Temperature-responsive degradable polymers and methods for making the same

Abstract

The application discloses a kind of temperature response degradable polymer and preparation method thereof, the polymer is the terpolymer P (AAm-co-MI-co-MDO) of AAm, MI and MDO.It is prepared by the radical ring-opening polymerization of RAFT control, and is reacted in DMSO after being purified with initiator AIBN, chain transfer reagent CDSPA.The critical solubility temperature characteristics are given to polymer by hydrogen bond interaction between AAm and MI unit, and by changing monomer molar ratio, polymer phase transition temperature can be controlled in 20~65 ℃ interval;Meanwhile, the ring-opening rate of MDO is increased to more than 85% by using the donor-acceptor copolymerization effect of MI and MDO, and the hydrolyzable ester bond is efficiently embedded in the main chain to realize degradability.The polymer has temperature response and controllable degradability, and the synthesis method is simple and efficient, which has application potential in the field of drug controlled release, tissue engineering and other biomedical fields.

Description

Technical Field

[0001] This invention relates to the field of functional polymer materials technology, specifically to a temperature-responsive biodegradable polymer and its preparation method. Background Technology

[0002] Temperature-responsive polymers, a key branch of smart materials, can undergo reversible phase transitions in response to changes in ambient temperature, thereby precisely controlling their solubility, hydrophilicity-hydrophobicity balance, and gelation behavior. They show broad application prospects in areas such as drug delivery carriers, tissue engineering scaffolds, and environmentally responsive repair materials. Based on their phase transition behavior, these polymers are mainly divided into two categories: lower critical temperature (LCST) type and upper critical temperature (UCST) type. Among them, UCST type polymers, with their unique "low-temperature aggregation, high-temperature dissolution" characteristics, demonstrate irreplaceable application advantages in specific scenarios such as low-temperature protein enrichment, controlled adsorption and separation, and photothermal therapy.

[0003] However, at present, the upper critical dissolution temperature of most UCST polymers is difficult to be precisely controlled over a wide range, which limits their application in physiologically relevant temperature ranges. In addition, the main chain of the polymer is based on a non-degradable carbon-carbon covalent structure, which cannot degrade itself after fulfilling its functional mission, making it difficult to meet the strict requirements of biomedical fields for the biodegradability of materials.

[0004] In recent years, radical ring-opening polymerization (rROP) of cycloenone acetals (CKA) and vinyl monomers has provided an effective way to embed degradable ester bonds into the carbon-carbon backbone of vinyl polymers. Furthermore, combining this with reversible deactivating radical polymerization (RDRP) technology has enabled the design and controllable preparation of degradable vinyl polymers. However, traditional CKA-vinyl monomer copolymerization systems typically face inherent problems such as low ring-opening efficiency and poor sequence regularity of CKA monomers, resulting in a low embedding rate of ester bonds in the polymer backbone. This, to some extent, limits the functional realization and application of such materials in high-end biomedical fields.

[0005] Therefore, based on the aforementioned background and problems, this invention provides a temperature-responsive degradable polymer and its preparation method. A terpolymer, denoted as poly(acrylamide-maleimide-2-methylene-1,3-dioxane), is prepared by radical ring-opening copolymerization of acrylamide, maleimide, and 2-methylene-1,3-dioxane under the control of a reversible addition-fragmentation chain transfer polymerization reagent. The UCST-type temperature-responsive behavior is constructed using the hydrogen bonding between acrylamide and maleimide, and the donor-acceptor copolymerization effect of maleimide and 2-methylene-1,3-dioxane significantly enhances the ring-opening efficiency of 2-methylene-1,3-dioxane. This efficiently and uniformly introduces hydrolyzable ester bonds into the polymer backbone, ultimately achieving integrated control of the material's phase transition temperature within the range of 20–65°C and its controllable degradation function. Summary of the Invention

[0006] The purpose of this invention is to provide a temperature-responsive biodegradable polymer and its preparation method, so as to achieve the integrated function of controlling the phase change temperature of the material within the range of 20~65℃ and the controllable degradation function.

