CN115746033B - Catechol modification-based aza-BODIPY, nanoparticle formed by complexing catechol modification-based aza-BODIPY with iron ions, and biological application of nanoparticle - Google Patents
Catechol modification-based aza-BODIPY, nanoparticle formed by complexing catechol modification-based aza-BODIPY with iron ions, and biological application of nanoparticle Download PDFInfo
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- CN115746033B CN115746033B CN202211104427.7A CN202211104427A CN115746033B CN 115746033 B CN115746033 B CN 115746033B CN 202211104427 A CN202211104427 A CN 202211104427A CN 115746033 B CN115746033 B CN 115746033B
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- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 43
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 title claims abstract description 26
- -1 iron ions Chemical class 0.000 title claims abstract description 24
- 229910052742 iron Inorganic materials 0.000 title claims abstract description 21
- 230000000536 complexating effect Effects 0.000 title claims abstract description 14
- 230000004048 modification Effects 0.000 title claims abstract description 13
- 238000012986 modification Methods 0.000 title claims abstract description 13
- 229910052751 metal Inorganic materials 0.000 claims abstract description 16
- 239000002184 metal Substances 0.000 claims abstract description 16
- 239000000126 substance Substances 0.000 claims abstract description 15
- 238000011282 treatment Methods 0.000 claims abstract description 15
- 150000004696 coordination complex Chemical class 0.000 claims abstract description 13
- 229920001992 poloxamer 407 Polymers 0.000 claims abstract description 7
- 239000003504 photosensitizing agent Substances 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 9
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 238000000502 dialysis Methods 0.000 claims description 8
- 239000004721 Polyphenylene oxide Substances 0.000 claims description 6
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- 239000003054 catalyst Substances 0.000 claims description 4
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- 229910021641 deionized water Inorganic materials 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 238000009210 therapy by ultrasound Methods 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
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- 238000005481 NMR spectroscopy Methods 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
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- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
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- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
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- NQXWGWZJXJUMQB-UHFFFAOYSA-K iron trichloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].Cl[Fe+]Cl NQXWGWZJXJUMQB-UHFFFAOYSA-K 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
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- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 239000012028 Fenton's reagent Substances 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical class [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
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- 210000004204 blood vessel Anatomy 0.000 description 1
- DEGAKNSWVGKMLS-UHFFFAOYSA-N calcein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(CN(CC(O)=O)CC(O)=O)=C(O)C=C1OC1=C2C=C(CN(CC(O)=O)CC(=O)O)C(O)=C1 DEGAKNSWVGKMLS-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 230000001659 chemokinetic effect Effects 0.000 description 1
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- 229910052802 copper Inorganic materials 0.000 description 1
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- 238000013461 design Methods 0.000 description 1
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- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- MGZTXXNFBIUONY-UHFFFAOYSA-N hydrogen peroxide;iron(2+);sulfuric acid Chemical compound [Fe+2].OO.OS(O)(=O)=O MGZTXXNFBIUONY-UHFFFAOYSA-N 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
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- 229910021645 metal ion Inorganic materials 0.000 description 1
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- 239000011733 molybdenum Substances 0.000 description 1
- 229960002378 oftasceine Drugs 0.000 description 1
- 239000013110 organic ligand Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000002428 photodynamic therapy Methods 0.000 description 1
- 238000001126 phototherapy Methods 0.000 description 1
- 239000012221 photothermal agent Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
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- 238000000746 purification Methods 0.000 description 1
- BJDYCCHRZIFCGN-UHFFFAOYSA-N pyridin-1-ium;iodide Chemical compound I.C1=CC=NC=C1 BJDYCCHRZIFCGN-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an aza-BODIPY modified based on catechol, a nanoparticle formed by complexing the aza-BODIPY and iron ions, and biological application thereof. The catechol modified aza-BODIPY is complexed with iron ions to obtain the nanoparticle ABFe NPs based on the metal coordination complex under the wrapping modification of pluronic F127. The nano-particle ABFe NPs can be used as photosensitizer and can be applied to biological imaging guided treatment. The nanoparticle has the capacity of near infrared two-region absorption, the win-win chemical kinetics/photo-thermal combined treatment effect, and good biocompatibility and strong phototoxicity are shown in vitro.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and relates to an aza-BODIPY modified based on catechol, a nanoparticle formed by complexing the aza-BODIPY with iron ions, and biological application of the nanoparticle.
