Polyhedral oligomeric silsesquioxane-amino acid multi-arm polymer as well as preparation method and application thereof

Abstract

The invention provides a polyhedral oligomeric silsesquioxane-amino acid multi-arm polymer and a preparation method and application thereof.The polyhedral oligomeric silsesquioxane is composed of inorganic cores composed of silicon-oxygen frameworks alternately connected with Si-O and branched chain aminopropyl with the corresponding number, the number of the inorganic cores is 8, 10 and 12, and the number of the branched chain aminopropyl is 1-3. The amino acids comprise alpha amino acids such as glutamic acid, lysine, aspartic acid, phenylalanine and the like, the polymerization degree of the synthesized polymer can be adjusted by adjusting the link number of the amino acids, and hybrid polymers with different side chain lengths are obtained. The method disclosed by the invention is simple and convenient, and the synthesized polymer can be used as a drug cross-linked hydrogel carrier for loading drugs such as cis-platinum and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of polymer materials, and in particular relates to a polyhedral oligomeric silsesquioxane-amino acid multi-arm polymer and a preparation method and application thereof. Background Art

[0002] Polyamino acid materials are polymers made of amino acids as repeating units connected by peptide bonds. As early as 1906, H. Loche reported on the synthesis and properties of N-carboxy anhydride (NCA) of α-amino acids, laying the foundation for the synthesis of polyamino acids using ring-opening polymerization. Since the 1940s, ring-opening polymerization has become the main method for large-scale synthesis of high molecular weight polyamino acids. Polypeptide polymers synthesized based on α-amino acids have a multi-level specific structure, and therefore have good biocompatibility and biodegradability, as well as biological activity and stimulus responsiveness conferred by functional modification. They can be used as functional and structural materials and are widely concerned.

[0003] The active ring-opening polymerization method based on NCA is constantly developing, for example: initiating polymerization under high vacuum environment, using auxiliary initiators such as thioethers, secondary amines, tertiary amines, etc.; developing new initiators such as organosilicon amines, hydrochlorides or borates, metal complexes, rare earth metals, etc. to initiate polymerization. The development of these synthetic technologies has brought opportunities for constructing multifunctional polyamino acid materials and broadening the application of polyamino acids in biomedicine and nanomaterials.

[0004] Polyhedral oligomeric silsesquioxane (POSS) is an inorganic molecule with nano-size and three-dimensional cage structure, which is widely used in polymer material modification, electronic materials, biomedicine and other fields. In the field of biomedicine, it has the advantages of good biocompatibility and low immunogenicity, easy functionalization and nano-size effect, which has made it widely interested in drug delivery research in recent years. However, due to the limited problem of its terminal active groups, its drug loading and modifiability are subject to certain restrictions. Polyamino acid materials have a large number of active functional groups, which can effectively overcome the above problems. In addition, compared with linear polyamino acids, polyamino acid organic-inorganic dendritic hybrid polymer materials with POSS as the core have the advantages of regular topological structure, good structural stability, high drug loading, etc., which helps to improve the biodistribution and metabolic behavior of drugs, and is a new multifunctional material with great application potential. However, such materials and preparation technologies are still relatively lacking. Summary of the invention

[0005] The first object of the present invention is to provide a POSS-amino acid multi-arm polymer in view of the deficiencies in the prior art. The polymer provided by the present invention has the application potential of forming a drug cross-linked hydrogel.

[0006] A polyhedral oligomeric silsesquioxane-amino acid multi-arm polymer, the structural formula of which is shown in the following formula (I): (I) Wherein, R1 is selected from one of the following structures: -CH2COOH, -(CH2)2COOH, -(CH2)4NH2, -CH2C6H6.

[0007] x is the degree of polymerization, 1≤x≤200.

[0008] POSS is selected from one of the following structures:

[0009]

[0010]

[0011] in" " is the connection site.

[0012] The second object of the present invention is to provide a method for preparing a polyhedral oligomeric silsesquioxane-amino acid multi-arm polymer, comprising the following steps: The amino acid derivative-N-carboxylic acid anhydride is dissolved in an organic solvent A to obtain a solution A, the polyhedral oligomeric silsesquioxane (POSS) is dissolved in an organic solvent B to obtain a solution B, the solution A and the solution B are mixed and a catalyst is added to cause a polymerization reaction to generate the polyhedral oligomeric silsesquioxane-amino acid multi-arm polymer (I); POSS is selected from one of the following structures: (II) (III) (IV).

