CN111320749A - Preparation method of photoresponse antibacterial clustered peptide polymer and hydrogel - Google Patents
Preparation method of photoresponse antibacterial clustered peptide polymer and hydrogel Download PDFInfo
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- 239000000017 hydrogel Substances 0.000 title claims abstract description 40
- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 31
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 15
- 229920001184 polypeptide Polymers 0.000 claims abstract description 13
- 239000000178 monomer Substances 0.000 claims abstract description 7
- 238000005286 illumination Methods 0.000 claims abstract description 6
- 230000000845 anti-microbial effect Effects 0.000 claims abstract description 5
- 238000007151 ring opening polymerisation reaction Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 30
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
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- 238000006243 chemical reaction Methods 0.000 claims description 16
- -1 N-o-nitrobenzyloxycarbonyl-ethylamino Chemical group 0.000 claims description 12
- IVLXQGJVBGMLRR-UHFFFAOYSA-N 2-aminoacetic acid;hydron;chloride Chemical compound Cl.NCC(O)=O IVLXQGJVBGMLRR-UHFFFAOYSA-N 0.000 claims description 11
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- 239000000203 mixture Substances 0.000 claims description 5
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- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 claims description 3
- 238000004140 cleaning Methods 0.000 claims description 3
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- BXRNXXXXHLBUKK-UHFFFAOYSA-N piperazine-2,5-dione Chemical compound O=C1CNC(=O)CN1 BXRNXXXXHLBUKK-UHFFFAOYSA-N 0.000 claims description 3
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- 238000001291 vacuum drying Methods 0.000 claims description 3
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- 238000006116 polymerization reaction Methods 0.000 claims description 2
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- 230000002194 synthesizing effect Effects 0.000 claims 1
- 229920002521 macromolecule Polymers 0.000 abstract description 2
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- 238000001308 synthesis method Methods 0.000 description 9
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- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
- 241000894006 Bacteria Species 0.000 description 7
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- 239000000243 solution Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- UVJZOCJVCJZDER-UHFFFAOYSA-N (2-nitrophenyl)methyl n-(2-aminoethyl)carbamate Chemical compound NCCNC(=O)OCC1=CC=CC=C1[N+]([O-])=O UVJZOCJVCJZDER-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
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- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- PDWUDQKIQYSAEA-UHFFFAOYSA-N (2-nitrophenyl)methyl carbonochloridate Chemical compound [O-][N+](=O)C1=CC=CC=C1COC(Cl)=O PDWUDQKIQYSAEA-UHFFFAOYSA-N 0.000 description 4
- 210000000170 cell membrane Anatomy 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 4
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 229920002118 antimicrobial polymer Polymers 0.000 description 3
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- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
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- AOCSUUGBCMTKJH-UHFFFAOYSA-N tert-butyl n-(2-aminoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCN AOCSUUGBCMTKJH-UHFFFAOYSA-N 0.000 description 2
- 102000044503 Antimicrobial Peptides Human genes 0.000 description 1
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- 241000588724 Escherichia coli Species 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
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- 241000191967 Staphylococcus aureus Species 0.000 description 1
- BTXLWRWDYZKCPQ-UHFFFAOYSA-N [nitro(phenyl)methyl] carbonochloridate Chemical compound ClC(=O)OC([N+](=O)[O-])C1=CC=CC=C1 BTXLWRWDYZKCPQ-UHFFFAOYSA-N 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
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- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
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- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- MOOYVEVEDVVKGD-UHFFFAOYSA-N oxaldehydic acid;hydrate Chemical compound O.OC(=O)C=O MOOYVEVEDVVKGD-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
- C08G69/40—Polyamides containing oxygen in the form of ether groups
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
- C08J3/075—Macromolecular gels
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/28—Treatment by wave energy or particle radiation
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
- C08J2305/12—Agar-agar; Derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2477/00—Characterised by the use of polyamides obtained by reactions forming a carboxylic amide link in the main chain; Derivatives of such polymers
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Abstract
The invention discloses an antibacterial polypeptide polymer with a side chain containing a photoresponsive group and a preparation method of photoresponsive hydrogel. The method is characterized in that photoresponse antibacterial polymer is prepared by introducing photoresponse groups into monomers and further performing ring-opening polymerization. Meanwhile, the polymer is doped into the hydrogel to construct the photoresponse antibacterial hydrogel. And further adjusting the illumination time to realize the regulation and control of the antibacterial performance of the clustered peptide macromolecules. The photoresponsive hydrogel exhibits excellent antimicrobial properties after light exposure.