[0007] The objective of this invention is achieved through the following technical solution:

[0008] A temperature-responsive biodegradable polymer, wherein the polymer is a terpolymer of acrylamide (AAm), maleimide (MI), and 2-methylene-1,3-dioxane (MDO), denoted as poly(acrylamide-maleimide-2-methylene-1,3-dioxane) (P(AAm-co-MI-co-MDO)), has the following general structural formula:

[0009] ;

[0010] Where n is the degree of polymerization, n = 40~100;

[0011] The polymer's main chain contains hydrolyzable ester bond structural units formed by the ring-opening polymerization of monomer 2-methylene-1,3-dioxane-heptane, giving it biodegradability.

[0012] In the polymer, acrylamide (AAm) units and maleimide (MI) units interact through hydrogen bonds to form a dynamic physical cross-linking network, which causes it to exhibit an upper critical solution temperature (UCST) type phase transition temperature response behavior in aqueous solution. The phase transition temperature can be controlled within the range of 20℃ to 65℃ by adjusting the molar ratio of AAM units to MI units. The molar ratio of AAM units to MI units is 4 to 19:1, and the molar ratio of MI units to 2-methylene-1,3-dioxane (MDO) units is 0.5 to 2:1.

[0013] Preferably, the molar ratio of the AAm unit, the MI unit, and the MDO unit is (8~15):(1):(1).

[0014] This application also claims a method for preparing the above-mentioned temperature-responsive degradable polymer, comprising the following steps:

[0015] (1) Purification of monomers and reagents: The monomers AAm, MI, MDO, azobisisobutyronitrile (AIBN) initiator and dimethyl sulfoxide (DMSO) were purified respectively.

[0016] (2) Polymerization reaction: Under an inert atmosphere, the monomers AAm, MI and MDO purified in step (1), as well as the reversible addition-fragmentation chain transfer polymerization (RAFT) reagent 4-cyano-4-[(dodecylthioalkylthiocarbonyl)thioalkyl]valeric acid (CDSPA) and initiator AIBN are dissolved in the anhydrous DMSO purified in step (1) to form a homogeneous reaction solution; the reaction system is stirred at 65~70℃ for 12~24 hours;

[0017] (3) Product purification: Cool the reaction solution of step (2) after stirring for 12-24 hours to room temperature, and then add it dropwise to ice-cold methanol for precipitation; centrifuge to obtain polymer precipitate, wash the precipitate with cold methanol, and repeat the washing 3-5 times; then vacuum dry the obtained polymer to obtain the target product P(AAm-co-MI-co-MDO).

[0018] Preferably, in step (2), the total molar ratio of the monomers AAm, MI, and MDO to the initiator AIBN is 200:1; and the total molar ratio of the monomers AAm, MI, and MDO to the RAFT reagent CDSPA is 40:1.

[0019] Preferably, in step (1), the purification process of the monomer AAm is as follows: crude acrylamide is dissolved in chloroform at 60~70℃, hot filtered and cooled to crystallize, filtered and washed with pre-cooled diethyl ether, vacuum dried to obtain purified AAm monomer, and stored frozen in the dark.

[0020] Preferably, in step (1), the purification process of the monomer MI is as follows: the crude maleimide is dissolved in dichloromethane at 60~70℃ to form a saturated solution, petroleum ether or n-hexane is added to the hot saturated solution until slight turbidity appears, the solution is cooled and crystallized, filtered, the crystals are washed with a pre-cooled mixed solvent of petroleum ether or n-hexane and dichloromethane or ethanol, and the purified MI monomer is obtained after vacuum drying at 25~40℃.

[0021] Preferably, in step (1), the purification process of the monomer MDO is as follows: the target monomer is purified by layer chromatography, with 200-300 mesh alkaline alumina as the stationary phase and n-hexane as the mobile phase for elution, the eluent containing MDO is collected, and the purified MDO monomer is obtained after rotary evaporation, concentration and drying.

[0022] Preferably, in step (1), the purification treatment of the initiator AIBN is as follows: crude AIBN is dissolved in methanol at 50~60℃ to form a saturated solution, cooled to precipitate crystals, the crystals are separated and dried at 25~35℃ under vacuum to obtain purified initiator AIBN.