[0013] Preferably, the molar ratio of polyhedral oligomeric silsesquioxane POSS to amino acid derivative-N-carboxylic acid anhydride is 1:(100-2400).

[0014] Preferably, the polymerization reaction temperature is 10°C to 50°C.

[0015] Preferably, the polymerization reaction time is 12 h to 72 h.

[0016] Preferably, the catalyst is a crown ether.

[0017] Preferably, the organic solvent A is dichloromethane or N,N-dimethylformamide, and the organic solvent B is dimethyl sulfoxide.

[0018] The third object of the present invention is to provide the use of the above-mentioned polyhedral oligomeric silsesquioxane-amino acid multi-arm polymer as a drug cross-linked hydrogel carrier.

[0019] Preferably, the drug is cisplatin.

[0020] Compared with the prior art, the present invention has the following beneficial effects: The present invention introduces an amino acid derivative into the POSS structure to obtain a novel POSS multi-arm polymer, expands the application field of POSS, enables it to be used for drug cross-linked hydrogel carriers to load cisplatin, and has good drug loading and modifiability. The present invention has simple steps for preparing the multi-arm polymer, easy control of preparation process conditions, and easy construction of synthesis equipment, which fills the gap in related technologies. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is the polymer prepared in Example 1 of the present invention, wherein A is the structural formula and B is the hydrogen nuclear magnetic resonance spectrum.

[0022] Figure 2 This is the polymer prepared in Example 7 of the present invention, wherein A is the structural formula and B is the hydrogen nuclear magnetic resonance spectrum.

[0023] Figure 3 This is the hydrogel transition image prepared in Example 13 of the present invention, wherein A is sol and B is gel.

[0024] Figure 4 This is the modulus of the hydrogel prepared in Example 14 of the present invention.

[0025] Figure 5 This is the SEM image of the hydrogel prepared in Example 15 of the present invention. DETAILED DESCRIPTION

[0026] In order to further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the present invention.

[0027] The present invention provides a polyamino acid initiated by a polyhedral polysilsesquioxane containing amino side chains and a preparation method thereof, wherein the polymer structure is shown in formula (I).

[0028] (I) The R1 is independently selected from -CH2COOH, -(CH2)2COOH, -(CH2)4NHCOOH, -CH2C6H6; x is the degree of polymerization, 1≤x≤200.

[0029] The present invention provides a method for preparing a polyhedral oligomeric silsesquioxane grafted polyamino acid material (I). Specifically, the corresponding γ-benzyl-L-glutamate-N-internal carboxylic acid anhydride or β-benzyl-L-aspartate-N-internal carboxylic acid or N6-benzyloxycarbonyl-L-lysine ring anhydride is dissolved in a dry organic solvent, and nitrogen is replaced to obtain a first solution under a nitrogen atmosphere. 18-crown ether-6 is dissolved in an organic solvent, and nitrogen is replaced to obtain a second solution under a nitrogen atmosphere; the polyhedral oligomeric silsesquioxane containing amino side chains is dissolved in an organic solvent, and nitrogen is replaced to obtain a third solution under a nitrogen atmosphere. The amino acid of the present invention is preferably γ-benzyl-L-glutamate-N-internal carboxylic acid anhydride or β-benzyl-L-aspartate-N-internal carboxylic acid or N6-benzyloxycarbonyl-L-lysine ring anhydride. The present invention has no special restrictions on the concentration of the first solution, and is preferably 0.1 g / mL. The present invention has no special restrictions on the concentration of the second solution. The present invention has no particular limitation on the concentration of the third solution. The organic solvents of the first solution and the second solution are preferably dichloromethane or N,N-dimethylformamide, more preferably dry dichloromethane or dry N,N-dimethylformamide. The organic solvent of the third solution is preferably dimethyl sulfoxide, more preferably dry dimethyl sulfoxide.