Description
Technical Field
The invention belongs to the field of biopolymer synthesis, and particularly relates to an antibacterial polypeptide polymer with a side group containing a photoresponse group and preparation of a photoresponse antibacterial hydrogel.
Background
Abuse of antibiotics leads to the development of resistant bacteria, and development and research of new antibacterial agents becomes particularly important in order to contain the resistant bacteria. Natural antimicrobial peptides are widely present in animals, plants and microorganisms, and have broad-spectrum antimicrobial properties and immune-modulating functions, so that people have attracted extensive attention and research in recent years. The antibacterial mechanism of natural antibacterial peptides is roughly divided into two types: the first method is that the cell membrane of the bacteria is destroyed, the antibacterial peptide is combined with the cell membrane with negative charge through self positive charge, the hydrophobic end of the antibacterial peptide is inserted into the cell membrane, the cell membrane is broken, the cell content is leaked, and the bacteria die; secondly, entry into the cytoplasm interferes with the metabolic process. However, the antibacterial peptide is easily hydrolyzed by protease to lose antibacterial activity during in vivo treatment, and the development and application of the antibacterial peptide are greatly limited. It becomes important to research and develop some polymer materials which are difficult to be enzymolyzed and simulate natural antibacterial peptides. Therefore, the polymer materials with positive charges and hydrophilic-hydrophobic amphiphilic structures simulating natural antibacterial peptides are widely noticed. The clustered peptide is a high molecular material with good biocompatibility. The main chain structure of the polypeptide polymer is similar to that of the antibacterial peptide, the side chain substituent group is positioned on the main chain nitrogen atom, and active hydrogen on the nitrogen atom is substituted, so that the main chain of the polypeptide polymer does not have a chiral center and an enzyme degradation site, the flexibility of the main chain is relatively good, the polypeptide polymer is not easy to hydrolyze by protease, and the like, and the antibacterial polypeptide polymer with amphipathy can be prepared by regulating and controlling the side chain structure. The antibacterial peptide cluster can be an ideal antibacterial agent capable of replacing natural antibacterial peptide by virtue of excellent antibacterial property, biocompatibility and property of difficult enzymolysis.
The photoresponse polymer material is a functional polymer material which can generate chemical or physical changes in molecules or between molecules after absorbing light energy. The photoresponsive polymer has unique advantages compared with other responsive polymers: the light source is safe and clean, and meanwhile, in the light reaction process, the light control process can be started and stopped at fixed points in real time without adding other reagents, and byproducts are not generated in the whole process. By adjusting parameters such as wavelength, intensity and the like of light, the properties of the photoresponse intelligent polymer can be successfully adjusted and controlled in a fixed-point, timing, speed-adjusting and quantity-adjusting mode. Due to the unique advantages of the photoresponse polymer, the photoresponse polymer has wide application in photoresponse intelligent biological switches, photoresponse shape memory, photoresponse polymer gel, photoresponse biosensors, photoresponse mechanical actuators, photoresponse drug release and the like. Among them, the hydrogel is a polymer network system having a hydrophilic three-dimensional network cross-linked structure, and thus can maintain a moist microenvironment, allow good oxygen and water permeability, absorb excessive exudates, shield microorganisms, and be easily removed without being injured. The photoresponse hydrogel is a kind of stimuli-responsive hydrogel containing photoresponse groups in a hydrogel system, and has the advantages of photoresponse macromolecules and the hydrogel, so that the photoresponse hydrogel is widely concerned. In recent years, light-responsive hydrogels have found wide application in drug delivery, self-healing materials, and tissue engineering.