Background
Tumor microenvironment (tumor microenvironment, TEM) is the internal environment in which tumors develop and develop, and is a complex integrated system that appears as slightly acidic, hypoxic, incomplete blood vessels, over-expressing hydrogen peroxide, and the like. Studies have shown that tumor development, progression and metastasis are closely related to TEM, and thus improving or utilizing TEM characteristics can control or inhibit tumor growth and metastasis.
Chemical kinetic therapy (chemodynamic therapy, CDT) is a method of using Fenton's reactionExcessive H generated in TEM by reaction of Fenton-like reaction 2 O 2 The novel anti-tumor strategy converted into hydroxyl free radical (OH) has the advantages of selectivity and activation of endogenous substances, and is not limited by tumor hypoxia, depth of penetration of external field and the like similar to photodynamic therapy. Common Fenton reaction catalysts are inorganic nanocrystals, including iron, manganese, copper, molybdenum, and the like. However, since CDT active oxygen production is not efficient and is limited in tumor treatment, enhancing the catalytic rate of the Fenton reaction is important for improving the anti-tumor efficiency of CDT. Heating is one of the methods of increasing the Fenton reaction rate, so increasing the local temperature of the tumor region can accelerate HO. Generation. Photothermal therapy is just a treatment method for using a photothermal agent to convert light energy into heat to destroy cells, and has the advantages of low cost, good specificity, small side effects on normal tissues and the like. Similar reports are more common for inorganic nanocrystals, and nano-coordination compounds/polymers formed by complexing organic ligands with metal ions can achieve similar effects, but most research is focused on NIR-I. NIR-II can achieve a stronger tissue penetration depth due to low tissue background and less photon scattering than NIR-I, and maximum allowable exposure (1.0W/cm) 2 ) Higher. Thus, the discovery of NIR-II absorbing organo-metallic Fenton's reagent is of great interest for photothermal/chemokinetic synergistic treatment.
Disclosure of Invention
The first object of the present invention is to address the deficiencies of the prior art by providing a catechol modified aza-BODIPY (azaborodipyrrole) based molecule ABOH that incorporates ortho-diphenol capable of complexing with iron ions, whereas the introduction of iron ions induces a ligand-metal electron transfer effect, extending the absorption range of the resulting nanoparticle ABFe NPs after complexing with iron ions to NIR-II.
The chemical structural formula is as follows:
the second object of the present invention is to provide a method for synthesizing the above-mentioned catechol-modified aza-BODIPY compound ABOH, comprising the steps of:
adding the compound ABOMe into a dry reaction container under the protection of nitrogen, adding anhydrous dichloromethane for dissolution, cooling for a period of time at low temperature, dripping an acidic demethylating reagent for reaction for a period of time, transferring to normal temperature for reaction until the reaction is finished, and performing post-treatment to obtain the compound ABOH.
The synthetic route is as follows:
preferably, the ratio of the amounts of substances of the compounds ABOMe, boron tribromide is 1:10 to 30, more preferably 1:20, a step of;
preferably, the low temperature is-78 ℃;
preferably, the acidic demethylating agent is selected from boron tribromide, aluminum trichloride, hydrobromic acid, sulfuric acid and the like, and more preferably boron tribromide;
preferably, the post-treatment method comprises the following steps: the methylene dichloride solvent is removed from the reactant, the ethyl acetate and the water mixed solvent with the volume ratio of 1:1 are added and stirred for 1 hour, the ethyl acetate is removed, and a black crude product is obtained through suction filtration, and then the volume ratio is 20:1, separating and purifying by a silica gel chromatographic column to obtain the compound ABOH.