[0030] After obtaining the first solution, the second solution is mixed with the first solution under a nitrogen atmosphere and stirred continuously, and then the third solution is added and stirred continuously, and in the obtained mixed solution, the polyhedral oligomeric silsesquioxane containing amino branches and γ-benzyl-L-glutamate-N-internal carboxylic acid anhydride or β-benzyl-L-aspartate-N-internal carboxylic acid or N6-benzyloxycarbonyl-L-lysine ring internal anhydride undergo polymerization reaction, and the amino acid block polymer is obtained by sedimentation, suction filtration, etc. The block polymer is redissolved in an organic solvent to obtain a fourth solution, and an appropriate amount of an acidic reagent is added to remove the protective group (benzyl ester group) on the polyamino acid chain, and then sedimentation and suction filtration are performed to obtain a solid polymer.

[0031] The molar ratio of the polyhedral oligomeric silsesquioxane containing amino branches to γ-benzyl-L-glutamate-N-internal carboxylic acid anhydride or β-benzyl-L-aspartate-N-internal carboxylic acid or N6-benzyloxycarbonyl-L-lysine ring internal anhydride is preferably 1: (100-2400), more preferably 1: (200-800). The polymerization reaction temperature is preferably 10 ℃ ~ 50 ℃, more preferably 25 ℃ ~ 30 ℃, and the polymerization reaction time is preferably 24 h to 72 h, more preferably 48 h to 72 h. The organic solvent of the fourth solution is preferably dichloroacetic acid, and the acidic reagent is preferably 33% hydrobromic acid acetic acid solution. The ratio of the block polymer, organic solvent, and acidic reagent is preferably 1 g: 10 mL: 4 mL.

[0032] Example 1

[0033] Dissolve 10 mg of 18-crown-6 in 1 mL of dry dichloromethane to obtain the first solution, and dissolve 38 mg of octahedral 3-aminopropyl polyhedral oligomeric silsesquioxane in 2 mL of dry dimethyl sulfoxide to obtain the second solution; place 4 g of γ-benzyl-L-glutamate-N-inner carboxylic anhydride in a flask, add 40 mL of dry dichloromethane, and after the solid is completely dissolved, add the first solution and the second solution in sequence in a nitrogen atmosphere and stir thoroughly. Replace nitrogen, maintain a slight negative pressure in the flask and stir at 25 °C for 72 h, then precipitate the solution in 800 mL of ice ether for 8 h to obtain a white solid, which is redissolved in N, N-dimethylformamide, dialyzed with distilled water for 72 h, and then freeze-dried to obtain a white solid product. 1 g of white solid was dissolved in 10 mL of dichloroacetic acid. After fully dissolved, 3 mL of 33% hydrobromic acid acetic acid solution was added. After reacting at 30 °C for 1 h, the solution was precipitated in 300 mL of ice ether for 8 h to obtain a light yellow solid. The solid was redissolved in N, N-dimethylformamide, dialyzed with distilled water for 48 h, and then freeze-dried to obtain the target product 1. H NMR spectrum ( Figure 1 ).

[0034] Example 2

[0035] Dissolve 10 mg of 18-crown ether-6 in 1 mL of dry dichloromethane to obtain the first solution, and dissolve 38 mg of eight-arm 3-aminopropyl polyhedral oligomeric silsesquioxane in 2 mL of dry dimethyl sulfoxide to obtain the second solution; place 4 g of γ-benzyl-L-glutamate-N-inner carboxylic anhydride in a flask, add 40 mL of dry dichloromethane, and after the solid is completely dissolved, add the first solution and the second solution in sequence in a nitrogen atmosphere and stir thoroughly. Replace nitrogen, maintain a slight negative pressure in the flask and stir at 25 ℃ for 36 hours, then precipitate the solution in 800 mL of ice ether for 8 hours to obtain a white solid, which is redissolved in N, N-dimethylformamide, dialyzed with distilled water for 72 hours, and then freeze-dried to obtain a white solid product. 1 g of white solid was dissolved in 10 mL of dichloroacetic acid. After it was fully dissolved, 3 mL of 33% hydrobromic acid acetic acid solution was added. After reacting at 30 °C for 1 h, the solution was precipitated in 300 mL of ice ether for 8 h to obtain a light yellow solid. The solid was re-dissolved in N, N-dimethylformamide, dialyzed with distilled water for 48 h, and then freeze-dried to obtain the target product 2.

