CN113943305B - Phthalocyanine fluorescent molecular compound, preparation method and phthalocyanine fluorescent nano material - Google Patents
Phthalocyanine fluorescent molecular compound, preparation method and phthalocyanine fluorescent nano material Download PDFInfo
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- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 title claims abstract description 148
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- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
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Images
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- 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
- A61K49/0036—Porphyrins
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- 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
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0054—Macromolecular compounds, i.e. oligomers, polymers, dendrimers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
-
- 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
-
- 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
- C09K2211/18—Metal complexes
- C09K2211/188—Metal complexes of other metals not provided for in one of the previous groups
Abstract
The invention discloses a phthalocyanine fluorescent molecular compound, a preparation method, a phthalocyanine fluorescent nano material and an amphiphilic phthalocyanine fluorescent molecular compound, wherein the amphiphilic phthalocyanine fluorescent molecular compound comprises the following components in parts by weight: hydrophobic phthalocyanine groups, hydrophilic polyethylene glycol segments, and biologically reactive groups.
Description
Technical Field
The invention relates to the technical field of biosensors, in particular to a phthalocyanine fluorescent molecular compound, a preparation method and a phthalocyanine fluorescent nano material.
Background
Cancer has developed into one of the major diseases threatening human health, and it is of great importance to find a safe and efficient treatment. Light-responsive Therapy is a main means for treating cancer, and among them, light-responsive Therapy mainly includes Photodynamic Therapy (PDT) and Photothermal Therapy (PTT), which have drawn attention due to good therapeutic effects and low toxic and side effects. But the two treatment mechanisms are obviously different, the photodynamic therapy is to generate Reactive Oxygen Species (ROS) to cause oxidative damage of cells and tumor capillaries by a photosensitizer in the presence of light, and the photothermal therapy is to realize local high temperature thermal damage by utilizing the photothermal conversion capability of a thermotherapy agent.
The compounds currently approved for the treatment of various cancers (e.g., photofrin and Foscan), among others, are mostly porphyrin-based compounds that are associated with the development of skin phototoxicity. To ameliorate this deficiency, studies and investigations of the use of phthalocyanines and related phthalocyanine systems have been carried out.
These compounds of phthalocyanine and related phthalocyanine systems, in the 650-800 nm range, exhibit long wavelength absorption and fluorescence, have high singlet oxygen generating capacity and can be used to destroy superficial and deep tumors in the skin.
Unlike porphyrins, phthalocyanine molecules exhibit weak absorption in the 400-600 nm range, which minimizes skin phototoxicity.
Similar to porphyrin, phthalocyanine system can also form metal complex, which is a kind of molecular dye with 18 pi electronic structure, and has the advantages of long absorption wavelength, high extinction coefficient, excellent photochemical characteristics, etc., but also has the disadvantages of poor water solubility and easy aggregation, etc., which greatly limits the application of phthalocyanine system in biomedicine.
Disclosure of Invention
In view of this, the invention provides a phthalocyanine fluorescent molecular compound, a preparation method thereof and a phthalocyanine fluorescent nano material.
In order to solve the technical problems.
To achieve the above technical objects, as one aspect of the present invention, there is provided a phthalocyanine fluorescent molecular compound comprising:
hydrophobic phthalocyanine groups, hydrophilic polyethylene glycol segments, and biologically reactive groups.
According to the embodiment of the invention, the structure of the fluorescent molecular compound is shown as formula (I):
the compound of the formula (I), wherein,
represents a bioreactive group, n =4 or 8.
According to an embodiment of the present invention, the bio-reactive group includes: any one of structures represented by formula (II), formula (III), formula (IV) and formula (V):
as another aspect of the present invention, the present invention also provides a method for preparing the above fluorescent molecular compound, comprising:
reacting tetraethylene glycol and 4-nitrophthalonitrile in an anhydrous and oxygen-free environment to produce a phthalocyanine group precursor;
reacting the phthalocyanine group precursor with n-amyl alcohol, zinc acetate and diazabicyclo to generate a phthalocyanine group;
and reacting the phthalocyanine group with an isocyanate group to obtain the amphiphilic phthalocyanine fluorescent molecular compound.
According to an embodiment of the present invention, wherein the above tetraethylene glycol and 4-nitrophthalonitrile are reacted in an anhydrous and oxygen-free environment to produce a phthalocyanine group precursor, comprising:
reacting tetraethylene glycol, 4-nitrophthalonitrile and anhydrous K 2 CO 3 Reacting for 24-56 h in N, N-dimethylformamide solvent at 40-80 ℃ in nitrogen atmosphere to obtain the phthalocyanine group precursor.
According to an embodiment of the present invention, the reacting the phthalocyanine group precursor with n-pentanol, zinc acetate, diazabicyclo to generate the phthalocyanine group includes:
adding the phthalocyanine group precursor into an n-amyl alcohol solvent, and stirring for 10-60 min at 80-110 ℃ under the protection of nitrogen to obtain a first mixed solution;
and adding zinc acetate and diazabicyclo into the first mixed solution, and reacting for 12-48 h at 120-160 ℃ to obtain the phthalocyanine group.
