Bottle brush type polymer containing pH responsive poly-alpha-lysine side chain as well as preparation method and application of bottle brush type polymer

Abstract

The invention discloses a bottle brush type polymer containing a pH-responsive poly-alpha-lysine side chain, and belongs to the technical field of high-molecular compounds, the structural formula of the polymer is as follows: # imgabs0 #, and a preparation method comprises the following specific steps: (1) taking 6-amino protected L-lysine-NCA as a monomer, adding primary amine containing polymerizable double bonds, and reacting at the temperature of 60-80 DEG C for 1-2 hours; initiating a ring-opening polymerization reaction of the monomer to obtain a 6-amino protected L-lysine macromonomer containing polymerizable double bonds at the tail end; and (2) reacting the macromonomer under the action of a catalyst or an initiator to obtain the bottle brush type polymer containing the pH responsive poly-alpha-lysine side chain. The high-density side chain modified bottle brush type polymer prepared by the invention has zero shear viscosity, low entanglement platform modulus and unique mechanical and rheological properties, and polypeptide is adopted as a side chain of the bottle brush type polymer, so that the biocompatibility of the bottle brush type polymer can be improved, and the functionality of the bottle brush type polymer can be enriched.

Description

Technical Field

[0001] The invention belongs to the technical field of polymer compounds, and in particular relates to a bottle brush polymer containing a pH responsive poly-α-lysine side chain and a preparation method and application thereof. Background Art

[0002] Bottlebrush polymer (BBP) is a type of comb-shaped polymer with a cylindrical structure, a sufficiently high side chain grafting density, high main chain rigidity, and a fully extended main chain due to the steric repulsion effect between the side chains, and no entanglement between the side chains. Functional BBP has a wide range of application values ​​in the fields of ultra-soft elastomers, optical crystals, biomimetic soft tissues, biomimetic friction and lubrication, self-assembly, solid polymer electrolytes, and dynamic adaptive networks.

[0003] There are three main strategies for the synthesis of BBP: "grafting to", "grafting from" and "grafting through". Among them, "grafting through" can ensure that each monomer unit on the main chain has side chain modification and high grafting density. The ring-opening metathesis polymerization of norbornene catalyzed by Grubbs catalyst is the most commonly used reaction type for synthesizing BBPs using the "grafting through" strategy. BBPs with polypeptide side chains have the advantages of rich functions and good biocompatibility. Such BBPs are very suitable for use as nano-drug carriers, biomimetic soft tissues, etc.; the synthesis of such BBPs using the "grafting from" method requires the selection of a suitable skeleton structure as the main chain, and then the modification of the amino initiation site. The synthesis steps are complicated, and the synthesis process cannot guarantee that each initiation site can initiate the ring-opening polymerization of the NCA monomer, and the side chain grafting density is uncontrollable; the "grafting to" method cannot guarantee 100% side chain modification, and usually requires a very efficient coupling reaction (such as azide-alkyne click reaction).

[0004] To this end, it is an urgent problem for those skilled in the art to provide an efficient bottle-brush polymer and a method for synthesizing the same, while ensuring that each monomer unit of the main chain is modified with a side chain polyamino acid and that the side chain density, length and polypeptide type are also controllable. Summary of the invention

[0005] In order to solve the above problems, the present invention provides a bottle brush polymer containing pH responsive poly-α-lysine side chains and a preparation method and application thereof.

[0006] In order to achieve the above object, the present invention adopts the following technical solution:

[0007] A bottle brush polymer containing a pH responsive poly-α-lysine side chain, the structural formula of the polymer is as follows:

[0008]

[0009] Wherein, the R is selected from

[0010]

[0011] Any of the following:

[0012] Wherein, the R1 is selected from

[0013] Any one of .

[0014] The high-density side-chain modified bottlebrush polymer prepared by the present invention has zero shear viscosity and low entanglement platform modulus, presenting unique mechanical and rheological properties. Using polypeptides as bottlebrush polymer side chains can improve the biocompatibility of bottlebrush polymers and enrich the functionalization of bottlebrush polymers.

[0015] The method for preparing a bottle brush polymer containing a pH-responsive poly-α-lysine side chain as described above comprises the following specific steps:

[0016] (1) using 6-amino-protected L-lysine-NCA as a monomer, adding a primary amine containing a polymerizable double bond, initiating a ring-opening polymerization reaction of the monomer, and obtaining a macromolecular monomer of 6-amino-protected L-lysine containing a polymerizable double bond at the end;

[0017] (2) The macromolecular monomer is reacted under the action of a catalyst or an initiator to obtain a bottle brush polymer containing a pH-responsive poly-α-lysine side chain.