[0036] Example 3

[0037] Dissolve 10 mg of 18-crown-6 in 1 mL of dry dichloromethane to obtain the first solution, and dissolve 38 mg of eight-arm 3-aminopropyl polyhedral oligomeric silsesquioxane in 2 mL of dry dimethyl sulfoxide to obtain the second solution; place 4 g of γ-benzyl-L-glutamic acid-N-carboxylic anhydride in a flask, add 40 mL of dry dichloromethane, and after the solid is completely dissolved, add the first solution and the second solution in sequence in a nitrogen atmosphere and stir thoroughly. Replace nitrogen, maintain a slight negative pressure in the flask, and stir at 50 °C for 72 h, then precipitate the solution in 800 mL of ice ether for 8 h to obtain a white solid, which is redissolved in N, N-dimethylformamide, dialyzed with distilled water for 72 h, and then freeze-dried to obtain a white solid product. 1 g of white solid was dissolved in 10 mL of dichloroacetic acid. After it was fully dissolved, 3 mL of 33% hydrobromic acid acetic acid solution was added. After reacting at 30 °C for 1 h, the solution was precipitated in 300 mL of ice ether for 8 h to obtain a light yellow solid. The solid was re-dissolved in N, N-dimethylformamide, dialyzed with distilled water for 48 h, and then freeze-dried to obtain the target product 3.

[0038] Example 4

[0039] Dissolve 10 mg of 18-crown-6 in 1 mL of dry dichloromethane to obtain the first solution, and dissolve 38 mg of eight-arm 3-aminopropyl polyhedral oligomeric silsesquioxane in 2 mL of dry dimethyl sulfoxide to obtain the second solution; place 4 g of γ-benzyl-L-glutamate-N-inner carboxylic anhydride in a flask, add 40 mL of dry dichloromethane, and after the solid is completely dissolved, add the first solution and the second solution in sequence in a nitrogen atmosphere and stir thoroughly. Replace nitrogen, maintain a slight negative pressure in the flask and stir at 10 °C for 72 h, then precipitate the solution in 800 mL of ice ether for 8 h to obtain a white solid, which is redissolved in N, N-dimethylformamide, dialyzed with distilled water for 72 h, and then freeze-dried to obtain a white solid product. 1 g of white solid was dissolved in 10 mL of dichloroacetic acid. After it was fully dissolved, 3 mL of 33% hydrobromic acid acetic acid solution was added. After reacting at 30 °C for 1 h, the solution was precipitated in 300 mL of ice ether for 8 h to obtain a light yellow solid. The solid was re-dissolved in N, N-dimethylformamide, dialyzed with distilled water for 48 h, and then freeze-dried to obtain the target product 4.

[0040] Example 5

[0041] Dissolve 4 mg of 18-crown ether-6 in 1 mL of dry dichloromethane to obtain the first solution, and dissolve 15.2 mg of eight-arm 3-aminopropyl polyhedral oligomeric silsesquioxane in 2 mL of dry dimethyl sulfoxide to obtain the second solution; place 4 g of γ-benzyl-L-glutamate-N-inner carboxylic anhydride in a flask, add 40 mL of dry dichloromethane, and after the solid is completely dissolved, add the first solution and the second solution in sequence in a nitrogen atmosphere and stir thoroughly. Replace nitrogen, maintain a slight negative pressure in the flask and stir at 25 ℃ for 72 hours, then precipitate the solution in 800 mL of ice ether for 8 hours to obtain a white solid, which is redissolved in N, N-dimethylformamide, dialyzed with distilled water for 72 hours, and then freeze-dried to obtain a white solid product. 1 g of white solid was dissolved in 10 mL of dichloroacetic acid. After it was fully dissolved, 3 mL of 33% hydrobromic acid acetic acid solution was added. After reacting at 30 °C for 1 h, the solution was precipitated in 300 mL of ice ether for 8 h to obtain a light yellow solid. The solid was re-dissolved in N, N-dimethylformamide, dialyzed with distilled water for 48 h, and then freeze-dried to obtain the target product 5.

