Poly (2-oxazoline) thermo-sensitive polymer with side chain containing sulfoxide structure as well as preparation method and application of poly (2-oxazoline) thermo-sensitive polymer
By introducing thioethers onto the side chains of poly(2-oxazoline) and oxidizing them to sulfoxide structures, the problem of regulating thermosensitive polymers has been solved, resulting in polymers with controllable structures, unique thermosensitivity, and good biocompatibility, suitable for applications such as drug controlled release and smart hydrogels.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SHENZHEN UNIV GENERAL HOSPITAL
- Filing Date
- 2026-03-18
- Publication Date
- 2026-05-12
Smart Images
Figure CN122011380A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of functional polymer materials technology, and in particular to a poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in the side chain, its preparation method and application. Background Technology
[0002] In recent years, poly(2-oxazoline) has attracted widespread attention as a type of polymer obtained through controlled living ring-opening polymerization. Poly(2-oxazoline) possesses advantages such as structural diversity, controllable polymerization, and good biocompatibility, and is considered a strong alternative to polyethylene glycol (PEG). By controlling the side chains of 2-oxazoline monomers, a series of functional polymers with diverse properties can be obtained, including thermosensitive polymers. For example, when a certain proportion of hydrophilic / hydrophobic monomers are introduced, poly(2-oxazoline) can exhibit phase transition behavior at the lower critical solution temperature (LCST) or upper critical solution temperature (UCST). However, current research on the thermosensitivity of poly(2-oxazoline) remains insufficient: its thermosensitivity mainly relies on copolymerization with mixed monomers, lacking systematic research on the refined structure-property relationship of the side chains; furthermore, how to achieve controllable adjustment of the thermosensitive transition point while maintaining the excellent water solubility of the polymer remains a challenge.
[0003] Furthermore, the types of existing thermosensitive polymers are limited, and the temperature transition point is difficult to control flexibly; the structure-property relationship is unclear, and there is a lack of systematic methods to study thermosensitivity in detail through a single variable (such as the length of the side chain carbon chain); there is a lack of novel materials that combine good water solubility, reversible thermosensitivity, and biocompatibility.
[0004] Therefore, existing technologies still need to be improved and developed. Summary of the Invention
[0005] In view of the shortcomings of the prior art, the purpose of this invention is to provide a poly(2-oxazoline) thermosensitive polymer with a side chain containing a sulfoxide structure, its preparation method and application, aiming to solve the problems of fixed temperature response point, difficult control and insufficient functionality of existing thermosensitive polymers.
[0006] The technical solution of the present invention is as follows: A poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in its side chain, wherein the general structural formula of the poly(2-oxazoline) thermosensitive polymer is as follows: ; Where n takes values in the range of 50-200 and is an integer; R is a C2-C6 alkyl chain.
[0007] The poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in the side chain, wherein R is selected from one of ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl.
[0008] A method for preparing a poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in the side chain, comprising the steps of: 4-Pentenoyl chloride, 2-chloroethylamine hydrochloride and triethylamine were mixed and subjected to an amidation reaction to obtain an intermediate product; The intermediate product was mixed with anhydrous potassium hydroxide and subjected to a cyclization reaction to obtain a 2-oxazoline monomer with carbon-carbon double bonds. The 2-oxazoline monomer was mixed with an initiator and subjected to polymerization to obtain poly(2-oxazoline) with carbon-carbon double bonds in the side chain. The poly(2-oxazoline) with carbon-carbon double bonds in its side chain, thiols, and free radical initiators were mixed and subjected to a mercapto-olefin click reaction to obtain poly(2-oxazoline) containing a thioether structure. The poly(2-oxazoline) containing a sulfide structure is mixed with an oxidant and subjected to an oxidation reaction to obtain a thermosensitive poly(2-oxazoline) polymer with a sulfoxide structure in the side chain.
[0009] The method for preparing the poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in the side chain, wherein the molar ratio of 4-pentenoyl chloride, 2-chloroethylamine hydrochloride and triethylamine is 1:(1.2-1.5):(2.5-3.0); the amidation reaction temperature is 25℃-35℃, and the amidation reaction time is 12h-24h.
