Dynamic bonding temperature-sensitive chiral polymer microsphere and preparation method thereof

Abstract

The invention discloses a dynamic bonding temperature-sensitive chiral polymer microsphere and a preparation method thereof, and relates to the technical field of chiral polymer microspheres, a copolymer with alanine as a chiral center, phenylacetylene as a main chain and dendronized alkoxy ether as a temperature-sensitive hydrophilic side group is synthesized through molecular design, an aqueous solution of the copolymer is induced to be subjected to phase change by utilizing temperature to form an aggregate, and the dynamic bonding temperature-sensitive chiral polymer microsphere is prepared. And constructing a dynamic acylhydrazone bond cross-linked network through in-situ cross-linking to prepare the microspheres. The method is mild in reaction in water, additives such as an initiator do not need to be added, and the process is simple, convenient and environment-friendly. The obtained microspheres are complete in morphology and uniform in size, and the particle size and the temperature-sensitive behavior can be accurately adjusted by adjusting and controlling the copolymerization ratio, the dosage of the cross-linking agent, the heating rate and the like; the helical conformation is fixed, the chirality is stable, and the quick and reversible temperature-sensitive characteristic is realized. The method has a wide application prospect in the fields of asymmetric catalysis, chiral recognition, drug loading slow release, enantiomer separation and the like.

Description

Technical Field

[0001] The present invention relates to the technical field of chiral polymer microspheres, specifically to a dynamically bonded temperature-sensitive chiral polymer microsphere and a preparation method thereof, and particularly to a method for preparing the temperature-sensitive chiral microspheres by in-situ crosslinking reaction of a temperature-sensitive aggregate of a dendritic helical copolymer. The present invention belongs to the field of intelligent chiral polymer microspheres and also to the field of chiral materials. Background Art

[0002] Chiral materials, due to their unique structural symmetry-breaking properties, offer significant advantages in a wide range of practical applications. The optical rotation effects of chiral structures can be leveraged in areas such as chiral recognition, asymmetric catalysis, optical sensing, and liquid crystal displays. Microspheres, as small materials, possess a high surface area, resulting in abundant active sites on their surfaces, making them suitable for use as catalytic supports, drug loading media, and adsorption materials. Furthermore, microspheres are easily surface-modified and functionalized. Combined with their controllable size and morphology, they also hold valuable applications in 3D printing, photonic crystals, biomedicine, and sensors. In recent years, research integrating chirality with microsphere materials has garnered significant attention. With the advancement of artificial intelligence, the development of intelligent materials to meet the demands of high-end markets has become a hot topic. Intelligent chiral microspheres possess chiral structures on or within their surfaces, possess high surface area and controllable morphology, and can reversibly change their physical or chemical properties in response to external stimuli such as light, temperature, magnetic fields, and pH. Therefore, these advanced functional materials, combining chirality with intelligent responsiveness, hold great promise for applications in controlled drug release, biosensing, and catalysis. Currently, mature and widely used methods for preparing chiral polymer microspheres include self-assembly, emulsion polymerization, precipitation polymerization, dispersion polymerization, suspension polymerization, microfluidics, etc. Chiral polymer microspheres can be achieved by direct polymerization of chiral monomers, or by combining achiral monomers and chiral templates through heterogeneous polymerization technology. Currently, traditional methods for preparing polymer chiral microspheres, such as emulsion polymerization and dispersion polymerization, require the addition of surfactants to stabilize the system, which increases the instability of the system and the difficulty of post-processing. Microfluidics process equipment is expensive, mass production is difficult, and the high operating threshold limits its application. Therefore, the development of a method for preparing functionalized polymer chiral microspheres with a simple preparation process, convenient operation, environmental friendliness, and simple post-processing is of great significance for actual production and a wide range of applications. Summary of the Invention

[0003] In view of this, the present invention aims to provide dynamically linked temperature-sensitive chiral polymer microspheres and a method for preparing the same. The method involves temperature-induced dehydration aggregation of dendritic helical poly(phenylene vinylene) copolymers in an aqueous phase. After forming aggregates, the aggregates undergo dynamic covalent crosslinking with a crosslinker, adipic acid dihydrazide, to produce chiral polymer microspheres. Because the aldehyde groups on the polymer form dynamic acylhydrazone bonds with the hydrazide bonds in the crosslinker, the resulting microspheres exhibit dynamic properties and temperature sensitivity. Furthermore, the crosslinking yields stable chiral characteristics. These microspheres are expected to be used in areas such as encapsulation and release of active drugs, enantiomeric separation, and chiral recognition.

