder solid and 20 times the amount of sodium azide were dissolved in 10 mL of a 1 / 4 volume ratio of water / DMF mixed solvent. After mixing uniformly, it was placed in a 45 °C oil bath and stirred for 48 h. After the reaction was completed and cooled, it was transferred to a dialysis bag and dialyzed with ultrapure water for 48 h. After freeze-drying, a white powder solid of azidation product was obtained.

[0070] 5) In a 1 L three-necked flask, 750 mL of DMF was poured in, stirred and heated to 100 °C, and high-purity nitrogen was introduced to remove oxygen. After about 1 h, 0.366 g of PMDETA and 0.303 g of CuBr powder were added into the flask. 0.1 g of the above azidation product was dissolved in 10 mL of DMF, and after oxygen removal, it was slowly injected into the three-necked flask. After injection, the reaction was continued for 24 h. After the completion of the reaction, most of the DMF solvent was removed by rotary evaporation, and the crude product was dialyzed with water for 48 h. After freeze-drying, a white powder solid, i.e., a cyclic polymer PHEMA, was obtained.

[0071] 6) 0.03 g of the cyclic polymer PHEMA was dissolved in 0.2 mL of anhydrous DMF, and then 0.82 g of caprolactone monomer and 3.08 mg of Sn(Oct)2 were added. After complete dissolution, it was transferred into a polymerization reaction tube. After freeze-thaw-lysis cycle for three times, it was sealed and reacted in a 115 °C oil bath for 6 h. After the completion of the reaction, the product was diluted with THF, precipitated with excess cold methanol, centrifuged, and the above steps were repeated three times. After vacuum drying, a purified white powder solid P(HEMA-g-PCL) was obtained. The degree of polymerization of PCL was calculated by nuclear magnetic resonance to be b = 28.

[0072] 7) 0.2 g of the above white powder P(HEMA-g-PCL) was dissolved in 5 mL of anhydrous pyridine, stirred under nitrogen protection, the reaction temperature was reduced to 0°C, and then 75 mg of BuBr was added dropwise at room temperature for 24 h. After the reaction was completed, the product was precipitated with distilled water, centrifuged, and then dissolved in a small amount of THF and precipitated with distilled water twice, and then vacuum dried to obtain the purified product P(HEMA-g-PCL-iBuBr). i BuBr, and reacted at room temperature for 24 h. After the reaction was completed, the product was precipitated with distilled water, centrifuged, and then dissolved in a small amount of THF and precipitated with distilled water twice, and then vacuum dried to obtain the purified product P(HEMA-g-PCL-iBuBr).

[0073] 8) 0.1 g of P(HEMA-g-PCL-iBuBr) was dissolved in 3 mL of a mixed solution of anisole and DMF (1:2, by volume), and then 0.25 g of OEGMA and 0.017 g of bpy were added, and after being mixed uniformly, the oil pump freeze-thaw-extraction cycle was performed three times, and then 0.008 g of CuBr was quickly added under nitrogen protection, and the freeze-thaw-extraction cycle was continued for three times, and then sealed and placed in a 60°C oil bath for reaction. During the set reaction time, the reaction tube was taken out and quenched, precipitated with excess anhydrous ether, centrifuged, and then dialyzed with water to remove the copper catalyst and unreacted monomer, and then freeze-dried to obtain the product. The degree of polymerization of OEGMA was calculated to be c=8 by nuclear magnetic resonance.

[0074] Table 1: Raw material molar ratio in each step

[0075]

[0076] Performance test:

[0077] The biodegradable two-faced brush-shaped polymers prepared in each example and comparative example were respectively tested for particle size according to the following method: the two-faced brush-shaped polymers were prepared into a polymer solution with a concentration of 0.125 mg / mL using a phosphate buffer solution (PBS, pH 7.4, ionic strength 150 mM), and then the average particle size of the polymer solution was measured using a dynamic laser light scattering instrument. The specific results are shown in the following table. The measurement results of Example 1 are shown in Table 1. Figure 2 As can be seen from Table 1, the particle size of the polymer prepared in Example 1 is 34 nm. Figure 2

[0078] The biodegradable two-faced brush-shaped polymers prepared in each example and comparative example were respectively subjected to drug physical encapsulation test. The specific experimental process, drug encapsulation rate and drug loading rate calculation method refer to the literature (Tao XY, Liu WX, Wei H. Synthesis and self-assembly of core-shell-crown amphiphilic brush-shaped copolymer. Polymer Materials Science and Engineering, 2020, 36(7): 23-30.).

[0079] Table 2: Structure and performance test results of each example and comparative example ​

[0080] m n p Particle size, nm Drug loading, % Encapsulation efficiency, % Example 1 28 8 8 34 8.90 89.25 Example 2 10 12 2 30 8.62 84.50 Example 3 50 5 15 42 7.84 79.02 Example 4 42 20 3 40 8.10 80.83 Comparative Example 1 5 8 8 30 4.60 40.36 Comparative Example 2 28 25 8 43 5.72 55.86 Comparative Example 3 28 8 20 40 6.05 59.55 Comparative Example 4 28(b) 8(a) 8(c) 30 4.20 40.88

[0081] From the data in the above table, it can be seen that the particle sizes of Examples 1-4 and Comparative Examples 1-4 are all between 30-50 nm, but the drug loading rate and encapsulation rate of the examples are significantly higher than those of the comparative examples, wherein the drug loading rate is above 7.80% and the encapsulation rate is above 79.00%, which is mainly due to the fact that the hydrophobic structure in the biodegradable two-sided cyclic brush-shaped polymer micelles is mainly on the cyclic inner core, which has a large space and can encapsulate more drugs, and the hydrophilic brush-shaped segment on the branched chain has good hydrophilicity, which can prevent the polymer molecules from easily aggregating, thereby better protecting the drugs from falling off.

