Thermo-sensitive triblock copolymer with lateral group containing polyethylene glycol and preparation method of thermo-sensitive triblock copolymer

Abstract

The invention provides a thermo-sensitive triblock copolymer with a lateral group containing polyethylene glycol and a preparation method of the thermo-sensitive triblock copolymer, and relates to the field of polymer synthesis. The preparation method comprises the following steps: carrying out a reaction on hydroxyl-terminated polyether PAGE and single carboxyl-terminated polyethylene glycol monomethyl ether (mPEG-COOH) under the action of N-bromosuccinimide to prepare a polymer brush PAGE-g-mPEG; and reacting the polymer brush PAGE-g-mPEG with poly (N-isopropylacrylamide) to generate a thermo-sensitive triblock copolymer of which the side group contains polyethylene glycol. The thermo-sensitive triblock copolymer disclosed by the invention is endowed with good biocompatibility, hydrophilicity and low-temperature performance, has a good thermo-sensitive characteristic, and can be widely applied to the fields of drug-loaded controlled release, sewage treatment and nanoparticles; the invention also provides a preparation method of the thermo-sensitive triblock copolymer, which overcomes the defects of harsh reaction conditions and easy chain extension reaction, and realizes accurate control of the molecular weight of the prepared copolymer.

Description

Technical Field

[0001] The present invention relates to the field of polymer synthesis, in particular to a temperature-sensitive triblock copolymer containing polyethylene glycol in a side group and a preparation method thereof. Background Art

[0002] Block copolymers are specialized polymers composed of two or more distinct polymer segments bonded together within a single macromolecular chain. The synergistic interaction between these distinct polymer segments imparts diverse properties to block copolymers. Due to the unique characteristics of the macromolecular block chains, the properties of these copolymers differ significantly from those of random copolymers or mixtures of homopolymers, effectively complementing the unique properties of two or more polymers. In recent years, with the advancement of controlled living polymerization technology, the synthesis of block copolymers with ordered microstructures through molecular design has become a significant area of ​​research in polymer synthesis and modification.

[0003] Thermosensitive polymers are polymers that undergo phase transitions in solution when the temperature changes within a certain range. There are generally two types of phase transitions for thermosensitive polymers in solution: one is when the temperature rises above a certain critical temperature, the polymer becomes insoluble; this temperature is called the lower critical solution temperature (LCST); the other is when the polymer is soluble above a certain temperature but undergoes phase separation below this temperature; this temperature is called the upper critical solution temperature (UCST).

[0004] Poly(N-isopropylacrylamide), or PNIPAM, exhibits amphiphilic properties due to the presence of both hydrophilic amide groups and hydrophobic isopropyl groups within its molecule. According to the equation ΔG = ΔH - TΔS, when the temperature is below the lower critical solution temperature (LCST), hydrogen bonds form between water molecules and the polymer's amide bonds, releasing heat (ΔH < 0). An ordered layer of water molecules forms around the amide groups, reducing the system's entropy, pushing ΔS < 0. At this point, TΔS is minimal, and the resulting system ΔG < 0. PNIPAM dissolves in aqueous solution, exhibiting a flexible, expanded, random coil conformation. Conversely, when the temperature exceeds the LCST, hydrogen bonds between the hydrophilic groups and water molecules weaken, while hydrophobic interactions with the isopropyl groups on the PNIPAM strengthen, leading to water expulsion from the polymer and a larger ΔS value (ΔG > 0). The PNIPAM chains dehydrate and aggregate into tightly packed globules. Phase separation is driven by this change in ΔS, so the reversible transition from coil to globule structure in the polymer network is entropy-driven. Partially dehydrated polymer chains have a refractive index sufficiently different from that of the bulk solvent to cause turbidity. Therefore, the LCST is often determined by the cloud point. Existing studies have shown that the LCST of PNIPAM is close to 32°C, comparable to human body temperature and normal room temperature. Furthermore, the LCST of PNIPAM is largely unaffected by polymer concentration, ionic strength, and pH.