[0010] The method for preparing the poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in the side chain, wherein the molar ratio of the intermediate product to the anhydrous potassium hydroxide is 1:(1.0-1.1); the cyclization reaction temperature is 65℃-70℃, and the cyclization reaction time is 12h-24h.
[0011] The method for preparing the poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in the side chain, wherein the initiator is methyl trifluoromethanesulfonate; the molar ratio of the 2-oxazoline monomer to the initiator is (50-200):1; the polymerization temperature is 80℃-120℃; and the polymerization time is 12h-24h.
[0012] The method for preparing the poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in the side chain, wherein the molar ratio of the poly(2-oxazoline) with carbon-carbon double bonds in the side chain to the thiol is 1:(1.5-1.8); the temperature of the mercapto-alkene click reaction is 70℃-75℃, and the time of the mercapto-alkene click reaction is 12h-24h.
[0013] The method for preparing the poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in the side chain, wherein the thiol is selected from one of ethanethiol, n-propanethiol, n-butanethiol, n-pentanethiol, and n-hexanethiol.
[0014] The method for preparing the poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in the side chain, wherein the molar ratio of the poly(2-oxazoline) containing a sulfide structure to the oxidant is 1:(4.0-4.5); the oxidation reaction temperature is 20℃-25℃, and the oxidation reaction time is 60min-70min.
[0015] Applications of a poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in its side chain, the applications including drug controlled release systems, cell separation and embedding, temperature-switched hydrogels, environmental sensors, and biomedical materials.
[0016] Beneficial Effects: This invention provides a poly(2-oxazoline) thermosensitive polymer with a sulfoxide-containing side chain, its preparation method, and its applications. The invention introduces sulfides of different carbon chain lengths onto the poly(2-oxazoline) side chain via a mercapto-olefin click reaction, followed by further oxidation to a sulfoxide structure, thus forming a poly(2-oxazoline) thermosensitive polymer with a sulfoxide-containing side chain. Since the sulfoxide itself has a certain degree of hydrophobicity, and its hydrophilicity is significantly enhanced after oxidation to sulfoxide, this provides an effective way to controllably regulate the hydrophilicity-hydrophobicity balance of the molecule. Furthermore, this poly(2-oxazoline) thermosensitive polymer with a sulfoxide-containing side chain... The thermosensitive polymer exhibits a distinct LCST-type thermosensitivity, with its cloud point temperature gradually decreasing with increasing concentration, revealing a correlation between thermosensitivity and polymer structure and concentration. By controlling the carbon chain length of the sulfide and the polymer concentration, thermosensitive polymers with different temperature response points can be obtained. Furthermore, this polymer shows no significant toxicity to cells at low to medium concentrations, demonstrating good biocompatibility. Therefore, this thermosensitive polymer possesses controllable structure, unique thermosensitivity, and good biocompatibility, making it a potential application in fields such as controlled drug release, smart hydrogels, and tissue engineering. Attached Figure Description
[0017] Figure 1 This is a schematic diagram of the preparation process of a poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in the side chain according to the present invention; Figure 2 This is a synthetic route diagram of the 2-oxazoline monomer containing a carbon-carbon double bond in Example 1; Figure 3 This is the synthetic route for the poly(2-oxazoline) with carbon-carbon double bonds in the side chain in Example 1; Figure 4The 1H NMR spectrum of poly(2-oxazoline) with carbon-carbon double bonds in the side chain in Example 1; Figure 5 This is a route diagram for the side chain modification of poly(2-oxazoline) with carbon-carbon double bonds in the side chain in Example 1; Figure 6 The 1H NMR spectrum of the reaction product of poly(2-oxazoline) and ethanethiol and its oxidation product in Example 1; Figure 7 The 1H NMR spectrum of the reaction product of poly(2-oxazoline) and n-propanethiol and its oxidation product in Example 1; Figure 8 The 1H NMR spectrum of the reaction product of poly(2-oxazoline) and n-butanethiol and its oxidation product in Example 1; Figure 9 The 1H NMR spectrum of the reaction product of poly(2-oxazoline) and n-pentanethiol and its oxidation product in Example 1; Figure 10 The 1H NMR spectrum of the reaction product of poly(2-oxazoline) and n-hexylthiol and its oxidation product in Example 1; Figure 11 The graph shows the transmittance of the butanethiol polymer solutions of different concentrations in Example 1 as a function of temperature. Figure 12 The graph shows the change in cloud point of the butanethiol polymers as a function of concentration. Figure 13 The figure shows the cell compatibility test results of polymers with different concentrations of butanethiol. Detailed Implementation
[0018] This invention provides a poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in its side chain, its preparation method, and its applications. To make the objectives, technical solutions, and effects of this invention clearer and more explicit, the invention is further described in detail below. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
[0019] It will be understood by those skilled in the art that, unless otherwise defined, all terms used herein (including technical and scientific terms) have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. It should also be understood that terms such as those defined in general dictionaries should be understood to have the same meaning as in the context of the prior art, and should not be interpreted in an idealized or overly formal sense unless specifically defined as herein.
