CN114957706A - Vesicle with stability and permeability as well as preparation method and application thereof - Google Patents
Vesicle with stability and permeability as well as preparation method and application thereof Download PDFInfo
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- CN114957706A CN114957706A CN202210572208.5A CN202210572208A CN114957706A CN 114957706 A CN114957706 A CN 114957706A CN 202210572208 A CN202210572208 A CN 202210572208A CN 114957706 A CN114957706 A CN 114957706A
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- 230000035699 permeability Effects 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 239000000178 monomer Substances 0.000 claims abstract description 33
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 7
- 150000002433 hydrophilic molecules Chemical class 0.000 claims abstract description 6
- 238000011065 in-situ storage Methods 0.000 claims abstract description 5
- 238000012650 click reaction Methods 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000012074 organic phase Substances 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 claims description 6
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 claims description 6
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 6
- 150000003573 thiols Chemical group 0.000 claims description 6
- 102000004190 Enzymes Human genes 0.000 claims description 5
- 108090000790 Enzymes Proteins 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical group SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
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- OXBLVCZKDOZZOJ-UHFFFAOYSA-N 2,3-Dihydrothiophene Chemical compound C1CC=CS1 OXBLVCZKDOZZOJ-UHFFFAOYSA-N 0.000 claims 1
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 8
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- 238000003786 synthesis reaction Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
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- UOWNEWCMPHICQH-UHFFFAOYSA-N 1,2-bis(2-bromoethoxy)ethane Chemical compound BrCCOCCOCCBr UOWNEWCMPHICQH-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 238000003917 TEM image Methods 0.000 description 3
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- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 3
- KIUMMUBSPKGMOY-UHFFFAOYSA-N 3,3'-Dithiobis(6-nitrobenzoic acid) Chemical compound C1=C([N+]([O-])=O)C(C(=O)O)=CC(SSC=2C=C(C(=CC=2)[N+]([O-])=O)C(O)=O)=C1 KIUMMUBSPKGMOY-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
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- PXEZTIWVRVSYOK-UHFFFAOYSA-N 2-(3,6-diacetyloxy-2,7-dichloro-9h-xanthen-9-yl)benzoic acid Chemical compound C1=2C=C(Cl)C(OC(=O)C)=CC=2OC2=CC(OC(C)=O)=C(Cl)C=C2C1C1=CC=CC=C1C(O)=O PXEZTIWVRVSYOK-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- 239000000592 Artificial Cell Substances 0.000 description 1
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 241000283891 Kobus Species 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
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- 238000003384 imaging method Methods 0.000 description 1
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- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
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Images
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
-
- 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
- C08G75/00—Macromolecular compounds obtained by reactions forming a linkage containing sulfur with or without nitrogen, oxygen, or carbon in the main chain of the macromolecule
- C08G75/02—Polythioethers
- C08G75/04—Polythioethers from mercapto compounds or metallic derivatives thereof
- C08G75/045—Polythioethers from mercapto compounds or metallic derivatives thereof from mercapto compounds and unsaturated compounds
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N11/00—Carrier-bound or immobilised enzymes; Carrier-bound or immobilised microbial cells; Preparation thereof
- C12N11/02—Enzymes or microbial cells immobilised on or in an organic carrier
- C12N11/08—Enzymes or microbial cells immobilised on or in an organic carrier the carrier being a synthetic polymer
- C12N11/089—Enzymes or microbial cells immobilised on or in an organic carrier the carrier being a synthetic polymer obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/0004—Oxidoreductases (1.)