[0018] The present invention can effectively control the length of the side chain through the ring-opening polymerization of the NCA monomer initiated by the primary amine containing an unsaturated double bond, and the reaction conditions are mild. The double bonds at the ends of the macromolecular monomer can be further synthesized into BBPs through the "grafting through" strategy to ensure high-density modification of the side chain.

[0019] Preferably, in step (1), the mass ratio of the 6-amino-protected L-lysine-NCA to the primary amine containing a polymerizable double bond is 2-46:0.06-0.15;

[0020] The primary amine containing a polymerizable double bond is at least one of 5-norbornene-2-methylamine, 2-methylallylamine, 3-butene-1-amine, allylamine, 4-vinylbenzylamine, 2-aminoethyl acrylate and 2-aminoethyl acrylamide;

[0021] The conditions of the ring-opening polymerization reaction are: reacting at room temperature for 3-12 hours.

[0022] Preferably, the ring-opening polymerization reaction in step (1) further comprises a solvent, and the solvent is DMF or tetrahydrofuran THF. Using DMF and THF with high dielectric constants as solvents can ensure that the polypeptide chain segments are in a randomly coiled state, so that the polymerization reaction is not affected.

[0023] The mass ratio of the solvent to the 6-amino-protected L-lysine-NCA is 9-180:2-46.

[0024] Preferably, the preparation method of 6-amino-protected L-lysine-NCA in step (1) is to uniformly mix 6-amino-protected L-lysine, triphosgene and a solvent, and then add epichlorohydrin to react to obtain 6-amino-protected L-lysine-NCA. The use of solid phosgene (triphosgene) can reduce the hazards in the synthesis process of NCA monomers, and epichlorohydrin can absorb the hydrogen chloride gas generated during the reaction, thereby avoiding equipment corrosion and environmental pollution.

[0025] Preferably, the mass ratio of the 6-amino-protected L-lysine, the triphosgene, the solvent and the epichlorohydrin is 2-6:1-3:9-90:1-3;

[0026] The reaction conditions are: reacting at 25-66°C for 0.5-2h;

[0027] The solvent is tetrahydrofuran;

[0028] The 6-amino protected L-lysine is at least one of 6-aminoBoc protected L-lysine, 6-aminoFmoc protected L-lysine, 6-aminotrifluoroacetyl protected L-lysine and 6-aminoacetyl protected L-lysine.

[0029] Preferably, in step (2), the mass ratio of the macromonomer to the catalyst is 1-50:0.005-0.009, and the mass ratio of the macromonomer to the initiator is 1-50:0.003-0.008;

[0030] The reaction conditions are: reacting at 50-80°C for 0.5-8h;

[0031] The catalyst is at least one of the second generation and third generation of Grubbs;

[0032] The initiator is at least one of an organic azo initiator and a peroxide initiator.

[0033] Preferably, the organic azo compounds include azobisisobutyronitrile and / or azobisisoheptanenitrile, and the peroxide compounds include benzoyl peroxide and / or tert-butyl hydroperoxide.

[0034] Preferably, the reaction in step (2) further comprises a solvent, the solvent is tetrahydrofuran, and the mass ratio of the solvent to the macromonomer is 1-14:1-50;

[0035] The bottle brush polymer further comprises a step of removing the protecting group on the side chain amino group by reaction under the action of a mixed solvent of trifluoroacetic acid and dichloromethane or N,N-dimethylformamide and piperidine to obtain a pure bottle brush polymer;

[0036] Wherein, the mass ratio of the bottle brush polymer, the trifluoroacetic acid and the dichloromethane is 2-5:1.5-5:1-5;

[0037] The mass ratio of the bottle brush polymer, the N,N-dimethylformamide and the piperidine is 1:0.5-5:0.2-2;

[0038] The reaction conditions are to react at room temperature for 1-3 hours.

[0039] Application of the bottle brush polymer described above or the bottle brush polymer prepared by the preparation method described above in the fields of ultra-soft elastomers, dynamic adaptive networks, biofriction and lubrication, and nano drug carriers.

[0040] Compared with the prior art, the present invention has the following beneficial effects:

[0041] The present invention uses a primary amine containing a polymerizable double bond as an initiator to initiate a ring-opening polymerization reaction of a 6-amino-protected L-lysine NCA monomer through a primary amine mechanism, and controls the length of the side chain by controlling the feed ratio of the monomer and the primary amine. In addition, the present invention uses an olefin metathesis reaction catalyzed by a Grubbs catalyst or a thermally initiated polymerization to synthesize a bottle brush polymer through a "grafting through" strategy, and the double bond at the end of the macromolecular monomer can ensure that each monomer unit on the main chain can modify the side chain, thereby ensuring 100% side chain grafting density. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying creative work.