[0023] Preferably, in step (1), the purification process of the solvent DMSO is as follows: anhydrous DMSO solvent is placed in a reaction vessel and frozen into a solid state in low-temperature liquid nitrogen; then a high vacuum (e.g., <0.1 Pa) is drawn into the system; the system is sealed and allowed to naturally rise to room temperature so that the solvent is completely thawed into a liquid state; this freezing-vacuuming-thawing cycle is repeated 2 to 4 times, and finally restored to normal pressure under the protection of inert gas to obtain deeply deoxygenated DMSO solvent.

[0024] Preferably, the polymer can undergo hydrolytic cleavage of the main chain ester bonds in an alkaline aqueous solution, thereby achieving degradation.

[0025] The working mechanism of this invention is as follows: the sequence structure of the terpolymer is controlled by reversible addition-fragmentation chain transfer polymerization, in which acrylamide and maleimide units form a physical cross-linking network through dynamic hydrogen bonding, endowing the polymer with unique upper critical solution temperature-type phase transition characteristics; at the same time, maleimide is used as an electron-deficient monomer to undergo donor-acceptor alternating copolymerization with electron-rich 2-methylene-1,3-dioxane, which significantly improves the ring-opening efficiency of cyclic monomers, thereby regularly embedding hydrolyzable ester bonds in the polymer backbone, and finally achieving synergistic regulation of temperature response behavior and degradation performance.

[0026] Due to the application of the above technical solution, the present invention has the following beneficial effects compared with the prior art:

[0027] 1. This invention achieves functional integration and performance breakthrough. Through innovative molecular structure design, it successfully integrates the hydrogen bonding units of acrylamide (AAm) and maleimide (MI) and the hydrolyzable ester bond units of 2-methylene-1,3-dioxane (MDO) into the same polymer chain, endowing traditional UCST-type polymers with degradability and preparing a new generation of smart materials that simultaneously possess temperature responsiveness and degradability.

[0028] 2. This invention improves polymerization efficiency and structural controllability. By utilizing maleimide as an electron-deficient acceptor and the donor-acceptor alternating copolymerization effect between electron-rich MDO monomers, the ring-opening rate of MDO is increased to over 85%, which significantly suppresses the side reactions that retain the cyclic structure. This achieves efficient and uniform insertion of hydrolyzable ester bonds into the main chain, overcoming the limitations of low ring-opening efficiency and poor polymer sequence structure controllability in traditional CKA copolymerization with vinyl monomers.

[0029] 3. This invention enables the customization of phase transition temperature. By precisely controlling the monomer feeding ratio of AAm, MI and MDO, the upper critical dissolution temperature of the polymer can be controlled within the range of 20~65℃. This temperature range fully covers the physiologically relevant temperature range, providing key performance assurance for biomedical applications such as drug controlled release and smart gels.

[0030] 4. This invention expands the design and application space of materials. The synthetic route is simple, efficient, and mild, and the raw materials and processes are green and safe. It not only achieves the synergistic regulation of the UCST temperature window and degradation kinetics, but also provides a new paradigm for the molecular design of multifunctional smart materials, showing broad application prospects in high-end fields such as tissue engineering and environmental remediation. Attached Figure Description

[0031] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, some of the drawings in the following description are some embodiments of the present invention. For those skilled in the art, other drawings can be made based on these drawings without creative effort.

[0032] Figure 1 The polymer P(AAm-co-MI-co-MDO) of Example 1 of this invention 1 HNMR spectrum;

[0033] Figure 2 This is a synthetic route diagram of polymer P(AAm-co-MI-co-MDO) in Example 1 of the present invention;

[0034] Figure 3 This is a temperature-transmittance curve of the temperature-responsive biodegradable polymer P (AAm-co-MI-co-MDO) solution from Example 1 of the present invention.

[0035] Figure 4 This is a DLS curve of the temperature-responsive biodegradable polymer P(AAm-co-MI-co-MDO) solution at different temperatures in Example 1 of the present invention.

[0036] Figure 5This is a temperature-transmittance curve of P(AAm-co-MI-co-MDO) solution at different concentrations in Example 1 of the present invention, which is a temperature-responsive biodegradable polymer 2.

[0037] Figure 6 This is a DLS curve of temperature-responsive biodegradable polymer 2, P(AAm-co-MI-co-MDO) solution at different concentrations and temperatures in Example 1 of the present invention.