It is a third object of the present invention to provide the above water-soluble nanoparticle based on complexing of catechol-modified aza-BODIPY compound ABOH with iron ions.
Preferably, the molar ratio of the catechol modification-based aza-BODIPY compound ABOH to iron ions is 1:0.5 to 2, more preferably 1:1.
a fourth object of the present invention is to provide a method for synthesizing the above water-soluble nanoparticle, comprising the steps of:
(1) Dissolving an aza-BODIPY compound ABOH and FeCl3.6H2O modified by catechol in an N, N-dimethylformamide solution, dropwise adding a catalyst triethylamine, and stirring for 1-3 hours at room temperature to obtain a metal coordination complex; adding the metal coordination complex into deionized water under stirring, dispersing by stirring, then placing into a dialysis bag, and dialyzing in water;
(2) Dropping polyether pluronic F127 water solution into the dialyzed solution under ultrasonic treatment, stirring for a period of time, and treating to obtain nano-particles ABFe NPs; wherein the mass ratio of the metal coordination complex to the polyether pluronic F127 is 1:2 to 3.
Specifically, ABOH and FeCl 3 ·6H 2 O is dissolved in N, N-dimethylformamide solution, and triethylamine as a catalyst is added dropwise for complexing; dialysis is performed after complexation is completed, and the function of the dialysis is to make uncomplexed ABOH and FeCl 3 ·6H 2 O was removed, and thus, a dialysis bag having a molecular weight of 3500 was selected, stirred at room temperature for 24 hours under aeration, and then the mixture was passed through a 0.22 μm aqueous filter, frozen, and concentrated to a solid powder under low temperature and low pressure conditions.
It is a fifth object of the present invention to provide the use of water-soluble nanoparticles based on catechol functionalized aza-BODIPY coordinated with metal of iron ions as photosensitizers in bioimaging and therapy.
The beneficial effects of the invention are as follows:
according to the invention, by introducing catechol groups, the aza-BODIPY compound ABOH capable of complexing with iron ions is designed and synthesized. The absorption range of the water-soluble nano particle ABFeNPs formed by coordination of the catechol modified aza-BODIPY compound ABOH and metal of iron ions reaches a near infrared two-region, and the water-soluble nano particle ABFeNPs has excellent photothermal conversion capability and chemical kinetics treatment effect, so that the water-soluble nano particle ABFeNPs can be used as a photosensitizer for biological imaging and treatment. In vitro experiments, water-soluble nanoparticles ABFeNPs show good biocompatibility and strong phototoxicity.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of the compound ABOH synthesized in example one (deuterated dimethyl sulfoxide as solvent).
FIG. 2 is a nuclear magnetic resonance fluorine spectrum of the compound ABOH synthesized in example one (deuterated dimethyl sulfoxide as solvent).
FIG. 3 is a liquid-phase mass spectrum of the compound ABOH synthesized in example one.
FIG. 4 is a compound structural formula of the compound ABOH synthesized in example one.
FIG. 5 is an optical property of ABFe nanoparticles; wherein (a) ABOH, ABOHNPs, ABFe and ABFeNPs; (b) fluorescence emission spectra of ABOH and ABOHNPs; (c) In DMF solution, fe 3+ Ultraviolet absorption spectrum after gradually adding into ABOH solution; (d) Absorption intensity at 730nm with Fe 3+ Concentration graph.
FIG. 6 is an in vitro photo-thermal property of ABFe nanoparticles; wherein (a) the temperature of different concentrations of ABFe NPs changes under 1064nm laser (1.0W/cm 2) irradiation; (b) Temperature change of 30 mug/mL ABFe NPs under different power laser irradiation; (c) temperature change of ABFe NPs in laser on/off cycle; (d) ABFe NPs versus temperature change and time versus ln (θ) for water-light cooling processes.