[0043] Figure 1Schematic diagram of the synthetic route of the bottle brush polymer of the present invention;

[0044] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of the bottle brush polymer macromonomer of Example 1 of the present invention;

[0045] Figure 3 This is the circular dichroism spectrum of the bottle brush polymer macromonomer of Example 1 of the present invention. DETAILED DESCRIPTION

[0046] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. 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.

[0047] Example 1

[0048] like Figure 1 The present invention provides a method for preparing a bottle brush polymer containing a pH-responsive poly-α-lysine side chain, comprising the following specific steps:

[0049] (1) First, 6-aminoBoc-protected L-lysine, triphosgene and tetrahydrofuran (THF) are mixed in a thick-walled pressure bottle in a mass ratio of 2:1:9, and then 5 times the mass of epichlorohydrin is added, the pressure bottle is immediately sealed, and the reaction is stirred at room temperature to ensure that all components are evenly mixed; as the reaction proceeds, the temperature of the reaction system gradually increases until the tetrahydrofuran solvent boils, and as the reaction is gradually completed (0.5h), the system exotherm decreases, and the temperature of the reaction bottle gradually returns to room temperature to obtain a mixed solution; according to the volume ratio of n-hexane to ethyl acetate of 2:1, the sum of the volumes of n-hexane and ethyl acetate is 10 times the volume of tetrahydrofuran, the mixed solution obtained in step (1) is added dropwise to a flask containing a mixed solvent of n-hexane and ethyl acetate; after the dropwise addition is completed, the flask is placed in a 4°C refrigerator and allowed to stand overnight, a white solid is gradually precipitated, and white crystals are obtained after suction filtration, and the recrystallization step is repeated twice, and the final product, 6-aminoBoc-protected L-lysine NCA monomer, is obtained after suction filtration and drying;

[0050] (2) 5-norbornene-2-methylamine, 6-aminoBoc-protected L-lysine NCA and THF were mixed uniformly in a mass ratio of 0.1:2:9, placed in a double-necked round-bottom flask, and reacted at 25° C. for 12 h. After the reaction was completed, ether was used for precipitation and the product was separated from the solvent by a suction filtration device, and then vacuum dried at 50° C. to remove residual solvent and moisture, thereby obtaining a macromolecular monomer of 6-amino-protected L-lysine containing a polymerizable double bond at the end;

[0051] (3) mixing a macromolecular monomer of 6-amino-protected L-lysine containing a polymerizable double bond at the end, a Grubbs catalyst and dichloromethane in a mass ratio of 1:0.005:1, placing the mixture in a double-necked round-bottom flask, reacting the mixture at 50° C. for 8 h, and after the reaction, using ether precipitation and separating the product from the solvent using a suction filtration device, and then vacuum drying the mixture at 50° C. to remove residual solvent and moisture, thereby obtaining a bottle brush polymer;

[0052] (4) dissolving one part by mass of the obtained bottle brush polymer in ten parts by mass of dichloromethane, adding ten parts by mass of trifluoroacetic acid, stirring at room temperature for 2 hours, and then removing the solvent by rotary evaporation, adding 0.1M hydrochloric acid solution to the obtained residual solid, dialyzing in a dialysis bag for 48 hours, and freeze-drying to obtain a pure bottle brush polymer with a main chain degree of polymerization of 200 and a side chain degree of polymerization of 20;

[0053] Among them, the bottle brush type polymer based on poly-L-lysine obtained in this example has very good water solubility and biocompatibility. Figure 2 The H NMR spectrum accurately characterized the chemical structure of the bottlebrush polymer macromonomer. Figure 3 Its α-helix and random coil conformational transitions can be confirmed; the bottlebrush polymer synthesized in this embodiment through the "grafting through" strategy has unique configurational characteristics, lower entanglement platform elastic modulus and shear modulus, and the pH responsiveness and biocompatibility of the polypeptide side chain can meet the use requirements of ultra-soft elastomers and biomaterials, and can be used as biomimetic soft tissue structures, nano-drug carriers, etc.

