CN113321596B - Photochromic controllable permeable small-molecule cross-linked vesicle and preparation method and application thereof - Google Patents
Photochromic controllable permeable small-molecule cross-linked vesicle and preparation method and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 150000003384 small molecules Chemical class 0.000 title claims description 26
- DMLAVOWQYNRWNQ-UHFFFAOYSA-N azobenzene Chemical compound C1=CC=CC=C1N=NC1=CC=CC=C1 DMLAVOWQYNRWNQ-UHFFFAOYSA-N 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 238000004132 cross linking Methods 0.000 claims abstract description 6
- 239000000243 solution Substances 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 239000003431 cross linking reagent Substances 0.000 claims description 6
- -1 azobenzene amphiphile compounds Chemical class 0.000 claims description 4
- 230000002209 hydrophobic effect Effects 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 2
- 238000013270 controlled release Methods 0.000 abstract description 12
- 230000035699 permeability Effects 0.000 abstract description 11
- 201000010099 disease Diseases 0.000 abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 5
- 206010028980 Neoplasm Diseases 0.000 abstract description 4
- 201000011510 cancer Diseases 0.000 abstract description 3
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 3
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- 229920000642 polymer Polymers 0.000 abstract description 2
- 238000001338 self-assembly Methods 0.000 abstract description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Natural products CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 19
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- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
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- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- ZPLCXHWYPWVJDL-UHFFFAOYSA-N 4-[(4-hydroxyphenyl)methyl]-1,3-oxazolidin-2-one Chemical compound C1=CC(O)=CC=C1CC1NC(=O)OC1 ZPLCXHWYPWVJDL-UHFFFAOYSA-N 0.000 description 5
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 238000002296 dynamic light scattering Methods 0.000 description 4
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- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- UOWNEWCMPHICQH-UHFFFAOYSA-N 1,2-bis(2-bromoethoxy)ethane Chemical compound BrCCOCCOCCBr UOWNEWCMPHICQH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
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- 229940125898 compound 5 Drugs 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methyl-N-phenylamine Natural products CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
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- 230000002000 scavenging effect Effects 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- VPYJNCGUESNPMV-UHFFFAOYSA-N triallylamine Chemical compound C=CCN(CC=C)CC=C VPYJNCGUESNPMV-UHFFFAOYSA-N 0.000 description 2
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 2
- 210000003606 umbilical vein Anatomy 0.000 description 2
- GIJSVMOPNUOZBC-UHFFFAOYSA-N (4-methylphenyl)-phenyldiazene Chemical compound C1=CC(C)=CC=C1N=NC1=CC=CC=C1 GIJSVMOPNUOZBC-UHFFFAOYSA-N 0.000 description 1
- DMLAVOWQYNRWNQ-BUHFOSPRSA-N (E)-azobenzene Chemical compound C1=CC=CC=C1\N=N\C1=CC=CC=C1 DMLAVOWQYNRWNQ-BUHFOSPRSA-N 0.000 description 1
- NYJYFSGMYHSTNZ-UHFFFAOYSA-N 1-methyl-4-nitrosobenzene Chemical compound CC1=CC=C(N=O)C=C1 NYJYFSGMYHSTNZ-UHFFFAOYSA-N 0.000 description 1
- 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
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 1
- 241000723806 Sugarcane mosaic virus Species 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
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- 206010003246 arthritis Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
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- 229940049706 benzodiazepine Drugs 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
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- 230000001276 controlling effect Effects 0.000 description 1
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- VENHFCZBHVZHMO-UHFFFAOYSA-N gold;triphenylphosphane Chemical compound [Au].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 VENHFCZBHVZHMO-UHFFFAOYSA-N 0.000 description 1
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
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- VOFUROIFQGPCGE-UHFFFAOYSA-N nile red Chemical compound C1=CC=C2C3=NC4=CC=C(N(CC)CC)C=C4OC3=CC(=O)C2=C1 VOFUROIFQGPCGE-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
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- C07C245/02—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides
- C07C245/06—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides with nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings
- C07C245/10—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides with nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings with nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems
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Abstract
The invention discloses a photochromic controllable permeable micromolecule cross-linked vesicle CSMVs and a preparation method and application thereof, belonging to the technical field of micromolecule self-assembly. The invention firstly synthesizes an azobenzene amphiphilic compound, and then the photochromic controllable permeable micromolecule cross-linked vesicle is prepared by further cross-linking. The invention establishes a controlled release system based on the cross-linked micromolecular vesicles through amphiphilic molecules consisting of photochromic azobenzene, the novel controlled release system is simple to prepare, has enhanced stability and intelligent control, shows real-time controllable permeability in time and space, and has wide application prospect in the precise treatment of diseases such as cancer, diabetes, bacterial infection and the like, because CSMVs (Carrier sense multiple molecules) present instantaneous controlled release in the molecular level due to the molecular structure of the vesicle wall compared with polymer vesicles.