FIG. 7 is an in vitro chemical kinetic characterization of ABFe nanoparticles.
FIG. 8 shows the in vitro photothermal therapeutic effect of ABFe nanoparticles (4T 1 cells); wherein (a) is cell viability after co-incubation with different concentrations of ABFe NPs; (b) After different medicines are treated, detecting the generation of ROS in cells by taking DCFH-DA as a fluorescent probe; (c) Live/dead staining of 4T1 cells under different drug and condition treatments.
Detailed Description
As described above, in view of the shortcomings of the prior art, the present inventors have long studied and practiced in a large number of ways, and have proposed the technical solution of the present invention, which is based on at least: (1) Introducing o-diphenol into the molecule to complex with iron ions, wherein the introduction of the iron ions induces ligand-metal electron transfer effect, so that the absorption range of the ABFe NPs is extended to NIR-II; (2) Catalysis of H by Fenton reaction 2 O 2 Generating hydroxyl free radicals which have killing effect on tumor cells; and can realize higher photo-thermal conversion efficiency through reasonable molecular design; meanwhile, under the photo-thermal stimulation, the Fenton reaction rate can be accelerated, and the win-win conversion is realizedThe effect of the combination of pharmacokinetics and photo-thermal treatment.
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention. In addition, the technical features of the embodiments of the present invention described below may be combined with each other as long as they do not collide with each other.
In a first aspect, there is provided ABOH having iron ion complexing ability based on catechol modification, which is synthesized by the route:
compound ABOMe was added to a dry two-necked flask under nitrogen blanket and dissolved by adding anhydrous dichloromethane. After the reaction flask was cooled in a low-temperature bath at-78 ℃ for 10 minutes, an acidic demethylating reagent was slowly added dropwise, and after 10 minutes, the reaction flask was transferred to room temperature for reaction for 2 hours. After the reaction is finished, the compound ABOH is obtained through post-treatment. The ratio of the amounts of substances of the compound ABOMe and the boron tribromide is 1:20, a step of;
the acidic demethylating agent can be boron tribromide, aluminum trichloride, hydrobromic acid, sulfuric acid and the like.
Preferably, the post-treatment method comprises the following steps: after the methylene chloride solvent was removed from the reaction mixture, the mixture was stirred with a mixed solvent (ethyl acetate/water, 1/1, v/v) for 1 hour, ethyl acetate was removed, and a black crude product was obtained by suction filtration, followed by a volume ratio of methylene chloride to methanol of 20: and 1, using the mixed solution as an eluent, and separating and purifying by a silica gel chromatographic column to obtain the compound ABOH.
In a second aspect, the water-soluble nanoparticle based on complexing catechol-modified ABOH with iron ions is synthesized by the following steps:
(1) ABOH and FeCl 3 ·6H 2 O is dissolved in N, N-dimethylformamide, and triethylamine as catalyst is added dropwise, and the mixture is stirred for 1 to 3 hours at room temperature to obtain a metal compoundA bit complex; after the complexation is completed, the metal coordination complex is added to deionized water under stirring, and stirred for 2 hours for dispersion. Then put into a dialysis bag with molecular weight of 3500, and dialyzed in water.
(2) The metal coordination complex is physically encapsulated in order to improve stability of the complex. Under the ultrasonic treatment, an aqueous solution of polyether pluronic F127 is dropped into the dialyzed solution. After stirring for 24 hours at room temperature by ventilation, the mixture was further frozen by passing through a 0.22 μm aqueous filter and concentrated to black dry solid nanoparticles ABFe NPs under low temperature and low pressure conditions.
The compounds ABOH and FeCl 3 ·6H 2 The ratio of O is 1:0.5-2.
The mass ratio of the metal coordination complex to F127 is 1:2 to 3.