[0042] Example 6

[0043] Dissolve 38 mg of eight-arm 3-aminopropyl polyhedral oligomeric silsesquioxane in 2 mL of dry dimethyl sulfoxide to obtain the first solution; place 4 g of γ-benzyl-L-glutamate-N-inner carboxylic anhydride in a branched bottle, add 40 mL of dry N,N-dimethylformamide, and after the solid is completely dissolved, add the first solution in a nitrogen atmosphere and stir thoroughly. Replace nitrogen, maintain a slight negative pressure in the branched ampoule and stir at 25 ℃ for 72 hours, then precipitate the solution in 800 mL of ice ether for 8 hours to obtain a white solid, which is redissolved in N, N-dimethylformamide, dialyzed with distilled water for 72 hours, and then freeze-dried to obtain a white solid product. 1 g of white solid was dissolved in 10 mL of dichloroacetic acid. After it was fully dissolved, 3 mL of 33% hydrobromic acid acetic acid solution was added. After reacting at 30 °C for 1 h, the solution was precipitated in 300 mL of ice ether for 8 h to obtain a light yellow solid. The solid was re-dissolved in N, N-dimethylformamide, dialyzed with distilled water for 48 h, and then freeze-dried to obtain the target product 6.

[0044] Example 7

[0045] Dissolve 8.6 mg of 18-crown ether-6 in 1 mL of dry dichloromethane to obtain the first solution, and dissolve 32.6 mg of eight-arm 3-aminopropyl polyhedral oligomeric silsesquioxane in 2 mL of dry dimethyl sulfoxide to obtain the second solution; place 2 g of N6-benzyloxycarbonyl-L-lysine ring anhydride in a branched ampoule, add 20 mL of dry dichloromethane, and after the solid is completely dissolved, add the first solution and the second solution in sequence in a nitrogen atmosphere and stir thoroughly. Replace the nitrogen and keep After stirring for 72 h at 25 °C with a slight negative pressure in the ampoule, the solution was precipitated in 400 mL of ice ether for 8 h to obtain a white solid, which was redissolved in N, N-dimethylformamide, dialyzed with distilled water for 72 h, and then freeze-dried to obtain a white solid product. 0.5 g of the white solid was dissolved in 5 mL of dichloroacetic acid. After fully dissolved, 1.5 mL of 33% hydrobromic acid acetic acid solution was added. After reacting at 30 °C for 1 h, the solution was precipitated in 200 mL of ice ether for 8 h to obtain a light yellow solid. The target product 7 was obtained after redissolved in N, N-dimethylformamide, dialyzed with distilled water for 48 h, and then freeze-dried (NMR hydrogen spectrum). Figure 2 ).

[0046] Example 8

[0047] Dissolve 15.1 mg of 18-crown ether-6 in 1 mL of dry dichloromethane to obtain the first solution, and dissolve 57 mg of eight-arm 3-aminopropyl polyhedral oligomeric silsesquioxane in 2 mL of dry dimethyl sulfoxide to obtain the second solution; place 3 g of γ-benzyl-L-aspartic acid ester-N-inner carboxylic anhydride in a branched ampoule, add 60 mL of dry dichloromethane, and after the solid is completely dissolved, add the first solution and the second solution in sequence in a nitrogen atmosphere and stir thoroughly. Replace nitrogen, maintain a slight negative pressure in the branched ampoule and stir at 25 ℃ for 72 hours, then precipitate the solution in 800 mL of ice ether for 8 hours to obtain a white solid, which is redissolved in N, N-dimethylformamide, dialyzed with distilled water for 72 hours, and then freeze-dried to obtain a white solid product. 1 g of white solid was dissolved in 10 mL of dichloroacetic acid. After it was fully dissolved, 3 mL of 33% hydrobromic acid acetic acid solution was added. After reacting at 30 °C for 1 h, the solution was precipitated in 300 mL of ice ether for 8 h to obtain a light yellow solid. The solid was re-dissolved in N, N-dimethylformamide, dialyzed with distilled water for 48 h, and then freeze-dried to obtain the target product 8.

[0048] Example 9

[0049] 5 mg of 18-crown ether-6 was dissolved in 1 mL of dry dichloromethane to obtain the first solution, and 19 mg of 8-arm 3-aminopropyl polyhedral oligomeric silsesquioxane was dissolved in 2 mL of dry dimethyl sulfoxide to obtain the second solution; 2 g of L-phenylalanine-N-carboxyl ring anhydride was placed in a flask, and 20 mL of dry dichloromethane was added. After the solid was completely dissolved, the first solution and the second solution were added in sequence in a nitrogen atmosphere and stirred thoroughly. After nitrogen was replaced, a slight negative pressure was maintained in the flask and stirred at 25 °C for 72 h, the solution was precipitated in 400 mL of ice ether for 8 h to obtain a white solid, which was redissolved in N, N-dimethylformamide, dialyzed with distilled water for 48 h, and then freeze-dried to obtain the target product 9.