[0054] Example 2

[0055] like Figure 1 The present invention provides a method for preparing a bottle brush polymer containing a pH-responsive poly-α-lysine side chain, comprising the following specific steps:

[0056] (1) The preparation method of 6-aminoBoc-protected L-lysine NCA monomer is the same as step (1) in Example;

[0057] (2) 2-methylallylamine, 6-aminoBoc-protected L-lysine NCA and THF were mixed uniformly in a mass ratio of 0.07:2:9, placed in a double-necked round-bottom flask, and reacted at 25° C. for 12 h. After the reaction was completed, ether was used for precipitation and the product was separated from the solvent by a suction filtration device, and then vacuum dried at 50° C. to remove residual solvent and moisture, thereby obtaining a macromolecular monomer of 6-amino-protected L-lysine containing a polymerizable double bond at the end;

[0058] (3) mixing a macromonomer of 6-amino-protected L-lysine containing a polymerizable double bond at the end, azobisisobutyronitrile and dichloromethane in a mass ratio of 1:0.005:1, placing the mixture in a double-necked round-bottom flask, reacting the mixture at 50° C. for 3 h, and after the reaction, using ether precipitation and separating the product from the solvent using a suction filtration device, and then vacuum drying the mixture at 50° C. to remove residual solvent and moisture, thereby obtaining a bottle brush polymer;

[0059] (4) One part by mass of the obtained bottle brush polymer was dissolved in one part by mass of dichloromethane, and 1.5 parts by mass of trifluoroacetic acid was added. After stirring at room temperature for 1 hour, the mixture was neutralized with 0.1 M hydrochloric acid solution to pH 7.4, dialyzed in a dialysis bag for 48 hours, and freeze-dried to obtain a pure bottle brush polymer with a main chain degree of polymerization of 200 and a side chain degree of polymerization of 30.

[0060] Example 3

[0061] like Figure 1 The present invention provides a method for preparing a bottle brush polymer containing a pH-responsive poly-α-lysine side chain, comprising the following specific steps:

[0062] (1) First, 6-aminoFmoc-protected L-lysine, triphosgene and tetrahydrofuran (THF) are mixed in a thick-walled pressure bottle in a mass ratio of 2:1:9, and then 5 times the mass of epichlorohydrin is added, the pressure bottle is immediately sealed, and the reaction is stirred at room temperature to ensure that all components are evenly mixed; as the reaction proceeds, the temperature of the reaction system gradually increases until the tetrahydrofuran solvent boils, and as the reaction is gradually completed (0.5), the system exotherm decreases, and the temperature of the reaction bottle gradually returns to room temperature to obtain a mixed solution; according to the volume ratio of n-hexane to ethyl acetate being 2:1, the sum of the volumes of n-hexane and ethyl acetate being 10 times the volume of tetrahydrofuran, the mixed solution obtained in step (1) is added dropwise to a flask containing a mixed solvent of n-hexane and ethyl acetate; after the dropwise addition is completed, the flask is placed in a 4°C refrigerator and allowed to stand overnight, a white solid is gradually precipitated, and white crystals are obtained after suction filtration, and the recrystallization step is repeated twice, and the final product, 6-aminoFmoc-protected L-lysine NCA monomer, is obtained after suction filtration and drying;

[0063] (2) 3-butene-1-amine, 6-aminoBoc-protected L-lysine NCA and THF were mixed uniformly in a mass ratio of 0.1:2:9, placed in a double-necked round-bottom flask, and reacted at 25° C. for 12 h. After the reaction was completed, ether was used for precipitation and the product was separated from the solvent by a suction filtration device, and then vacuum dried at 50° C. to remove residual solvent and moisture, thereby obtaining a macromolecular monomer of 6-amino-protected L-lysine containing a polymerizable double bond at the end;

[0064] (3) mixing a macromonomer of 6-amino-protected L-lysine containing a polymerizable double bond at the end, azobisisoheptanenitrile and dichloromethane in a mass ratio of 1:0.002:1, placing the mixture in a double-necked round-bottom flask, reacting the mixture at 50° C. for 3 h, and after the reaction, using ether precipitation and separating the product from the solvent using a suction filtration device, and then vacuum drying the mixture at 50° C. to remove residual solvent and moisture, thereby obtaining a bottle brush polymer;

[0065] (4) One part by mass of the obtained bottle brush polymer was dissolved in one part by mass of dichloromethane, and 1.5 parts by mass of trifluoroacetic acid was added. After stirring at room temperature for 1 hour, the mixture was neutralized with 0.1 M hydrochloric acid solution to pH 7.4, dialyzed in a dialysis bag for 48 hours, and freeze-dried to obtain a pure bottle brush polymer with a main chain degree of polymerization of 500 and a side chain degree of polymerization of 20.

[0066] The various embodiments are described in a progressive manner, and each embodiment focuses on the differences from other embodiments. The same or similar parts between the various embodiments can be referred to in detail.

[0067] The above description of the disclosed embodiments enables one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but rather to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A bottle brush polymer containing pH responsive poly-α-lysine side chains, characterized in that The structural formula of the polymer is as follows: Wherein, the R is selected from Any of the following: Wherein, the R1 is selected from Any one of .