The following description of the present invention is further provided with reference to several preferred embodiments, but the experimental conditions and setting parameters should not be construed as limiting the basic technical scheme of the present invention. And the scope of the present invention is not limited to the following examples.
Embodiment one: preparation of ABOH having iron ion complexing ability based on catechol modification
Step (1) -preparation of compound ABOH:
compound ABOMe (100.0 mg,0.16 mmol) was added to a dry two-necked flask and dissolved by adding 25mL of anhydrous dichloromethane under nitrogen. After the reaction flask was cooled in a low-temperature bath at-78℃for 10 minutes, boron tribromide (3.2 mL,3.2 mmol) was slowly added dropwise, and after 10 minutes the reaction flask was transferred to room temperature for 2 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure by a rotary evaporator, and the mixed solvent (ethyl acetate/water, 1/1, v/v) was added and stirred for 1 hour. Ethyl acetate was removed by rotary evaporator and filtered to give a black crude product. Purification by column chromatography (eluent dichloromethane/methanol, 20/1, v/v) afforded black compound ABOH (5 g, 5%).
As shown in fig. 1-3: 1 H NMR(500MHz,DMSO-d 6 ,298K)δ(ppm):10.03(s,2H),9.33(s,2H),8.15(d,J＝7.3Hz,4H),7.65(d,J＝2.1Hz,2H),7.59(dd,J＝8.5,2.2Hz,2H),7.54–7.41(m,8H),6.90(d,J＝8.4Hz,2H). 19 F NMR(471MHz,DMSO-d 6 ,298K)δ(ppm):-129.81(dd,J＝64.7,32.1Hz,BF 2 ).ESI-HRMS[M+Na] + :calcd.for[C 32 H 22 BF 2 N 3 NaO 4 ] + 584.1569,found 584.1572. The structural formula of ABOH is shown in FIG. 4, and single crystal data is shown in Table 1.
Single crystal data for compound ABOH of table 1
Embodiment two: preparation of ABFe nanoparticles
(1) ABOH (8.0 mg,0.014 mmol) and FeCl3.6H2O (4.0 mg,0.014 mmol) were dissolved in 2.5mL of N, N-dimethylformamide, 35. Mu.L of triethylamine was added dropwise, and the mixture was stirred at room temperature for 2 hours to obtain a metal complex. After the complexation was completed, the mixture was slowly added dropwise to rapidly stirred deionized water (25 mL) and stirred for 2 hours for dispersion. After this, the solution was placed in a dialysis bag having a molecular weight of 3500, and dialysis was performed in water.
(2) The metal coordination complex is physically encapsulated in order to improve stability of the complex. An aqueous solution of polyether pluronic F127 (34 mg) was dropped into the dialyzed solution under ultrasonic treatment. And freeze-drying the obtained nanoparticle solution by using a freeze dryer to obtain black dry solid.
Embodiment III: optical Properties of ABFe nanoparticles
Slowly dropwise adding Fe into ABOH solution (30 mu M) 3+ Solution, using ultraviolet spectrophotometer to make ABOH and Fe 3+ The complexation behavior between them was characterized. With Fe 3+ The absorption peak type of the mixture is changed, and the difference of the absorption spectrum of the ABFe and the ABOH is proved to be caused by metal organic coordination. After F127 physical encapsulation, the absorption peaks of the ABFe NPs are mainly about 610nm and 800nm, and the absorption range is further expanded compared with ABFe. And because of the addition of Fe3+, the fluorescence intensity of ABFe and ABFe NPs is weakened, which cannot be detected. The results are shown in FIG. 5.