[0020] Thermosensitive polymers are a class of functional materials that exhibit significant reversible phase transition behavior under changes in ambient temperature. Their typical characteristic is a dissolution-precipitation transition, meaning they dissolve well at low temperatures but undergo phase separation upon heating to a certain temperature. Common thermosensitive polymers mainly exhibit lower critical solution temperature (LCST) or upper critical solution temperature (UCST) type phase transition behavior, such as poly(N-isopropylacrylamide) (PNIPAM), which has a distinct dissolution-precipitation transition point around 32°C. Because thermosensitive polymers can undergo reversible phase transitions within physiologically relevant temperature ranges, they are widely used in intelligent drug delivery systems, cell separation and embedding, temperature-switching hydrogels, environmental sensors, and biomedical materials.
[0021] However, existing thermosensitive polymers also have many shortcomings. Although polymers represented by PNIPAM are the most widely studied, they have the following problems in biological environments: (1) their temperature transition point is fixed at around 32°C, which is difficult to adjust flexibly through molecular design, thus limiting their application scenarios; (2) their polymer structure is simple, making it difficult to introduce additional functional groups while maintaining thermosensitivity; (3) their biocompatibility and degradability are limited, which may cause adverse reactions in long-term use. To this end, researchers have begun to try to expand the types of thermosensitive polymers by introducing other structural units.
[0022] Sulfur-containing functional groups (such as sulfides, sulfoxides, and sulfones) have attracted attention in polymer materials due to their unique hydrophilicity / hydrophobicity regulation capabilities and redox responsiveness. Sulfides themselves possess a certain degree of hydrophobicity, but their hydrophilicity significantly increases after oxidation to sulfoxides, thus providing an effective pathway for the controllable regulation of molecular hydrophilicity / hydrophobicity balance. However, current research on the application of the "sulfide-sulfoxide conversion" strategy in thermosensitive polymers is relatively limited, with most work focusing on small molecule models or traditional polymer modifications, lacking in-depth exploration of structurally controllable poly(2-oxazoline) systems. Therefore, combining the structural diversity of poly(2-oxazoline) with the hydrophilicity / hydrophobicity regulation characteristics of the sulfide / sulfoxide system could potentially lead to the development of a new class of thermosensitive, structurally defined, and functionally diverse polymer materials.
[0023] Based on this, the present invention provides a poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in the side chain, wherein the general structural formula of the poly(2-oxazoline) thermosensitive polymer is as follows: ; Where n takes values in the range of 50-200 and is an integer; R is a C2-C6 alkyl chain.
[0024] In this embodiment, sulfides of different carbon chain lengths are introduced onto the side chain of the poly(2-oxazoline) via a mercapto-olefin click reaction, and then further oxidized to a sulfoxide structure, thereby forming a poly(2-oxazoline) thermosensitive polymer with a sulfoxide-containing side chain. Since the sulfide itself has a certain degree of hydrophobicity, and its hydrophilicity is significantly enhanced after oxidation to sulfoxide, an effective way is provided for the controllable adjustment of the molecular hydrophilic-hydrophobic balance. Furthermore, this polymer exhibits thermosensitive phase transition characteristics due to its unique side chain structure. Further, this poly(2-oxazoline) thermosensitive polymer with a sulfoxide-containing side chain... The compound exhibits significant LCST-type thermosensitivity, and its cloud point temperature gradually decreases with increasing concentration, revealing the correlation between thermosensitivity and polymer structure and concentration. By controlling the carbon chain length of the sulfide and the polymer concentration, thermosensitive polymers with different temperature response points can be obtained. Furthermore, this polymer shows no significant toxicity to cells at low to medium concentrations and exhibits good biocompatibility. Therefore, this thermosensitive polymer possesses controllable structure, unique thermosensitivity, and good biocompatibility, making it a potential application in fields such as controlled drug release, smart hydrogels, and tissue engineering.
