CN116874502A - Activated near infrared two-region fluorescent probe and preparation method and application thereof - Google Patents
Activated near infrared two-region fluorescent probe and preparation method and application thereof Download PDFInfo
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- CN116874502A CN116874502A CN202310846351.3A CN202310846351A CN116874502A CN 116874502 A CN116874502 A CN 116874502A CN 202310846351 A CN202310846351 A CN 202310846351A CN 116874502 A CN116874502 A CN 116874502A
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- fluorescent probe
- near infrared
- region
- activated near
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1074—Heterocyclic compounds characterised by ligands containing more than three nitrogen atoms as heteroatoms
- C09K2211/1081—Heterocyclic compounds characterised by ligands containing more than three nitrogen atoms as heteroatoms with sulfur
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1092—Heterocyclic compounds characterised by ligands containing sulfur as the only heteroatom
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1096—Heterocyclic compounds characterised by ligands containing other heteroatoms
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
- G01N2021/6432—Quenching
Abstract
The application belongs to the technical field of biological medicines, and relates to an activated near infrared two-region fluorescent probe and a preparation method and application thereof. Performing Suzuki coupling reaction on the intermediate a and alkoxy substituted aryl boric acid under the action of a palladium catalyst and a first base to obtain an intermediate b; intermediate b at BBr 3 Under the action of (2), carrying out demethylation reaction to obtain an intermediate c; and (3) performing condensation reaction on the intermediate c and the response structure compound under the action of second alkali to obtain the activated near infrared two-region fluorescent probe I. The donor-acceptor in the activated near infrared two-region fluorescent probeThe fluorophore skeleton can increase the light stability of the probe, has higher optical activity, and the fluorescence intensity of the probe after response is increased along with the concentration, so that the optical brightness is obviously improved. The activated small molecule near infrared two-region optical probe aiming at the specific response of the major disease microenvironment has deeper penetration depth, and can effectively improve the signal to noise ratio.
Description
Technical Field
The application belongs to the technical field of biological medicines, and relates to an activated near infrared two-region fluorescent probe and a preparation method and application thereof.
Background
The incidence rate of major diseases such as tumors, cardiovascular diseases and the like is increasing, the trend of younger is presented, the occurrence and development of the major diseases are seriously threatening the life and health of human beings, and the major diseases bring about an intolerable influence on patients. The rapid development of medical molecular imaging plays an increasingly important role in early diagnosis of diseases, evaluation of real-time therapeutic effects and the like. Compared with the traditional molecular imaging technology, the optical imaging technology, in particular to the fluorescent imaging technology, has the advantages of high space-time resolution, high sensitivity, non-ionizing radiation, real-time imaging, easy operation of an imaging device and the like. The optical probe is used as an important component of fluorescence imaging, and the imaging effect is a key factor affecting the accurate detection of diseases.
Near-infrared (NIR-II, 900-1700 nm) fluorescence imaging remarkably reduces absorption and scattering effects of biological tissues on light and autofluorescence of the tissues, greatly improves tissue penetration depth and imaging signal-to-noise ratio, and can realize deep living tissue imaging. Most of the reported novel near infrared two-region optical probes are 'normally bright' fluorescent probes, and the signal intensity of the novel near infrared two-region optical probes can be improved only through passive or active enrichment at focus positions. Compared with normal tissues, the generation and development of major diseases are almost accompanied by the change of physiological and pathological microenvironment and the over-expression of certain biomolecules, and the research of a 'response' near infrared two-region optical probe for specific activation of pathological biological environment at focus parts such as tumor microenvironment is limited, wherein the probe has the characteristics of hypoxia, extracellular weak acidity, various reactive oxygen species (Reactive oxygen species, ROS), reactive nitrogen species (Reactive nitrogen species), reactive sulfur species (Reactive sulfur species, RSS), enzymes, biological macromolecules and the like. Compared with a normally-bright optical probe, the activated optical probe has the advantages of high signal-to-noise ratio, low false positive signal and the like in the accurate detection of tumors, so that the construction of the response type near infrared two-region optical probe with excellent imaging performance is beneficial to the realization of high-sensitivity accurate detection of serious diseases. However, most "active" near infrared two-zone optical probes currently suffer from the following problems: (1) Because of pi-pi stacking effect, the optical brightness of the planar stronger molecules is sharply reduced under a certain environment, so that the application of the planar stronger molecules in vivo disease diagnosis and treatment is limited; (2) Is easy to be bleached by light, and reduces the detection sensitivity and optical stability of the probe.
Disclosure of Invention
Aiming at the defects of the prior art, the application provides the activated near infrared two-region fluorescent probe which can efficiently respond to various active oxygen species, active nitrogen species, active sulfur species and biological macromolecules in the micro-environment of the focus part of the serious disease, thereby realizing early detection and accurate diagnosis of the serious disease.
The application also solves the technical problem of providing a preparation method of the activated near infrared two-region fluorescent probe.
The application finally aims to provide the application of the activated near infrared two-region fluorescent probe.
The application is characterized in that: aiming at the limitation of the activated near infrared two-region fluorescent probe, the design strategy of the activated near infrared two-region fluorescent probe is as follows: on the basis of a donor-acceptor structure, the optical brightness and the optical stability are improved by increasing the distortion degree of molecules, meanwhile, a response group recognition site is modified on a donor side, an activated near infrared two-region optical probe skeleton is constructed, the change of optical signals is realized through an ICT effect, a donor-acceptor structure activated near infrared two-region probe capable of efficiently responding to various active oxygen species, active nitrogen species, active sulfur species and biological macromolecules in the micro-environment of a focus part of a serious disease is developed, the imaging signal-to-noise ratio and the detection sensitivity of the activated near infrared two-region optical probe are improved, and early detection and accurate diagnosis of the serious disease are realized.