The invention reports that a photoresponse group is introduced into primary amine to prepare a photoresponse N-substituted carboxylic anhydride (NNCA) monomer, the photoresponse polypeptide is prepared by ring-opening polymerization, and the antibacterial polypeptide is obtained by ultraviolet irradiation. Furthermore, agarose is used as a hydrogel substrate for the clustering peptide without illumination to prepare the photoresponse hydrogel. The patent researches the change of the antibacterial effect of the photoresponse polypeptide along with the illumination time and the change of the antibacterial performance of the photoresponse hydrogel before and after the illumination in detail.
Disclosure of Invention
The invention aims to prepare a polymer containing photoresponse antibacterial polypeptide and photoresponse hydrogel
1. According to the embodiment of the invention, the photoresponse antibacterial peptide polymer is a polymer shown as a formula (I):
the invention relates to a synthetic method of antibacterial polypeptide, which comprises the following steps:
(1) reacting o-nitrobenzyl alcohol with triphosgene to obtain o-nitrobenzyl chloroformate;
(2) reacting chloroformic acid o-nitrobenzyl ester with N-BOC ethylenediamine to prepare N-tert-butyloxycarbonyl-N-o-nitrobenzyloxycarbonyl-ethylenediamine;
(3) using trifluoroacetic acid to carry out deprotection on N-tert-butoxycarbonyl-N-o-nitrobenzyloxycarbonyl-ethylenediamine so as to prepare N-o-nitrobenzyloxycarbonyl-ethylenediamine;
(4) reacting N-o-nitrobenzyloxycarbonyl-ethylenediamine with glyoxylic acid monohydrate, and refluxing with 1M hydrochloric acid to prepare (N-o-nitrobenzyloxycarbonyl-ethylamino) glycine hydrochloride;
(5) (N-o-nitrobenzyloxycarbonyl-ethylamino) glycine hydrochloride reacts with triethylamine and di-tert-butyl dicarbonate to prepare (N-tert-butoxycarbonyl-N-o-nitrobenzyloxycarbonyl-ethylamino) glycine hydrochloride;
(6) (N-tert-butoxycarbonyl-N-o-nitrobenzyloxycarbonyl-ethylamino) glycine hydrochloride and phosphorus trichloride are reacted to prepare (N-o-nitrobenzyloxycarbonyl-ethylamino) glycine anhydride (NNCA).
(7) Weighing a proper amount of NNCA in a polymerization tube, adding primary amine initiators with different proportions, and polymerizing in anhydrous tetrahydrofuran for 24 hours to prepare a polymer poly (N-o-nitrobenzyloxycarbonyl-ethylamino) glycine (PN (oNB) G).
(8) Dissolving PN (oNB) G in chloroform, and irradiating for different times to prepare the antibacterial polymer (PN (oNB) G-co-PNAG).
(9) The polymer PN (oNB) G and agarose are used together to prepare hydrogel, and the hydrogel is irradiated by ultraviolet light for 3 hours to prepare the photoresponse antibacterial hydrogel.
In the synthesis method, the mass ratio of the triphosgene to the o-nitrobenzyl alcohol in the step (1) is 3:1, the reaction solvent is anhydrous tetrahydrofuran, the reaction temperature is room temperature, and the reaction time is 24 hours. After the reaction, the solvent was removed by a rotary evaporator, and then dissolved in ethyl acetate, washed with deionized water 3 times, washed with saturated brine 3 times, and dried over night with anhydrous magnesium sulfate. Anhydrous magnesium sulfate was removed by filtration, and ethyl acetate was removed by a rotary evaporator to give nitrobenzyl chloroformate.
