Preparation method of random cluster peptide, prepared random cluster peptide and application of random cluster peptide

Abstract

The invention belongs to the technical field of polymer synthesis, and relates to a preparation method of a random cluster peptide, the prepared random cluster peptide and application of the random cluster peptide, and the random cluster peptide is prepared by carrying out random copolymerization on two or more N-phenoxycarbonyl-N-substituted glycine (NNPC) monomers under the action of an initiator, organic acid and organic alkali. The monomer used in the invention has better nucleophilic substance tolerance, storage stability and polymerization operability, the polymerization condition is mild through the use of organic acid and organic alkali, and the preparation of the random clustered peptide with controllable molecular weight and composition and with the reactivity rate of NNPC monomers with different substituent groups close to 1 is realized at the same time. Besides, through optimization of a monomer substituent group, the random cluster peptide is endowed with an LCST property, so that the random cluster peptide has a good application prospect in the field of biomedicine.

Description

Technical Field

[0001] The invention relates to the technical field of polymer synthesis, and in particular to a method for preparing a random polymerized peptide, the prepared random polymerized peptide and applications thereof. Background Art

[0002] Polypeptides are a type of polymer whose repeating units are composed of N-substituted glycine. They are similar to proteins in structure and have good biocompatibility and degradability. Compared with peptides, there are no hydrogen atoms in the amide bonds in the main chain of peptides, and hydrogen bonds cannot be formed within or between molecular chains. Therefore, peptides have good solubility and processability, and are widely used in self-assembly, drug loading, surface modification, etc. In general, functional groups can be introduced into the side chains of peptide polymers to give them different stimulus responsiveness, so as to broaden the application of peptides in the biomedical field.

[0003] There are two main methods for synthesizing polypeptides, solid phase synthesis and ring-opening polymerization. At present, the main method for synthesizing polypeptides is the ring-opening polymerization of N-substituted glycine-N-carboxylic anhydride (NNCA) and N-substituted glycine-N-thiocarboxylic anhydride (NNTA) monomers. For example, Chinese invention patent application CN105199098A discloses a method for synthesizing polypeptides, using alkyl primary amine or aromatic primary amine as an initiator, NNCA as a monomer, and initiating the solution ring-opening polymerization of the monomer under nitrogen flow to synthesize polypeptides in one step. Chinese invention patent application CN118027391A discloses a method for preparing polypeptides based on aromatic amine initiation, its products and applications, using aromatic amine as an initiator, and preparing polypeptides by one-step reaction of aromatic amine and N-substituted glycine-N-thiocarboxylic anhydride. By selecting a variety of N-substituted glycine-N-thiocarboxylic anhydrides with different structures, various types of polypeptides such as random or block can be prepared. However, the yield of copolymerization of some monomers is only 50%.

[0004] However, the synthesis of the above two types of monomers requires the use of phosgene derivatives and phosphorus halides, respectively, and the synthesis process is complicated and dangerous. In addition, the activity of the same monomers with different substituents varies greatly, as reported in "Polypeptoids with tunable cloudpoint temperatures synthesized from N-substituted glycine N-thiocarboxyanhydrides" (Polymer Chemistry 2015, 6 (16): 3164-3174): the reactivity ratios of the copolymerization of sarcosine NTA and N-butylglycine NTA are: r (sarcosine NTA) = 1.707 and r (N-butylglycine NTA) = 0.637. When the competitive polymerization rate difference is large during the copolymerization process, the polymerization product is a gradient peptide or even a block peptide. The stimulus-responsive peptides reported so far, especially the temperature-responsive peptide polymers with adjustable transition temperature, are mostly random copolymers composed of hydrophilic polysarcosine (PSar) or poly(N-(ethyl)glycine) (PNEG) and hydrophobic poly(N-(butyl)glycine) (PNBG). The synthesis of such random peptides from NNCA and NNTA monomers has certain limitations.

[0005] In order to further expand the types of temperature-responsive peptide polymers, it is necessary to develop their monomers and achieve random copolymerization through process improvements. N-phenyloxycarbonyl-N-substituted glycine monomers (NNPC) can be synthesized by direct reaction of phenyl chloroformate and sarcosine, and purification and storage are also relatively convenient. So far, there have been no reports on random copolymerization of NNPC monomers with different substituents.