[0038] Figure 7 This is a GPC curve of the degradation products of the temperature-responsive degradable polymer P(AAm-co-MI-co-MDO) in Example 1 of the present invention.

[0039] Figure 8 This is a structure-property relationship diagram of the temperature-responsive degradable polymer P(AAm-co-MI-co-MDO) from Example 1 of the present invention. Detailed Implementation

[0040] To provide a clearer understanding of the technical features, objectives, and effects of this invention, specific implementation schemes are now described in detail.

[0041] The present invention will be further described below with reference to embodiments, but the present invention is not limited to the following embodiments. The implementation conditions used in the embodiments can be further adjusted according to different requirements of specific use, and the implementation conditions not specified are conventional conditions in the industry. The technical features involved in the various embodiments of the present invention can be combined with each other as long as they do not conflict with each other.

[0042] Example 1

[0043] See appendix Figure 1 ~Appendix Figure 8 This embodiment provides a method for preparing a temperature-responsive degradable polymer, comprising the following steps:

[0044] (1) Purification of monomers and reagents: The monomers AAm (acrylamide), MI (maleimide), MDO (2-methylene-1,3-dioxane), AIBN initiator and DMSO (anhydrous dimethyl sulfoxide) were purified respectively.

[0045] Specifically, the purification process of the monomer AAm (acrylamide) is as follows: crude acrylamide is dissolved in chloroform at 65°C, hot filtered and cooled to crystallize, filtered and washed with pre-cooled diethyl ether, vacuum dried to obtain purified AAm monomer, and stored frozen in the dark.

[0046] The purification process of the monomer MI (maleimide) is as follows: crude maleimide is dissolved in dichloromethane at 65°C to form a saturated solution. Petroleum ether or n-hexane is added to the hot saturated solution until slight turbidity appears. After cooling and crystallization, the solution is filtered. The crystals are washed with a mixture of pre-cooled petroleum ether or n-hexane and dichloromethane or ethanol. The purified MI monomer is obtained after vacuum drying at 35°C.

[0047] The purification process of the monomer MDO (2-methylene-1,3-dioxane) is as follows: the target monomer is purified by layer chromatography, with 200-mesh basic alumina as the stationary phase and n-hexane as the mobile phase for elution. The eluent containing MDO is collected, concentrated by rotary evaporation, and dried to obtain the purified MDO monomer.

[0048] The purification process of the initiator AIBN is as follows: crude AIBN is dissolved in methanol at 55°C to form a saturated solution, cooled to precipitate crystals, the crystals are separated and dried at 30°C under vacuum to obtain purified initiator AIBN.

[0049] The purification process of the solvent DMSO is as follows: anhydrous DMSO solvent is placed in a reaction vessel and frozen into a solid state in liquid nitrogen at low temperature; then the system is evacuated to a high vacuum (<0.1 Pa); the system is sealed and allowed to naturally heat up to room temperature to completely thaw the solvent into a liquid state; this freezing-evacuation-thawing cycle is repeated 4 times, and finally restored to atmospheric pressure under the protection of inert gas to obtain deeply deoxygenated DMSO solvent;

[0050] (2) Polymerization reaction: Under the protection of an inert atmosphere, the monomers AAm, MI and MDO purified in step (1), as well as the RAFT reagent CDSPA and the initiator AIBN, are dissolved in the anhydrous DMSO purified in step (1) to form a homogeneous reaction solution; the reaction system is stirred at 70°C for 16 hours.

[0051] (3) Product purification: The reaction solution of step (2) stirred for 16 hours was cooled to room temperature and then added dropwise to ice-cold methanol for precipitation; after ultrasonic dispersion for 5 minutes, the polymer precipitate was collected by centrifugation and washed with cold methanol. The washing was repeated 3 to 5 times; the obtained polymer was then placed in a vacuum drying oven and dried for 12 hours to obtain the target product P(AAm-co-MI-co-MDO).

[0052] In this embodiment, by adjusting the feed ratios of monomers AAm, MI, and MDO, three UCST polymers with different compositions were prepared, labeled as follows:

[0053] UCST polymer 1 (AAm:MI:MDO=180:20:40);

[0054] UCST polymer 2 (AAm:MI:MDO = 160:40:40);

[0055] UCST polymer 3 (AAm:MI:MDO = 150:50:40);

[0056] The degree of polymerization n of all three is controlled at 60.