In the synthesis method, the substance weight ratio of the o-nitrobenzyl chloroformate to the N-BOC in the step (2) is 1:1, the reaction temperature is 0, the reaction time is 2 hours, the reaction is filtered, and the ethyl acetate and the petroleum ether are mixed according to the weight ratio of 5: the product was settled three times in a ratio of 1 to give a white product.
In the synthesis method, the ratio of trifluoroacetic acid to dichloromethane in the step (3) is 2:5, the reaction is carried out for 24 hours at room temperature, ether is used for settling after the reaction, and the solid is settled for 3 times by using methanol and ether after the filtration, so as to obtain the white solid.
In the synthesis method, the mass ratio of the glyoxylic acid to the N-o-nitrobenzyloxycarbonyl-ethylenediamine in the step (4) is 2:1, the mass ratio of the hydrochloric acid to the N-o-nitrobenzyloxycarbonyl-ethylenediamine is 1:5, the hydrochloric acid is refluxed, water is distilled off, and then the mixture is settled for 3 times by using methanol and ether to obtain a white solid.
In the synthesis method, the ratio of the (N-o-nitrobenzyloxycarbonyl-ethylamino) glycine hydrochloride to triethylamine and di-tert-butyl dicarbonate in the step (5) is 1:5:2, the reaction solvent is deionized water, the reaction time is 24 hours, after the reaction, the water phase is extracted three times by using normal hexane to remove the redundant di-tert-butyl dicarbonate, then the pH is adjusted to about 3 by using 4mol/L hydrochloric acid, the water phase is extracted three times by using ethyl acetate, then the water phase is demulsified by using saturated saline solution, and finally the ethyl acetate phase is dried by using anhydrous magnesium sulfate for 12 hours, filtered and evaporated to obtain colorless oily matter.
In the synthesis method, the ratio of (N-tert-butoxycarbonyl-N-o-nitrobenzyloxycarbonyl-ethylamino) glycine hydrochloride to phosphorus trichloride in the step (6) is 1:1.2, the reaction solvent is anhydrous dichloromethane, the reaction temperature is 0, the reaction time at the temperature of 4 hours is 4 hours, after the reaction, the solvent is removed by a rotary evaporator, the solid is recrystallized for 3 times by anhydrous tetrahydrofuran and anhydrous N-hexane in a glove box, and the ratio of the N-hexane to the tetrahydrofuran is 5:1, and then white crystals are obtained after the recrystallization.
In the synthesis method, the ratio of the monomer and the initiator in the step (7) is 40:1, the reaction temperature is 56 ℃, the reaction time is 24 hours, and after the reaction is finished, the mixture is settled by cold ether for three times to obtain the polymer PN (oNB) G.
In the above synthesis method, the reaction solvent in step (8) is chloroform, and the light irradiation is performed for 2 hours, 4 hours, 8 hours and 12 hours, respectively. After the reaction is finished, the mixture is settled for three times by cold diethyl ether and then dried to obtain the antibacterial polymer (PN (oNB) G-co-PNAG)
In the synthesis method, the ratio of the agarose in the step (9) to the polymer PN (oNB) G is 3:2, after the agarose is completely dissolved, the polymer is added until the system is completely dissolved, and the hydrogel is obtained after cooling to room temperature. And (3) illuminating for 3h under ultraviolet light, and then cleaning with deionized water for three times to obtain the photoresponse antibacterial hydrogel.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of the photoresponse NNCA.
FIG. 2 nuclear magnetic hydrogen spectrum of photoresponsive polypeptidic PEG-b-PN (oNB) G.
FIG. 3 is a nuclear magnetic hydrogen spectrum of the cationic antimicrobial polymer PEG-b- (PN (oNB) G-co-PNAG).
FIG. 4 is a graph showing the shedding rate of o-nitrobenzene from a polymer as a function of time.