[0005] Polymer brushes are a class of polymer systems with a unique structure formed by grafting polymer chains onto a polymer backbone. Due to steric hindrance, these polymer side chains repel each other and extend outward, resulting in a structure similar to a laboratory flask brush at the molecular level. Nonlinear polyethylene glycol (PEG) polymers are a new class of thermosensitive polymers. Due to their PEG backbone, nonlinear PEG polymers share the good biocompatibility of linear PEG polymers. However, due to their unique structure, they exhibit properties not found in linear polymers, such as a liquid crystal structure (LCST) in water and a chromatographic curve (UCST) in alcohols. These LCSTs or UCSTs can be easily adjusted by varying the degree of polymerization (DP) of the PEG side chains. The inventors discovered that the macromolecular backbone of PAGE, with the exception of the terminal groups, consists of nonpolar segments, resulting in excellent flexibility and the ability to impart exceptional low-temperature mechanical properties.

[0006] The advantages of using end-group reactions to prepare novel block copolymers are that the raw materials are mostly readily available commercial products, and the macromolecular structure and molecular weight are well-defined, resulting in relatively low synthesis costs. However, the reaction conditions are demanding, generally requiring strong acid or base catalysis. Furthermore, the reactant ratio must be precisely controlled, otherwise chain extension reactions are likely to occur, and the molecular weight can only increase exponentially, preventing true and flexible molecular weight control.

[0007] Thus, a new thermosensitive triblock copolymer is provided, which not only has good biocompatibility, hydrophilicity and low-temperature performance, but also has good temperature-sensitive properties, and can be widely used in the fields of drug delivery and controlled release, sewage treatment, and nanoparticles; and a preparation method of the thermosensitive triblock copolymer is provided, which overcomes the defects of harsh reaction conditions and easy occurrence of chain extension reactions during its preparation process, and realizes precise control of the molecular weight of the prepared copolymer, which has important technical significance and research value. Summary of the Invention

[0008] In order to solve the technical problems existing in the prior art, the present invention provides a thermosensitive triblock copolymer containing polyethylene glycol in the side group. While giving it good biocompatibility, hydrophilicity, and low-temperature performance, it also has good temperature-sensitive properties and can be widely used in the fields of drug delivery and controlled release, sewage treatment, and nanoparticles. The present invention also provides a preparation method of the thermosensitive triblock copolymer, which overcomes the defects of harsh reaction conditions and easy occurrence of chain extension reactions, and realizes precise control of the molecular weight of the prepared copolymer.

[0009] In order to solve the above technical problems, the technical solutions adopted by the present invention are as follows: A method for preparing a thermosensitive triblock copolymer containing polyethylene glycol in side groups comprises reacting hydroxyl-terminated polyether PAGE and single-carboxyl-terminated polyethylene glycol monomethyl ether mPEG-COOH in the presence of N-bromosuccinimide to produce a polymer brush PAGE-g-mPEG; the polymer brush PAGE-g-mPEG reacts with poly(N-isopropylacrylamide) to produce a thermosensitive triblock copolymer containing polyethylene glycol in side groups; The hydroxyl-terminated polyether PAGE is prepared by reacting 1,4-butanediol with allyl glycidyl ether in tetrahydrofuran.

[0010] Furthermore, the method for preparing the thermosensitive triblock copolymer containing polyethylene glycol in the side group comprises the following steps: preparing a polymer brush PAGE-g-mPEG; The method for preparing the polymer brush PAGE-g-mPEG comprises: dissolving hydroxyl-terminated polyether PAGE and single-carboxyl-terminated polyethylene glycol monomethyl ether mPEG-COOH in a solvent under anhydrous conditions; adding N-bromosuccinimide in an ice-water bath under a nitrogen atmosphere; reacting in an ice-water bath; and then continuing the reaction at room temperature to obtain a crude product; and dialyzing and distilling the crude product under reduced pressure to obtain the polymer brush PAGE-g-mPEG.