- C12N9/0065—Oxidoreductases (1.) acting on hydrogen peroxide as acceptor (1.11)
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y111/00—Oxidoreductases acting on a peroxide as acceptor (1.11)
- C12Y111/01—Peroxidases (1.11.1)
- C12Y111/01006—Catalase (1.11.1.6)
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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
- C08J2381/00—Characterised by the use of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing sulfur with or without nitrogen, oxygen, or carbon only; Polysulfones; Derivatives of such polymers
- C08J2381/02—Polythioethers; Polythioether-ethers
Abstract
The invention discloses a vesicle with stability and permeability as well as a preparation method and application thereof. The preparation method comprises the following steps: under the conditions of no need of monomer pre-self-assembly or template induction and under the action of photocatalysis, hydrophobic monomers and hydrophilic monomers are gradually polymerized to form double-head hydrophilic molecules through mercaptan-alkene click reaction in an environment with proper polarity, and then the vesicles with stability and permeability can be prepared through in-situ self-assembly. According to the invention, the vesicle is constructed by in-situ generation of the double-headed parent molecule and covalent bond self-assembly, and the prepared vesicle is an ultrathin unilamellar vesicle and has excellent stability and permeability.
Description
Technical Field
The invention belongs to the technical field of vesicle preparation, and particularly relates to a vesicle with stability and permeability as well as a preparation method and application thereof.
Background
The vesicle is formed by self-assembly of phospholipids from natural sources, and provides an impermeable compartment for vital activities of eukaryotic cells. In the past decades, artificially synthesized vesicle systems have attracted great interest in the fields of biomedicine, nanoreactors, artificial organelles, and the like. In addition to natural lipids, synthetic amphiphilic block copolymers are the most common material for constructing vesicular systems. However, polymersome have been greatly limited in practical use due to their poor stability.
The most straightforward approach to improve vesicle stability is covalent cross-linking of dynamically self-assembled nanostructures. However, this method usually requires multiple steps in the synthesis process, and can change the morphology of the nanostructure, which also has some effect on the precipitation of aggregates. To date, direct synthesis of vesicles using irreversible covalent bonds without the aid of any pre-organization, template or emulsifier remains a formidable challenge. In recent years, Kim and co-workers have found that irreversible covalent bonds can be used to synthesize a variety of nanostructured materials with well-defined structures. Compared with self-assembly controlled by thermodynamics, the polymer nanocapsule needs to be covalently crosslinked through a pre-organized rigid building element in the preparation process to form a covalent spherical nanostructure with stable shape. However, as is well known, no method for directly synthesizing covalent vesicles having high stability and high permeability by using a flexible monomer with a high degree of freedom to react with each other has been developed. . The reason is that functional groups with high degrees of freedom and multivalency may cause non-directional cross-linked structures during the flexible monomer interaction and also controlled sequential polymerization and shape-durability induced metastable morphological transformations may not occur.
In addition, stability and permeability are two important properties in practical applications of vesicles. To solve the problem of vesicle permeability, researchers in various countries around the world have performed a lot of work, and through physical or chemical modification approaches, methods for improving permeability have been found. However, the stability and permeability of vesicles are often contradictory properties, i.e., it is difficult to increase the permeability while increasing the stability, and even the permeability becomes worse. Similarly, increasing vesicle permeability also decreases vesicle stability. In order to solve this problem, researchers often adopt a chemical crosslinking method to firstly improve the stability of the vesicle, and then adjust the bilayer membrane of the vesicle to improve the permeability. Among them, covalent crosslinking is the most direct method for improving vesicle stability, but as described above, crosslinking can improve stability but often leads to a decrease in permeability. Furthermore, to date, direct synthesis of vesicles using irreversible covalent bonds without the aid of any pre-organization, template or emulsifier remains a formidable challenge. Therefore, there is an urgent need for a rapid and simple method for preparing vesicles having both excellent stability and permeability.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a vesicle with stability and permeability as well as a preparation method and application thereof, and can effectively solve the problem that the stability and the permeability of the vesicle prepared by the prior art can not be considered at the same time.
In order to achieve the purpose, the technical scheme adopted by the invention for solving the technical problems is as follows:
a preparation method of vesicles with stability and permeability is characterized in that hydrophobic monomers and hydrophilic monomers are polymerized to form double-headed hydrophilic molecules through mercaptan-alkene click reaction in an environment with proper polarity under the photocatalysis effect without the need of monomer pre-self-assembly or template induction, and then the double-headed hydrophilic molecules are self-assembled in situ.