Embodiment four: in vitro photo-thermal properties of ABFe nanoparticles
1mL of the nanoparticle solution prepared in example two was placed in a 1.5mL centrifuge tube, and nanoparticle aqueous solutions of different concentrations were irradiated with 1064nm laser having a laser power density of 1.0W/cm 2 Photothermal images and temperatures of the solutions were recorded. The same concentration of nanoparticle aqueous solution (30. Mu.g/mL) was irradiated with different power lasers and the photothermal image and temperature of the solution were recorded. The aqueous nanoparticle solution (30. Mu.g/mL) was irradiated with a laser and the temperature change of the solution over 5 radiation cooling cycles was measured to detect photostability. Under 1064nm laser irradiation, the photo-thermal conversion efficiency of the nanoparticle aqueous solution (30 mug/mL) was calculated to be 55.0% by measuring the temperature change of the nanoparticle aqueous solution and the water illumination cooling process.
As shown in fig. 6: it was observed that the temperature rise of the solution was positively correlated with the laser power and concentration, and exhibited good photo-stability and photo-thermal conversion efficiency.
Fifth embodiment: in vitro chemical kinetics characterization of ABFe nanoparticles
To verify that the metal complex ABFe NPs can catalyze the generation of active oxygen by the fenton reaction, 5-dimethyl-1-pyrroline-N-oxide (DMPO) was used as a radical scavenger, detected by electron spin resonance spectroscopy, and analyzed by the cwresr software.
As shown in fig. 7: in ABFe NPs-H 2 O 2 In the system, hydroxyl adducts (DMPO-OH) and superoxide adducts (DMPO-OOH) were detected, whereas in ABFe-only NPs or H 2 O 2 In the absence of any signal, it was demonstrated that hydrogen peroxide can be converted into hydroxyl radicals (. OH) or superoxide anion radicals (O) under the catalysis of ABFe NPs 2 ·- )。
Example six: in vitro phototherapy effect of ABFe nanoparticles
The photothermal effect of ABFe NPs on cells was detected using MTT method. 4T1 or 293T cells were seeded in 96-well plates at a density of 1X 104 cells per well, a light combined dark group was set, incubated for 24 hours, and then incubated with different concentrations of ABFe NPs (10, 20, 30, 40, 50. Mu.g/mL) for 24 hours. Wherein the light group was subjected to light (1064 nm,1.0W/cm2,1 min) after 4 hours of incubation with the added material, and then the incubation was continued for 20 hours. Next, MTT solution (0.5 mg mL) -1 ) Incubation was performed in replacement medium, after 4 hours, with 100 μl of dimethyl sulfoxide per well. Spectrophotometric measurements were performed on ELISA readers (model 550, bio-Rad) at 570 nm. Untreated cells were used as a 100% viable cell control and water treated cells were used as a fully dead cell control. Cell viability was calculated from absorbance.
In addition, the conditions of generating active oxygen in cells by ABFe NPs were investigated by using DCFH-DA as a fluorescent probe. 4T1 cells were seeded in 24-well plates at a density of 1X 104 cells per well, and a light-combined dark control was set and cultured for 24 hours. The medium was aspirated from each well, and materials ABFe NPs (30. Mu.g/mL), H were added 2 O 2 (50. Mu.M) or ABFe+H 2 O 2 Incubate for 24 hours. Washed twice with DMEM, added 500. Mu.L of 10. Mu.M DCFH-DA solution and incubated at 37℃for 30 minutes. The DCFH-DA solution was removed and washed twice with DMEM, and 500. Mu.L of DMEM solution was added to each well. The illumination group was illuminated (1064 nm, 1.0W/cm) 2 5 min), and one well was set as a positive control group for active oxygen as a reference. The light was terminated and observed by CLSM after 30 minutes of addition with active oxygen positive control group.
Then, living and dead cells are stained, which can more intuitively prove the in vitro photothermal treatment effect of the nano particles, and the 4T1 cells are 1 multiplied by 10 per hole 4 Density of individuals in 24-well plates, light and dark control groups were set and incubated for 24 hours. Adding material ABFe NPs (30 mug/mL) and H 2 O 2 (50. Mu.M) or ABFe+H 2 O 2 Incubate for 24 hours. The light group was subjected to light (1064 nm, 1.0W/cm) 2 5 min) and then incubation was continued for 20 hours. Next, the culture solution was removed. Washing gently with PBS, addingStaining working solution (pyridine iodide and calcein) was incubated for 30-45 min at room temperature. The working fluid was aspirated, washed with PBS and observed through CLSM.