[0006] Based on this, the synthesis of random clustered peptides is achieved by using NNPC monomers through process improvements, which has important research significance for expanding the application of clustered peptides in the biomedical field. Summary of the invention

[0007] In order to solve the problems existing in the prior art, the present invention provides a method for preparing a random polymerized peptide, the prepared random polymerized peptide and its application, specifically a method for preparing a polymerized peptide by random copolymerization of N-phenoxycarbonyl-N-substituted glycine (NNPC) monomers, which controls the reactivity rate of NNPC monomers with different substituents by adding organic acids and organic bases for the first time, and obtains a random polymerized peptide with controllable molecular weight and polymer composition.

[0008] The technical solution of the present invention is as follows:

[0009] The present invention provides a method for preparing a random polymerized peptide, which specifically comprises the following steps: under the action of an initiator, an organic base and an organic acid, two or more N-phenoxycarbonyl-N-substituted glycine monomers are randomly copolymerized to obtain the peptide.

[0010] Further, the N-phenoxycarbonyl-N-substituted glycine monomer is selected from a combination of two or more of the following structures:

[0011]

[0012] Among them, R 1 Any one selected from the group consisting of an alkyl group, a halogenated alkyl group, an aromatic group, a cyano group, a hydroxyl group, a carboxyl group and a nitro group.

[0013] It is worth noting that in the random copolymerization reaction of the present invention, different N-phenoxycarbonyl-N-substituted glycine monomers can be reacted in any molar ratio, and the monomer composition and feed ratio of the prepared random polymerized peptide can be kept consistent.

[0014] Furthermore, the N-phenoxycarbonyl-N-substituted glycine monomers include at least one N-phenoxycarbonyl-N-substituted glycine monomer containing a hydrophilic group and one N-phenoxycarbonyl-N-substituted glycine monomer containing a hydrophobic group.

[0015] In some preferred embodiments of the present invention, the molar percentage of the hydrophilic group-containing N-phenoxycarbonyl-N-substituted glycine monomers to all N-phenoxycarbonyl-N-substituted glycine monomers is 58-71%. The random peptide prepared under this feed ratio has significant LCST performance.

[0016] Those skilled in the art should understand that the N-phenoxycarbonyl-N-substituted glycine monomer containing a hydrophilic group is all N-phenoxycarbonyl-N-substituted glycine monomers containing a hydrophilic group.

[0017] In addition, it should be noted that in the present invention, the type and amount of initiator, the type and amount of organic acid and organic base in the random copolymerization process of NNPC, and the temperature and time of the random copolymerization reaction have almost no effect on whether the random polymerized peptide has LCST.

[0018] One of the random copolymerization routes of the present invention is:

[0019]

[0020] Among them, R 1 and R 2 They contain hydrophilic groups and hydrophobic groups respectively; x is the molar percentage of the monomer.

[0021] Preferably, the value range of x is 0.5-0.8, and the degree of polymerization n is ≥20.

[0022] The random copolymerization reaction route of the present invention can also be:

[0023]

[0024] Among them, R 1 , R 2 , R m At least one hydrophilic group and one hydrophobic group; 1 、x 2 ,......x m is the molar percentage of the corresponding monomer, x 1 +x 2 +......+x m =1.

[0025] It is worth noting that the end groups of the random copolymer products in the above synthetic route depend on the type of initiator. For example, when benzylamine is used as the initiator, the end groups of the copolymer products connected to C=O are The terminal group connected to N is H.

[0026] Preferably, based on molar percentage, the N-phenoxycarbonyl-N-substituted glycine monomers containing a hydrophilic group account for 50-80% of all N-phenoxycarbonyl-N-substituted glycine monomers, and the degree of polymerization n is ≥20.

[0027] In some preferred embodiments of the present invention, the N-phenoxycarbonyl-N-substituted glycine monomer is a combination of N-phenoxycarbonylsarcosine (Sar-NPC) and N-phenoxycarbonyl-N-butylglycine (NBuG-NPC).