FIG. 5 is a potential diagram of PEG-b- (PN (oNB) G-co-PNAG) cationic antimicrobial polymer.
FIG. 6 shows the minimum inhibitory concentration of the cationic antimicrobial polymer PEG-b- (PN (oNB) G-co-PNAG).
FIG. 7 is a graph of the bactericidal effect of a photoresponsive hydrogel.
Detailed Description
The present invention is further illustrated by the following examples, but is not limited thereto. Embodiments of the present invention will allow those skilled in the art to more fully understand the present invention.
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified. NCA purity was determined by NMR Hydrogen spectrometer Bruker 500MHz, CDCl3Or deuterated DMSO as solvent, polymer number average molecular weight is determined by gel permeation chromatography, SSI pump connected to Wyatt Optilab DSP, DMF as solvent, and flow rate of 1mL min-1The test temperature was 50 ℃.
Example 1 preparation of the Polypeptoid of formula (II)
1. O-nitrobenzyl alcohol (10.5g,0.069mol) was dissolved in anhydrous tetrahydrofuran and triphosgene (13.7g, 0.046mol) was added. After reacting for 24 hours at room temperature, removing the solvent by rotary evaporation, adding 100mL of ethyl acetate for dissolving, washing with deionized water for three times, washing with saline water for three times, drying an organic phase with anhydrous magnesium sulfate for 12 hours after washing, filtering, and rotating to obtain the chloroformic acid o-nitrobenzyl ester.
2. Ortho-nitrobenzyl chloroformate (15.3g, 0.7mol) was dissolved in zero degrees of diethyl ether. N-BOC ethylenediamine (12g, 0.7mol) was dissolved in a 2M sodium carbonate solution and added dropwise to the above solvent. Reacting for 2 hours, filtering the obtained solid, and settling for three times by using petroleum ether and ethyl acetate to obtain the compound N-tert-butyloxycarbonyl-N-o-nitrobenzyloxycarbonyl-ethylenediamine.
3. N-tert-Butoxycarbonyl-N-o-nitrobenzyloxycarbonyl-ethylenediamine (18g, 0.053mol) was dissolved in dichloromethane (100mL), 40mL of trifluoroacetic acid was added, the reaction was allowed to react for 24h, the ether was settled and then recrystallized three times in methanol and ether. Drying to obtain the N-o-nitrobenzyloxycarbonyl-ethylenediamine.
4. N-O-nitrobenzyloxycarbonyl-ethylenediamine (10g) and glyoxylic acid (7.7g) were dissolved in 100mL of methanol and reacted at room temperature for 24 hours. Methanol is dried by spinning, 200mL of hydrochloric acid 1M is added, the temperature is kept overnight at 110 ℃, after water is dried by spinning, methanol and ether are used for recrystallization three times to obtain (N-o-nitrobenzyloxycarbonyl-ethylamino) glycine hydrochloride.
5. (N-O-nitrobenzyloxycarbonyl-ethylamino) glycine hydrochloride (5g) was dissolved in 200mL of water, and triethylamine (10.42mL) and di-tert-butyl dicarbonate (6.55g) were added to the solution to react at room temperature for 24 hours. After 24 hours, extraction was carried out three times with 100mL of n-hexylamine, and the aqueous phase was neutralized with triethylamine with 4M hydrochloric acid, and the pH was adjusted to about 3. The aqueous layer was extracted three times with ethyl acetate. Demulsifying with saturated saline solution, drying ethyl acetate with anhydrous magnesium sulfate for 12 hr, and rotary evaporating to remove ethyl acetate to obtain anhydrous oily (N-tert-butoxycarbonyl-N-o-nitrobenzyloxycarbonyl-ethylamino) glycine hydrochloride.