Description
Technical Field
The invention belongs to the technical field of small molecule self-assembly, and particularly relates to a photochromic controllable permeable small molecule cross-linked vesicle and a preparation method and application thereof.
Background
Currently, precise therapy is prevalent in clinical practice because it can be used to target diseases accurately and effectively. The controlled release of the drug is essential for the precise delivery of the drug to the affected area, and particularly in the treatment of tumors, the precise treatment can effectively reduce the damage to healthy tissues and avoid the drug resistance generated by the body by controlling and rapidly releasing the drug, thereby achieving the effect of curing the patient with the minimum dose of the drug.
Block copolymer vesicles have received much attention as one of the first carriers for drug delivery. The vesicle is an important carrier for transporting drugs, and is widely applied to the treatment of various diseases. To promote vesicle permeability, a great deal of effort has been made, including the use of stimulus responsive polymers. By slight changes in the external environment, e.g. pH, CO2Temperature, reduction potential, light, etc. can trigger the controllable permeability of the vesicle. Among these stimuli, light can be applied to trigger points of controlled release, since it has the advantage of being most easily focused and controlled in time. However, a thicker hydrophobic layer in a polymersome also impairs its permeability, reducing permeability proportionally, which is proportional to the inverse of the membrane thickness. In addition, the presence of larger hydrophobic (macromolecular) segments slows response times. For precise treatment, it is urgently required that the vesicles instantaneously respond to external stimuli so as to rapidly release the drugs at the lesion site.
Disclosure of Invention
In order to solve the problems in the prior art, the invention firstly provides an azobenzene amphiphilic compound, which takes quaternary ammonium salt as a hydrophilic part and azobenzene as a hydrophobic part, and has the following structure:
furthermore, the critical vesicle concentration of the azobenzene amphiphilic compound is 30-55 mug/mL.
The invention further provides a preparation method of the azobenzene amphiphilic compound, and the synthetic route is as follows:
the invention further provides a photochromic controllable permeable small-molecule cross-linked vesicle, which is obtained by cross-linking the azobenzene amphiphilic compound.
The shell layer of the small molecular cross-linked vesicle is formed by cross arrangement of two azobenzene molecules.
Furthermore, the thickness of the shell layer of the small molecule cross-linked vesicle is 2.0-3.0 nm.
Furthermore, the double bonds of the small molecule monomers on the inner and outer surfaces of the small molecule cross-linked vesicle are fixed by covalent bonds
Wherein, the crosslinking agent structure adopted by crosslinking is as follows:
the invention further provides a preparation method of the photochromic controllable permeable micromolecule cross-linked vesicle, a cross-linking agent is added into the aqueous solution of the amphiphilic compound to obtain an optically clear solution, and a catalyst PPh is added3AuNTf2Dissolving in THF, adding into the above solution, keeping out of the sun, stirring at a certain temperature, dialyzing, and purifying to obtain CSMVs.