[0028] In some preferred embodiments of the present invention, the N-phenoxycarbonyl-N-substituted glycine monomer is a combination of N-phenoxycarbonylsarcosine (Sar-NPC), N-phenoxycarbonyl-N-ethylglycine (NEtG-NPC) and N-phenoxycarbonyl-N-butylglycine (NBuG-NPC).

[0029] Furthermore, the initiator is one or more of primary amines, secondary amines or silylamines; specifically, at least one selected from neopentylamine, n-hexylamine, benzylamine, diethylamine, polyethylene glycolamine or trimethylsilylamine; preferably, benzylamine.

[0030] Furthermore, the organic acid is a carboxylic acid; specifically, at least one selected from formic acid, acetic acid, benzoic acid, n-butyric acid, n-hexanoic acid or pivalic acid; preferably benzoic acid.

[0031] Furthermore, the organic base is a tertiary amine or a nitrogen heterocyclic compound; specifically, at least one selected from triethylamine, N,N-diisopropylethylamine, quinoline or 4-dimethylaminopyridine; preferably N,N-diisopropylethylamine.

[0032] It is worth noting that in the random copolymerization reaction of the present invention, when different types of initiators, organic acids and organic bases are used, there is no significant difference in the copolymerization effect, that is, the yield of the obtained polypeptide can reach more than 99%, and the competitive polymerization rate of each monomer is close to 1.

[0033] Furthermore, the random copolymerization reaction is carried out in an organic solvent.

[0034] Furthermore, the organic solvent is selected from at least one of dioxane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, sulfolane, acetonitrile, benzonitrile, dichloromethane, dichloroethane, chloroform or toluene.

[0035] Furthermore, the molar ratio of the initiator to the total amount of N-phenoxycarbonyl-N-substituted glycine monomer is 1:5-300; preferably 1:5-100; and more preferably 1:5-25.

[0036] Furthermore, the molar ratio of the organic acid to the total amount of N-phenoxycarbonyl-N-substituted glycine monomer is 1:0.1-0.5, preferably 1:0.2.

[0037] Furthermore, the molar ratio of the organic base to the total amount of N-phenoxycarbonyl-N-substituted glycine monomer is 1:0.5-5; preferably 1:1.

[0038] Furthermore, the random copolymerization reaction temperature is 20-100°C.

[0039] Furthermore, the random copolymerization reaction time is 0.5-96h.

[0040] The present invention provides a random polymerized peptide prepared by the above preparation method.

[0041] Furthermore, the random peptide is a temperature-sensitive random peptide

[0042] The present invention also provides application of the random polymerized peptide in biomedical materials.

[0043] Compared with the prior art, the present invention has the following beneficial effects:

[0044] (1) The N-phenoxycarbonyl-N-substituted glycine (NNPC) monomer used in the polymerization method provided by the present invention has better nucleophilic tolerance, synthesis and storage stability, and polymerization operability than the common NNCA monomer and NNTA monomer; the random copolymerization reaction of the present invention can control the polymerization reaction rate of NNPC monomers with different substituents to be consistent in the presence of organic acid and organic base, especially in the presence of organic acid, and finally achieve the reactivity ratio of each NNPC monomer close to 1, realize complete random copolymerization, and obtain random polymerized peptides;

[0045] (2) The random polymerization reaction conditions of the present invention are mild, and random peptides with controllable molecular weight and composition can be obtained by controlling the feed ratio of different NNPC monomers and the feed ratio of NNPC monomers and initiators;

[0046] (3) In addition, by further limiting the monomer type and ratio, the random polymer peptide is endowed with excellent thermosensitivity, and its critical co-solubility temperature can be regulated according to the feed ratio of different types of monomers, giving it a good application prospect in the biomedical field. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 The peptide product prepared in Example 1 1 H NMR spectrum; A is the complete spectrum, B is the partial enlarged spectrum;

[0048] Figure 2 This is the MALDI-ToF MS spectrum of the clustered peptide product prepared in Example 1; wherein A is the complete spectrum and B is the enlarged view;