6. (N-tert-butoxycarbonyl-N-o-nitrobenzyloxycarbonyl-ethylamino) glycine hydrochloride (1.9g) was dissolved in 100mL of anhydrous dichloromethane, phosphorus trichloride (565. mu.L) was added, the reaction was carried out in an ice bath for 2 hours, the dichloromethane was removed by rotary evaporation after filtration, and the resulting solution was recrystallized three times from tetrahydrofuran and N-hexane in a glove box to obtain white crystals (N-o-nitrobenzyloxycarbonyl-ethylamino) glycine anhydride (NNCA).
7. NNCA (1g) was dissolved in dry tetrahydrofuran (100mg/mL) and initiator (n-hexylamine, mPEG) dissolved in dry tetrahydrofuran was added44-NH2) (Wt%) was stirred in a 56 deg.C oil bath for 24 h. Then precipitating with glacial ethyl ether for three times, drying at 40 deg.C in vacuum drying oven to constant weight to obtainTo a pale yellow solid.
8. Polymer PN (oNB) G was dissolved in chloroform to give a 10mg/mL solution, which was exposed to mercury high pressure lamp for various periods of time (2h, 4h, 8h, 12h, 16 h). After irradiation, it was precipitated three times with ether. Drying in a vacuum drying oven to constant weight.
9. 30 mg of agarose is weighed, 1mL of water is added, the agarose is heated until the agarose is completely dissolved, 20 mg of PEG-b-PN (oNB) G is added, and after the PEG-b-PN (oNB) G is completely dissolved, the agarose is naturally cooled. And (3) placing the hydrogel under ultraviolet light for illumination, and after the hydrogel is illuminated for 3 hours, washing the hydrogel with deionized water for three times to obtain the photoresponse antibacterial hydrogel.
Antibacterial characterization of the Polypeptides and hydrogels shown in example 1
1. Minimum Inhibitory Concentration (MIC) test
Photoresponsive polymers were tested for antimicrobial activity against Staphylococcus aureus (gram positive), Escherichia coli and Pseudomonas aeruginosa (gram negative) using the broth microdilution MIC method logarithmic growth bacteria were taken and diluted to 3 × 10 in Mueller Hinton Broth (MHB)5Bacterial suspension of colony-forming units (CFU) per milliiter (CFU/mL). The polymer was dissolved in deionized water at a concentration of 10mg/mL, 100. mu.L of MHB was added in columns 2-10, 180. mu.L of MHB was added in column 11 of a 96-well plate, 20. mu.L of the polymer solution was added, 100. mu.L was removed after the eleventh column was mixed completely, added to column 10, and so on, and finally the volume of columns 2-11 was 100. mu.L. 100 μ L of the bacterial suspension was added to the well plate. Incubated at 37 ℃ for 18 hours and the OD was measured at 600nm using a microplate reader.
2. Antimicrobial testing of photoresponsive hydrogels
Before the experiment, the hydrogel was washed three times with PBS buffer solution and placed in a 24-well plate, and the log-grown bacteria were taken and diluted to 3 × 10 in MHB medium8CFU/mL. On the hydrogel surface, 5. mu.L of bacterial suspension was added dropwise. After culturing at 37 ℃ for 1 hour, 1mL of MHB culture solution was added to each air, and the surface of the hydrogel was repeatedly washed to recover viable bacteria. After dilution, 100. mu.L of the bacterial suspension was applied to the surface of LB agar and incubated for 18h to take pictures.
Claims (10)
1. A method for preparing photoresponsive antibacterial polypeptide polymer and hydrogel.
2. The method of claim 1, wherein the polymer is a clustered peptide having antibacterial properties synthesized by pre-modifying monomers, ring-opening polymerization and photocleavage, and the polymer is represented by formula I.
3. The polymer of claim 2, wherein the photoresponsive group is introduced into the monomer by a method of pre-modifying the monomer.
4. The method of claim 2, wherein said polymers are polymerized by different initiators (PEG-NH)2(Mn. RTM. 2000 and 5000g/mol) and n-hexylamine).