[0011] Furthermore, the method for preparing the thermosensitive triblock copolymer containing polyethylene glycol as a side group comprises the following steps: preparing the thermosensitive triblock copolymer containing polyethylene glycol as a side group; The method for preparing a thermosensitive triblock copolymer containing polyethylene glycol in side groups comprises dissolving a polymer brush PAGE-g-mPEG and poly(N-isopropylacrylamide) in a solvent, heating the mixture to 70-75° C., adding toluene-2,4-diisocyanate and bismuth-2-ethylhexanoate, and carrying out a reaction at the same temperature to obtain a crude product. The crude product is subjected to reduced pressure distillation to obtain a thermosensitive triblock copolymer containing polyethylene glycol in side groups.

[0012] Furthermore, the method for preparing the thermosensitive triblock copolymer containing polyethylene glycol in the side group comprises the following steps: preparing hydroxyl-terminated polyether PAGE; The method for preparing the hydroxyl-terminated polyether PAGE comprises dissolving 1,4-butanediol in tetrahydrofuran, adding boron trifluoride ether under ice bath conditions, mixing evenly, and then dripping allyl glycidyl ether; after the dripping of allyl glycidyl ether is completed, continuing the reaction to obtain a crude product; and washing and distilling the crude product under reduced pressure to obtain the hydroxyl-terminated polyether PAGE.

[0013] Furthermore, the method for preparing the thermosensitive triblock copolymer containing polyethylene glycol in the side group comprises the following steps: preparing single-terminal carboxyl polyethylene glycol monomethyl ether mPEG-COOH; The method for preparing single-end carboxyl polyethylene glycol monomethyl ether mPEG-COOH comprises the following steps: dissolving polyethylene glycol monomethyl ether with a number average molecular weight of 750 g / mol and succinic anhydride in a solvent; adding triethylamine in a nitrogen atmosphere; and reacting at room temperature to obtain a crude product; concentrating the crude product by rotary evaporation, and then adding diethyl ether to precipitate; separating and obtaining a precipitate, washing, drying, and evaporating under reduced pressure to obtain the single-end carboxyl polyethylene glycol monomethyl ether mPEG-COOH.

[0014] Preferably, in the preparation of the polymer brush PAGE-g-mPEG, the molar ratio of the hydroxyl-terminated polyether PAGE, the single-terminated carboxyl-terminated polyethylene glycol monomethyl ether mPEG-COOH, and N-bromosuccinimide is 2-6:1:2-3; The reaction time of the ice-water bath reaction is 1-2 hours; the reaction time at room temperature is 20-24 hours; The molecular weight cut-off of the dialysis was 1000D.

[0015] Preferably, in the thermosensitive triblock copolymer containing polyethylene glycol as a side group, the molar ratio of the polymer brush PAGE-g-mPEG, poly (N-isopropylacrylamide), and toluene-2,4-diisocyanate is 1:1-4:1-4; The insulation reaction time is 4-10 hours.

[0016] Preferably, in the preparation of the hydroxyl-terminated polyether PAGE, the molar ratio of 1,4-butanediol, boron trifluoride ethyl ether, and allyl glycidyl ether is 1-1.5:0.7-1:20-25; The dropping time of the allyl glycidyl ether is 1-2h; The reaction time after the allyl glycidyl ether is added dropwise is 4-6 hours.

[0017] Preferably, in the preparation of the single-terminal carboxyl polyethylene glycol monomethyl ether mPEG-COOH, the molar ratio of the polyethylene glycol monomethyl ether, succinic anhydride, and triethylamine is 0.5-1:1:0.1-0.2; The reaction time at room temperature is 20-24 hours.