[0025] In some embodiments, R is selected from, but not limited to, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl.
[0026] In addition, such as Figure 1 As shown, the present invention also provides a method for preparing a poly(2-oxazoline) thermosensitive polymer with a side chain containing a sulfoxide structure, comprising the following steps: Step S10: 4-pentenoyl chloride, 2-chloroethylamine hydrochloride and triethylamine are mixed and subjected to amidation reaction to obtain intermediate product; Step S20: The intermediate product is mixed with anhydrous potassium hydroxide and subjected to a cyclization reaction to obtain a 2-oxazoline monomer with carbon-carbon double bonds; Step S30: The 2-oxazoline monomer is mixed with an initiator and subjected to polymerization to obtain poly(2-oxazoline) with carbon-carbon double bonds in the side chain. Step S40: The poly(2-oxazoline) with carbon-carbon double bonds in the side chain, thiol and free radical initiator are mixed and subjected to mercapto-olefin click reaction to obtain poly(2-oxazoline) containing thioether structure. Step S50: The poly(2-oxazoline) containing a sulfide structure is mixed with an oxidant and subjected to an oxidation reaction to obtain a thermosensitive poly(2-oxazoline) polymer with a sulfoxide structure in the side chain.
[0027] In this embodiment, the poly(2-oxazoline) obtained by cationic ring-opening polymerization has a controllable molecular weight and a narrow distribution. Then, through a mercapto-olefin click reaction, thioether groups of different carbon chain lengths can be successfully introduced into the polymer side chain. Further oxidation with an oxidant yields a polymer containing a sulfoxide structure. The thermosensitive poly(2-oxazoline) with a sulfoxide structure in the side chain prepared by this method exhibits obvious temperature response behavior. Its solution is transparent at low temperature and becomes turbid after heating, showing a typical LCST phase transition. Moreover, its thermosensitivity is highly correlated with the structure and concentration of the polymer, causing its cloud point temperature to gradually decrease with increasing concentration. In addition, the thermosensitive poly(2-oxazoline) with a sulfoxide structure in the side chain has no obvious toxicity to cells at concentrations below 50 μg / mL, and only shows a certain inhibitory effect at concentrations above 50 μg / mL, showing good overall biocompatibility.
[0028] In some embodiments, the molar ratio of 4-pentenoyl chloride, 2-chloroethylamine hydrochloride, and triethylamine is 1:(1.2-1.5):(2.5-3.0); the amidation reaction temperature is 25°C-35°C, and the amidation reaction time is 12-24 hours. Under these conditions, excess 2-chloroethylamine hydrochloride, triethylamine, and prolonged reaction time facilitate the conversion of 4-pentenoyl chloride to the intermediate product. The chemical structure of the intermediate product is as follows: .
[0029] In some embodiments, the molar ratio of the intermediate product to the anhydrous potassium hydroxide is 1:(1.0-1.1); the cyclization reaction temperature is 65℃-70℃, and the cyclization reaction time is 12h-24h. Controlling the molar ratio of the intermediate product to anhydrous potassium hydroxide within 1:(1.0-1.1), and controlling the temperature and time of the cyclization reaction within the above range, can avoid side reactions and obtain a high-purity 2-oxazoline monomer with carbon-carbon double bonds. Excessive residual moisture, excessive potassium hydroxide, excessively high reaction temperature, and excessively long reaction time can lead to an increase in side reactions.
[0030] In a preferred embodiment, the cyclization reaction is carried out at a temperature of 70°C for 24 hours.