[0004] The object of the present invention is achieved through the following technical solutions:

[0005] <First Aspect>

[0006] The present invention provides a method for preparing chiral polyphenylene vinylene microspheres, comprising the following steps:

[0007] dissolving the dendritic alkoxy ether helical phenylacetylene copolymer in a buffer solution to obtain a copolymer aqueous solution;

[0008] dissolving a cross-linking agent in a buffer solution to obtain a cross-linking solution;

[0009] The copolymer aqueous solution and the crosslinker solution are mixed at a molar ratio of hydrazide bond to aldehyde group of 0.5 to 3, and then heated to a phase transition temperature of 40 to 50° C. for crosslinking reaction. After sufficient reaction, the reaction product is extracted to obtain the microspheres.

[0010] As an embodiment, the structural formula of the dendronized alkoxy ether spiral phenyl acetylene copolymer is:

[0011] Among them, m:n = 3 to 21:1.

[0012] As an embodiment, the cross-linking agent is adipic acid dihydrazide.

[0013] In some embodiments, the cross-linking agent is adipic acid dihydrazide.

[0014] As an embodiment, the buffer solution is a buffer solution with a pH of 3 to 5.

[0015] As an embodiment, the buffer is a phosphate buffer.

[0016] In some embodiments, the buffer is a phosphate buffer at pH=5.

[0017] In some embodiments, the phase transition temperature is 45°C.

[0018] <Second Aspect>

[0019] The present invention provides a dendronized alkoxy ether spiral phenylacetylene copolymer, the structural formula of which is:

[0020] Among them, m:n = 3 to 21:1.

[0021] <Third Aspect>

[0022] The present invention provides a method for preparing the above-mentioned dendronized alkoxy ether spiral phenylacetylene copolymer, comprising the following steps:

[0023] The copolymer is obtained by random copolymerization of a dendronized alkoxy ether spirophenyl acetylene monomer and an aldehyde-containing p-alkynylbenzaldehyde at a molar ratio of 3 to 21:1, wherein the structural formula of the dendronized alkoxy ether spirophenyl acetylene monomer is:

[0024]

[0025] As an embodiment, the random copolymerization method is: dissolving the dendritic alkoxy ether spirophenyl acetylene monomer and the aldehyde-containing p-alkynylbenzaldehyde in dry tetrahydrofuran, and removing the water by freeze-extraction to obtain a mixed monomer, thawing the mixed monomer and mixing it with the catalyst solution under nitrogen protection, and after the reaction is completed, extracting the product to obtain the copolymer.

[0026] As an embodiment, the catalyst solution is triethylamine and rhodium catalyst dissolved in tetrahydrofuran.

[0027] As an embodiment, the molar ratio of the mixed monomer, triethylamine and rhodium catalyst is 250:300:1.

[0028] As an embodiment, the ratio of the rhodium catalyst to tetrahydrofuran is 0.2 mol:10-50 mL.

[0029] In some embodiments, the rhodium catalyst is [Rh(nbd)Cl]2.

[0030] In some embodiments, the molar ratio of the mixed monomer, triethylamine, and rhodium catalyst is 250:300:1.

[0031] As an embodiment, the extraction method is: dissolving the reaction product with dichloromethane, and purifying it with dichloromethane by column chromatography, and finally drying it by spin drying to obtain the copolymer.

[0032] <Fourth Aspect>

[0033] The present invention provides applications of chiral polyphenylene vinylene microspheres prepared by the method.

[0034] As an embodiment, the microspheres are used in the field of chiral recognition.

[0035] As an embodiment, the microspheres are used in the field of asymmetric catalysis.

[0036] As an embodiment, the microspheres are used in the field of drug loading and sustained release.

[0037] As an embodiment, the microspheres are used in the field of enantiomer separation.