[0018] Furthermore, the method for preparing the thermosensitive triblock copolymer containing polyethylene glycol as a side group comprises the following steps: preparing poly(N-isopropylacrylamide); The method for preparing poly(N-isopropylacrylamide) comprises dissolving N-isopropylacrylamide in a solvent, adding mercaptoethanol and azobisisobutyronitrile in a nitrogen atmosphere at 20-30°C, and reacting at 70-75°C to obtain a crude product; concentrating the crude product by vacuum distillation, and then adding the product to ether for precipitation; separating the precipitate, and freeze-drying the precipitate to obtain poly(N-isopropylacrylamide).

[0019] Preferably, in the preparation of poly(N-isopropylacrylamide), the molar ratio of N-isopropylacrylamide, mercaptoethanol, and azobisisobutyronitrile is 30-36:1:0.3-0.5.

[0020] The reaction time at 70-75° C. is 22-28 hours.

[0021] A thermosensitive triblock copolymer with polyethylene glycol as a side group is prepared by the above-mentioned preparation method.

[0022] Compared with the prior art, the present invention has the following beneficial effects: (1) The method for preparing a thermosensitive triblock copolymer containing polyethylene glycol as a side group of the present invention comprises the following steps: first, using ring-opening metathesis polymerization to prepare hydroxyl-terminated polyether (PAGE) and single-carboxyl-terminated polyethylene glycol monomethyl ether (mPEG-COOH), respectively; then, using these two products to modify into a polymer brush PAGE-g-mPEG under the action of N-bromosuccinimide (NBS); the polymer brush PAGE-g-mPEG is reacted with polyisopropylacrylamide (PNIPAM) obtained by polymerization of N-isopropylacrylamide (NIPAM) initiated by azobisisobutyronitrile (AIBN) to form a triblock copolymer PNIPAM-b-(PAGE- g-mPEG)-b-PNIPAM; wherein, by targetedly driving the aggregation of polymer segments in a solution with hydrophobic segments, the synergistic effect of the polymer segments enables them to form high-molecular micelles with rich morphological structures, thereby obtaining a thermoresponsive triblock polymer having a hydroxyl-terminated polyether (PAGE) as an intermediate segment, poly(N-isopropylacrylamide) (PNIPAM) as a terminal segment, and a side group containing polyethylene glycol with a hydroxyl group as the terminal group; the preparation method can overcome the defects of harsh reaction conditions and easy occurrence of chain extension reactions, achieve precise control of the molecular weight of the prepared copolymer, and further improve the technical system for synthesizing temperature-responsive triblock copolymers.

[0023] (2) The thermosensitive triblock copolymer containing polyethylene glycol as the side group of the present invention is modified by modifying the terminal hydroxyl polyether (PAGE) and the single terminal carboxyl polyethylene glycol monomethyl ether (mPEG-COOH) into a polymer brush PAGE- g -mPEG improves the biocompatibility and hydrophilicity of the triblock copolymer; at the same time, because the liquid bromine environment provided by N-bromosuccinimide (NBS) reacts with the double bond, the side group contains bromine, which will give it a certain antibacterial effect. g -mPEG reacts with polymerized poly(isopropylacrylamide) (PNIPAM) to form a thermoresponsive triblock copolymer PNIPAM-b-(PAGE- g-mPEG)-b-PNIPAM, while giving it good biocompatibility, biodegradability, hydrophilicity, low-temperature performance and certain antibacterial properties, has good temperature-sensitive properties and can be effectively used for drug-loaded controlled release. It can be widely used in drug-loaded controlled release, sewage treatment, nanoparticles and other fields, providing important safety guarantees for its practical application in the biomedical field. It is a "smart" material with broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is the reaction equation for preparing hydroxyl-terminated polyether PAGE in Example 1.

[0025] Figure 2 This is the SEC-MALLS chromatogram of the hydroxyl-terminated polyether PAGE prepared in Example 1.