Further, the vesicle formation process is as follows:
adding a hydrophobic monomer and a hydrophilic monomer into a mixed solution of methanol and water with the polarity of 7-7.5, purging with nitrogen, illuminating at room temperature for 60-80 min, dialyzing for 2-3 days, concentrating under reduced pressure, and drying under vacuum to obtain the vesicle.
Further, the polarity of the mixed solution is 7.2-7.32.
Further, the hydrophobic monomer is tetra-o-allyl pentaerythritol, and the chemical structural formula is as follows:
further, the preparation method of the tetra-o-allyl pentaerythritol comprises the following steps:
dissolving pentaerythritol in a 33% NaOH aqueous solution, adding tetrabutylammonium bromide, heating to 40-50 ℃, adding allyl bromide within 1h, stirring at room temperature for 12-15 h, adding toluene for extraction, washing an organic phase, and concentrating and purifying the organic phase.
Furthermore, the molar ratio of the pentaerythritol to the tetrabutylammonium bromide to the allyl bromide is 20-22: 4-6.2: 100-118.
Further, the preparation method of the tetra-o-allyl pentaerythritol comprises the following steps:
pentaerythritol (6.3g,22mmol) was dissolved in 33% aqueous NaOH (50 mL). Tetrabutylammonium bromide (2g,6.2mmol) was added, the temperature was raised to 40 ℃ and allyl bromide (10mL,118mmol) was added dropwise over 1 h. The reaction mixture was stirred vigorously at room temperature for 12h until stirred well. Toluene (100mL) was added, the organic phase was washed with water, concentrated in vacuo, and purified by flash chromatography (toluene: ethyl acetate, 20:1) to give the allylated product as a colorless syrup (3.84g,13mmol, 59%)
Further, the hydrophilic monomer is thiol having hydrophilicity; the thiol contains at least 2 thiol groups.
Further, the hydrophilic monomer is dithiothreitol or 1-mercapto-3, 6-dioxetane.
The present invention detects particles with an average particle size of 5nm starting from 2.5 minutes after uv irradiation and the internal particle size rapidly increases to about 100nm within ten minutes and then slowly increases to the final particle size (-125 nm) and remains unchanged thereafter. The growth process of the particle size completely accords with the formation and self-assembly concept of the bipitch parent molecule. The initial phase of the reaction (-2.5 min) can be assumed to be the formation of the bipitch parent molecule, and once the concentration of bipitch parent molecule reaches the requirement for self-assembly, the pre-organized covalent vesicle intermediates will begin to grow. Also, TEM monitored this process of vesicle formation (fig. 2).
Before UV irradiation, no pre-organization was observed, and after UV irradiation, small plaques (2-5nm) appeared at 2.5min (FIG. 2a), and then these plaques began to curl up, forming bowl-like nanostructures and completing further transformation and growth in the transverse direction within a few minutes (FIGS. 2 b-d). Reasonable integration processes and large numbers of covalent vesicles were observed within the next 10-15 minutes (FIGS. 2 d-f).
The vesicle prepared by the method.
The vesicle can be used for preparing drug carriers, catalysts, chemical sensors, nanoreactors and enzyme immobilization.
The invention has the beneficial effects that:
according to the invention, the vesicle is self-assembled and constructed by using the double-headed amphiphilic molecule and the flexible monomer in a form of forming an irreversible covalent bond, and the prepared vesicle is an ultrathin unilamellar vesicle and has excellent stability and permeability.
Drawings
FIG. 1 is a graph showing the detection of the properties of vesicles prepared according to the present invention; wherein a is a TEM image; b is an AFM picture; c is a SAXS map; d is the size and PDI of the vesicle;
FIG. 2 is an animated image and a TEM image of vesicles prepared according to the present invention at each time point during their polymerization;
FIG. 3 shows the results of the enzyme encapsulation assay; wherein, a is an experimental device established by connecting the pump and the plastic model system; b is the effect of shear forces on the fractional release of content encapsulated in vesicles and in commercially available polymers; c is free and coated CAT catalytic H under 40Pa shearing stress and with or without trypsin 2 O 2 Comparison of degradation kinetics of; d is the superposition of the fluorescence image of intracellular ROS (reactive oxygen species) levels after different treatments (first line), the bright field image (second line) and the fluorescence image combined with the bright field (third line); e is ROS level detection.