[0038] Compared with the prior art, the present invention has the following beneficial effects:

[0039] Through molecular design and in-situ crosslinking, this paper has developed a method for preparing polymer microspheres that combines dynamic responsiveness, chiral stability, and temperature-sensitive control properties. The microspheres are prepared by temperature-induced polymer phase transition to form aggregates, followed by in-situ crosslinking. The technical benefits are reflected in the following aspects:

[0040] 1) Dynamic covalent cross-linking and thermosensitive properties

[0041] The present invention designs and synthesizes dendritic alkoxy ether helical phenylacetylene copolymers with different copolymerization ratios, wherein alanine serves as the chiral center, the phenylacetylene main chain is a rigid structure and is relatively hydrophobic, the dendritic alkoxy ether serves as a hydrophilic side group and has temperature-sensitive properties, and the aldehyde groups on the side groups provide cross-linking sites;

[0042] The copolymer aqueous solution begins to dehydrate and collapse above the phase transition temperature. To maintain the hydrophilic-hydrophobic balance of the system, it aggregates to form aggregates. The aldehyde cross-linking sites on the aggregates and the hydrazide bonds on the cross-linker form a dynamic acylhydrazone cross-linking network in situ, resulting in dynamically linked thermosensitive chiral polymer microspheres with intact morphology and sensitive reversible temperature response behavior.

[0043] The aldehyde groups on the copolymer and the hydrazide bonds on the cross-linker provide dynamic covalent cross-linking sites, and the branched alkoxy ether units give the polymer hydrophilicity and temperature sensitivity. The polymer exhibits rapid phase transition behavior with small hysteresis during heating and cooling.

[0044] 2) Chirality fixation and conformational stability

[0045] Polyphenylene vinylene is a typical dynamic helical polymer that exhibits left-handed helical chirality at room temperature. As the temperature rises, the chiral signal gradually weakens and flips to a right-handed helix near the phase transition temperature. As the temperature continues to rise, the signal gradually increases, and the chirality can be restored after returning to room temperature. After being prepared into microspheres, the helical conformation is fixed, and the polymer microspheres exhibit right-handed helices. The chiral signal does not change much with temperature.

[0046] 3) Simple process and environmentally friendly

[0047] The method for preparing chiral microspheres by temperature-induced in-situ crosslinking of aggregates is simple to operate, operates in water, and is environmentally friendly under mild conditions. It does not require the addition of initiators, emulsifiers, or dispersants, and eliminates the need for post-processing of impurities. This method overcomes the problems of traditional methods with complex equipment and numerous additives.

[0048] 4) Flexible shape and size control

[0049] The thermosensitive chiral polyphenylene vinylene microspheres of the present invention are relatively uniform in size, have a complete morphology, and exhibit thermosensitive properties. The size of the microspheres can be controlled by varying the copolymerization ratio, crosslinking agent, and heating rate.

[0050] By varying the feed ratio of G1Me to EB, polymers with varying copolymerization ratios can be prepared. Changing the copolymerization ratio also results in different sizes of the resulting polymer microspheres, increasing with the dendritic alkoxy ether content in the polymer. The temperature-sensitive behavior of the chiral polymer microspheres can also be regulated. Temperature is a key factor in controlling the preparation process, and polymers of varying concentrations can all produce microspheres of relatively uniform size. The particle size of the microspheres can be controlled by adjusting the copolymerization ratio, the amount of crosslinker added, and the heating rate.

[0051] 5) Functional application potential

[0052] The polyphenylene vinylene microspheres prepared by the present invention have temperature sensitivity, chiral stability and dynamic cross-linking properties, and are expected to be applied in the fields of chiral recognition, asymmetric catalysis, drug loading and sustained release, enantiomer separation, etc., especially the encapsulation and controlled release of active drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Other features, objects and advantages of the present invention will become more apparent upon reading the detailed description of non-limiting embodiments with reference to the following drawings:

[0054] Figure 1 The copolymer PG1Me3EB1 in DMSO-d6 1 H NMR spectrum;

[0055] Figure 2 This is an AFM image of the purified PG1Me3EB1-NPs microspheres prepared in Example 5;

[0056] Figure 3 The UV-visible spectra of the copolymer PG1Me3EB1 dissolved in phosphate buffer solution at pH=5 at different concentrations are shown;

[0057] Figure 4 For copolymers PG1Me3EB1, PG1Me 10 EB1 and PG1Me 21UV-visible spectra of EB1 dissolved in phosphate buffer solution at pH = 5 at the same concentration;

[0058] Figure 5 The thermosensitive aggregation behavior of the copolymer PG1Me3EB1 aqueous solution was observed under an optical microscope;

[0059] Figure 6 Figure 2 is the DLS graph of the copolymer PG1Me3EB1 aqueous solution, where (a) shows the process of temperature-induced dehydration, collapse, and aggregation of polymers to form aggregates, as shown by the change in particle size with temperature. The test temperature range is 0–45°C. (b) shows the stability of the aggregate particle size at 45°C, as shown by the change in particle size with time at 45°C. (c) shows the stability of the aggregate particle size at 50°C, as shown by the change in particle size with time at 50°C.