[0026] Figure 3 The hydroxyl-terminated polyether PAGE prepared in Example 1 1 H NMR spectrum.

[0027] Figure 4 This is the infrared spectrum of the hydroxyl-terminated polyether PAGE prepared in Example 1.

[0028] Figure 5 This is the reaction equation for preparing single-terminal carboxyl polyethylene glycol monomethyl ether mPEG-COOH in Example 2.

[0029] Figure 6 This is the SEC-MALLS chromatogram of the single-terminal carboxyl polyethylene glycol monomethyl ether mPEG-COOH prepared in Example 2.

[0030] Figure 7 The single-terminal carboxyl polyethylene glycol monomethyl ether mPEG-COOH prepared in Example 2 1 H NMR spectrum.

[0031] Figure 8 This is the infrared spectrum of the single-terminated carboxyl polyethylene glycol monomethyl ether mPEG-COOH prepared in Example 2.

[0032] Figure 9 The poly (N-isopropylacrylamide) PNIPAM prepared in Example 4 is 1 H NMR spectrum.

[0033] Figure 10 This is the SEC-MALLS chromatogram of the triblock thermosensitive copolymer PNIPAM-b-(PAGE-g-mPEG)-b-PNIPAM containing polyethylene glycol in the side groups prepared in Example 5. DETAILED DESCRIPTION

[0034] In order to provide a clearer understanding of the technical features, objectives, and effects of the present invention, specific embodiments of the present invention are now described. It should be noted that the following detailed description is illustrative and is intended to further illustrate the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0035] It should be noted that the terms used herein are intended only to describe specific embodiments and are not intended to limit the exemplary embodiments of the present invention. As used herein, "first," "second," and the like are used to distinguish similar objects and are not used to describe a specific order or precedence. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0036] The present invention will be further described below with reference to some specific embodiments.

[0037] Example 1 Preparation of hydroxyl-terminated polyether PAGE: To a 50 mL single-necked flask, add 354 μL of 1,4-butanediol and 32.5 mL of tetrahydrofuran to fully dissolve the 1,4-butanediol. The system was then transferred to a low-temperature reaction bath at 0°C and stirred on ice for 0.5 h. After the internal and external temperatures equilibrated, 504 μL (0.0039 mol) of boron trifluoride ether was added and stirring continued. After equilibrium, 9.32 mL (0.08 mol) of allyl glycidyl ether was added dropwise using a constant-pressure dropping funnel. This addition was continued for 1 h. After the addition was complete, the reaction was continued for 4 h, for a total reaction time of 5.5 h. After the reaction was complete, stirring was increased and deionized water was added to terminate the reaction to obtain a crude product. The crude product was transferred to a separatory funnel and washed with deionized water several times. The oil phase was distilled under reduced pressure at 65°C to remove residual water and solvent to obtain the product (i.e., hydroxyl-terminated polyether PAGE). The product was a colorless viscous liquid, and was characterized by gel permeation chromatography-laser light scattering: Mn = 3005 g / mol, Mw / Mn = 1.356.

[0038] The reaction equation for preparing hydroxyl-terminated polyether PAGE in this embodiment is as follows: Figure 1 As shown; SEC-MALLS chromatogram of the prepared hydroxyl-terminated polyether PAGE, 1 H NMR spectrum and infrared spectrum are shown in Figure 2-4 shown.