[0049] Figure 3 The polymerized peptide product prepared in Example 2 1 H NMR spectrum; A is the complete spectrum and B is the enlarged spectrum;

[0050] Figure 4 This is the MALDI-ToF MS spectrum of the clustered peptide product prepared in Example 2; wherein A is the complete spectrum and B is a partial enlarged view;

[0051] Figure 5 This is a diagram showing the temperature-sensitive transition effect of the polymerized peptide product prepared in Example 3;

[0052] Figure 6 This is the temperature-sensitive transition curve of the polymerized peptide product prepared under different monomer ratios in Example 13. DETAILED DESCRIPTION

[0053] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0054] The N-phenoxycarbonyl-N-substituted glycine (NNPC) monomers used in the present invention are synthesized according to the document "Facile synthesis of N-phenoxycarbonyl amino acids by a two-phase reaction for direct polymerization" (Polymer Chemistry, 2024, 15(2): 97-105), and other raw materials are commercially available.

[0055] The molecular weight, composition and structure of peptides were determined by 1 H NMR and MALDI-ToF MS measurements;

[0056] The absolute molecular weight of the peptide was expressed as 1 H NMR end group method calibration;

[0057] 1 HNMR was measured on a Bruker Avance DMX 400 (400 MHz) instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), the internal standard was tetramethylsilane (TMS);

[0058] MALDI-ToF MS analysis was performed on a Bruker UltraFLEX MALDI-ToF mass spectrometer in linear mode using 2,5-dihydroxybenzoic acid (DHB) as the matrix.

[0059] Monomer reactivity ratio: determined by Fineman-Ross method.

[0060] Minimum co-solvent temperature (LCST): The polymerized peptide samples were dissolved in deionized water at 25°C. The polymer concentration was 3 mg / mL. The polymer solution was then heated at a rate of 1°C / min. The transmittance was measured every three minutes using a UV spectrophotometer with a detection wavelength of 450nm until the transmittance was less than 1%. The temperature corresponding to a transmittance of 50% is the LCST.

[0061] Example 1

[0062] N-phenyloxycarbonylsarcosine monomer (Sar-NPC, 0.209 g, 1.000 mmol) and N-phenyloxycarbonyl-N-ethylglycine monomer (NEtG-NPC, 0.223 g, 1.000 mmol) were added to the reaction bottle, dissolved with 4 mL of N,N-dimethylacetamide, acetic acid (0.024 g, 0.400 mmol) and N,N-diisopropylethylamine (0.258 g, 2.000 mmol) were added, and then 0.80 mL of N,N-dimethylacetamide solution (0.100 mmol / mL) of benzylamine was added. The molar ratio of benzylamine to total NNPC monomer was 1:25. After sealing, the reaction was placed in a 70°C oil bath for 24 hours. After the reaction, the polymerization solution was poured into ether for precipitation, and the obtained polymer was vacuum dried to obtain the corresponding poly-peptide (poly(sarcosine-co-N-phenyloxycarbonyl-N-ethylglycine)) with a yield of 99%.

[0063] The experimentally measured reactivity ratio of the two monomers is r Sar-NPC =1.113, r NEtG-NPC =0.969, the average absolute molecular weight of the obtained poly(sarcosine-co-N-phenoxycarbonyl-N-ethylglycine) was 2.1 kg / mol, the molar ratio of the two components in the polymer was 1:1, which was equivalent to the feed ratio, and the molecular weight distribution was 1.13 (the 1 H NMR spectrum Figure 1 As shown, the MALDI-ToF spectrum is as follows Figure 2 The polymer is completely soluble in water and has no LCST.

[0064] Example 2

[0065] The preparation method is the same as that in Example 1, except that the monomers used are N-phenoxycarbonylsarcosine and N-phenoxycarbonyl-N-butylglycine (NBuG-NPC), and the yield of the prepared polypeptide (poly(sarcosine-co-N-phenoxycarbonyl-N-butylglycine)) is 99%.