[0050] Example 10

[0051] 38 mg of eight-arm 3-aminopropyl polyhedral oligomeric silsesquioxane was dissolved in 2 mL of dry dimethyl sulfoxide to obtain the first solution; 2 g of γ-benzyl-L-glutamate-N-inner carboxylic anhydride and 2 g of L-phenylalanine-N-carboxyl ring inner carboxylic anhydride were placed in a branch-mouthed bottle, and 40 mL of dry N,N-dimethylformamide was added. After the solid was completely dissolved, the first solution was added in a nitrogen atmosphere and stirred thoroughly. After nitrogen was replaced, a slight negative pressure was maintained in the branch-mouthed ampoule and stirring was carried out at 25 ℃ for 72 hours, the solution was precipitated in 800 mL of ice ether for 8 hours to obtain a white solid, which was redissolved in N, N-dimethylformamide, dialyzed with distilled water for 72 hours, and then freeze-dried to obtain a white solid product. 1 g of white solid was dissolved in 10 mL of dichloroacetic acid. After it was fully dissolved, 3 mL of 33% hydrobromic acid acetic acid solution was added. After reacting at 30 °C for 1 h, the solution was precipitated in 300 mL of icy ether for 8 h to obtain a light yellow solid. The solid was re-dissolved in N, N-dimethylformamide, dialyzed with distilled water for 48 h, and then freeze-dried to obtain the target product 10.

[0052] Embodiment 11

[0053] Dissolve 10 mg of 18-crown ether-6 in 1 mL of dry dichloromethane to obtain the first solution, and dissolve 47.5 mg of ten-arm 3-aminopropyl polyhedral oligomeric silsesquioxane in 2 mL of dry dimethyl sulfoxide to obtain the second solution; place 4 g of γ-benzyl-L-glutamate-N-inner carboxylic anhydride in a flask, add 40 mL of dry dichloromethane, and after the solid is completely dissolved, add the first solution and the second solution in sequence in a nitrogen atmosphere and stir thoroughly. Replace nitrogen, maintain a slight negative pressure in the flask and stir at 25 ℃ for 72 hours, then precipitate the solution in 800 mL of ice ether for 8 hours to obtain a white solid, which is redissolved in N, N-dimethylformamide, dialyzed with distilled water for 72 hours, and then freeze-dried to obtain a white solid product. 1 g of white solid was dissolved in 10 mL of dichloroacetic acid. After it was fully dissolved, 3 mL of 33% hydrobromic acid acetic acid solution was added. After reacting at 30 °C for 1 h, the solution was precipitated in 300 mL of ice ether for 8 h to obtain a light yellow solid. The solid was re-dissolved in N, N-dimethylformamide, dialyzed with distilled water for 48 h, and then freeze-dried to obtain the target product 11.

[0054] Example 12

[0055] Dissolve 10 mg of 18-crown ether-6 in 1 mL of dry dichloromethane to obtain the first solution, and dissolve 47.5 mg of 12-arm 3-aminopropyl polyhedral oligomeric silsesquioxane in 2 mL of dry dimethyl sulfoxide to obtain the second solution; place 4 g of γ-benzyl-L-glutamate-N-inner carboxylic anhydride in a flask, add 40 mL of dry dichloromethane, and after the solid is completely dissolved, add the first solution and the second solution in sequence in a nitrogen atmosphere and stir thoroughly. Replace nitrogen, maintain a slight negative pressure in the flask and stir at 25 °C for 72 h, then precipitate the solution in 800 mL of ice ether for 8 h to obtain a white solid, which is redissolved in N, N-dimethylformamide, dialyzed with distilled water for 72 h, and lyophilized to obtain a white solid product. 1 g of white solid was dissolved in 10 mL of dichloroacetic acid. After it was fully dissolved, 3 mL of 33% hydrobromic acid acetic acid solution was added. After reacting at 30 °C for 1 h, the solution was precipitated in 300 mL of ice ether for 8 h to obtain a light yellow solid. The solid was re-dissolved in N, N-dimethylformamide, dialyzed with distilled water for 48 h, and then freeze-dried to obtain the target product 12.