Detailed Description
The following description of the embodiments of the present invention is provided to facilitate the understanding of the present invention by those skilled in the art, but it should be understood that the present invention is not limited to the scope of the embodiments, and it will be apparent to those skilled in the art that various changes may be made without departing from the spirit and scope of the invention as defined and defined in the appended claims, and all matters produced by the invention using the inventive concept are protected.
Example 1
1. Synthesis of Tetrao-allylpentaerythritol (monomer 1)
Pentaerythritol (6.3g,22mmol) was dissolved in 33% aqueous NaOH (50 mL). Tetrabutylammonium bromide (2g,6.2mmol) was added, the temperature was raised to 40 ℃ and allyl bromide (10mL,118mmol) was added dropwise over 1 h. The reaction mixture was stirred vigorously at room temperature for 12h until stirred well. Toluene (100mL) was added, the organic phase was washed with water, concentrated in vacuo, and purified by flash chromatography (toluene: ethyl acetate, 20:1) to give the allylated product as a colorless syrup (3.84g,13mmol, 59%). The nuclear magnetic data are as follows: 1 H NMR(400MHz,CDCl 3 ) δ:3.91(dd, J ═ 5.9Hz,2H),3.62(dd, J ═ 7.7Hz,2H),3.08-3.12(m,2H),2.88-2.91(m,2H),2.05(s, 1H). The reaction formula is as follows:
2. dithiothreitol (monomer 2) is a commercially available product.
3. Construction of monomer 3
Synthesis of 1, 2-bis (2-bromoethoxy) ethane: to a solution containing triethylene glycol (1.5g,10mmol) in 20mL of anhydrous dichloromethane was added phosphorus tribromide (8.1g,30mmol) dropwise, and the reaction mixture was stirred at reflux for 24 h. The reaction solution was then diluted with dichloromethane (40mL) and neutralized with saturated aqueous NaHCO3 solution. The organic phase was collected, washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give 1, 2-bis (2-bromoethoxy) ethane (1.9g, 69%) as a yellow oil. 1H NMR (400MHz, CDCl3) δ:3.44(t, J ═ 1.2Hz,4H),3.65(s,4H),3.79(t, J ═ 1.2Hz,4H).
Synthesis of 1, 8-dimercapto-3, 6-dioxaheptane: 1, 2-bis (2-bromoethoxy) ethane (304mg,1.0mmol) and thiourea (365.8mg,4.8mmol) were dissolved in 95% ethanol (30 mL). The reaction mixture was stirred under reflux for 3h,then 20mL of sodium hydroxide solution (1.0mol/L) was added and reflux was continued for 2 h. The aqueous layer was separated and acidified (pH 1) by addition of dilute hydrochloric acid (2.0 mol/L). The acidic solution was then extracted with petroleum ether (3X 30 mL). The organics were combined, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give the compound as a colorless oil (156mg, 85.7%). The nuclear magnetic data are: 1 H NMR(400MHz,CDCl 3 ) δ:3.91(dd, J ═ 5.9Hz,2H),3.62(dd, J ═ 7.7Hz,2H),3.08-3.12(m,2H),2.88-2.91(m,2H),2.05(s, 1H). The reaction formula is as follows:
example 2
1. Preparation of vesicles from monomer 1 and monomer 2
Tetrao-allylpentaerythritol (monomer 1) and dithiol (monomer 2) were added to MeOH/H 2 O(v/v＝5:1，P AB 7.25) in a ratio of 1:2 (allyloxy: thiol ═ 1:1), purged with nitrogen, irradiated with 365nm ultraviolet light at room temperature for 60 minutes, dialyzed in water for two days, concentrated under reduced pressure, and dried under vacuum to obtain the vesicle (yield: 98%).
The morphology and size of the covalent vesicles can be characterized by spectroscopic, light scattering and imaging techniques (fig. 1), and it can be seen from fig. 1 that the size and PDI are independent of concentration, which confirms the cross-linking properties of the vesicles, indicating that the vesicles have good stability (d in fig. 1).