[0057] Take the UCST polymer 2 (AAm:MI:MDO = 160:40:40) prepared in this embodiment, dissolve it in deuterated dimethyl sulfoxide (DMSO-d6), and perform structural characterization by nuclear magnetic resonance hydrogen spectrum ( 1 H NMR). As Figure 1 shown, the d peak (δ = 6.70 - 7.35 ppm) belongs to the secondary amine (-NH-) protons in the maleimide unit, the f peak is the proton signal of the amide group (-CONH2) in the acrylamide unit, and the e peak (δ = 5.35 ppm) corresponds to the protons of the methylene adjacent to the ester group (-COO-CH2-) formed by the ring-opening of MDO. The appearance and attribution of each characteristic peak are consistent, indicating that the target copolymer has been successfully synthesized.

[0058] Use a temperature-controlled ultraviolet-visible spectrophotometer to measure the transmittance of the polymer aqueous solution to characterize its UCST phase transition behavior. The test conditions are as follows: detection wavelength 500 nm, optical path 2 mm, and the sample cell is in a continuous magnetic stirring state; place the polymer aqueous solution with a concentration of 20 mg / mL in a quartz cuvette and heat it from a low temperature (T < UCST) at a constant rate of 1 °C / min; the upper critical solution temperature (UCST) is defined as the temperature corresponding to the inflection point of the transmittance-temperature curve during the heating process, and this inflection point is determined by the maximum value of the first derivative of the curve.

[0059] The results are as Figure 3 shown. The polymer samples with different monomer ratios show significantly different UCST values:

[0060] The UCST of UCST polymer 1 (AAm: MI: MDO = 180:20:40) is about 20 °C;

[0061] The UCST of UCST polymer 2 (AAm: MI: MDO = 160:40:40) is about 50 °C;

[0062] The UCST of UCST polymer 3 (AAm: MI: MDO = 150:50:40) is about 60 °C.

[0063] The above results show that by adjusting the feeding ratio of AAm and MI, the effective regulation of the UCST value of the polymer can be achieved, providing a basis for the directional design of intelligent thermosensitive materials.

[0064] like Figure 4 As shown, the thermal response behavior of the polymers was systematically characterized by transmittance testing and dynamic light scattering (DLS). The cloud point (Tcp) of polymers prepared with different monomer feed ratios could be effectively controlled within the range of 20–65 °C. When the temperature was above the UCST, the copolymers were completely dissolved in water, exhibiting an average hydrodynamic diameter (Dz) of approximately 10 nm; when the temperature dropped below the UCST, the polymer chains rapidly aggregated, resulting in a significant increase in Dz to 2–5 µm. The results of temperature-controlled UV analysis and DLS showed high agreement, jointly verifying the accuracy and consistency of the thermal transition behavior of this series of polymers.

[0065] Different concentrations of aqueous solutions of UCST polymer 3 (AAm: MI: MDO = 150:50:40) were prepared, and the effect of concentration on thermal response behavior was studied using a temperature-controlled UV-Vis spectrophotometer. The test conditions were as follows: wavelength 500 nm, heating rate 1℃ / min, concentration range 5–50 mg / mL; the results are as follows. Figure 5 As shown, all concentration samples exhibited clear UCST phase transition behavior, and the transmittance change curves displayed a typical "S"-shaped characteristic; as the polymer concentration increased from 10 mg / mL to 25 mg / mL, its UCST value showed a regular change:

[0066] 10 mg / mL: UCST = 15℃;

[0067] 15 mg / mL: UCST = 30℃;

[0068] 20 mg / mL: UCST = 50℃;

[0069] 25 mg / mL: UCST = 60℃;

[0070] It is worth noting that UCST shows a non-monotonic trend with concentration: in the range of 10~25 mg / mL, UCST increases with increasing concentration; the phase transition process of all samples shows good reversibility, and the transmittance curves basically overlap after three heating-cooling cycles, indicating that the material has stable thermal response performance.