The invention has the beneficial effects that:
the invention provides a cross-linked small molecular vesicle (CSMVs) with light as a trigger to control permeability, wherein the main part of the vesicle is composed of azobenzene units, the units can be easily switched between a trans structure and a cis structure, and the vesicle has controllable permeability through polarity switching;
the release capacity of the CSMVs can be controlled by ultraviolet light/visible light irradiation, and the CSMVs have faster response time than the classical polymersomes, in vitro experiments show that the CSMVs have a response process to permeability, release the carried cysteamine, and reduce Reactive Oxygen Species (ROS) at both time and space levels, so that the CSMVs response light technology has wide application prospect in the accurate treatment of diseases such as cancer, diabetes, bacterial infection and the like;
the invention can establish a controlled release system based on the cross-linked small molecular vesicles through amphiphilic molecules consisting of photochromic azobenzene, the novel controlled release system has the advantages of simple preparation, enhanced stability and intelligent control, and shows real-time controllable permeability in time and space.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of compound 4-methylazobenzene;
FIG. 2 is a nuclear magnetic hydrogen spectrum of Compound 1;
FIG. 3 is a nuclear magnetic carbon spectrum of Compound 1;
FIG. 4 is a high resolution mass spectrum of Compound 1;
fig. 5 is a transmission electron microscope image and a particle size distribution of small molecule vesicles formed by compound 1 in an aqueous solution;
FIG. 6 shows Compound 1 in aqueous solution subjected to UV light (365nm,50mW cm)-2) Irradiating the uncrosslinked small molecular carrier for 4min to form (a) particle size distribution and (b) transmission electron microscope image;
FIG. 7 shows the visible light (530nm,0.5mW cm) of Compound 1-23min) forming transmission electron microscope images of the vesicles in the aqueous solution after irradiation;
FIG. 8 is a transmission electron microscope image and a particle size distribution of a CSMV (small molecule cross-linked vesicle);
FIG. 9 shows the CSMV-cross-linked vesicles in aqueous solution subjected to UV light (365nm,50mW cm)-2) Irradiating for 4min to obtain transmission electron microscope image and particle size distribution;
FIG. 10(a) is a controlled release profile at different UV exposure times, (b) is a chromogenic gel experiment in which a polyacrylamide gel (PAMG) was prepared in the presence of bromothymol blue (0.1mg/mL) and TEA @ CSMVs (3mg/mL), (c) is a 1 minute UV exposure of the PAMG gel and photographs were recorded at different time points, (d) is a photograph of the PAMG gel after exposure to different UV exposure times (0.5min, 1.5min, 2.5min, 3.5min, and 4.5min) and 8 min;
FIG. 11 is a fluorescent image of vesicles scavenging reactive oxygen species levels in human umbilical vein endothelial cells (a) the corresponding quantitative analysis of ROS levels by flow cytometry at different time points (left) 1min after UV irradiation (right); (b) standing for 8min (left) at different ultraviolet irradiation time intervals, and carrying out quantitative analysis on the corresponding ROS level by using a flow cytometer (right), wherein the scale bar is 20 mu m, (c) fluorescent images of the intracellular ROS level within 8min under different ultraviolet irradiation time, and the scale bar is 200 mu m.
Detailed Description
The materials and reagents used in the present invention were as follows:
p-toluidine, oxo ketone, aniline, Triethylamine (TEA), cysteamine (Cys), carbon tetrabromide, N-bromosuccinimide, (NBS), Azobisisobutyronitrile (AIBN), triallylamine, triethylene glycol, 2 ', 7' -dichlorodihydrofluorescein diacetate (DCFH-DA) cell counting kit-8 (CCK-8) was purchased from Tansula, Shanghai, China. [ bis (trifluoromethanesulfonylimide) ] (triphenylphosphine) gold (PPh3AuNTf2) was obtained from Qiangsheng, Beijing. All reagents were used without further purification unless otherwise indicated. All solvents were freshly distilled before use. Deionized water was used for all water experiments.
Example 1
In this example, amphiphilic micromolecules containing azobenzene were synthesized by the following synthetic route:
methyl-4-nitrosobenzene (compound 3): the ketoxime (1.598g,2.6mmol) was dissolved in water (40mL) and added to a solution of p-toluidine (0.139g,1.3mmol) in dichloromethane (10 mL). The reaction mixture was stirred vigorously for 1h until the organic phase turned green. Then extracted 3 times with 3X 40mL of dichloromethane and rinsed with 50mL of brine. The organic layer was dried (Na)2SO4) And concentrated to obtain a green solid nitrosotoluene.