As shown in fig. 8: with increasing nanoparticle concentration, cell viability remained above 90%. After the laser irradiation treatment, the cell viability was significantly reduced, and at a concentration of 50. Mu.g/mL, the cell viability was less than 20%. The above results demonstrate that ABFe NPs have good biocompatibility and excellent cell killing ability. And ABFe NPs+H 2 O 2 The +laser group observed a clear green fluorescence, indicating an efficient generation of active oxygen, embodying a photo-thermal enhanced chemical kinetics. In the dead-living staining pattern, H can be observed 2 O 2 Group, ABFe group, H 2 O 2 The +Laser groups all have bright green fluorescence, show higher cell survival rate, and ABFe+H 2 O 2 The group and abfe+laser group had partial cell death, and the damage of the cell by the chemical kinetics and photothermal effects were verified, respectively. Abfe+h 2 O 2 The highest apoptosis rate of +laser group demonstrates an effective synergy of chemical kinetics and photothermal therapy.
Claims (5)
1. The application of water-soluble nano particles in preparing a chemical kinetics-photo-thermal combination treatment photosensitizer is characterized in that the water-soluble nano particles are formed by complexing an aza-BODIPY compound based on catechol modification with iron ions; the chemical structural formula of the catechol modification-based aza-BODIPY compound is as follows:
the water-soluble nano particles are prepared by the following steps:
(1) The catechol modification-based aza-BODIPY compound and FeCl 3 ·6H 2 O is dissolved in N, N-dimethylformamide solution, triethylamine as a catalyst is added dropwise, and the mixture is stirred for 1 to 3 hours at room temperature to obtain a metal coordination complex; stirring the metalAdding the coordination complex into deionized water, dispersing by stirring, then placing into a dialysis bag, and dialyzing in water;
(2) Dropping polyether pluronic F127 water solution into the dialyzed solution under ultrasonic treatment, stirring for a period of time, and treating to obtain nano-particles ABFe NPs; wherein the mass ratio of the metal coordination complex to the polyether pluronic F127 is 1:2 to 3.
2. Use according to claim 1, characterized in that the molar ratio of the catechol-modified aza-BODIPY-based compound to the iron ion is 1:0.5-2.
3. The use according to claim 1, wherein the catechol modification-based aza-BODIPY compound is synthesized by:
adding compound ABOMe into dry reaction vessel under nitrogen protection, adding anhydrous dichloromethane for dissolving, cooling at low temperature for a period of time, and dropwise adding BBr 3 After the reaction is carried out for a period of time, the reaction is carried out at normal temperature until the reaction is finished, and the Aza-BODIPY compound ABOH based on catechol modification is obtained through post-treatment;
the synthetic route is as follows:
4. use according to claim 3, characterized in that the ratio of the amounts of substances of the compounds ABOMe and boron tribromide is 1:10 to 30 percent.
5. The use according to claim 3, wherein the post-processing is performed by: the methylene dichloride solvent is removed from the reactant, the ethyl acetate and the water mixed solvent with the volume ratio of 1:1 are added and stirred for 1 hour, the ethyl acetate is removed, and a black crude product is obtained through suction filtration, and then the volume ratio is 20:1 as eluent, and separating and purifying by a silica gel chromatographic column to obtain the catechol modified aza-BODIPY compound.
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| CN111234256A (en) * | 2020-03-13 | 2020-06-05 | 南京基树医药科技有限公司 | Hydrogen peroxide responsive metal-polyphenol coordination polymer nanoparticle and preparation method and application thereof |
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