[0071] like Figure 6As shown, the hydrodynamic diameter (Dz) of UCST polymer 3 at different concentrations (10, 15, 20, and 25 mg / mL) was investigated by dynamic light scattering (DLS) as a function of temperature. The results are in high agreement with the phase transition behavior observed by temperature-controlled ultraviolet (TUV) measurements. When the temperature is below the cloud point, all samples exhibit micron-sized aggregates (Dz > 2 μm). As the temperature increases to near the cloud point corresponding to each concentration (15, 30, 45, and 50 °C, respectively), Dz drops sharply to the 1000–2000 nm range, indicating that the polymer chains have completely dissolved into single-chain conformations. Notably, the phase transition temperature increases accordingly with increasing concentration from 10 mg / mL to 25 mg / mL, reflecting that higher concentration solutions require more thermal energy to disrupt the hydrogen bond physical cross-linking network formed between chains. The phase transition temperature observed by DLS is consistent with the UV transmittance measurements, jointly verifying that this UCST polymer possesses significant and repeatable thermal response characteristics at different concentrations.

[0072] Polymer 3 was subjected to accelerated degradation in a 5wt% KOH solution at room temperature for 24 hours to systematically evaluate its hydrolysis performance. Figure 7 As shown, gel permeation chromatography (GPC) analysis of the degraded polymer revealed a significant shift of the main peak of copolymer P(AAm-co-MI-co-MDO) towards the lower molecular weight region, with the molecular weight distribution broadening from Đ=1.4 to Đ=4.2. This change confirms that the ester bonds in the polymer backbone undergo selective cleavage under alkaline conditions, leading to molecular chain degradation. Notably, the degraded fragments remained uniformly dispersed in solution, without exhibiting insoluble aggregation, indicating that the chain cleavage process was effective and did not induce secondary crosslinking or phase separation.

[0073] like Figure 8 As shown, the cloud point (T) of different polymer samples was systematically investigated. cp The molar fraction (F) of maleimide (MI) and 2-methylene-1,3-dioxane-heptane (MDO) in the copolymer. MI With F MDO The variation of the MI molar fraction revealed the structure-property relationship between monomer composition and temperature response behavior. As the MI molar fraction gradually increased from 0.056 to 0.127, the Tcp of the polymer could be continuously controlled within the range of 20–65 °C, indicating that MI, as a hydrogen bond donor-acceptor functional unit, has a dominant influence on the phase transition temperature. This trend confirms that by precisely controlling the proportion of the functional monomer MI in the copolymer, the density and stability of the hydrogen bond physical crosslinking network can be effectively controlled, thereby achieving the directional design of the UCST-type thermal response behavior of the material.

[0074] The testing and characterization methods used in the embodiments of the present invention are as follows:

[0075] 1H NMR spectrum ( 1 Characterization by 1H NMR: The polymer was characterized using deuterated dimethyl sulfoxide (DMSO-d6, δ=2.50ppm) as solvent and internal standard, and NMR data were collected on a Bruker AVANCE III 400MHz NMR spectrometer. 1 HNMR spectrum. Sample concentration: approximately 10 mg / mL -1 The concentration was prepared and sonicated before testing to ensure complete dissolution. Fourier transform, phase and baseline corrections were performed on the obtained data using MestReNova 11.0.4 software, followed by normalization for peak assignment and integral analysis.

[0076] Molecular weight determination: The molecular weight and distribution of the polymer were characterized using a Waters E2695 gel permeation chromatography system equipped with a differential refractive index detector. Ultrapure water containing 0.1 M LiBr was used as the mobile phase, and the flow rate was set to 0.5 mL / min. -1 The chromatographic column (PL aquagel-OH MIXED-M, 7.8 × 300 mm) was maintained at 70 °C. The system was calibrated using linear polyethylene glycol standards to calculate the apparent number-average molecular weight and dispersion factor (Đ) of the samples. Samples were dissolved in ultrapure water (2–3 mg / mL) before injection. -1 After being filtered through a 0.45μm PTFE membrane, the data were collected and processed using the Empower software system.

[0077] Transmittance was tested using a UV-Vis spectrophotometer: polymer aqueous solutions of different concentrations were placed in quartz cuvettes with an optical path of 2 mm and measured under constant magnetic stirring conditions at a wavelength of 500 nm; during the test, the solution was heated from the initial temperature (below its UCST) at a heating rate of 1 °C / min; the upper critical dissolution temperature (UCST) was determined by analyzing the extreme points of the first derivative of the transmittance-temperature curve.