[0031] In some embodiments, the initiator is methyl trifluoromethanesulfonate; the molar ratio of the 2-oxazoline monomer to the initiator is (50-200):1; the polymerization temperature is 80℃-120℃, and the polymerization time is 12h-24h. Residual moisture in the system can hinder the polymerization reaction. The molar ratio of monomer to initiator directly affects the degree of polymerization of the product. More monomer and less initiator will lead to a higher degree of polymerization. By controlling the molar ratio of the 2-oxazoline monomer to the initiator within the above range, poly(2-oxazoline) with a degree of polymerization between 50-200 can be obtained. Furthermore, by controlling the temperature and time of the polymerization reaction, the polymerization rate can be increased, and the reaction time can be saved.
[0032] In a preferred embodiment, the polymerization reaction is carried out at a temperature of 120°C for 24 hours.
[0033] In some embodiments, the molar ratio of the poly(2-oxazoline) with carbon-carbon double bonds in the side chain to the thiol is 1:(1.5-1.8); the temperature of the thiol-ene click reaction is 70°C-75°C, and the reaction time is 12-24 h. Using an excess of thiol facilitates the complete conversion of the carbon-carbon double bond to a thioether structure, and under these thiol-ene click reaction conditions, a thioether structure can be introduced into the polymer side chain.
[0034] In a preferred embodiment, the temperature of the mercapto-alkene click reaction is 70°C, and the time of the mercapto-alkene click reaction is 12 hours.
[0035] In some embodiments, the amount of the free radical initiator added is 5%-10% of the total mass of the poly(2-oxazoline) with carbon-carbon double bonds in the side chain and the thiol.
[0036] In some embodiments, the free radical initiator is selected from, but not limited to, azobisisobutyronitrile (AIBN), which, under its initiation, allows thiols to be introduced onto the side chains of the polymer via a mercapto-olefin click reaction.
[0037] In some embodiments, the thiol is selected from one of ethanethiol, n-propanethiol, n-butanethiol, n-pentanethiol, and n-hexanethiol. The above-mentioned thiols can be used to introduce sulfur atoms into poly(2-oxazoline) with carbon-carbon double bonds in the side chain via a mercapto-olefin click reaction, followed by oxidative modification to obtain a poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in the side chain.
[0038] In some embodiments, the molar ratio of the poly(2-oxazoline) containing the sulfide structure to the oxidant is 1:(4.0-4.5); the oxidation reaction temperature is 20℃-25℃, and the oxidation reaction time is 60min-70min. Excessively high reaction temperature and excessively long reaction time can lead to further oxidation of the sulfoxide structure into a sulfone structure.
[0039] In some embodiments, the oxidant is selected from, but is not limited to, hydrogen peroxide, which can further oxidize the sulfide structure in the polymer side chain to a sulfoxide structure.
[0040] In some embodiments, the preparation process of the poly(2-oxazoline) thermosensitive polymer with sulfoxide structure in the side chain is carried out under an inert atmosphere; the inert atmosphere includes, but is not limited to, one or more of nitrogen, argon, and helium.
[0041] In addition, the present invention also provides an application of a poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in the side chain, the application including a drug controlled release system, cell separation and embedding, temperature-switched hydrogel, environmental sensor, and biomedical material.
[0042] In this embodiment, the thermosensitive polymer prepared by the present invention has controllable structure, unique thermosensitivity and good biocompatibility, and has potential application value in the fields of drug controlled release, smart hydrogels and tissue engineering.
[0043] The following examples further illustrate the present invention in detail. It should also be understood that the following examples are only for further explanation of the present invention and should not be construed as limiting the scope of protection of the present invention. Any non-essential improvements and adjustments made by those skilled in the art based on the above description of the present invention are within the scope of protection of the present invention.
[0044] Example 1 In this embodiment, thioether groups of different carbon chain lengths can be successfully introduced into the polymer side chain via a mercapto-olefin click reaction. Further oxidation with hydrogen peroxide yields a polymer containing a sulfoxide structure, as detailed below: 1) Synthesis of 2-oxazoline monomers containing carbon-carbon double bonds, the synthetic route is as follows: Figure 2 As shown.