In order to solve the technical problems, the application adopts the following technical scheme:
the application discloses an activated near infrared two-region fluorescent probe, which has a structural general formula shown in formula I:
the structure of the activated near infrared two-region fluorescent probe comprises an electron acceptor structural unit A, an electron donor structural unit D and a response structural unit R;
wherein the electron acceptor structural unit A is selected from
Wherein the electron donor building block D is selected from
Wherein the response building block R is selected from
Wherein R is 1 Selected from C 0 -C 20 Linear or branched alkyl; r is R 2 Selected from C 0 -C 20 Linear or branched alkyl;
wherein the oxygen atom end in the electron donor structural unit D is connected with the response structural unit R.
Wherein, the liquid crystal display device comprises a liquid crystal display device,is pi bridge.
In some embodiments, the activated near infrared two-region fluorescent probe is any one of the following structures:
further, the application discloses a preparation method of the activated near infrared two-region fluorescent probe, which comprises the following steps: the method comprises the following steps: intermediate a and alkoxy substituted aryl boric acid in palladiumUnder the action of a catalyst and a first base, carrying out a Suzuki coupling reaction to obtain an intermediate b; intermediate b at BBr 3 Under the action of (2), carrying out demethylation reaction to obtain an intermediate c; the intermediate c and the response structure compound undergo condensation reaction under the action of second alkali, so that an activated near infrared two-region fluorescent probe I is obtained;
wherein the alkoxy-substituted aryl boronic acid is selected from
Wherein the responsive structural compound is selected from
The structure of the activated near infrared two-region fluorescent probe comprises an electron acceptor structural unit A, an electron donor structural unit D and a response structural unit R;
wherein the electron acceptor structural unit A is selected from
Wherein the electron donor building block D is selected from
Wherein the response building block R is selected from
Wherein R is 1 Selected from C 0 -C 20 Linear or branched alkyl; r is R 2 Selected from C 0 -C 20 Straight or branched chain alkaneA base;
wherein the oxygen atom end in the electron donor structural unit D is connected with the response structural unit R.
In some embodiments, the palladium catalyst is tetrakis (triphenylphosphine) palladium, palladium acetate, bis (diphenylphosphino) ferrocene palladium dichloride, tris (dibenzylideneacetone) dipalladium, or bis triphenylphosphine palladium dichloride; the first base is potassium carbonate, cesium carbonate or potassium phosphate; the second base is potassium carbonate, cesium carbonate, potassium phosphate, triethylamine, N-diisopropylethylamine or 4-dimethylaminopyridine.
In some embodiments, preferably, the palladium catalyst is tetrakis (triphenylphosphine) palladium; the first base is potassium carbonate; the second base is potassium carbonate or triethylamine.
In some embodiments, the molar ratio of intermediate a to alkoxy-substituted aryl boronic acid, palladium catalyst, first base is 1:3.5 to 5:0.04 to 0.10:5 to 15; the Suzuki coupling reaction is carried out at the reaction temperature of 60-120 ℃ for 2-24 hours.
In some embodiments, preferably, the molar ratio of intermediate a to alkoxy substituted aryl boronic acid, palladium catalyst, first base is 1:4:0.05:9, a step of performing the process; the Suzuki coupling reaction is carried out at the reaction temperature of 60 ℃ for 2 hours.
The solvent used in the Suzuki coupling reaction is any one or a combination of several of toluene, water, tetrahydrofuran and absolute ethyl alcohol, preferably a mixture of the absolute ethyl alcohol and toluene in any proportion, and more preferably the volume ratio of the absolute ethyl alcohol to the toluene is 0.2:1, a mixture of two or more of the above-mentioned materials; the volume dosage of the solvent is that the reaction raw materials in the reaction system are dissolved and the viscosity is moderate.
Wherein, the Suzuki coupling reaction is carried out under the protection of inert gas; the inert gas is preferably argon.
In some embodiments, the intermediate b is a salt of BBr 3 The molar ratio of (2) is 1:5 to 10; the demethylation reaction is carried out at a reaction temperature of 0-25 ℃ for 2-6 h.
In some embodiments, preferably, the intermediate b is in combination with BBr 3 The molar ratio of (2) is 1:8, 8; the demethylation reaction is carried out at a reaction temperature of 0 ℃ for 2 hours.
Wherein the solvent used in the demethylation reaction is ultra-dry dichloromethane; the volume dosage of the solvent is that the reaction raw materials in the reaction system are dissolved and the viscosity is moderate.
Wherein the demethylation reaction is carried out under the protection of inert gas; the inert gas is preferably nitrogen.
In some embodiments, the molar ratio of intermediate c to the responsive structural compound, second base is 1:4 to 6:3 to 9; the condensation reaction is carried out at the reaction temperature of 0-60 ℃ for 10 min-24 h.
In some embodiments, preferably, the molar ratio of intermediate c to the responsive structural compound, the second base is 1:4:3.5.
wherein the solvent used in the condensation reaction is dichloromethane, acetonitrile or N, N-dimethylformamide; the volume dosage of the solvent is that the reaction raw materials in the reaction system are dissolved and the viscosity is moderate.
Furthermore, the application discloses application of the activated near infrared two-region fluorescent probe in preparing a nano fluorescent probe for responding active species in disease microenvironment.
Specifically, the preparation method of the nano fluorescent probe comprises the following steps: mixing the activated near infrared two-region fluorescent probe with self-assembly packaging material, tetrahydrofuran and water, performing ultrasonic treatment, removing tetrahydrofuran, and filtering to obtain the nano fluorescent probe.