[0066] The experimentally measured reactivity ratio of the two monomers is r Sar-NPC =1.067, r NBuG-NPC =1.038, the number average absolute molecular weight is 2.4kg / mol, the molar ratio of the two components in the polymer is 1:1, which is equivalent to the feed ratio, and the molecular weight distribution is 1.15 (the 1 HNMR spectrum Figure 3 As shown, the MALDI-ToF spectrum is as follows Figure 4 The LCST of the polymer is 20°C.

[0067] Example 3

[0068] The preparation method is the same as that in Example 2, except that the molar ratio of monomer to initiator used is Sar-NPC:NBuG-NPC:benzylamine=62:38:1, and the yield of the obtained polypeptide (poly(sarcosine-co-N-phenoxycarbonyl-N-butylglycine)) is 99%.

[0069] The experimentally measured reactivity ratio of the two monomers is r Sar-NPC =1.067, r NBuG-NPC =1.038, the number average absolute molecular weight is 8.7 kg / mol, the molar ratio of the two components in the polymer is 62:38, which is equivalent to the feed ratio, the molecular weight distribution is 1.12, and the LCST of the polymer is 42 ° C (the temperature sensitive transition effect diagram is shown in Figure 5 shown).

[0070] Example 4

[0071] The preparation method is the same as that in Example 3, except that N,N-diisopropylethylamine is not added, and the yield of the obtained polypeptide is 0%.

[0072] Example 5

[0073] The preparation method is the same as that of Example 3, except that acetic acid is not added. The experimentally measured reactivity ratio of the two monomers is r Sar-NPC =1.315, r NBuG-NPC =0.712, the yield of the obtained polymer peptide is 85%, the number average absolute molecular weight is 7.2 kg / mol, and the LCST of the polymer is 61°C.

[0074] Example 6

[0075] The preparation method is the same as that in Example 3, except that the molar ratio of the monomers and the initiator used is Sar-NPC:NBuG-NPC:benzylamine=40:60:1, the yield of the obtained polypeptide (poly(sarcosine-co-N-phenoxycarbonyl-N-butylglycine)) is 99%, the molar ratio of the two components in the polymer is 40:60, which is equivalent to the feed ratio, and the polymer is completely insoluble in water and does not have LCST.

[0076] Example 7

[0077] The preparation method is the same as that in Example 3, except that the molar ratio of the monomers and the initiator used is Sar-NPC:NBuG-NPC:benzylamine=90:10:1, the yield of the obtained polypeptide (poly(sarcosine-co-N-phenoxycarbonyl-N-butylglycine)) is 99%, and the molar ratio of the two components in the polymer is 90:10, which is equivalent to the feed ratio. The polymer is completely soluble in water and does not precipitate even in water at 100°C, and there is no LCST.

[0078] Example 8

[0079] The preparation method is the same as that in Example 3, except that the monomers used are N-phenoxycarbonylsarcosine (Sar-NPC), N-phenoxycarbonyl-N-ethylglycine (NEtG-NPC) and N-phenoxycarbonyl-N-butylglycine (NBuG-NPC), and the feed ratio is Sar-NPC:NEtG-NPC:NBGNPC:benzylamine=30:30:30:1. The yield of the obtained peptide is 99%.

[0080] The experimental results show that the competitive polymerization ratios of the monomers are r(SE)=1.102, r(SB)=1.005, r(ES)=0.978, r(EB)=1.056, r(BS)=1.130, r(BE)=0.993, the number average absolute molecular weight is 8.1 kg / mol, and the ratio of the three components in the polymer is 30:30:30, which is equivalent to the feed ratio.

[0081] Example 9

[0082] The preparation method is the same as that in Example 1, except that the monomers used are N-phenoxycarbonylsarcosine (Sar-NPC) and N-phenoxycarbonyl-N-benzylglycine (NBnG-NPC), the initiator used is neopentylamine, the organic acid is formic acid, the organic base is triethylamine, the molar ratio of neopentylamine to total NNPC monomer is 1:5, the molar ratio of Sar-NPC monomer to NBnG-NPC monomer is 2:1, the solvent is acetonitrile, and the reaction conditions are 48 hours in an oil bath at 40°C. The obtained poly-peptide (poly(sarcosine-co-N-phenoxycarbonyl-N-benzylglycine)) has a yield of 99%.