[0045] 10.6 g of 2-chloroethylamine hydrochloride was dissolved in 80 mL of anhydrous N,N-dimethylformamide (DMF), and the system was cooled to 0 °C. Then, 19.6 g of triethylamine was added, and stirring continued. 9.12 g of 4-pentenoyl chloride was pre-dissolved in 75 mL of anhydrous dichloromethane (DCM) and slowly added dropwise to the above reaction system. The reaction was stirred at room temperature for 24 h. After the reaction was complete, the byproduct solid was removed by filtration, the solvent was removed by vacuum distillation, and the residue was dissolved in dichloromethane. The reaction solution was washed once each with 0.5 M dilute hydrochloric acid, saturated sodium bicarbonate solution, and saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed to obtain the target intermediate product.
[0046] 4.48 g of potassium hydroxide was dissolved in 40 mL of anhydrous methanol, followed by the addition of 12.9 g of the above intermediate product. The mixture was stirred at 70 °C for 24 h. After the reaction was complete, the insoluble matter was removed by filtration, and the solvent was removed by vacuum distillation. The crude product was then subjected to vacuum distillation in the presence of calcium hydride (82 °C, 6 mbar) to obtain a colorless, transparent 2-oxazoline monomer containing carbon-carbon double bonds.
[0047] 2) Synthesis of poly(2-oxazoline) with carbon-carbon double bonds in the side chain, the synthetic route is as follows: Figure 3 As shown.
[0048] Eight mL of a 2-oxazoline monomer containing carbon-carbon double bonds was dissolved in 40 mL of anhydrous acetonitrile, followed by the addition of 72 μL of methyl trifluoromethanesulfonate (MeOTf) as an initiator. The reaction was stirred at 120 °C for 24 h. After the reaction was completed, 1 mL of deionized water was added to terminate the polymerization. The resulting reaction solution was transferred to a dialysis bag in a MWCO 3500 dialysis machine and dialyzed for 3 days with acetonitrile as the dialysis solvent to remove small molecule impurities, yielding pure poly(2-oxazoline) with carbon-carbon double bonds in the side chains (abbreviated as poly(2-oxazoline)).
[0049] Gel permeation chromatography was performed on poly(2-oxazoline) with carbon-carbon double bonds in its side chains. The results are shown in Table 1, indicating that it has a controllable molecular weight and a narrow distribution. The 1H NMR spectra of poly(2-oxazoline) with carbon-carbon double bonds in its side chains are shown in Table 1. Figure 4 As shown, the 1H NMR spectrum results verified the correctness of the monomer polymerization and structure.
[0050] Table 1
[0051] 3) Synthesis of poly(2-oxazoline) containing thioether structures, the synthetic route is as follows: Figure 5 As shown.
[0052] Five 330 mg portions of poly(2-oxazoline) with carbon-carbon double bonds in the side chains were weighed and dissolved in 9.1 mL of anhydrous N,N-dimethylformamide (DMF). Then, 2 equivalent amounts of thiols with different carbon chain lengths (ethanethiol, n-propanethiol, n-butanethiol, n-pentanethiol, n-hexanethiol) and 5% azobisisobutyronitrile (AIBN) equivalent to the total mass of the reactants were added. Argon gas was bubbled into the reaction solution for 15 min to remove dissolved oxygen, and then the reaction was stirred overnight at 70 °C. After the reaction was completed, the reaction solution was transferred to a dialysis bag in a MWCO 3500 and dialyzed with dichloromethane as the dialysis solvent for 5 days to remove small molecule impurities, finally yielding poly(2-oxazoline) polymers with sulfur atoms of different carbon chain lengths introduced into the side chains.
[0053] 4) Synthesis of poly(2-oxazoline) thermosensitive polymers with sulfoxide structures in the side chains, the synthetic route is as follows: Figure 5 As shown.
[0054] Two mmol of poly(2-oxazoline) with sulfur-containing side chains of different carbon chain lengths were dissolved in 2 mL of glacial acetic acid, followed by the addition of four equivalents of hydrogen peroxide (H2O2). The mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction solution was transferred to a dialysis bag of a MWCO3500 and dialyzed with methanol as the dialysis solvent for 5 days to remove small molecule impurities, finally yielding thermosensitive poly(2-oxazoline) polymers with sulfoxide structures in the side chains of different carbon chain lengths.