[0039] Example 2 Preparation of single-terminated carboxyl polyethylene glycol monomethyl ether mPEG-COOH: To a 100-mL single-necked flask, 20 g of polyethylene glycol monomethyl ether (mPEG, Mn = 750 g / mol, 0.0267 mol) was added. 10 mL of tetrahydrofuran was added to fully dissolve the mPEG. In a 50-mL beaker, 4 g (0.04 mol) of succinic anhydride was dissolved in 25 mL of tetrahydrofuran, using ultrasonication to accelerate dissolution. After dissolution, the solution was added to the reaction system. N2 was bubbled through the reaction system in an oil bath at 25°C for 20 minutes. After the internal and external temperatures equilibrated, 5.546 mL (0.00439 mol) of triethylamine was added. The reaction lasted 24 hours. After the reaction, the product was concentrated by rotary evaporation at 60°C. After completion of the rotary evaporation, 300 mL of diethyl ether was added dropwise to the diethyl ether to precipitate the product. The mixture was allowed to stand for 6 hours, and the lower precipitate was removed. The precipitate was washed several times with deionized water until the water became neutral to remove triethylamine and unreacted polyethylene glycol monomethyl ether. Water in the crude product was removed with anhydrous magnesium sulfate. The solvent in the crude product was removed by rotary evaporation under reduced pressure to obtain the product (i.e., single-terminal carboxyl polyethylene glycol monomethyl ether mPEG-COOH), which was a colorless to light yellow viscous liquid.

[0040] The reaction equation for preparing single-terminal carboxyl polyethylene glycol monomethyl ether mPEG-COOH in this embodiment is as follows: Figure 5 As shown, the SEC-MALLS chromatogram of the prepared single-terminal carboxyl polyethylene glycol monomethyl ether mPEG-COOH, 1 H NMR spectrum and infrared spectrum are shown in Figure 6-7 shown.

[0041] Example 3 Polymer Brush PAGE- g Preparation of PEG-mPEG To a 50 mL single-necked flask, 1.1348 g of dehydrated hydroxyl-terminated polyether PAGE (Mn = 5150 g / mol, 0.022 mol) was added. 15 mL of tetrahydrofuran was added to fully dissolve the hydroxyl-terminated polyether. 6.6375 g of monocarboxyl-terminated polyethylene glycol monomethyl ether mPEG-COOH (8.8 mmol) was then added. The mixture was transferred to a low-temperature reaction bath maintained at 0°C. N2 was bubbled through the reaction system for 30 min. After the internal and external temperatures equilibrated, 3.15 g of N-bromosuccinimide (NBS) (0.0177 mol) was added. The reaction was stirred in an ice bath at 0°C for 1 h, then transferred to room temperature at 25°C and continued for 24 h. The total reaction time was 25.5 h, yielding the crude product.

[0042] The crude product was filtered to remove some NBS, and then concentrated by rotary evaporation to remove some THF. The product was then transferred to a 1000D dialysis bag, which was cut to a length of 5 cm. The mass volume ratio of the crude product to water was 1 g:500 mL. The dialysis time was 2 days to remove excess N-bromosuccinimide. After the dialysis, the crude product was freeze-dried for 2 days. After freeze-drying to remove water, the product was dissolved in 20 mL of THF and transferred to a 50 mL flask. The product was rotary evaporated under reduced pressure at 60 ° C to remove tetrahydrofuran in the crude product to obtain the product (i.e., polymer brush PAGE- g -mPEG), the product is a colorless to light yellow viscous liquid.

[0043] Example 4 Preparation of poly (N-isopropylacrylamide) PNIPAM 6.5 g (0.058 mol) of N-isopropylacrylamide was dissolved in 10 mL of DMF, and the system was transferred to a constant temperature reaction bath at 25°C. After the internal temperature of the reaction system was balanced with the external temperature, 0.13 g (0.00167 mol) of mercaptoethanol was added. After the addition, N2 was bubbled into the system for 30 min; 0.12 g (0.00075 mol) of azobisisobutyronitrile was added, and the reaction was stirred in an oil bath at 70°C under N2 atmosphere for 24 h, and the total reaction time was 24.5 h to obtain a crude product.

[0044] The crude product was concentrated by vacuum distillation at 65°C, and then dropped into 300 mL of ether for precipitation for 12 hours. Finally, the product was freeze-dried for 2 days in a freeze dryer to remove water from the crude product to obtain a white solid product, namely poly(N-isopropylacrylamide) PNIPAM.