[0083] The experimental results show that the reactivity ratios of the monomers are r(Sar-NPC)=1.024, r(NBnG-NPC)=1.076, the molecular weight is 0.6 kg / mol, and the polymer composition is equivalent to the feed ratio.

[0084] Example 10

[0085] The preparation method is the same as that in Example 1, except that the monomers used are N-phenoxycarbonyl-N-trifluoromethylglycine (N3FMeG-NPC) and N-phenoxycarbonyl-N-carboxyethylglycine (NCEtG-NPC), the initiator used is n-hexylamine, the organic acid is benzoic acid, the organic base is 4-dimethylaminopyridine, the molar ratio of 4-dimethylaminopyridine to the total NNPC monomer is 1:100, the molar ratio of N3FMeG-NPC monomer to NCEtG-NPC monomer is 1:5, the solvent is dimethyl sulfoxide, the reaction conditions are 20°C oil bath for 96 hours, and the yield of the obtained poly-peptide (poly(trifluoromethyl-co-N-phenoxycarbonyl-N-carboxyethylglycine)) is 99%.

[0086] The experimental results show that the reactivity ratios of the monomers are r(N3FMeG-NPC)=0.977, r(NCEtG-NPC)=1.012, the molecular weight is 11.2 kg / mol, and the polymer composition is equivalent to the feed ratio.

[0087] Embodiment 11

[0088] The preparation method is the same as that in Example 1, except that the monomers used are N-phenoxycarbonyl-N-cyanoglycine (NCNG-NPC) and N-phenoxycarbonyl-N-nitroglycine (NNiG-NPC), the initiator used is polyethylene glycol amine with a molecular weight of 2000, the organic acid is n-hexanoic acid, the organic base is quinoline, the molar ratio of polyethylene glycol amine to the total NNPC monomer is 1:200, the molar ratio of NCNG-NPC monomer to NNiG-NPC monomer is 10:1, the solvent is N-methylpyrrolidone, the reaction conditions are 80°C in an oil bath for 6 hours, and the yield of the obtained polypeptide (poly(cyano-co-N-phenoxycarbonyl-N-nitroglycine)) is 99%.

[0089] The experimental results show that the reactivity ratios of the monomers are r(NCNG-NPC)=0.959, r(NNiG-NPC)=0.968, the molecular weight is 18.8 kg / mol, and the polymer composition is equivalent to the feed ratio.

[0090] Example 12

[0091] The preparation method is the same as that in Example 1, except that the monomers used are N-phenoxycarbonyl-N-cyclohexylglycine (NCyG-NPC) and N-phenoxycarbonyl-N-ethoxyglycine (NEtOG-NPC), the initiator used is diethylamine, the organic acid is pivalic acid, the organic base is triethylamine, the molar ratio of diethylamine to the total NNPC monomer is 1:300, the molar ratio of NCyG-NPC monomer to NEtOG-NPC monomer is 1:20, the solvent is benzonitrile, the reaction conditions are 100°C oil bath for 0.5 hour, and the yield of the obtained polypeptide (poly(cyclohexyl-co-N-phenoxycarbonyl-N-ethoxyglycine)) is 99%.

[0092] The experimental results show that the reactivity ratios of the monomers are r(NCyG-NPC)=1.026, r(NEtOG-NPC)=0.912, the molecular weight is 32.4 kg / mol, and the polymer composition is equivalent to the feed ratio.

[0093] It can be seen from the results of the above embodiments that when N-phenoxycarbonyl-N-substituted glycine (NNPC) monomers containing different substituents are copolymerized in the presence of organic acid and organic base, the reactivity ratio of each monomer is close to 1, and random copolymerization can be achieved to obtain random peptides.

[0094] In addition, when Example 1 uses two NNPC monomers containing hydrophilic groups and Example 11 uses NNPC monomers containing two hydrophobic groups, the resulting random peptides do not have a minimum critical solution temperature LCST; in Examples 8-10 and Example 12, the ratio of the two monomers is too high or too low, and no LCST exists.