Specifically, the self-assembled encapsulation material is F127, DSPE-PEG or PLGA-PEG; the mass ratio of the activated near infrared two-region fluorescent probe to the self-assembly packaging material is 0.1:1 to 0.1:2; the mass volume ratio of the self-assembly packaging material to tetrahydrofuran is 1mg:1mL; the volume ratio of tetrahydrofuran to water is 1:9, a step of performing the process; the ultrasonic treatment is carried out, the ultrasonic frequency is 40KHz, the ultrasonic temperature is 25 ℃, and the ultrasonic time is 10-30 min; the filtration was carried out 5 times with an ultrafiltration tube having a molecular weight of 100000 as a cut-off after filtration with a 0.22. Mu.M filter membrane.
Specifically, preferably, the self-assembled encapsulation material is F127; the mass ratio of the activated near infrared two-region fluorescent probe to the self-assembly packaging material is 0.1:1, a step of; the mass volume ratio of the self-assembly packaging material to tetrahydrofuran is 1mg:1mL; the volume ratio of tetrahydrofuran to water is 1:9, a step of performing the process; the ultrasonic treatment is carried out, the ultrasonic frequency is 40KHz, the ultrasonic temperature is 25 ℃, and the ultrasonic time is 10min; the filtration was carried out 5 times with an ultrafiltration tube having a molecular weight of 100000 as a cut-off after filtration with a 0.22. Mu.M filter membrane.
Specifically, the active species is an active oxygen species, an active nitrogen species, an active sulfur species, or a biological macromolecule.
Specifically, the active oxygen species is O 2 ·- The method comprises the steps of carrying out a first treatment on the surface of the The active nitrogen species is ONOO - The method comprises the steps of carrying out a first treatment on the surface of the The active sulfur species is H 2 S, S; the biological macromolecule is glutathione.
In particular, the disease is a tumor or a cardiovascular disease.
Wherein, when the activated near infrared two-region fluorescent probe is
When the corresponding responsive active species is active sulfur species H 2 S。
Wherein, when the activated near infrared two-region fluorescent probe is
When the corresponding responsive active species is active oxygen species O 2 ·- 。
Wherein, when the activated near infrared two-region fluorescent probe is
When the corresponding responsive active species is the active nitrogen species ONOO - 。
Wherein, when the activated near infrared two-region fluorescent probe is
When the active species to which it corresponds responds is the biological macromolecule Glutathione (GSH).
The application of the activated near infrared two-region fluorescent probe in preparing the nano fluorescent probe for responding active species in disease microenvironment is also within the protection scope of the application.
The beneficial effects are that:
(1) The cyanine or fluoroborodipyrrole probes are often designed into an activated near infrared two-region optical probe for detecting internal and external biomarkers of a disease body, however, the cyanine and fluoroborodipyrrole probes are easy to perform fluorescence quenching in a high concentration or aggregation state, the cyanine fluorescent probes have the defects of easy photobleaching and the like, the optical brightness and the optical stability of the probes are reduced, and the activated small-molecule near infrared two-region optical probe for the microenvironment specific response of the serious disease, which is prepared by the application, has deeper penetration depth, and can effectively improve the signal to noise ratio.
(2) The application uses a donor-acceptor type fluorophore framework, increases optical brightness by adjusting the plane configuration and electron cloud distribution of the fluorophore, and designs an activated near infrared two-region fluorescent probe by adopting an intramolecular charge transfer (Intramolecular Charge Transfer, ICT) effect. The activated near infrared two-region fluorescent probe comprises: (1) Compared with the cyanine probe, the donor-acceptor type fluorophore framework can increase the photostability of the probe; (2) The alkyl chain is modified at different positions on the pi bridge side of the molecular structure, the included angle between the pi bridge and the receptor is moderately increased, the planeness is reduced, on one hand, the effective transmission of electrons in the response process can be maintained, and on the other hand, the reduction of fluorescence brightness caused by pi-pi accumulation is weakened, and experimental results show that the fluorescence intensity is increased by 11.9 times after the response, the optical activity is higher, the fluorescence intensity of the probe after the response is increased along with the concentration, and the optical brightness is obviously improved; (3) The application modifies the recognition group at the electron donor side of the molecular structure to widen the response biomarker category in the major disease process, taking malignant tumor as an example, including various biomarkers of tumor microenvironment, such as active oxygen species, active nitrogen species, active sulfur species or biological macromolecules, and the like, to realize the accurate detection at tumor sites.
Drawings
The foregoing and/or other advantages of the application will become more apparent from the following detailed description of the application when taken in conjunction with the accompanying drawings and detailed description.
FIG. 1 shows NIR-II-H in example 1 of the application 2 And adding an ultraviolet absorption spectrum change chart of NaHS into the S nano fluorescent probe.
FIG. 2 shows NIR-II-H in example 1 of the application 2 And adding NaHS into the S nano fluorescent probe to obtain a change chart of fluorescence emission spectrum.
FIG. 3 shows NIR-II-H in example 1 of the application 2 Titration fluorescence change pattern of NaHS is added into the S nano fluorescent probe.
FIG. 4 shows NIR-II-H in example 1 of the application 2 Response selectivity test pattern for S nano-fluorescent probe.
FIG. 5 shows NIR-II-H in example 1 of the application 2 Optical brightness test pattern of S nano fluorescent probe.
FIG. 6 shows NIR-II-H in example 1 of the application 2 Optical stability test pattern of S nano fluorescent probe.