[0078] Dynamic light scattering (DLS) testing: A dynamic light scattering instrument equipped with a 4mW He-Ne laser source (λ=633nm) was used to determine the hydrodynamic diameter and its distribution of the samples at a scattering angle of 173°. Polymer aqueous solutions of different concentrations were placed in quartz cuvettes, and sample preparation was performed according to the same procedure as for UV-Vis testing. The test started at a temperature below the UCST, with the temperature gradually increased in 1°C increments. Data was collected after equilibration for 60 seconds at each temperature point. The above critical dissolution temperature (UCST) was defined as the inflection point temperature of the hydrodynamic diameter-temperature curve, and the obtained UCST values ​​were corroborated by the UV analysis results.

[0079] Example 2

[0080] The preparation method of the polymer in this embodiment is the same as that of the polymer in Example 1, and will not be repeated here. In this embodiment, the molar ratio of AAm:MI:MDO is set to 19:1:1. The resulting polymer exhibits a low upper critical eutectic temperature transition behavior. In the temperature range of 20℃ to 70℃, the transmittance of the polymer aqueous solution remains basically stable, and no obvious phase separation phenomenon is observed. When the temperature drops to 5℃, the solution becomes turbid, indicating that a reversible UCST-type phase transition has occurred in the system.

[0081] Comparative Example 1

[0082] The preparation method of the polymer in this comparative example is the same as that of the polymer in Example 1, and will not be repeated here. The molar ratio of AAm:MI:MDO in this comparative example is set to 20:1:1. The obtained polymer did not show obvious UCST transition behavior in aqueous solution, and the transmittance of the solution remained basically unchanged in the range of 20~70℃, indicating that its temperature responsiveness disappeared.

[0083] Comparative Example 2

[0084] The preparation method of the polymer in this comparative example is the same as that of the polymer in Example 1, and will not be repeated here. No MDO monomer was added in this comparative example. The UCST transition temperature decreased, and the resulting polymer structure had no ester group structure and did not exhibit degradation behavior.

[0085] The products prepared in the above examples and comparative examples were tested, and the test results are shown in Table 1.

[0086] Table 1

[0087]

[0088] In summary, the temperature-responsive degradable polymer and its preparation method provided by this invention have multiple significant advantages: Through innovative molecular structure design, the hydrogen bonding units of acrylamide and maleimide and the hydrolyzable ester bond units of MDO are successfully integrated into the same polymer chain, successfully preparing a smart responsive polymer that combines UCST responsiveness and degradability; by utilizing the donor-acceptor alternating copolymerization effect between maleimide as an electron-deficient acceptor and electron-rich MDO monomer, the ring-opening rate of MDO is increased to over 85%, achieving efficient and uniform embedding of hydrolyzable ester bonds in the main chain; by precisely controlling the monomer feeding ratio, the upper critical dissolution temperature can be adjusted within the range of 20~65°C, completely covering the physiologically relevant temperature range; this synthetic route is simple, efficient, and mild, not only achieving synergistic control of the UCST temperature window and degradation kinetics, but also providing a new paradigm for the molecular design of multifunctional smart materials, showing broad application prospects in high-end fields such as drug controlled release and tissue engineering.

[0089] The embodiments described above merely illustrate more specific and detailed implementations of the present invention, and should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A temperature-responsive biodegradable polymer, characterized in that, The polymer is a terpolymer of acrylamide, maleimide, and 2-methylene-1,3-dioxane, denoted as poly(acrylamide-maleimide-2-methylene-1,3-dioxane), and has the following general structural formula: ； Where n is the degree of polymerization, n = 40~100; The phase transition temperature can be controlled within the range of 20℃ to 65℃ by adjusting the molar ratio of acrylamide units to maleimide units in the polymer; the molar ratio of acrylamide units to maleimide units is 4~19:1; the molar ratio of maleimide units to 2-methylene-1,3-dioxane units is 0.5~2:

1.