[0055] The 1H NMR spectra of the reaction products of poly(2-oxazoline) and ethanethiol and their oxidation products are as follows: Figure 6 As shown; the 1H NMR spectra of the reaction products of poly(2-oxazoline) and n-propanethiol and their oxidation products are as follows. Figure 7 As shown; the 1H NMR spectra of the reaction products of poly(2-oxazoline) and n-butanethiol and their oxidation products are as follows. Figure 8 As shown; the 1H NMR spectra of the reaction products of poly(2-oxazoline) and n-pentanethiol and their oxidation products are as follows. Figure 9 As shown; the 1H NMR spectra of the reaction products of poly(2-oxazoline) with n-hexylthiol and their oxidation products are as follows. Figure 10 As shown; Figures 6-10 The proton NMR spectrum showed that the double bond reacted completely and the oxidation reaction proceeded smoothly, proving the feasibility and universality of the route of the present invention.
[0056] 5) Polymer temperature sensitivity test A thermosensitive poly(2-oxazoline) polymer, synthesized from poly(2-oxazoline) with carbon-carbon double bonds in its side chains and n-butanethiol, was dissolved in deionized water to prepare a series of solutions with different concentrations (0.5, 1, 2.5, 5, 7.5, 10, 15, 20 mg / mL), resulting in polymer solutions with different concentrations of butanethiol. The solutions were incubated to specific temperatures, and the absorbance at 500 nm was measured using a UV-Vis spectrophotometer. The transmittance was calculated according to the Lambert-Beer law, and a curve showing the transmittance of the polymer solution versus temperature was plotted to characterize its thermosensitivity.
[0057] The transmittance curves of butanethiol polymer solutions at different concentrations as a function of temperature are shown in the figure below. Figure 11 As shown; the cloud point curve of the butanethiol polymer group as a function of concentration is shown in the figure. Figure 12 As shown, the butanethiol polymer solutions of different concentrations all exhibit significant temperature response behavior. The solutions are transparent at low temperatures but become turbid upon heating, demonstrating a typical LCST phase transition. Furthermore, the cloud point temperature gradually decreases with increasing concentration, revealing a correlation between temperature sensitivity and polymer structure and concentration.
[0058] 6) Polymer cell compatibility test Rat bone marrow mesenchymal stem cells were used at a ratio of 1 × 10⁻⁶ per well 4 Cells were seeded at a density of [number] cells per well in 96-well plates. After cell attachment, the culture medium was replaced with medium containing different concentrations (0, 10, 25, 50, 75, 100 μg / mL) of a polymer (a thermosensitive polymer of poly(2-oxazoline) synthesized from n-butanethiol with carbon-carbon double bonds in the side chains) and cultured continuously. On days 1, 3, 5, and 7 after changing the medium, 10 μL of CCK-8 reagent was added to each well and incubated for 1 hour. Subsequently, the OD value of the cells at 450 nm was measured using a microplate reader to evaluate the cell compatibility of the polymer.
[0059] The cell compatibility test results of polymers with different concentrations of butanethiol are as follows: Figure 13 As shown, the cell compatibility evaluation results indicate that the butanethiol polymer group has no obvious toxicity to cells at low to medium concentrations, and only shows a certain inhibitory effect at high concentrations, indicating that it has good biocompatibility overall.
[0060] In summary, this invention provides a poly(2-oxazoline) thermosensitive polymer with a sulfoxide-containing side chain, its preparation method, and its applications. The invention introduces sulfides of different carbon chain lengths onto the poly(2-oxazoline) side chain via a mercapto-olefin click reaction, followed by further oxidation to a sulfoxide structure, thereby forming a poly(2-oxazoline) thermosensitive polymer with a sulfoxide-containing side chain. Since the sulfoxide itself has a certain degree of hydrophobicity, and its hydrophilicity is significantly enhanced after oxidation to sulfoxide, this provides an effective way to controllably regulate the hydrophilicity-hydrophobicity balance of the molecule. Furthermore, this poly(2-oxazoline) thermosensitive polymer with a sulfoxide-containing side chain... The thermosensitive polymer (azoline) exhibits significant LCST-type thermosensitivity, and its cloud point temperature gradually decreases with increasing concentration, revealing the correlation between thermosensitivity and polymer structure and concentration. By controlling the carbon chain length of the sulfide and the polymer concentration, thermosensitive polymers with different temperature response points can be obtained. Furthermore, this polymer shows no significant toxicity to cells at low to medium concentrations and exhibits good biocompatibility. Therefore, this thermosensitive polymer possesses controllable structure, unique thermosensitivity, and good biocompatibility, making it a potential application in fields such as controlled drug release, smart hydrogels, and tissue engineering.