5. The polymer of claim 2, which is obtained by photocleavage.
6. The method of claim 1, wherein the hydrogel is a photo-responsive antimicrobial hydrogel.
7. According to claim 3, the method for synthesizing the photo-responsive monomer is as follows:
(N-tert-butoxycarbonyl-N-o-nitrobenzyloxycarbonyl-ethylamino) glycine hydrochloride (1.9g) was dissolved in 100ml of anhydrous dichloromethane, phosphorus trichloride (565. mu.L) was added, the reaction was carried out in an ice bath for 2 hours, the dichloromethane was removed by rotary evaporation after filtration, and the mixture was recrystallized three times from tetrahydrofuran and N-hexane in a glove box to obtain (N-o-nitrobenzyloxycarbonyl-ethylamino) glycine anhydride (NNCA).
8. The method of claim 4, wherein the polymerization of the polymer is initiated by different initiators as follows:
NNCA (1g) was dissolved in anhydrous THF (100mg/mL) and then initiator (benzylamine, PEGm-NH2) dissolved in anhydrous THF was added (Wt%) and stirred in a 56 deg.C oil bath for 24 h. Then, the mixture was precipitated three times with ethyl acetate and dried in a vacuum oven at 40 ℃ to constant weight to obtain a pale yellow solid.
9. The method of claim 5, wherein the photocleavage is as follows:
the polymer was made up to 10mg/mL in chloroform and irradiated under a high pressure mercury lamp for various periods of time (2h, 4h, 8h, 12h, 16 h). After irradiation, it was precipitated three times with ether. Drying in a vacuum drying oven to constant weight.
10. The method of claim 6, wherein the photo-responsive antibacterial hydrogel is prepared by the following steps:
to agarose (60mg) was added 2mL of deionized water, heated until the agarose was completely dissolved, added the photo-responsive polymer PEG-b-PN (ONB) G (40mg) to completely dissolve, and cooled to room temperature. The cooled hydrogel was placed in deionized water and soaked for 24 hours. After cleaning, placing the hydrogel under an ultraviolet lamp for illumination, after illuminating for 3 hours, cleaning with deionized water for three times to obtain the photoresponse antibacterial hydrogel.
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| CN112126311A (en) * | 2020-08-25 | 2020-12-25 | 威高集团有限公司 | Antibacterial coating with bacterial enzyme response function, functional material with antibacterial coating and preparation method of functional material |
| CN113476614A (en) * | 2021-07-07 | 2021-10-08 | 青岛科技大学 | Uniform polyelectrolyte composite vesicle and preparation method thereof, antibacterial vesicle, hydrophobic substance-encapsulated vesicle and anti-adhesion vesicle |
| CN113583236A (en) * | 2021-07-22 | 2021-11-02 | 江苏大学 | Preparation method of amphiphilic carbohydrate-containing polypeptide simulating natural antifreeze protein structure |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112126311A (en) * | 2020-08-25 | 2020-12-25 | 威高集团有限公司 | Antibacterial coating with bacterial enzyme response function, functional material with antibacterial coating and preparation method of functional material |
| CN113476614A (en) * | 2021-07-07 | 2021-10-08 | 青岛科技大学 | Uniform polyelectrolyte composite vesicle and preparation method thereof, antibacterial vesicle, hydrophobic substance-encapsulated vesicle and anti-adhesion vesicle |
| CN113476614B (en) * | 2021-07-07 | 2023-08-25 | 青岛科技大学 | Homopolymeric electrolyte composite vesicle, preparation method thereof, antibacterial vesicle, vesicle coated with hydrophobic substance and anti-adhesion vesicle |
| CN113583236A (en) * | 2021-07-22 | 2021-11-02 | 江苏大学 | Preparation method of amphiphilic carbohydrate-containing polypeptide simulating natural antifreeze protein structure |
| CN113583236B (en) * | 2021-07-22 | 2022-07-22 | 江苏大学 | Preparation method of amphiphilic carbohydrate-containing polypeptide simulating natural antifreeze protein structure |
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