When studied using Transmission Electron Microscopy (TEM) and Atomic Force Microscopy (AFM), synthetic vesicles with nanoscale colloidal particle properties were first present (fig. 1a, b), and the diameter of the vesicles was well matched to the mean hydrodynamic diameter (125 ± 4nm) observed by Dynamic Light Scattering (DLS) (table 1).
Combined dynamic and static light scattering studies can also measure the radius of gyration (Rg 66nm), hydrodynamic radius (Rh 63nm) and Rg/Rh ratio (-1.05) of the vesicles, which data can be indicative of the hollow sphere properties of the vesicles.
Furthermore, TEM micrographs show a hollow interior surrounded by an ultrathin membrane (fig. 1a), again verifying the hollow sphere nature of the vesicles by small angle X-ray scattering (SAXS) analysis of the vesicles (fig. 1 c).
The average vesicle thickness (2.8 ± 0.4nm) calculated by SAXS analysis was consistent with the size of the bipitch parent molecular intermediate, indicating that a monolayer membrane was formed. From this, it was found that the synthetic vesicle is a nanostructure composed of a single-layer membrane and having a stable hollow sphere property. And the synthetic vesicles become more stable due to the formation of multiple C-S covalent bonds, which is clearly different from the self-assembled artificial vesicle system (fig. 1 d).
2. When monomer 1 is crosslinked with a thiol monomer that does not contain two hydrophilic hydroxyl groups, no well-defined covalent vesicles are obtained due to the lack of formation and self-assembly of double-headed hydrophilic molecules. If the dithiol crosslinker is converted into monomer 3 with an ethylene glycol segment in the middle, defined covalent vesicles can be formed again within the optimized polarity range.
Example 3
1. Vesicle permeability assay
Stability and permeability are two important properties of vesicles in practical applications, where membrane permeability is one of the most important properties determining its potential applications. Determination of organophosphorus reagent-loaded PP Using a reaction Rate assay for ADNB substrate (also known as Ellman reagent) 3 Membrane permeability of vesicles of TS.
Under the experimental conditions of (k)>10M -1 ·s -1 ) In the case of (3), DTNB is used together with free PP 3 TS reaction speed is very fast. Adding ADNB to a loaded PP 3 TS in aqueous solution. The substrate must penetrate into the vesicles together with the PP 3 TS reacted and converted to a colored product. These colored products are then detected by uv-vis spectroscopy. 0.5mL of vesicle-containing PP was added at room temperature 3 The TS solution was mixed with 2.5mL of ADNB aqueous solution (4.5. mu.M) and the reaction rate was measured in a 1cm silica glass reaction cup. The permeability of the vesicles was determined by recording the absorbance at 412nm every 20s (see table 1).
TABLE 1 comparison of vesicle permeability
As shown in Table 1, the highly chromogenic product 5-thio-2-nitrobenzoate (TNB) (14150M. epsilon. at 412 nm) was monitored -1 ·cm -1 ) To measure the permeability of synthetic vesicles, the substrate was 5,5- (2-aminoethyl) -dithio-2-nitrobenzoate (ADNB). Compared with polymer vesicles assembled by block copolymers, all the synthetic vesicles have extremely high permeability (as high as 57.9 +/-1.8 nm · s) to organic small molecules -1 ). And a reaction medium (P) AB 、MeOH/H 2 O) is more polar, the larger the hydrodynamic diameter of the synthetic vesicle, the greater the permeability.
It can be seen that, during the irreversible polymerization, the polarity of the reaction medium (P) AB Polarity of solvent, MeOH/H 2 O ratio) plays an important role in the synthesis of vesicles and in controlling the size of vesicles, and only at P AB In the range of 7.20-7.32, a definite vesicle can be formed.
Example 4
And (3) detecting the encapsulation performance of the enzyme, wherein the detection is as follows:
by exploring the encapsulation of Catalase (CAT) using synthetic vesicles, CAT need only be mixed with monomer 1 and monomer 2 to achieve encapsulation through in situ bipitch formation and self-assembly. .