[0045] The poly (N-isopropylacrylamide) PNIPAM prepared in this example 1 H NMR spectrum Figure 9 shown.

[0046] Example 5 Preparation of Thermosensitive Triblock Copolymer PNIPAM-b-(PAGE-g-mPEG)-b-PNIPAM 0.6 g polymer brush PAGE- g -mPEG (Mn = 5987 g / mol, 0.0001 mol) and 0.6 g PNIPAM (Mn = 2987 g / mol, 0.0002 mol), 30 mL toluene was added to make the polymer brush PAGE- gAfter fully dissolving the mPEG and PNIPAM, the temperature was raised to 120°C, and 15 mL of toluene was distilled off. After the system cooled to room temperature, it was transferred to a high-temperature reaction bath at 70°C. After the internal and external temperatures equilibrated, 0.35 g (0.0002 mol) of toluene-2,4-diisocyanate (2,4-TDI) was added. After equilibrium, 1 μL of bismuth 2-ethylhexanoate was added to the system, and the reaction was stirred in the reaction bath at an accelerated speed for 4 hours.

[0047] Separately, 0.6 g of PNIPAM (Mn = 2987 g / mol, 0.0002 mol) was added to 30 mL of toluene to fully dissolve it. The temperature was raised to 120°C, and 30 mL of toluene was distilled off to obtain the dehydrated PNIPAM. After a 4-hour reaction, 0.6 g of dehydrated PNIPAM (Mn = 2987 g / mol, 0.0002 mol) was added to the reaction system. Stirring was continued for another 4 hours, for a total of 8 hours. After the reaction, stirring was increased, and the oil phase was subjected to reduced pressure rotary distillation at 70°C to remove the toluene. The crude product was then spin-dried to obtain the thermosensitive triblock copolymer PNIPAM-b-(PAGE-g-mPEG)-b-PNIPAM.

[0048] The SEC-MALLS chromatogram of the thermosensitive triblock copolymer PNIPAM-b-(PAGE-g-mPEG)-b-PNIPAM prepared in this example is shown in FIG. Figure 10 shown.

[0049] Unless otherwise specified, all percentages used in the present invention are by mass.

[0050] Finally, it should be noted that the above descriptions are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art will be able to modify the technical solutions described in the aforementioned embodiments or substitute equivalents for some of the technical features. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention shall be included within the scope of protection of the present invention.

Claims

1. A method for preparing a thermosensitive triblock copolymer containing polyethylene glycol in side groups, characterized in that: Hydroxyl-terminated polyether PAGE and single-carboxyl-terminated polyethylene glycol monomethyl ether mPEG-COOH reacted in the presence of N-bromosuccinimide to prepare a polymer brush PAGE-g-mPEG. The polymer brush PAGE-g-mPEG then reacted with poly(N-isopropylacrylamide) to form a thermosensitive triblock copolymer containing polyethylene glycol side groups. The hydroxyl-terminated polyether PAGE is prepared by reacting 1,4-butanediol with allyl glycidyl ether in tetrahydrofuran.

2. The method for preparing the thermosensitive triblock copolymer containing polyethylene glycol in the side groups according to claim 1, characterized in that: The method comprises the following steps: preparing a polymer brush PAGE-g-mPEG; The method for preparing the polymer brush PAGE-g-mPEG comprises: dissolving hydroxyl-terminated polyether PAGE and single-carboxyl-terminated polyethylene glycol monomethyl ether mPEG-COOH in a solvent under anhydrous conditions; adding N-bromosuccinimide in an ice-water bath under a nitrogen atmosphere; reacting in an ice-water bath; and then continuing the reaction at room temperature to obtain a crude product; and dialyzing and distilling the crude product under reduced pressure to obtain the polymer brush PAGE-g-mPEG.