[0061] It should be understood that the application of the present invention is not limited to the examples above. Those skilled in the art can make improvements or modifications based on the above description, and all such improvements and modifications should fall within the protection scope of the appended claims.
Claims
1. A poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in its side chain, characterized in that, The general structural formula of the poly(2-oxazoline) thermosensitive polymer is as follows: ; Where n takes values in the range of 50-200 and is an integer; R is a C2-C6 alkyl chain.
2. The poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in its side chain according to claim 1, characterized in that, R is selected from one of ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl.
3. A method for preparing a poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in its side chain as described in any one of claims 1-2, characterized in that, Including the following steps: 4-Pentenoyl chloride, 2-chloroethylamine hydrochloride and triethylamine were mixed and subjected to an amidation reaction to obtain an intermediate product; The intermediate product was mixed with anhydrous potassium hydroxide and subjected to a cyclization reaction to obtain a 2-oxazoline monomer with carbon-carbon double bonds. The 2-oxazoline monomer was mixed with an initiator and subjected to polymerization to obtain poly(2-oxazoline) with carbon-carbon double bonds in the side chain. The poly(2-oxazoline) with carbon-carbon double bonds in its side chain, thiols, and free radical initiators were mixed and subjected to a mercapto-olefin click reaction to obtain poly(2-oxazoline) containing a thioether structure. The poly(2-oxazoline) containing a sulfide structure is mixed with an oxidant and subjected to an oxidation reaction to obtain a thermosensitive poly(2-oxazoline) polymer with a sulfoxide structure in the side chain.
4. The method for preparing the poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in the side chain according to claim 3, characterized in that, The molar ratio of 4-pentenoyl chloride, 2-chloroethylamine hydrochloride and triethylamine is 1:(1.2-1.5):(2.5-3.0); the amidation reaction temperature is 25℃-35℃, and the amidation reaction time is 12h-24h.
5. The method for preparing the poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in the side chain according to claim 3, characterized in that, The molar ratio of the intermediate product to the anhydrous potassium hydroxide is 1:(1.0-1.1); the cyclization reaction temperature is 65℃-70℃, and the cyclization reaction time is 12h-24h.
6. The method for preparing the poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in the side chain according to claim 3, characterized in that, The initiator is methyl trifluoromethanesulfonate; the molar ratio of the 2-oxazoline monomer to the initiator is (50-200):1; the polymerization temperature is 80℃-120℃, and the polymerization time is 12h-24h.
7. The method for preparing the poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in the side chain according to claim 3, characterized in that, The molar ratio of the poly(2-oxazoline) with carbon-carbon double bonds in the side chain to the thiol is 1:(1.5-1.8); the temperature of the mercapto-alkene click reaction is 70℃-75℃, and the time of the mercapto-alkene click reaction is 12h-24h.
8. The method for preparing the poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in the side chain according to claim 3, characterized in that, The thiol is selected from one of ethanethiol, n-propanethiol, n-butanethiol, n-pentanethiol, and n-hexanethiol.
9. The method for preparing the poly(2-oxazoline) thermosensitive polymer with a sulfoxide structure in the side chain according to claim 3, characterized in that, The molar ratio of the poly(2-oxazoline) containing the thioether structure to the oxidant is 1:(4.0-4.5); the oxidation reaction temperature is 20℃-25℃, and the oxidation reaction time is 60min-70min.
10. The application of a poly(2-oxazoline) thermosensitive polymer with a sulfoxide-containing side chain as described in any one of claims 1-2, characterized in that, The applications include one of the following: drug controlled release systems, cell separation and embedding, temperature-switched hydrogels, environmental sensors, and biomedical materials.