2. A method for preparing the temperature-responsive biodegradable polymer as described in claim 1, characterized in that, Includes the following steps: (1) Purification of monomers and reagents: The monomers acrylamide, maleimide, 2-methylene-1,3-dioxane, azobisisobutyronitrile (azobisisobutyronitrile), and dimethyl sulfoxide (DMSO) were purified respectively. (2) Polymerization reaction: Under an inert atmosphere, the monomers acrylamide, maleimide, and 2-methylene-1,3-dioxane purified in step (1), as well as the reversible addition-fragmentation chain transfer polymerization reagent 4-cyano-4-[(dodecylthioalkylthiocarbonyl)thioalkyl]valerate and the initiator azobisisobutyronitrile are dissolved in the anhydrous dimethyl sulfoxide purified in step (1) to form a homogeneous reaction solution; the reaction system is stirred at 65~70℃ for 12~24 hours; (3) Product purification: Cool the reaction solution from step (2) which has been stirred for 12 to 24 hours to room temperature, and then add it dropwise to ice-cold methanol for precipitation; The polymer precipitate was obtained by centrifugation and washed with cold methanol. The washing was repeated 3 to 5 times. The obtained polymer was then vacuum dried to obtain the target product poly(acrylamide-maleimide-2-methylene-1,3-dioxane).

3. The method for preparing the temperature-responsive biodegradable polymer according to claim 2, characterized in that, In step (2), the total molar ratio of the monomers acrylamide, maleimide, and 2-methylene-1,3-dioxane to the initiator azobisisobutyronitrile is 200:1; the total molar ratio of the monomers acrylamide, maleimide, and 2-methylene-1,3-dioxane to the reversible addition-fragmentation chain transfer polymerization reagent 4-cyano-4-[(dodecylthioalkylthiocarbonyl)thioalkyl]valerate is 40:

1.

4. The method for preparing the temperature-responsive biodegradable polymer according to claim 2, characterized in that, In step (1), the purification process of the monomer acrylamide is as follows: the crude acrylamide is dissolved in chloroform at 60~70℃, hot filtered and cooled to crystallize, filtered and washed with pre-cooled diethyl ether, vacuum dried to obtain purified acrylamide monomer, and stored frozen in the dark.

5. The method for preparing the temperature-responsive biodegradable polymer according to claim 2, characterized in that, In step (1), the purification process of the maleimide monomer is as follows: the crude maleimide is dissolved in dichloromethane at 60~70℃ to form a saturated solution, petroleum ether or n-hexane is added to the hot saturated solution until slight turbidity appears, the solution is cooled and crystallized, filtered, the crystals are washed with a pre-cooled mixed solvent of petroleum ether or n-hexane and dichloromethane or ethanol, and the purified maleimide monomer is obtained after vacuum drying at 25~40℃.

6. The method for preparing the temperature-responsive biodegradable polymer according to claim 2, characterized in that, In step (1), the purification process of the monomer 2-methylene-1,3-dioxane is as follows: the target monomer is purified by layer chromatography, with 200-300 mesh alkaline alumina as the stationary phase and n-hexane as the mobile phase for elution. The eluent containing 2-methylene-1,3-dioxane is collected, concentrated by rotary evaporation, and dried to obtain the purified 2-methylene-1,3-dioxane monomer.

7. The method for preparing the temperature-responsive biodegradable polymer according to claim 2, characterized in that, In step (1), the purification treatment of the initiator azobisisobutyronitrile is as follows: crude azobisisobutyronitrile is dissolved in methanol at 50~60℃ to form a saturated solution, cooled to precipitate crystals, the crystals are separated and dried at 25~35℃ under vacuum to obtain purified initiator azobisisobutyronitrile.

8. The method for preparing the temperature-responsive biodegradable polymer according to claim 2, characterized in that, In step (1), the purification process of the solvent dimethyl sulfoxide is as follows: the dimethyl sulfoxide solvent is placed in a reaction vessel and frozen into a solid state in liquid nitrogen at low temperature; then the system is evacuated to a high vacuum; the system is sealed and allowed to naturally rise to room temperature so that the solvent is completely thawed into a liquid state; this freezing-evacuation-thawing cycle is repeated 2 to 4 times, and finally restored to normal pressure under the protection of inert gas to obtain a deeply deoxygenated dimethyl sulfoxide solvent.

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