[0060] Figure 7 PG1Me3EB1, PG1Me 10 EB1 and PG1Me 21 Temperature-dependent CD and UV-vis spectra of aqueous solutions of EB1 copolymer;

[0061] Figure 8 PG1Me3EB1-NPs microspheres in DLS test diagram, where (a) is the microspheres temperature-sensitive change diagram, and (b) is the microspheres temperature-sensitive reversible curve diagram;

[0062] Figure 9 The three copolymerization ratios of microspheres PG1Me3EB1-NPs, PG1Me 10 EB1-NPs and PG1Me 21 Thermosensitive reversible curve of EB1-NPs;

[0063] Figure 10 PG1Me3EB1-NPs, PG1Me 10 EB1-NPs and PG1Me 21 Variable temperature CD and UV-vis spectra of EB1-NPs microspheres in aqueous solution, among which PG1Me3EB1-NPs corresponds to Figure 10 (a), PG1Me 10 EB1-NPs correspondence Figure 10 (b), PG1Me 21 EB1-NPs correspondence Figure 10 (c);

[0064] Figure 11 The effect of different cross-linking doses on the particle size of PG1Me3EB1-NPs microspheres;

[0065] Figure 12AFM images of the effects of different copolymerization ratios on microsphere particle size;

[0066] Figure 13 The heating rate of PG1Me 10 EB1-NPs and PG1Me 21 The particle size of EB1-NPs microspheres affects the AFM images. DETAILED DESCRIPTION

[0067] The present invention will be described in detail below with reference to the examples. The following examples will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that those skilled in the art may make several adjustments and improvements without departing from the scope of the present invention. These all fall within the scope of protection of the present invention.

[0068] For ease of understanding, the abbreviations or nouns mentioned below are first explained:

[0069] G1Me-NH2 structural formula:

[0070] DIEA: N,N-diisopropylethylamine;

[0071] 4-Ethynyl pentafluorophenol ester structural formula:

[0072] EB: p-Alkynylbenzaldehyde, structural formula is

[0073] TEA: triethylamine;

[0074] PBS: phosphate buffered saline, the PBS buffer used in the present invention is pH=5;

[0075] ADH: adipic acid dihydrazide.

[0076] Example 1

[0077] This embodiment provides a method for preparing a branched alkoxy ether spiral phenylacetylene monomer G1Me with a methoxy end group. The synthesis thereof can be referred to in the literature Wang F., et al. Macromolecules 2019, 52, 8631–8642.

[0078] In this embodiment, the preparation steps of G1Me are:

[0079] Compound G1Me-NH2 (16.6 g, 21.7 mmol), DIEA (13.6 g, 105.3 mmol) and 4-ethynyl pentafluorophenol ester (10.7 g, 34.3 mmol) were dissolved in dry dichloromethane (150 mL) in an ice bath, the temperature was raised to room temperature, and the reaction was carried out under nitrogen protection for 6 h. After the reaction was completed, the solvent was dried by spin drying and then purified by column chromatography to obtain the product as a colorless, transparent, oily liquid G1Me (17.8 g, yield 83.5%).

[0080] The synthetic reaction formula of G1Me is:

[0081]

[0082] Example 2

[0083] This embodiment provides a method for further preparing a dendritic phenylacetylene copolymer PG1Me using the above-mentioned G1Me. m EB n The preparation method of (m:n=3:1) comprises the following steps:

[0084] 314.1 mg (0.396 mmol) of G1Me monomer and 17.1 mg (0.132 mmol) of EB monomer were dissolved in dry tetrahydrofuran, frozen with liquid nitrogen and freeze-pumped under vacuum for 20 min. The freeze-pumping operation was repeated three times to remove water from the monomers to obtain a mixed monomer;

[0085] 0.2 mmolmol of [Rh(nbd)Cl]2 and 0.62 mol of TEA were dissolved in 50 μL of tetrahydrofuran to prepare a catalytic system;

[0086] Thaw the mixed monomer and return it to room temperature. Then, add the mixed monomer to 0.1 mL of the catalyst system using a syringe at a molar ratio of mixed monomer:TEA:[Rh(nbd)Cl]2=250:300:1 under nitrogen protection, and react at room temperature under nitrogen protection for 12 h.