(E) -1-phenyl-2- (p-toluene) diazene (compound 4): nitrosotoluene (0.145g,1.2mmol) was added to a solution of aniline (0.112g,1.2mmol) in acetic acid (40mL) and stirred at 25 ℃ for 24 h. Extracted 3 times with 3X 40mL of dichloromethane, then with 2X 50mL of water and 50mL of NaHCO3Washing with saturated aqueous solution. Organic phase in Na2SO4Drying, filtration and concentration gave (E) -1-phenyl-2- (p-toluene) diazoene as an orange crystalline solid (280mg, 45%). The product was not purified and used directly in the next step.1H NMR(400MHz,CDCl3,δ):7.75–7.84(m,J＝5.9Hz,2H),3.91(t,J＝5.8Hz,2H),3.61(t,J＝6.8Hz,2H),2.88(dd,J＝6.7Hz,4H),2.0(s,1H).
(E) -1- (4- (bromoethyl) phenyl) -2-benzodiazepine (compound 5): n-bromosuccinimide (1.869mg,10.5mmol) was added to a mixed solution of Azobisisobutyronitrile (AIBN) (189.6mg) and carbon tetrachloride of compound 4(1.96g,10mmol), reacted for 7 hours under reflux, filtered and concentrated to give compound 5 as a pale yellow solid. The product was not purified and used directly in the next step.
(E) -N, N-diallyl-N- (4- (benzodiazepinyl) benzyl) propen-2-en-1-ammonium bromide (compound 1): triallylamine (2.055g,15mmol) was added to a solution of compound 5(1.375g,5mmol) in acetone (10 mL). After 3 days at room temperature, the acetone was removed by rotary evaporation and the residue was purified by column chromatography on silica gel using CH2Cl2and/MeOH 20/1-10/1 as eluent to obtain yellow powder.1H NMR(400MHz,CDCl3,δ):7.90(t,6H),7.49–7.52(q,3H),6.07–6.15(m,3H),5.68–5.79(m,6H),5.20(s,2H),4.23(d,J＝8.0Hz,6H)。
This example synthesizes amphiphilic small molecules containing azobenzene with high yield,1H NMR、13the chemical structure of the amphiphilic small molecules is confirmed by C NMR and MS spectrum characterization, as shown in figures 1-4.
Example 2
Typical preparation of uncrosslinked small molecule vesicles: the amphiphilic small-molecule compound 1(10mg, 0.02mmol) obtained in example 1 was added to 2.0mL of deionized water, swirled at room temperature, and the resulting solution was allowed to stand, and the tyndall effect was observed, which indicates that small-molecule-based aggregates were formed, and the internal structure of the aggregates was studied by a fluorescence release experiment, confirming that the aggregates were vesicle structures, and spontaneously formed small-molecule vesicles that were not crosslinked within several minutes.
The size and morphology of these Small Molecule Vesicles (SMVs) were characterized by Dynamic Light Scattering (DLS) and Transmission Electron Microscopy (TEM), as shown in fig. 5, where spherical SMVs were about 100nm in diameter. Particles were not substantially detectable after 4.5min of uv irradiation, and the dissociation of the non-crosslinked vesicles was further confirmed by transmission electron microscopy, as shown in fig. 6. The isolated vesicles can be reassembled after 3min of visible light irradiation, as shown in fig. 7, with the azobenzene units converted back to trans.
Determination of Compound 1 Critical Vesicle Concentration (CVC) A series of vials were charged with a known amount of CH2Cl2Nile Red in (1), then evaporating CH2Cl2. The amount is selected so that the nile red concentration in the final solution is 1 × 10-6And M. A measured amount of 1 solution was added to each vial and deionized water was added to the vial to give a concentration of 2.4X 10 for Compound 1-4Between 1.28 mM. The intensity of fluorescence emission at 575nm (485nm excitation) was measured with shaking overnight at room temperature. The critical concentration of aggregation is obtained from the intersection of the tangents to the two linear portions of the fluorescence intensity map.