FIG. 7 shows NIR-II-O in example 2 of the application 2 ·- Nano fluorescent probe addition O 2 ·- Ultraviolet absorption spectrum change pattern of (2).
FIG. 8 is a NIR-II-ONOO of example 3 of the application - Nano fluorescent probe addition to ONOO - Ultraviolet absorption spectrum change pattern of (2).
FIG. 9 is a graph showing the change of ultraviolet absorption spectrum of the addition of GSH to the NIR-II-GSH nano fluorescent probe in example 4 of the present application.
FIG. 10 is a schematic diagram showing the molecular structure design of the active near infrared two-region optical probe according to the present application.
Detailed Description
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials, unless otherwise specified, are commercially available.
Glutathione used in the examples of the present application is abbreviated as GSH.
The molecular structure design schematic diagram of the active near infrared two-region optical probe is shown in fig. 10, and the design thought is as follows:
(1) Structure design of active near infrared two-zone optical probe with high optical brightness
Based on electron donors (phenols, naphthols, anthracenols, etc.), pi bridges (R 1 、R 2 Alkylated thiophene) and electron acceptors (benzothiadiazole, naphtothiadiazole, benzothiadiazole quinoxaline, etc.), etc., and the energy level matching of the corresponding electron donor and electron acceptor is regulated and controlled, thus constructing the near infrared two-region optical probe with the D-pi-A structure.
(2) High optical brightness active near infrared two-zone optical probe response performance and biological application
According to the micro-environmental biomarkers of different major diseases, cancers are exemplified, which include reactive oxygen species (O 2 ·- Etc.), active nitrogen species (ONOO - Etc.), active sulfur species (H 2 S, etc.), biomacromolecules (glutathione, GSH, etc.), selecting optical quenching groups capable of specifically recognizing the biomarkers, constructing an activated near infrared two-region optical probe library, and examining the application of the activated near infrared two-region optical probe in the aspect of accurate diagnosis of cancers.
Based on units such as electron donors (phenol, naphthol, anthracenol and the like), pi-bridge (alkylated thiophene), electron acceptors (benzothiadiazole, naphthacenethiadiazole, benzothiadiazole quinoxaline and the like) and the like, the energy level matching of the corresponding electron donors and electron acceptors is regulated and controlled, a D-pi-A structure near infrared two-region optical probe is constructed, a response group is modified at the electron donor side of a molecular structure, and the types of response species, including living active oxygen species (O) 2 ·- Etc.), active nitrogen species (ONOO - Etc.), active sulfur species (H 2 S, etc.) and biomacromolecules (glutathione, GSH, etc.), overcomes the problem of limited types of response groups modified from the side of an electron acceptor in the prior art, optimizes a response type near infrared two-region optical probe with high optical brightness, and realizesEarly detection and accurate diagnosis of major diseases.
Example 1: preparation of hydrogen sulfide activated near infrared two-region fluorescent probe and performance test of nano fluorescent probe
1. Preparation of hydrogen sulfide activated near infrared two-region fluorescent probe I-1
Synthesis of intermediate b-1: compound a-1 (1.0 mmol,1.0 equiv.), p-methoxyphenylboronic acid (4.0 mmol,4.0 equiv.), and potassium carbonate (9.0 mmol,9.0 equiv.) are dissolved in ethanol/toluene (20% V/V,5 mL), and after three argon substitutions, tetrakis (triphenylphosphine) palladium (0.05 mmol,5% equiv.) is rapidly added, and the reaction is carried out for 2 hours at 60 ℃ under argon protection, and after the reaction is completed, the residue is washed with celite, and the combined filtrates are concentrated under reduced pressure to obtain a crude product, which is purified by column chromatography with petroleum ether/dichloromethane (100% -50% V/V) to obtain a blue-green solid powder intermediate b-1, which is stored at 20 ℃ below zero in 68% by light shielding.
Nuclear magnetic data of intermediate b-1: 1 H NMR(400MHz,Chloroform-d)δ7.64(d,J＝8.8Hz,4H),7.29(s,2H),6.95(d,J＝8.8Hz,4H),3.86(s,6H),2.57(d,J＝7.0Hz,4H),1.36–1.27(m,2H),1.12–0.71(m,16H),0.72–0.57(m,6H),0.47(t,J＝7.4Hz,6H).
synthesis of intermediate c-1: intermediate b-1 (1.0 mmol,1.0 equiv.) is dissolved in 5mL of ultra-dry dichloromethane, replaced with nitrogen, boron tribromide (8.0 mmol,8.0 equiv.) is added dropwise at-15 ℃, and the mixture is stirred for 2 hours at 0 ℃ under nitrogen protection to carry out demethylation; and after the reaction is finished, adding ice water into the reaction solution for quenching, regulating the pH to 8 by using saturated sodium bicarbonate solution, extracting by using dichloromethane, drying by using sodium sulfate, filtering, spin-drying the filtrate, purifying by column chromatography, and obtaining a blue-green solid powder intermediate c-1, namely NIR-II-OH, by purifying by using dichloromethane as an eluent, wherein the yield is 75%, and storing in a dark place at the temperature of minus 20 ℃.