[0087] After the reaction was completed, the product was dissolved in dichloromethane and purified by column chromatography using dichloromethane. Finally, the solvent was dried to obtain an orange-red copolymer PG1Me3EB1 (261.9 mg, yield 83.4%).

[0088] It should be noted that the addition of a small amount of tetrahydrofuran allows for better dissolution of triethylamine and the rhodium catalyst, and the amount of tetrahydrofuran added is adjusted based on the condition that the rhodium catalyst is just dissolved.

[0089] The H NMR spectrum of copolymer PG1Me3EB1 is as follows Figure 1 shown.

[0090] The reaction process is as follows:

[0091]

[0092] Example 3

[0093] This embodiment provides a dendritic phenylacetylene copolymer PG1Me m EB n The preparation method of (m:n=10:1) is basically the same as that in Example 2, except that the feed ratio of G1Me monomer to EB monomer is different, and the copolymerization ratio of the polymer obtained by copolymerization is different. The specific steps are:

[0094] 290.3 mg (0.366 mmol) of G1Me monomer and 4.76 mg (0.0366 mmol) of EB monomer were dissolved in dry tetrahydrofuran, frozen with liquid nitrogen and freeze-pumped under vacuum for 20 min. The freeze-pumping operation was repeated three times to remove water from the monomers to obtain a mixed monomer;

[0095] 1.61 μmolmol of [Rh(nbd)Cl]2 and 0.474 mmol of TEA were dissolved in 50 μLmL of tetrahydrofuran to prepare a catalytic system;

[0096] Thaw the mixed monomer and return it to room temperature. Then, quickly add the mixed monomer to 0.1 mL of the catalytic solution using a syringe under nitrogen protection according to the molar ratio of mixed monomer:TEA:[Rh(nbd)Cl]2=250:300:1. React at room temperature under nitrogen protection for 12 h.

[0097] After the reaction was completed, the product was dissolved in dichloromethane and purified by column chromatography using dichloromethane. Finally, the solvent was dried to obtain an orange-red copolymer PG1Me3EB1 (258.4 mg, yield 89.0%).

[0098] Example 4

[0099] This embodiment provides a dendritic phenylacetylene copolymer PG1Me m EB n The preparation method of (m:n=21:1) is basically the same as the steps in Example 2, except that the feeding ratio of G1Me monomer to EB monomer is different, and the copolymerization ratio of the polymer obtained by copolymerization is different.

[0100] 210.5 mg (0.265 mmol) of G1Me monomer and 1.64 mg (0.0126 mmol) of EB monomer were dissolved in dry tetrahydrofuran, frozen with liquid nitrogen and freeze-pumped under vacuum for 20 min. The freeze-pumping operation was repeated three times to remove water from the monomers to obtain a mixed monomer;

[0101] 1.11 μmolmol of [Rh(nbd)Cl]2 and 0.327 mmol of TEA were dissolved in 50 μLmL of tetrahydrofuran to prepare a catalytic system;

[0102] Thaw the mixed monomer and return it to room temperature. Then, add the mixed monomer to 0.1 mL of the catalyst system using a syringe at a molar ratio of mixed monomer:TEA:[Rh(nbd)Cl]2=250:300:1 under nitrogen protection, and react at room temperature under nitrogen protection for 12 h.

[0103] After the reaction was completed, the product was dissolved in dichloromethane and purified by column chromatography using dichloromethane. Finally, the solvent was dried to obtain an orange-red copolymer PG1Me3EB1 (191.98 mg, yield 91.2%).

[0104] Example 5

[0105] This embodiment provides a method for preparing dynamically linked temperature-sensitive chiral polyphenylene vinylene microspheres using a dendritic phenylene vinylene copolymer, comprising the following steps:

[0106] The copolymer PG1Me3EB1 was added at 0.5 mg mL -1 concentration was dissolved in PBS buffer and fully dissolved for 36 h to obtain a copolymer aqueous solution;

[0107] The cross-linking agent ADH was added at a concentration of 10 mg mL -1 The concentration of 100 μg / ml was dissolved in PBS buffer and fully dissolved at -5°C for 36 h to obtain a cross-linking solution;

[0108] The copolymer aqueous solution was prepared according to n (-NH2-NH2-) / n (-CHO) =3 was added to the crosslinking solution, rapidly mixed on a shaker at room temperature for 30 seconds, and then placed in a 45°C oil bath with stirring at 300 rpm for a crosslinking reaction of 12 hours. It should be noted that experiments have shown that aggregates maintain a stable particle size at 45°C. Therefore, the crosslinking reaction temperature in this example was controlled at 45°C.