2. A method for preparing a bottle brush polymer containing pH responsive poly-α-lysine side chains as claimed in claim 1, characterized in that: The specific steps include: (1) using 6-amino-protected L-lysine-NCA as a monomer, adding a primary amine containing a polymerizable double bond, initiating a ring-opening polymerization reaction of the monomer, and obtaining a macromolecular monomer of 6-amino-protected L-lysine containing a polymerizable double bond at the end; (2) The macromolecular monomer is reacted under the action of a catalyst or an initiator to obtain a bottle brush polymer containing a pH-responsive poly-α-lysine side chain.

3. The method for preparing a bottle brush polymer containing pH responsive poly-α-lysine side chains according to claim 2, characterized in that: The mass ratio of the 6-amino-protected L-lysine-NCA to the primary amine containing a polymerizable double bond in step (1) is 2-46:0.06-0.15; The primary amine containing a polymerizable double bond is at least one of 5-norbornene-2-methylamine, 2-methylallylamine, 3-butene-1-amine, allylamine, 4-vinylbenzylamine, 2-aminoethyl acrylate and 2-aminoethyl acrylamide; The conditions of the ring-opening polymerization reaction are: reacting at room temperature for 3-12 hours.

4. The method for preparing a bottle brush polymer containing pH responsive poly-α-lysine side chains according to claim 2, characterized in that: The ring-opening polymerization reaction in step (1) further comprises a solvent, wherein the solvent is DMF or tetrahydrofuran, and the mass ratio of the solvent to the 6-amino-protected L-lysine-NCA is 9-180:2-46.

5. The method for preparing a bottle brush polymer containing pH responsive poly-α-lysine side chains according to claim 2, characterized in that: The preparation method of the 6-amino-protected L-lysine-NCA in step (1) is to uniformly mix the 6-amino-protected L-lysine, triphosgene and a solvent, and then add epichlorohydrin to react to obtain the 6-amino-protected L-lysine-NCA.

6. The method for preparing a bottle brush polymer containing pH responsive poly-α-lysine side chains according to claim 5, characterized in that: The mass ratio of the 6-amino-protected L-lysine, the triphosgene, the solvent and the epichlorohydrin is 2-6:1-3:9-90:1-3; The reaction conditions are: reacting at 25-66°C for 0.5-2h; The solvent is tetrahydrofuran; The 6-amino protected L-lysine is at least one of 6-aminoBoc protected L-lysine, 6-aminoFmoc protected L-lysine, 6-aminotrifluoroacetyl protected L-lysine and 6-aminoacetyl protected L-lysine.

7. The method for preparing a bottle brush polymer containing pH responsive poly-α-lysine side chains according to claim 2, characterized in that: In step (2), the mass ratio of the macromonomer to the catalyst is 1-50:0.005-0.009, and the mass ratio of the macromonomer to the initiator is 1-50:0.003-0.008; The reaction conditions are: reacting at 50-80°C for 0.5-8h; The catalyst is at least one of the second generation and third generation of Grubbs; The initiator is at least one of an organic azo initiator and a peroxide initiator.

8. The method for preparing a bottle brush polymer containing pH responsive poly-α-lysine side chains according to claim 7, characterized in that: The organic azo compounds include azobisisobutyronitrile and / or azobisisoheptanenitrile, and the peroxide compounds include benzoyl peroxide and / or tert-butyl hydroperoxide.

9. The method for preparing a bottle brush polymer containing pH responsive poly-α-lysine side chains according to claim 2, characterized in that: The reaction in step (2) further comprises a solvent, wherein the solvent is tetrahydrofuran or dichloromethane, and the mass ratio of the solvent to the macromonomer is 1-14:1-50; The bottle brush polymer further comprises a step of removing the protecting group on the side chain amino group by reaction under the action of a mixed solvent of trifluoroacetic acid and dichloromethane or N,N-dimethylformamide and piperidine to obtain a pure bottle brush polymer; Wherein, the mass ratio of the bottle brush polymer, the trifluoroacetic acid and the dichloromethane is 2-5:1.5-5:1-5; The mass ratio of the bottle brush polymer, the N,N-dimethylformamide and the piperidine is 1:0.5-5:0.2-2; The reaction conditions are to react at room temperature for 1-3 hours.

10. Application of the bottle brush polymer according to claim 1 or the bottle brush polymer prepared by the preparation method according to any one of claims 2 to 9 in the fields of ultra-soft elastomers, dynamic adaptive networks, biofriction and lubrication, and nano drug carriers.

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