Example 3
In this example, the cross-linking agent for preparing vesicles from the azobenzene amphipathic compound was synthesized by the following synthetic route:
1, 2-bis (2-bromoethoxy) ethane: triethylene glycol (1.5g, 10mmol) is added to 20mL of anhydrous dichloromethane, phosphorus tribromide (8.1g, 30mmol) is added dropwise, the mixture is refluxed and stirred for 24h, then the mixture is diluted with 40mL of dichloromethane and saturated NaHCO3Neutralizing with water solution. The organic phase was washed with brine and dried over anhydrous MgSO 4. The solvent was removed under vacuum and purified by column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give 1, 2-bis (2-bromoethoxy) ethane butter (1.9g, 69%).1H NMR(CDCl3,400MHz):δ3.44(t,J＝1.2Hz,4H),3.65(s,4H),3.79(t,J＝1.2Hz,4H).
Crosslinker (compound 2 in the above synthetic route): 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 1M hydrogen hydroxideSodium solution (2020 mL) was added and refluxing continued for 2 h. The aqueous layer was separated with 2.0M dilute hydrochloric acid and acidified (pH 1), and the acidic solution was then extracted with petroleum ether (3 × 30 ml). The organic phases were combined, washed with brine, over anhydrous MgSO4And drying. The solvent was removed under vacuum and purified by column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give compound 2 as a colourless oil (156mg, 85.7%).1H NMR(CDCl3,400MHz):δ1.56(t,J＝1.6Hz,2H),2.66-2.72(m,4H),3.60-3.63(m,8H).
Example 4
This example synthesizes photochromic controlled permeation small molecule cross-linked vesicles by adding cross-linking agent (5.4mg,0.03mmol) to compound 1(10.0mg,0.02mmol) in H2O (2.5mL) solution. The mixture was shaken by hand at room temperature and sonicated for 2 minutes to give an optically clear solution. 0.08 equivalent of catalyst PPh3AuNTf2Dissolved in THF, and added to the solution, the volume of THF is less than 2.5% of the volume of the solution. Protected from light and stirred at 100rpm for 20h at 40 ℃. After dialysis for 48h, the nanoparticles were purified to obtain SCMVs, which were then lyophilized.
The size and morphology of these small molecule cross-linked vesicles (CSMVs) were characterized by Dynamic Light Scattering (DLS) and Transmission Electron Microscopy (TEM), as shown in fig. 8, the spherical morphology of the cross-linked vesicles did not change, while the size of the vesicles was only slightly reduced, compared to the non-cross-linked Small Molecule Vesicles (SMVs). Further analysis showed that the shell thickness was in the order of 2.0-3.0nm, which is consistent with the theoretical length of the cross arrangement of two molecules. After 4min of uv irradiation, there was little change in the size and morphology of CSMVs due to the covalent cross-linking fixing the structure, as shown in fig. 9, whereas essentially all trans-azobenzene species converted to the cis state.
Example 5
Controlled release testing of CSMVs of the invention: hydrophilic Triethylamine (TEA) is used as a model drug, the TEA @ CSMVs are pre-encapsulated in vesicles to obtain TEA @ CSMVs, the accumulated release amount of the TEA @ CSMVs is measured under the stimulation of external ultraviolet light or visible light, as shown in figure 10a, the permeation amount of the model drug in the CSMVs is less than 2% under the condition of no ultraviolet irradiation within 160min, the permeability of the model drug is poor, about 40% of TEA is released from the vesicles when the model drug is placed in the dark for 160min after the stimulation of the ultraviolet light is performed for 1min, and the release rate can reach nearly 100% after the model drug is placed in the dark for 160min after the ultraviolet irradiation is performed for 4 min.
To analyze the spatiotemporal controlled release of CSMVs, a stained gel experiment was performed and, as shown in fig. 10b, a polyacrylamide gel (PAMG) containing Bromothymol Blue (BB) and TEA @ CSMVs was prepared. The gel appeared uniformly yellow before uv irradiation (fig. 10 c). After 1min of uv irradiation, a slight blue color was observed outside the covered area when the sample was left in the dark for 16 min. The blue color gradually darkened with the increase of the dark treatment time, and the dark blue color appeared after 128min, indicating that the release of TEA under light stimulation is controllable and continuous. BB is a well-known pH indicator that reacts in an alkaline environment to appear blue. TEA was sealed in the CSMVs in the vesicle cavity before uv irradiation, and the PAMG gel showed an original yellow color. Under uv light, the "gate" of TEA @ CSMVs opens due to the trans-cis transition of azobenzene. The release of TEA provides an alkaline environment, triggering a color change in BB, which appears blue in the irradiated space. As the time of processing in the dark increases, the "gate" remains open and TEA is continuously discharged. These observations confirm the cumulative release results shown in figure 10 a.