[0109] After the cross-linking reaction is completed, dynamic thermosensitive chiral microspheres PG1Me3EB1-NPs are obtained in the reaction system, and then the microspheres are purified and extracted by post-processing steps. The specific steps are as follows:

[0110] After cooling to room temperature, the reaction solution was removed and placed in a centrifuge tube. Centrifuge the solution at 20,000 rpm for 10 minutes. The supernatant was the unreacted polymer and crosslinker, while the pale yellow precipitate below was the microspheres. After removing the supernatant, deionized water was added to disperse and wash the microspheres. Centrifuge the solution again, repeating this process twice. The resulting microspheres were dispersed in deionized water for storage.

[0111] Figure 2 This is the AFM test image of PG1Me3EB1-NPs. It can be seen that the morphology of PG1Me3EB1-NPs microspheres is complete and clear, and the particle size is relatively uniform.

[0112] Example 6

[0113] This embodiment provides a method for preparing dynamically linked temperature-sensitive chiral polyphenylene vinylene microspheres using a dendritic phenylene vinylene copolymer. The steps are basically the same as those in Example 5, except that:

[0114] The copolymer PG1Me3EB1 was replaced by the copolymer PG1Me3EB1 prepared in Example 3. 10 EB1.

[0115] Prepared microspheres PG1Me 10 EB1-NPs.

[0116] Example 7

[0117] This embodiment provides a method for preparing dynamically linked temperature-sensitive chiral polyphenylene vinylene microspheres using a dendritic phenylene vinylene copolymer. The steps are basically the same as those in Example 5, except that:

[0118] The copolymer PG1Me3EB1 was replaced by the copolymer PG1Me3EB1 prepared in Example 4. 21 EB1.

[0119] Prepared microspheres PG1Me 21 EB1-NPs.

[0120] Example 8

[0121] This embodiment provides a method for preparing dynamically linked temperature-sensitive chiral polyphenylene vinylene microspheres using a dendritic phenylene vinylene copolymer. The steps are basically the same as those in Example 5, except that:

[0122] Copolymer aqueous solution and cross-linking solution according to n (-NH2-NH2-) / n (-CHO) =1 for mixing.

[0123] Example 9

[0124] This embodiment provides a method for preparing dynamically linked temperature-sensitive chiral polyphenylene vinylene microspheres using a dendritic phenylene vinylene copolymer. The steps are basically the same as those in Example 5, except that:

[0125] Copolymer aqueous solution and cross-linking solution according to n (-NH2-NH2-) / n (-CHO) The mixture was mixed at an equivalent ratio of =1.5.

[0126] Example 10

[0127] This embodiment provides a method for preparing dynamically linked temperature-sensitive chiral polyphenylene vinylene microspheres using a dendritic phenylene vinylene copolymer. The steps are basically the same as those in Example 5, except that:

[0128] Copolymer aqueous solution and cross-linking solution according to n (-NH2-NH2-) / n (-CHO) =2 for mixing.

[0129] Detection and analysis:

[0130] 1. Characterization of aggregation behavior of copolymers in buffer solution

[0131] (1) The copolymer PG1Me3EB1 was dissolved in PBS buffer for 36 h to obtain copolymer aqueous solutions with concentrations of 0.5, 1.0, and 2.0 mg mL -1 .

[0132] Under refrigerated conditions, the copolymer aqueous solution appears orange-yellow and transparent.

[0133] The temperature-sensitive properties and recovery of the copolymer aqueous solution were characterized by UV-visible spectroscopy. Figure 3 It was found that as the temperature increases, the hydrophilic dendrons gradually become hydrophobic and need to maintain the balance of the microenvironment through dehydration and aggregation. When the temperature is higher than the cloud point, the originally transparent solution becomes turbid. When the temperature is lowered from high temperature to room temperature, the turbid solution can become clear and transparent again.

[0134] (2) The copolymer PG1Me3EB1, PG1Me 10 EB1、PG1Me 21 EB1 was dissolved in PBS buffer for 36 h to obtain aqueous copolymer solutions with different copolymerization ratios, with a concentration of 0.5 mg mL -1 .