[0082] The above examples are typical examples listed to illustrate the technical solutions of the present application, and the protection scope of the present application is subject to the protection scope of the claims and the invention content, and is not limited by the described examples. Simple replacement or change of the present application is still within the protection scope of the present application.

Claims

1. A biodegradable two-faced toroidal brush polymer, characterized in that, A polymer having the structure of formula I: Formula I wherein m is a natural number of 10-50, n is a natural number of 5-20, and p is a natural number of 2-15.

2. A process for the preparation of a biodegradable two-faced toroidal brush-shaped polymer, characterized by, The method comprises the following steps: Step 1, propynol and caprolactone are subjected to ring-opening polymerization to generate a polymer having the structure of formula II; Step 2, the polymer having the structure of formula II is subjected to substitution reaction with 2-bromoisobutyryl bromide to generate a polymer having the structure of formula III; Step 3, the polymer having the structure of formula III is subjected to atom transfer radical polymerization with 2-hydroxyethyl methacrylate to generate a polymer having the structure of formula IV; Step 4, the polymer having the structure of formula IV is subjected to azidation reaction with sodium azide to generate a polymer having the structure of formula V; Step 5, the polymer having the structure of formula V is subjected to click chemistry to generate a polymer having the structure of formula VI; Step 6, the polymer having the structure of formula VI is subjected to substitution reaction with 2-bromoisobutyryl bromide; Step 7, the polymer having the structure of formula VII is subjected to atom transfer radical polymerization with oligo(ethylene glycol methoxymethyl methacrylate) to generate the biodegradable two-faced loop brush-shaped polymer having the structure of formula I; wherein m is a natural number of 10-50, n is a natural number of 5-20, and p is a natural number of 2-15.

3. The production method according to claim 2, wherein In step 1, propynol and caprolactone are subjected to ring-opening polymerization under the action of a catalyst in an oxygen-free condition.

4. The production method according to claim 2, wherein In step 2, the polymer having the structure of formula II is subjected to substitution reaction with 2-bromoisobutyryl bromide in an alkaline condition, wherein the molar ratio of the polymer having the structure of formula II, the base and 2-bromoisobutyryl bromide is 1:4-16:3-12.

5. The production method according to claim 2, wherein In step 3, the polymer having the structure of formula III is subjected to atom transfer radical polymerization with 2-hydroxyethyl methacrylate under the action of a catalyst in an oxygen-free condition, wherein the catalyst comprises CuBr and a ligand selected from 2,2'-bipyridine or tris(2-dimethylaminoethyl amine).

6. The production method according to claim 2, wherein In step 4, the molar ratio of the polymer having the structure of formula IV and sodium azide is 1:10-50.

7. The production method according to claim 2, wherein In step 5, the polymer having the structure of formula V is subjected to click chemistry under the catalysis of N',N',N',N',N'-pentamethyl diethylene triamine and CuBr in an oxygen-free condition.

8. The production method according to claim 2, wherein In step 6, the polymer having the structure of formula VI is subjected to substitution reaction with 2-bromoisobutyryl bromide in an alkaline condition, wherein the molar ratio of the polymer having the structure of formula VI, the base and 2-bromoisobutyryl bromide is 1:2-8:2-6.

9. The production method according to claim 2, wherein In step 7, the polymer having the structure of formula VII is subjected to atom transfer radical polymerization with oligo(ethylene glycol methoxymethyl methacrylate) under the catalysis of 2,2'-bipyridine and CuBr in an oxygen-free condition, wherein the molar ratio of the polymer having the structure of formula VII, oligo(ethylene glycol methoxymethyl methacrylate), 2,2'-bipyridine and CuBr is 1:5-30:2:

1.

10. The production method according to claim 3, wherein In step 1, the molar ratio of propynol, caprolactone and the catalyst is 1:15-60:0.02-0.

1.

11. The production method according to claim 3, wherein In step 1, the catalyst is stannous octoate, stannous iso-octoate or tetraphenyl tin.

12. The production method according to claim 4, wherein In step 2, the base is a weak organic base.

13. The production method according to claim 4, wherein In step 2, the base is triethylamine or pyridine.

14. The production method according to claim 5, wherein In step 3, the molar ratio of the polymer of formula III, 2-hydroxyethyl methacrylate, 2,2'-bipyridine and CuBr is 1:8~25:2:1; the molar ratio of the polymer of formula III, 2-hydroxyethyl methacrylate, tris(2-dimethylaminoethylamine) and CuBr is 1:8~25:1:

1.

15. The production method according to claim 7, wherein In step 5, the molar ratio of the polymer of formula V, N',N',N',N',N'-pentamethyldiethylenetriamine and CuBr is 1:10~50:10~50.

16. The production method according to claim 8, wherein In step 6, the base is an organic weak base.

17. The production method according to claim 8, wherein In step 6, the base is selected from triethylamine or pyridine.

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