Nuclear magnetic data of intermediate c-1: 1 H NMR(400MHz,Chloroform-d)δ7.58(d,J＝8.6Hz,4H),7.27(s,2H),6.87(d,J＝8.6Hz,4H),2.56(dt,J＝7.2,1.7Hz,4H),1.53(s,2H),1.36–1.27(m,2H),1.12–0.71(m,16H),0.68–0.59(m,6H),0.47(t,J＝7.4Hz,6H).
synthesis of hydrogen sulfide activated near infrared two-region fluorescent probe I-1: intermediate c-1 (1.0 mmol,1.0 equiv.) is dissolved in dichloromethane, triethylamine (3.5 mmol,3.5 equiv.) is added at 0deg.C and stirred for 10 minutes, followed by 2, 4-dinitrobenzenesulfonyl chloride (4.0 mmol,4.0 equiv.) at 0deg.C for 10 minutes for condensation reaction; quenching the mixture by using saturated ammonium chloride after the reaction is finished, extracting the mixture by using dichloromethane, combining organic phases, drying the mixture by using sodium sulfate, concentrating the mixture, purifying the mixture by using column chromatography, wherein an eluent is petroleum ether/dichloromethane (90 to 0 percent of V/V), and purifying the mixture to obtain blue solid powder hydrogen sulfide activated near infrared two-region fluorescent probe I-1, namely a compound NIR-II-H 2 S, yield 88%, and storing at minus 20 ℃ in dark.
Nuclear magnetic data of activated near infrared two-region fluorescent probe I-1: 1 H NMR(400MHz,Chloroform-d)δ8.68(d,J＝2.2Hz,2H),8.51(dd,J＝8.7,2.2Hz,2H),8.22(d,J＝8.6Hz,2H),7.69(d,J＝8.8Hz,4H),7.37(s,2H),7.26(d,J＝8.8Hz,4H),2.56(d,J＝7.0Hz,4H),1.36–1.27(m,2H),1.12–0.71(m,16H),0.63(td,J＝7.0,1.5Hz,6H),0.46(t,J＝7.3Hz,6H).
2、NIR-II-H 2 preparation of S nano fluorescent probe
The compound NIR-II-H is treated with ultrasound at 40KHz and 25 DEG C 2 S (100. Mu.g) and F127 (M.W. =12700, 1 mg) were dissolved in 1mL of tetrahydrofuran to make the components uniformly mixed, and then rapidly injected into 9mL of deionized water, after continuous ultrasonic treatment for 10 minutes, THF was evaporated by a rotary evaporator, filtered with a 0.22. Mu.M filter membrane, and ultrafiltered 5 times with an ultrafiltration tube having a cut-off molecular weight of 100000, to finally obtain NIR-II-H in the near infrared two region 2 The encapsulation rate of the S nano fluorescent probe is 65%.
3. Near infrared two-zone NIR-II-H 2 Performance test of S nano fluorescent probe
Experimental test 1: NIR-II-H 2 Ultraviolet absorption spectrum change of sodium hydrosulfide (NaHS) added into S nano fluorescent probe
NIR-II-H at a final concentration of 50. Mu.g/mL 2 NaHS (final concentration 120. Mu.M) was added to the S PBS buffer (10 mM, pH 7.4), and after incubation at 37℃for 10 minutes, the UV absorbance spectrum was measured.
As can be seen from FIG. 1, with the addition of NaHS, the maximum absorption wavelength of the ultraviolet absorption spectrum is red shifted, which indicates that the nano fluorescent probe reacts with NaHS and has good response performance.
Experiment test 2: NIR-II-H 2 Fluorescence emission change of sodium hydrosulfide (NaHS) added to S nano fluorescent probe is NIR-II-H with final concentration of 50 mug/mL 2 NaHS (final concentration 120. Mu.M) was added to the S PBS buffer (10 mM, pH 7.4) and after incubation at 37℃for 10 minutes, the fluorescence emission spectrum at 808nm excitation wavelength was measured.
As shown in fig. 2, with the addition of NaHS, the maximum emission peak of the fluorescence emission spectrum is red shifted, and the fluorescence intensity at 1000 nm-1200 nm is significantly enhanced.
Experimental test 3: NIR-II-H 2 Titrated fluorescence emission change of sodium hydrosulfide (NaHS) added into S nano fluorescent probe
NIR-II-H at a final concentration of 50. Mu.g/mL 2 Fluorescence titration experiments were performed in S PBS buffer (10 mM, pH 7.4), naHS (final concentration 0-240. Mu.M) was added sequentially, and after incubation at 37℃for 10min, the fluorescence emission spectrum at excitation wavelength 808nm was measured.
As shown in FIG. 3, with the addition of NaHS, the maximum emission peak of the fluorescence emission spectrum is red shifted, and the fluorescence intensity at 1000 nm-1200 nm is enhanced sequentially with the increase of NaHS concentration, and the fluorescence probe has good response linearity with NaHS solution and higher sensitivity.
Experimental test 4: NIR-II-H 2 Response selectivity of S-nano fluorescent probe to different compounds
NIR-II-H at a final concentration of 50. Mu.g/mL 2 Different ionic solutions were added to the S PBS buffer system (10 mm, ph 7.4) for response selectivity test experiments, with different reagents added separately, including: 1. blank; na. Na 2 CO 3 (10mM)；3.KCl(10mM)；4.CaCl 2 (10mM)；5.MgCl 2 (10mM)；6.FeCl 2 (10mM)；7.NaCl(10mM)；8.NaHCO 3 (10mM)；9.Na 2 SO 4 (10mM)；10.KNO 2 (10mM)；11.KNO 3 (10mM)；12.H 2 O 2 (500μM)；13.GSH(1mM)；14.L-Cys(1mM)；15.H 2 S (100. Mu.M); (all final concentrations); followed by incubation at 37 ℃ for 10 minutes, and its fluorescence emission spectrum at an excitation wavelength of 808nm was tested.
As can be seen from FIG. 4, NIR-II-H 2 The S nano fluorescent probe has response specificity to NaHS and can not be interfered by other substances.