[0056] Embodiment 13

[0057] The alkalized glutamic acid polymer prepared in Example 1 of the present invention was dissolved in deionized water, a polyamino acid solution with a mass fraction of 2.0% was prepared, vortexed until fully dissolved and replaced with a nitrogen atmosphere, 15 mg / mL cisplatin was added, and the mixture was incubated in a shaker at 45°C for 48 h, and then incubated at room temperature of 25°C for 48 h to obtain a cisplatin cross-linked hydrogel.

[0058] Figure 3 The sol-gel transition image shows that a uniform and stable gel network is obtained after coordination with the cisplatin crosslinker.

[0059] Embodiment 14

[0060] 300 μL of cisplatin cross-linked hydrogel (polyglutamic acid mass fraction of 2.0%, cisplatin concentration of 15 mg / mL) prepared according to the method of Example 13 of the present invention was placed on a rotational rheometer, and the gel modulus was measured by time-frequency scanning.

[0061] Figure 4 This is the time-frequency scanning result diagram. It can be seen from the figure that the elastic modulus of the gel is stably maintained at 331 Pa, which can ensure drug delivery while meeting the injectability requirements.

[0062] Embodiment 15

[0063] 300 μL of cisplatin cross-linked hydrogel (polyglutamic acid mass concentration of 2.0%, cisplatin mass concentration of 15 mg / mL) prepared in Example 13 of the present invention was rapidly frozen by liquid nitrogen quick freezing method, and then its microstructure was observed by scanning electron microscopy.

[0064] Figure 5 This is a scanning electron microscope image of the gel. It can be seen from the figure that the gel presents an interconnected porous structure, which provides the possibility for subsequent drug release.

[0065] The above embodiments are not limitations of the present invention, and the present invention is not limited to the above embodiments. As long as the requirements of the present invention are met, they belong to the protection scope of the present invention.

Claims

1. A polyhedral oligomeric silsesquioxane-amino acid multi-arm polymer, It is characterized in that Its structural formula is shown in the following formula (I): （Ⅰ） Among them, R 1 Select one of the following structures: -CH 2 COOH, -(CH 2 ) 2 COOH, -(CH 2 ) 4 NH 2 、-CH 2 C 6 H 6 ; x is the degree of polymerization, 1≤x≤200; POSS is selected from one of the following structures: 、 、 ； in" " is the connection site.

2. A method for preparing the polyhedral oligomeric silsesquioxane-amino acid multi-arm polymer as claimed in claim 1, It is characterized in that The preparation method comprises the following steps: The amino acid derivative-N-carboxylic acid anhydride is dissolved in an organic solvent A to obtain a solution A, the polyhedral oligomeric silsesquioxane POSS is dissolved in an organic solvent B to obtain a solution B, the solution A is mixed with the solution B and a catalyst is added to cause a polymerization reaction to generate the polyhedral oligomeric silsesquioxane-amino acid multi-arm polymer; The polyhedral oligomeric silsesquioxane POSS is selected from one of the following structures: （Ⅱ） （Ⅲ） （Ⅳ）。 3. The preparation method according to claim 2, It is characterized in that The molar ratio of polyhedral oligomeric silsesquioxane POSS to amino acid derivative-N-carboxylic acid anhydride is 1:(100-2400).

4. The preparation method according to claim 2, It is characterized in that The polymerization reaction temperature is 10 ℃ ~ 50 ℃.

5. The preparation method according to claim 2, It is characterized in that The polymerization reaction time is 12 h~72 h.

6. The preparation method according to claim 2, It is characterized in that The catalyst is a crown ether.

7. The preparation method according to claim 2, It is characterized in that The organic solvent A is dichloromethane or N,N-dimethylformamide.

8. The preparation method according to claim 7, It is characterized in that The organic solvent B is dimethyl sulfoxide.

9. Use of the polyhedral oligomeric silsesquioxane-amino acid multi-arm polymer as claimed in claim 1 as a drug cross-linked hydrogel carrier.

10. The use according to claim 9, It is characterized in that The drug is cisplatin.

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