Example 6
Evaluation of the in vitro permeability of CSMVs to scavenge active oxygen according to the invention: in the organism, low concentrations of Reactive Oxygen Species (ROS) play a crucial role in regulating physiological functions. However, once the production of ROS exceeds a critical level, oxidative damage may be caused to intracellular biomolecules. This damage may lead to diseases such as cancer, atherosclerosis, diabetes and arthritis that inhibit the excess production of ROS effectively in time and space to help maintain normal physiological metabolism. It is known that Cysteamine (CS) is widely present in the body, has a strong antioxidant ability, and can inhibit the production of excessive ROS. Therefore, encapsulation of CS in CSMVs (CS @ CSMVs) and evaluation of its performance based on the decay of ROS based on the time and space controlled release of our proposed vesicle system, particularly as demonstrated by the experiment of vesicle controlled release of CS in human umbilical vein endothelial cells, the results of the test are shown in fig. 11, demonstrating that CSMVs can be applied to rapidly scavenge ROS in vitro.
After addition of CS @ CSMVs and irradiation with UV light for 1.0min, the cell fluorescence intensity gradually decreased with increasing dark treatment time (FIGS. 11a and b). After a period of release within 128min, the fluorescence intensity was as low as that observed for normal cells. This restoration of normal ROS concentration is due to the gradual release of CS to reduce ROS after uv irradiation.
CS @ CSMVs was UV-irradiated for 0.5min, and after 8min, the "door" was closed by visible light irradiation, and the fluorescence intensity decreased 20% from the initial state (FIG. 11 c). Excess ROS may be partially offset by redox reactions when uv light triggers the "gate" to open and release CS. As the uv light irradiation time was further extended, the fluorescence was observed to be weakened. After the ultraviolet light is irradiated for 3.5min, the fluorescence signal basically disappears. Quantitative results show that in this case the fluorescence intensity (ROS) is reduced by more than 95%, reducing the ROS concentration to the level of normal cells. This suggests that our system is capable of efficiently scavenging intracellular ROS. The above results indicate that CS @ CSMVs can control the transient release of CS in time in vitro to combat ROS.
The foregoing is a more detailed description of the invention in connection with specific/preferred embodiments and is not intended to limit the practice of the invention to those descriptions. Several alternatives or modifications to the described embodiments may be made without departing from the inventive concept and such alternatives or modifications should be considered as falling within the scope of the present invention.
Claims (7)
1. An azobenzene amphiphilic compound, which is characterized in that: quaternary ammonium salt is used as a hydrophilic part, azobenzene is used as a hydrophobic part, and the structure is as follows
2. The azobenzene amphiphilic compound according to claim 1, wherein: the critical vesicle concentration of the azobenzene amphiphilic compound is 30-55 mug/mL.
3. A process for the preparation of azobenzene amphiphile compounds as claimed in claim 1 or 2, characterized in that the synthetic route is as follows:
4. a photochromic controllable permeable small-molecule cross-linked vesicle is characterized in that: the small molecule cross-linked vesicle is obtained by cross-linking the azobenzene amphiphilic compound of claim 1 or 2; the crosslinking agent structure adopted by the crosslinking is as follows:
5. the photochromic controlled permeation small molecule cross-linked vesicle according to claim 4, wherein: the shell layer of the small molecular cross-linked vesicle is formed by cross arrangement of two azobenzene molecules.
6. The photochromic controlled permeation small molecule cross-linked vesicle according to claim 4, wherein: the thickness of the shell layer of the small molecule cross-vesicle is 2.0-3.0 nm.
7. The preparation method of the photochromic controlled-permeability small-molecule cross-linked vesicle according to any one of claims 4 to 6, wherein: adding a cross-linking agent to an aqueous solution of an amphiphilic compound according to claim 1 or 2 to obtain an optically clear solution, and adding the catalyst PPh3AuNTf2Dissolving in THF, adding into the above solution, stirring at a certain temperature in the dark, dialyzing, and purifyingCSMVs were prepared.
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