[0135] The temperature-sensitive properties and recovery of the copolymer aqueous solution were characterized by UV-visible spectroscopy. Figure 4 It can be seen that the EB unit is more hydrophobic, the EB ratio in PG1Me3EB1 is larger, its initial transmittance is lower, and its temperature-sensitive behavior is more sensitive.

[0136] The process of copolymerization from PG1Me3EB1 to aggregates in PBS was tracked by optical microscopy and dynamic light scattering (DLS). Figure 5 Optical microscope observation revealed that no obvious particulate matter could be observed at room temperature. When the temperature was raised to 45°C, obvious particle aggregates appeared. However, due to the limited observation magnification, the clear morphology could not be seen. Figure 6 (a) DLS observation shows the curve of particle size change with temperature. When the temperature rises to near the phase transition temperature, the kinetic radius increases suddenly. Figure 6 (b) and (c) show the relationship between the change of aggregate particle size and time at constant temperatures of 45°C and 50°C. It can be seen that at 45°C, the aggregate particle size fluctuates over time, but the overall change is not large, indicating that at this temperature, the particle radius is relatively stable for a long time; while at 50°C, the aggregate particle size continues to increase over time, indicating that at this temperature, the particles continue to grow or aggregate over time.

[0137] (3) The copolymer PG1Me3EB1, PG1Me 10 EB1、PG1Me 21 EB1 was dissolved in PBS buffer for 36 h to obtain aqueous copolymer solutions with different copolymerization ratios, with a concentration of 0.25 mg mL -1 .

[0138] The copolymer aqueous solutions with different copolymerization ratios were tested at variable temperatures, such as Figure 7 As shown. Copolymer PG1Me3EB1, PG1Me 10 EB1、PG1Me 21 EB1 has typical dynamic helical polymer characteristics. Alanine in the dendron provides a chiral center, and part of the chirality is transferred to the main chain through hydrogen bonding between side groups. The copolymer aqueous solution exhibits a left-handed helical structure at room temperature. As the temperature rises, the signal weakens, and when it reaches near the phase transition temperature, it flips to a right-handed helix. As the temperature continues to rise, the signal gradually increases, and the chirality can be restored after returning to room temperature.

[0139] 2. Characterization of the Thermosensitive Behavior of Polyphenylene Acetylene Microspheres

[0140] Figure 8 and Figure 9 Microspheres with three copolymerization ratios (PG1Me3EB1-NPs, PG1Me 10 EB1-NPs and PG1Me 21 The DLS test graph of EB1-NPs shows that all three microspheres have good thermosensitive responsiveness, among which PG1Me3EB1-NPs has better thermosensitive reversibility.

[0141] 3. Characterization of Chiral Behavior of Polystyrene Microspheres

[0142] Figure 10 The test graph of microspheres with three copolymerization ratios by circular dichroism spectroscopy shows that all three microspheres have fixed the dynamic helical conformation through cross-linking, and the chiral signal will not flip with the change of temperature. Figure 10 The PG1Me3EB1-NPs microspheres shown in (a) have smaller changes in chiral signals, indicating that the microspheres prepared by this copolymerization ratio have better chirality stabilization effect.

[0143] 4. Regulation of microsphere particle size by different crosslinker addition amounts

[0144] Figure 11 The figure shows the effect of different cross-linking agent addition amounts on the dynamic radius of the microspheres in Examples 5 and 8 to 10. As the amount of cross-linking agent added increases, the dynamic radius of the microspheres tends to decrease.

[0145] 5. Regulation of microsphere particle size by different copolymerization ratios

[0146] Figure 12 The changes in the dynamic radius of the microspheres prepared in the three copolymerization ratios of Examples 5 to 7. The dendron is a larger overhang and contributes more to the volume of the microsphere. As the proportion of the dendron increases, the dynamic radius of the microsphere also tends to increase. In addition, due to the crowding effect and shielding effect of the dendron alkoxy ether, when the proportion of the dendron is large, the cross-linking reaction is more difficult and the reaction rate decreases. It can be seen from this that the particle size of the PG1Me3EB1-NPs microspheres is smaller and the degree of reaction during preparation is higher. The polymer obtained by copolymerizing G1Me and EB at a ratio of 3:1 has more cross-linking sites at the same concentration due to the higher proportion of aldehyde groups, and the shielding effect of the dendron alkoxy ether on the cross-linking agent is relatively weaker. Therefore, the efficiency of preparing microspheres at this ratio is higher, and the prepared microspheres have a more uniform and complete morphology.