With the CAT loaded vesicles, we further used a test instrument to measure the stability of the CAT vascular mimics at different pressures (fig. 3 a). To highlight the advantages of vesicles, CAT @1V (CAT @ vesicles) and CAT @ polymersome (CAT @ polymersome) systems were measured for CAT release at different shear stresses (0-40 Pa). The CAT release rate of the CAT @ polymersome system based on the commercial polymer is high, whereas CAT @1V shows that the CAT release rate of the vesicles with compact cross-linked membrane layer is less than 5% even under the simulated shear stress (40Pa) of arterial constriction. (FIG. 3b)
The CAT @1V system obtains good stability after being enveloped and is connected withThe following CAT pair H was evaluated by FOX assay 2 O 2 Catalytic activity of decomposition. Compared with CAT @1V system, CAT @ polymersome system and CAT alone, we obtained higher Kobs (0.0473 s) -1 ) This indicates that vesicles are not only capable of efficient transmembrane transport of substrates and products, but also improve the catalytic activity of CAT. Moreover, the encapsulated CAT protected trypsin better than the other systems (fig. 3 c). .
In organisms, the production of Reactive Oxygen Species (ROS) above critical levels may cause oxidative damage to intracellular biomolecules, thereby inducing a number of diseases. To detect CAT versus hydrogen peroxide (H) in a living system 2 O 2 ) Catalytic activity of decomposition by introducing H into 2', 7' -dichlorodihydrofluorescein diacetate (DCFH-DA) as a fluorescent probe 2 O 2 Treated HUVEC cells were subjected to intracellular ROS studies.
As shown in FIG. 3d, H 2 O 2 The treated cells produce intense fluorescence due to the excess ROS. However, when the cells were incubated with CAT @1v, the fluorescence intensity dropped significantly, and after 128min of release, the fluorescence intensity was as low as that observed in normal cells. This ability to return to normal ROS concentrations is attributed to the stable catalytic performance of CAT @1v in living cells. In contrast, although the CAT @ polymersome system and CAT also catalyze the reaction, the catalytic efficiency is low due to the low stability and activity of the enzyme in living cells (FIG. 3 e).
Claims (10)
1. A preparation method of vesicles with stability and permeability is characterized in that hydrophobic monomers and hydrophilic monomers are polymerized to form double-headed hydrophilic molecules through thiol-ene click reaction, and then the double-headed hydrophilic molecules are self-assembled in situ.
2. The method according to claim 1, wherein the vesicle is formed by:
adding a hydrophobic monomer and a hydrophilic monomer into a mixed solution of methanol and water with the polarity of 7-7.5, purging with nitrogen, illuminating at room temperature for 10-80 min, dialyzing for 2-3 days, concentrating under reduced pressure, and drying under vacuum to obtain the vesicle.
3. The method according to claim 2, wherein the polarity of the mixed solution is 7.2 to 7.32.
4. The method of claim 1 or 2, wherein the hydrophobic monomer is tetra-o-allylpentaerythritol having a chemical formula:
5. the method according to claim 4, wherein the method for preparing tetra-o-allylpentaerythritol comprises:
dissolving pentaerythritol in a 33% NaOH aqueous solution, adding tetrabutylammonium bromide, heating to 40-50 ℃, adding allyl bromide within 1h, stirring at room temperature for 12-15 h, adding toluene for extraction, washing an organic phase, and concentrating and purifying the organic phase.
6. The method according to claim 5, wherein the molar ratio of pentaerythritol to tetrabutylammonium bromide to allyl bromide is 20-22: 4-6.2: 100-118.
7. The production method according to claim 1 or 2, characterized in that the hydrophilic monomer is a thiol having hydrophilicity; the thiol contains at least 2 thiol groups.
8. The method of claim 7, wherein the hydrophilic monomer is dithiothreitol or 1, 8-dimercapto-3, 6-dioxetane.
9. Vesicles prepared by the method of any one of claims 1 to 8.
10. Use of the vesicles of claim 9 in the preparation of drug carriers, catalysts, chemical sensors, nanoreactors, and enzyme immobilization.
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