Experimental test 5: NIR-II-H 2 S nano fluorescent probe optical brightness
NIR-II-H with final concentration of 0-200. Mu.g/mL was tested separately 2 Fluorescence emission spectrum of S PBS buffer system (10 mM, pH 7.4) at excitation wavelength 808 nm.
The results are shown in FIG. 5, with increasing concentration, NIR-II-H 2 The fluorescence intensity of the S nano fluorescent probe is sequentially increased, which indicates NIR-II-H 2 The S nano fluorescent probe has higher optical brightness.
Experimental test 6: NIR-II-H 2 S nano fluorescent probe photostability test
Using 808nm laser (80 mW cm power) -2 ) NIR-II-H with a final concentration of 50. Mu.g/mL was continuously irradiated 2 SPBS buffer (10 mM, pH 7.4) for 0min, 5min, 10min, 30min, 60min, while ICG PBS buffer (10 mM, pH 7.4) for 50 μg/mL was used as control, and also irradiated for 0min, 5min, 10min, 30min, 60min, respectively, to test fluorescence emission spectra at excitation wavelength of 808 nm.
The results are shown in FIG. 6, with increasing irradiation time, NIR-II-H 2 The fluorescence intensity of the S nano fluorescent probe is almost unchanged, while ICG is obviously photo-bleached, which shows that NIR-II-H 2 The S nano fluorescent probe has higher light stability.
Example 2: preparation of superoxide anion activated near infrared two-region fluorescent probe and performance test of nano fluorescent probe
1. Preparation of superoxide anion activated near infrared two-region fluorescent probe I-2
NIR-II-O 2 ·- Synthesis of activated near infrared two-region fluorescent probe I-2: intermediate c-1 (1.0 mmol,1.0equiv., prepared in example 1) was dissolved in 5mL of dichloromethane, triethylamine (3.5 mmol,3.5 equiv.) was added at 0deg.C and stirred for 10 minutes, followed by addition of trifluoromethanesulfonic anhydride (4.0 mmol,4.0 equiv.) and condensation reaction at 0deg.C for 30 minutes; quenching the mixture by using saturated ammonium chloride after the reaction is finished, extracting the mixture by using dichloromethane, combining organic phases, drying the mixture by using sodium sulfate, concentrating the mixture, purifying the mixture by using column chromatography, wherein an eluent is petroleum ether/dichloromethane (50% -0% V/V), purifying the mixture to obtain blue solid powder superoxide anion activated near infrared two-region fluorescent probe I-2, and recording the blue solid powder superoxide anion activated near infrared two-region fluorescent probe I-2 as a compound NIR-II-O 2 ·- The yield is 70 percent, and the product is preserved at minus 20 ℃ in dark.
Compound NIR-II-O 2 ·- Nuclear magnetic data of fluorescent probes: 1 H NMR(400MHz,Chloroform-d)δ7.77(d,J＝8.8Hz,4H),7.40(s,2H),7.33(d,J＝8.8Hz,4H),2.58(d,J＝7.0Hz,4H),1.36–1.27(m,2H),1.12–0.71(m,16H),0.64(td,J＝7.0,1.5Hz,6H),0.47(t,J＝7.3Hz,6H).
2、NIR-II-O 2 ·- preparation of nano fluorescent probe
The compound NIR-II-O is processed at an ultrasonic frequency of 40KHz and an ultrasonic temperature of 25deg.C 2 ·- (100. Mu.g) and F127 (M.W. =12700, 1 mg) were dissolved in 1mL of tetrahydrofuran to make the components uniformly mixed, and then rapidly injected into 9mL of deionized water, after ultrasonic treatment for 10 minutes, THF was evaporated by a rotary evaporator, filtered with a 0.22. Mu.M filter membrane, and ultrafiltered 5 times with an ultrafiltration tube having a cut-off molecular weight of 100000, to finally obtain NIR-II-O in the near infrared two region 2 ·- The encapsulation rate of the nano fluorescent probe is 58%.
3. Near infrared two-zone NIR-II-O 2 ·- Performance test of nano fluorescent probe
Experimental test1: testing NIR-II-O 2 ·- Ultraviolet absorption spectrum of NIR-II-OH
NIR-II-O at a final concentration of 50. Mu.g/mL 2 ·- KO was added to PBS buffer (10 mM, pH 7.4) 2 (final concentration 120. Mu.M), after incubation at 37℃for 30 minutes, the UV absorbance spectrum was measured.
As can be seen from FIG. 7, with KO 2 Is added, the maximum absorption wavelength of the ultraviolet absorption spectrum is red shifted, indicating NIR-II-O 2 ·- Nano fluorescent probe and O 2 ·- The reaction occurs, and the response performance is good.
Example 3: preparation of peroxynitroso anion activated near infrared two-region fluorescent probe and performance test of nano fluorescent probe
1. Preparation of peroxynitroso anion activated near infrared two-region fluorescent probe I-3
Synthesis of peroxynitroso anion activated near infrared two-region fluorescent probe I-3: intermediate c-1 (1.0 mmol,1.0equiv., prepared in example 1) was dissolved in 5mL acetonitrile, potassium carbonate (3.5 mmol,3.5 equiv.) was added at 0deg.C and stirred for 10 minutes, followed by 4-bromomethylphenylboronic acid pinacol ester (4.0 mmol,4.0 equiv.) was added and subjected to condensation reaction at 60deg.C for 24 hours; quenching the reaction product by using saturated ammonium chloride, extracting with dichloromethane, combining organic phases, drying with sodium sulfate, concentrating, purifying by column chromatography, wherein an eluent is dichloromethane, purifying to obtain blue solid powder peroxynitroso anion activated near infrared two-region fluorescent probe I-3, and recording as a compound NIR-II-ONOO - The yield is 70 percent, and the product is preserved at minus 20 ℃ in dark.