3. The method for preparing the thermosensitive triblock copolymer containing polyethylene glycol in the side groups according to claim 1, characterized in that: The method comprises the following steps: preparing a thermosensitive triblock copolymer containing polyethylene glycol in the side group; The method for preparing a thermosensitive triblock copolymer containing polyethylene glycol in side groups comprises dissolving a polymer brush PAGE-g-mPEG and poly(N-isopropylacrylamide) in a solvent, heating the mixture to 70-75° C., adding toluene-2,4-diisocyanate and bismuth-2-ethylhexanoate, and carrying out a reaction at the same temperature to obtain a crude product. The crude product is subjected to reduced pressure distillation to obtain a thermosensitive triblock copolymer containing polyethylene glycol in side groups.

4. The method for preparing the thermosensitive triblock copolymer containing polyethylene glycol in the side groups according to claim 1, characterized in that: The method comprises the following steps: preparing hydroxyl-terminated polyether PAGE; The method for preparing the hydroxyl-terminated polyether PAGE comprises dissolving 1,4-butanediol in tetrahydrofuran, adding boron trifluoride ether under ice bath conditions, mixing evenly, and then dripping allyl glycidyl ether; after the dripping of allyl glycidyl ether is completed, continuing the reaction to obtain a crude product; and washing and distilling the crude product under reduced pressure to obtain the hydroxyl-terminated polyether PAGE.

5. The method for preparing the thermosensitive triblock copolymer containing polyethylene glycol in the side groups according to claim 1, characterized in that: The method comprises the following steps: preparing single-terminal carboxyl polyethylene glycol monomethyl ether mPEG-COOH; The method for preparing single-end carboxyl polyethylene glycol monomethyl ether mPEG-COOH comprises the following steps: dissolving polyethylene glycol monomethyl ether with a number average molecular weight of 750 g / mol and succinic anhydride in a solvent; adding triethylamine in a nitrogen atmosphere; and reacting at room temperature to obtain a crude product; concentrating the crude product by rotary evaporation, and then adding diethyl ether to precipitate; separating and obtaining a precipitate, washing, drying, and evaporating under reduced pressure to obtain the single-end carboxyl polyethylene glycol monomethyl ether mPEG-COOH.

6. The method for preparing the thermosensitive triblock copolymer containing polyethylene glycol in the side groups according to claim 2, characterized in that: The molar ratio of the hydroxyl-terminated polyether PAGE, the single-carboxyl-terminated polyethylene glycol monomethyl ether mPEG-COOH, and N-bromosuccinimide is 2-6:1:2-3; The reaction time of the ice-water bath reaction is 1-2 hours; the reaction time at room temperature is 20-24 hours; The molecular weight cut-off of the dialysis was 1000D.

7. The method for preparing the thermosensitive triblock copolymer containing polyethylene glycol in the side groups according to claim 3, characterized in that: The molar ratio of the polymer brush PAGE-g-mPEG, poly (N-isopropylacrylamide), and toluene-2,4-diisocyanate is 1:1-4:1-4; The insulation reaction time is 4-10 hours.

8. The method for preparing the thermosensitive triblock copolymer containing polyethylene glycol in the side groups according to claim 4, characterized in that: The molar ratio of 1,4-butanediol, boron trifluoride ethyl ether, and allyl glycidyl ether is 1-1.5:0.7-1:20-25; The dropping time of the allyl glycidyl ether is 1-2h; The reaction time after the allyl glycidyl ether is added dropwise is 4-6 hours.

9. The method for preparing the thermosensitive triblock copolymer containing polyethylene glycol in the side groups according to claim 5, characterized in that: The molar ratio of polyethylene glycol monomethyl ether, succinic anhydride and triethylamine is 0.5-1:1:0.1-0.2; The reaction time at room temperature is 20-24 hours.

10. A thermosensitive triblock copolymer containing polyethylene glycol as a side group, characterized in that: The method is prepared according to any one of claims 1 to 9.

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