[0095] Embodiment 13

[0096] The preparation method is the same as that in Example 3, except that the molar fraction of Sar-NPC in all monomers is adjusted to 50%, 58%, 62%, 65%, 68%, 71%, and 80%, respectively, and the corresponding poly(sarcosine-co-N-phenoxycarbonyl-N-butylglycine) is obtained with a yield of 99%, and the molar fraction of the Sar structural unit in the polymer is equal to the feed ratio.

[0097] The LCST effects of samples with different Sar mole fractions are shown in Figure 2. Figure 6 As shown, when the molar fraction of Sar-NPC accounts for 50% of all monomers, the polymer is completely insoluble in water and there is no LCST; when the molar fraction of Sar-NPC accounts for 80% of all monomers, the polymer is completely dissolved, and even when heated to 100°C, it does not precipitate and there is no LCST. It can be seen that the random peptide of the present invention has an LCST effect that can be adjusted by the polymer composition.

[0098] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing a random polymerized peptide, characterized in that: Under the action of an initiator, an organic acid and an organic base, two or more N-phenoxycarbonyl-N-substituted glycine monomers are randomly copolymerized to obtain the product.

2. The preparation method according to claim 1, characterized in that: The general structural formula of the N-phenoxycarbonyl-N-substituted glycine monomer is as follows: Wherein, R1 is selected from any one of an alkyl group, a halogenated alkyl group, an aromatic group, a cyano group, a hydroxyl group, a carboxyl group and a nitro group.

3. The preparation method according to claim 1, characterized in that: The N-phenoxycarbonyl-N-substituted glycine monomers include at least one N-phenoxycarbonyl-N-substituted glycine monomer containing a hydrophilic group and one N-phenoxycarbonyl-N-substituted glycine monomer containing a hydrophobic group.

4. The preparation method according to claim 3, characterized in that: The molar percentage of the N-phenoxycarbonyl-N-substituted glycine monomer containing a hydrophilic group to all N-phenoxycarbonyl-N-substituted glycine monomers is 58-71%.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The N-phenoxycarbonyl-N-substituted glycine monomer is selected from: A combination of N-phenoxycarbonylsarcosine and N-phenoxycarbonyl-N-butylglycine; or a combination of N-phenoxycarbonylsarcosine, N-phenoxycarbonyl-N-ethylglycine and N-phenoxycarbonyl-N-butylglycine.

6. The preparation method according to claim 1, characterized in that: The initiator is one or more of primary amines, secondary amines or silylamines; specifically one or more of neopentylamine, n-hexylamine, benzylamine, diethylamine, polyethylene glycolamine or trimethylsilylamine; preferably benzylamine; The organic acid is a carboxylic acid, specifically at least one selected from formic acid, acetic acid, benzoic acid, n-butyric acid, n-hexanoic acid or pivalic acid; preferably benzoic acid; The organic base is a tertiary amine or a nitrogen heterocyclic compound; specifically, at least one selected from triethylamine, N,N-diisopropylethylamine, quinoline or 4-dimethylaminopyridine; preferably, N,N-diisopropylethylamine.

7. The preparation method according to claim 1, characterized in that: The molar ratio of the initiator to the total amount of N-phenoxycarbonyl-N-substituted glycine monomer is 1:5-300; preferably 1:5-100; more preferably 1:5-25; and / or the molar ratio of the organic acid to the total amount of N-phenoxycarbonyl-N-substituted glycine monomer is 1:0.1-0.5; preferably 1:0.2; And / or the molar ratio of the organic base to the total amount of N-phenoxycarbonyl-N-substituted glycine monomer is 1:0.5-5; preferably 1:

1.

8. The preparation method according to claim 1, characterized in that: The random copolymerization reaction is carried out in an organic solvent; The organic solvent is selected from one or more of dioxane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, sulfolane, acetonitrile, benzonitrile, dichloromethane, dichloroethane, chloroform or toluene; The random copolymerization reaction temperature is 20-100°C; The random copolymerization reaction time is 0.5-96h.

9. The random peptide prepared by the preparation method according to any one of claims 1 to 8, characterized in that: The random peptide is a temperature-sensitive random peptide.

10. Use of the randomly clustered peptide according to claim 9 in biomedical materials.

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