NIR-II-ONOO - Nuclear magnetic data of fluorescent probes: 1 H NMR(400MHz,Chloroform-d)δ8.37(d,J＝9.3,4H),7.82(d,J＝8.7Hz,4H),7.42(s,2H),7.20(d,J＝8.8Hz,4H),7.14(d,J＝9.3Hz,4H),5.30(s,4H),2.60(d,J＝7.1Hz,4H),1.36–1.27(m,2H),1.66(s,24H),1.12–0.71(m,16H),0.63(td,J＝7.0,1.5Hz,6H),0.46(t,J＝7.3Hz,6H).
2. preparation of NIR-II-ONOO-nano fluorescent probe
The compound NIR-II-ONOO is prepared at an ultrasonic frequency of 40KHz and an ultrasonic temperature of 25deg.C - (100. Mu.g) and F127 (M.W. =12700, 1 mg) were dissolved in 1mL of tetrahydrofuran to make the components uniformly mixed, and then rapidly injected into 9mL of deionized water, after ultrasonic treatment for 10 minutes, THF was evaporated by a rotary evaporator, filtered with a 0.22. Mu.M filter membrane, and ultrafiltered 5 times with an ultrafiltration tube having a cut-off molecular weight of 100000, to finally obtain NIR-II-ONOO in the near infrared two region - The encapsulation rate of the nano fluorescent probe is 60%.
3. Near infrared two-zone NIR-II-ONOO - Performance test of nano fluorescent probe
Experimental test 1: NIR-II-ONOO - Ultraviolet absorption spectrum of NIR-II-OH
ONOO - Preparing a solution: ONOO used in the present embodiment - The solution is prepared in a laboratory, wherein cations are sodium ions, and the specific synthesis method can refer to the prior art and can also be prepared according to the following method: 5mL of NaNO 2 Solution (0.6 mol.L) -1 ) With 350 mu L of H 2 O 2 Solution (0.7 mol.L) -1 ) Mix, then add 250. Mu.L HCl solution (0.6mol.L) with stirring -1 ) Pre-acidifying, and ultraviolet setting the concentration to 1 mM.
NIR-II-ONOO at a final concentration of 50. Mu.g/mL - The ONOO was added to PBS buffer (10 mM, pH 7.4) - After incubation of the solution (final concentration 120. Mu.M) at 37℃for 30 minutes, the UV absorption spectrum was measured.
As can be seen from FIG. 8, with ONOO - The addition of the solution shifted the maximum absorption wavelength of the UV absorption spectrum by red indicating NIR-II-ONOO - Nano fluorescent probe and ONOO - The reaction occurs, and the response performance is good.
Example 4: preparation of glutathione activated near-infrared two-region fluorescent probe and performance test of nano fluorescent probe
1. Preparation of glutathione activated near infrared two-region fluorescent probe I-4
Synthesis of glutathione activated near infrared two-region fluorescent probe I-4: intermediate c-1 (1.0 mmol,1.0equiv., prepared in example 1) was dissolved in 5mL of dichloromethane, triethylamine (3.5 mmol,3.5 equiv.) was added at 0deg.C and stirred for 10 minutes, followed by 2, 4-dinitrofluorobenzene (4.0 mmol,4.0 equiv.) at 0deg.C for 30 minutes for condensation reaction; after the reaction is finished, the mixture is quenched by saturated ammonium chloride, extracted by methylene dichloride, the organic phases are combined, dried by sodium sulfate, concentrated and purified by column chromatography, the eluent is petroleum ether/methylene dichloride (50% -10% V/V), and blue solid powder glutathione activated near infrared two-region fluorescent probe I-4 is obtained after purification and is recorded as NIR-II-GSH, the yield is 65%, and the blue solid powder glutathione activated near infrared two-region fluorescent probe I-4 is stored at minus 20 ℃ in a dark place.
Nuclear magnetic data of NIR-II-GSH fluorescent probe: 1 H NMR(400MHz,Chloroform-d)δ8.88(d,J＝2.7Hz,2H),8.37(dd,J＝9.3,2.7Hz,2H),7.81(d,J＝8.7Hz,4H),7.42(s,2H),7.20(d,J＝8.7Hz,4H),7.13(d,J＝9.3Hz,2H),2.60(d,J＝7.2Hz,4H)，1.36–1.27(m,2H),1.12–0.71(m,16H),0.63(td,J＝7.0,1.5Hz,6H),0.46(t,J＝7.3Hz,6H).
2. preparation of NIR-II-GSH nano fluorescent probe
The compounds NIR-II-GSH (100 μg) and F127 (m.w. =12700, 1 mg) were dissolved in 1mL of tetrahydrofuran at an ultrasonic frequency of 40KHz and an ultrasonic temperature of 25 ℃ to mix the components uniformly, which was then rapidly injected into 9mL of deionized water, after 10 minutes of continuous ultrasonic treatment, THF was evaporated by a rotary evaporator, filtered with a 0.22 μm filter membrane, and ultrafiltered 5 times with an ultrafiltration tube having a cut-off molecular weight of 100000 to finally obtain a near infrared two-region NIR-II-GSH nano fluorescent probe having an encapsulation rate of 63%.
3. Performance test of NIR-II-GSH nano fluorescent probe
Experimental test 1: testing of ultraviolet absorption spectra of NIR-II-GSH and NIR-II-OH
GSH (final concentration 500. Mu.M) was added to NIR-II-GSH PBS buffer (10 mM, pH 7.4) at a final concentration of 50. Mu.g/mL, and after incubation at 37℃for 1 hour, its UV absorption spectrum was measured.