[0147] 6. Control of Microsphere Particle Size by Different Heating Rates

[0148] Figure 13 The PG1Me prepared at different heating rates was compared. 10 EB1-NPs microspheres and PG1Me 21 The particle size of EB1-NPs microspheres. From the test results, it can be seen that the microspheres prepared by rapid heating have smaller particle size, while the microspheres prepared by slow heating have larger particle size.

[0149] In summary, the present invention provides a method for preparing temperature-sensitive chiral microspheres by in-situ crosslinking reaction of thermosensitive aggregates of dendritic helical copolymers. The present invention synthesizes dendritic alkoxy ether helical polyphenylene vinylene copolymers with different copolymerization ratios through molecular design. The temperature sensitivity of the dendritic helical phenylene vinylene copolymer is utilized to heat-induced dehydration of the copolymer and collapse into aggregates. The aldehyde functional groups on the aggregates form dynamic covalent bonds with the hydrazide bonds on the crosslinking agent to obtain polymer microspheres, which have stable chirality and temperature sensitivity. The preparation method is simple and easy to operate, the reaction environment in the aqueous phase is friendly, and the post-processing is simple without the addition of additional reagents. The prepared polymer microspheres exhibit excellent reversible temperature response function, the chirality of the polyphenylene vinylene main chain can be well fixed, and the size of the microspheres can be adjusted by changing the ratio of the copolymer, the amount of crosslinking agent added, and the heating rate. The preparation route developed by the present invention effectively solves the problems of complex equipment, troublesome post-processing of many additives, and many functionalization operation steps in the existing preparation method. The obtained material has good application prospects in the fields of chiral separation, chiral recognition, asymmetric catalysis, drug loading and sustained release, precision medicine, etc.

[0150] The above describes the specific embodiments of the present invention. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art may make various variations or modifications within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. A method for preparing chiral polyphenylene vinylene microspheres, characterized in that: The following steps are involved: dissolving the dendritic alkoxy ether helical phenylacetylene copolymer in a buffer solution to obtain a copolymer aqueous solution; dissolving a cross-linking agent in a buffer solution to obtain a cross-linking solution; The copolymer aqueous solution and the crosslinker solution are mixed at a molar ratio of hydrazide bond to aldehyde group of 0.5 to 3:1, and then heated to a phase transition temperature of 40 to 50° C. to perform a crosslinking reaction. After sufficient reaction, the reaction product is extracted to obtain the microspheres; The structural formula of the dendronized alkoxy ether spiral phenyl acetylene copolymer is: Among them, m:n = 3 to 21:

1.

2. The preparation method according to claim 1, characterized in that The cross-linking agent is adipic acid dihydrazide.

3. The preparation method according to claim 1, characterized in that The buffer solution is a buffer solution with a pH of 3 to 5.

4. A dendritic alkoxy ether spiral phenyl acetylene copolymer, characterized in that: The structural formula is: Among them, m:n = 3 to 21:

1.

5. A method for preparing a dendritic alkoxy ether spiral phenyl acetylene copolymer, characterized in that: The copolymer is obtained by random copolymerization of a dendronized alkoxy ether spirophenyl acetylene monomer and an aldehyde-containing p-alkynylbenzaldehyde at a molar ratio of 3 to 21:1, wherein the structural formula of the dendronized alkoxy ether spirophenyl acetylene monomer is:

6. The preparation method according to claim 5, characterized in that The random copolymerization method is as follows: a dendritic alkoxy ether spirophenyl acetylene monomer and an aldehyde-containing p-alkynylbenzaldehyde are dissolved in dry tetrahydrofuran, and water is removed by freeze extraction to obtain a mixed monomer. The mixed monomer is thawed and mixed with a catalyst solution under nitrogen protection. After the reaction is completed, the product is extracted to obtain the copolymer.

7. The preparation method according to claim 6, characterized in that The catalyst solution is a mixed solution obtained by dissolving triethylamine and rhodium catalyst in tetrahydrofuran.

8. The preparation method according to claim 7, characterized in that The molar ratio of the mixed monomer, triethylamine and rhodium catalyst is 250:300:

1.

9. Use of polyphenylene vinylene microspheres prepared according to the method according to any one of claims 1 to 3 in the fields of chiral recognition, asymmetric catalysis, drug loading and sustained release, or enantiomer separation.

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