As can be seen from fig. 9, with addition of GSH, the maximum absorption wavelength of the ultraviolet absorption spectrum is red shifted, which indicates that the NIR-II-GSH nano fluorescent probe reacts with GSH, and has good response performance.
The application provides an activated near infrared two-region fluorescent probe, a preparation method and an application thought and a method thereof, and particularly the method and the method for realizing the technical scheme are a plurality of methods, the above is only a preferred embodiment of the application, and it should be pointed out that a plurality of improvements and modifications can be made by one of ordinary skill in the art without departing from the principle of the application, and the improvements and the modifications are also regarded as the protection scope of the application. The components not explicitly described in this embodiment can be implemented by using the prior art.
Claims (13)
1. The activated near infrared two-region fluorescent probe is characterized by having a structural general formula shown in formula I:
the structure of the activated near infrared two-region fluorescent probe comprises an electron acceptor structural unit A, an electron donor structural unit D and a response structural unit R;
wherein the electron acceptor structural unit A is selected from
Wherein the electron donor building block D is selected from
Wherein the response building block R is selected from
Wherein R is 1 Selected from C 0 -C 20 Linear or branched alkyl; r is R 2 Selected from C 0 -C 20 Linear or branched alkyl;
wherein the oxygen atom end in the electron donor structural unit D is connected with the response structural unit R.
2. The activated near infrared two-region fluorescent probe according to claim 1, wherein the activated near infrared two-region fluorescent probe is any one of the following structures:
3. the method for preparing the activated near infrared two-region fluorescent probe according to claim 1, which is characterized by comprising the following steps: performing Suzuki coupling reaction on the intermediate a and alkoxy substituted aryl boric acid under the action of a palladium catalyst and a first base to obtain an intermediate b; intermediate b at BBr 3 Under the action of (2), carrying out demethylation reaction to obtain an intermediate c; the intermediate c and the response structure compound undergo condensation reaction under the action of second alkali, so that an activated near infrared two-region fluorescent probe I is obtained;
wherein the alkoxy-substituted aryl boronic acid is selected from
Wherein the responsive structural compound is selected from
The structure of the activated near infrared two-region fluorescent probe comprises an electron acceptor structural unit A, an electron donor structural unit D and a response structural unit R;
wherein the electron acceptor structural unit A is selected from
Wherein the electron donor building block D is selected from
Wherein the response building block R is selected from
Wherein R is 1 Selected from C 0 -C 20 Linear or branched alkyl; r is R 2 Selected from C 0 -C 20 Linear or branched alkyl;
wherein the oxygen atom end in the electron donor structural unit D is connected with the response structural unit R.
4. The method of claim 3, wherein the palladium catalyst is tetrakis (triphenylphosphine) palladium, palladium acetate, bis (diphenylphosphino) ferrocene palladium dichloride, tris (dibenzylideneacetone) dipalladium, or ditriphenylphosphine palladium dichloride; the first base is potassium carbonate, cesium carbonate or potassium phosphate; the second base is potassium carbonate, cesium carbonate, potassium phosphate, triethylamine, N-diisopropylethylamine or 4-dimethylaminopyridine.
5. A process according to claim 3, wherein the molar ratio of intermediate a to alkoxy substituted aryl boronic acid, palladium catalyst, first base is 1:3.5 to 5:0.04 to 0.10:5 to 15; the Suzuki coupling reaction is carried out at the reaction temperature of 60-120 ℃ for 2-24 hours.
6. A process according to claim 3, wherein intermediate b and BBr 3 The molar ratio of (2) is 1:5 to 10; the demethylation reaction is carried out at a reaction temperature of 0-25 ℃ for 2-6 h.
7. A process according to claim 3, wherein the molar ratio of intermediate c to the response structural compound, second base is 1:4 to 6:3 to 9; the condensation reaction is carried out at the reaction temperature of 0-60 ℃ for 10 min-24 h.
8. The use of the activated near infrared two-region fluorescent probe of claim 1 for the preparation of a nano-fluorescent probe responsive to active species in a disease microenvironment.
9. The use according to claim 8, wherein the preparation method of the nano-fluorescent probe comprises the following steps: mixing the activated near infrared two-region fluorescent probe with self-assembly packaging material, tetrahydrofuran and water, performing ultrasonic treatment, removing tetrahydrofuran, and filtering to obtain the nano fluorescent probe.
10. The use according to claim 9, wherein the self-assembled encapsulation material is F127, DSPE-PEG or PLGA-PEG; the mass ratio of the activated near infrared two-region fluorescent probe to the self-assembly packaging material is 0.1:1 to 0.1:2; the mass volume ratio of the self-assembly packaging material to tetrahydrofuran is 1mg:1mL; the volume ratio of tetrahydrofuran to water is 1:9, a step of performing the process; the ultrasonic treatment is carried out, the ultrasonic frequency is 40KHz, the ultrasonic temperature is 25 ℃, and the ultrasonic time is 10-30 min; the filtration was carried out 5 times with an ultrafiltration tube having a molecular weight of 100000 as a cut-off after filtration with a 0.22. Mu.M filter membrane.
11. The use according to claim 8, wherein the active species is an active oxygen species, an active nitrogen species, an active sulfur species or a biological macromolecule.
12. The use according to claim 11, wherein the active oxygen species isThe active nitrogen species is ONOO - The method comprises the steps of carrying out a first treatment on the surface of the The active sulfur species is H 2 S, S; the biological macromolecule is glutathione.
13. The use according to claim 8, wherein the disease is a tumor or a cardiovascular disease.
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