According to an embodiment of the present invention, the above-mentioned reacting the phthalocyanine group and the isocyanate group to obtain the amphiphilic phthalocyanine fluorescent molecular compound includes:
mixing the phthalocyanine unit and a catalyst in an organic solution to obtain a second mixed solution;
and adding the second mixed solution into isocyanate, and reacting for 10-24 h under the protection of nitrogen to obtain the phthalocyanine fluorescent molecule.
According to an embodiment of the present invention, wherein the catalyst comprises dibutyl tin dilaurate.
According to an embodiment of the present invention, wherein the above tetraethylene glycol, 4-nitrophthalonitrile and anhydrous K 2 CO 3 Comprises the following components in percentage by mass: 2-5;
the mass ratio of the phthalocyanine group precursor, the zinc acetate and the diazabicyclo comprises: 1-2.
As another aspect of the invention, the invention also provides phthalocyanine fluorescent nano-material, which comprises an assembly formed by the fluorescent molecular compound.
According to the embodiment of the invention, the amphiphilic phthalocyanine fluorescent molecular compound comprises a hydrophobic phthalocyanine group, a hydrophilic polyethylene glycol chain segment and a biological reaction group, has an amphiphilic group, is good in water solubility, avoids aggregation and has excellent biocompatibility, the biological reaction group can be used as a targeting group to capture polypeptide or protein elements containing sulfydryl to trigger and release fluorescence, so that the phthalocyanine fluorescent molecular compound can be used for capturing albumin, can trigger and release fluorescence by combining with albumin, can circulate in organisms for a long time, and further can be aggregated into cancer cells through the high permeability and retention effect of solid tumors, and singlet oxygen generated after illumination through illumination with a specific excitation wavelength has a photodynamic treatment effect on superficial tumors, so that the phthalocyanine fluorescent molecular compound has important application values in the aspects of early diagnosis and high-efficiency photodynamic treatment of tumors.
Drawings
Fig. 1 schematically shows a nuclear magnetic hydrogen spectrum of a phthalocyanine fluorescent molecular compound.
Fig. 2 schematically shows a mass spectrum of a phthalocyanine fluorescent molecular compound.
FIG. 3 schematically shows the infrared spectra of phthalocyanine fluorescent molecular compounds in aqueous solution and in dimethyl sulfoxide (dissolved state).
Fig. 4 schematically shows fluorescence spectra of the phthalocyanine fluorescent molecular compound in an aqueous solution and in dimethyl sulfoxide (dissolved state).
Fig. 5A-5B schematically show the ALV light scattering particle size test result and TEM electron micrograph of the side group post-modified phthalocyanine fluorescent nanomaterial forming an assembly in aqueous solution.
FIGS. 6A-6B are schematic diagrams showing the results of fluorescence spectrum changes of phthalocyanine fluorescent nano-material in the presence of dichlorofluorescein and irradiation of 660nm laser at different times
Fig. 7A-7B schematically show the results of the changes in fluorescence spectra of bovine serum albumin triggered phthalocyanine fluorescent nanomaterials implemented according to the present invention.
Fig. 8A-8B schematically show the results of the change in fluorescence spectrum of the glutathione triggered phthalocyanine fluorescent nanomaterial implemented according to the present invention.
Fig. 9A to 9D schematically show the results of bovine serum albumin triggered ALV particle size change of phthalocyanine fluorescent nanomaterial implemented according to the present invention.
FIG. 10 schematically shows the result of the change of the tumor-selective fluorescence signal amplification phthalocyanine fluorescent nano-material in the small animal living body imaging according to the invention.
Detailed Description
In order that the objects, technical solutions and advantages of the present invention will become more apparent, the present invention will be further described in detail with reference to the accompanying drawings in conjunction with the following specific embodiments.
The phthalocyanine and phthalocyanine system in the related art have the disadvantages of poor water solubility and easy aggregation, which greatly limits the application of the phthalocyanine system in biomedicine.
The invention introduces ions into the central ring of the phthalocyanine and changes the substituent groups around the phthalocyanine to modify or assemble the phthalocyanine to obtain a nano structure, which is more suitable for the application of phthalocyanine molecules and phthalocyanine nano particles in biomedicine. Nanomaterials are favored by researchers because of their controllable size and morphology. The nano material based on phthalocyanine overcomes the defects of the traditional treatment mode and has development potential. Attempts are being made to overcome the problems of poor water solubility and easy aggregation of phthalocyanines by incorporating them into suitable nanoparticles, which are biodegradable and biocompatible.
The development of a multifunctional nano-platform method has great hope in enhancing the tumor specificity of tumor-targeted drugs. These phthalocyanine nanomaterials also show great promise in cancer imaging and therapy.
The embodiment of the invention provides a phthalocyanine fluorescent molecular compound, a preparation method and a phthalocyanine fluorescent nano material.
As one aspect of the present invention, the present invention provides an amphiphilic phthalocyanine fluorescent molecular compound comprising:
hydrophobic phthalocyanine groups, hydrophilic polyethylene glycol segments, and biologically reactive groups.
In the embodiment of the invention, the amphiphilic phthalocyanine fluorescent molecular compound comprises a hydrophobic phthalocyanine group, a hydrophilic polyethylene glycol chain segment and a biological reaction group, and the amphiphilic group enables the phthalocyanine fluorescent molecular compound to have excellent biocompatibility, and overcomes the problems of poor water solubility and easy aggregation of phthalocyanine; the biological reaction group can be used as a targeting group to capture polypeptide or protein motif containing sulfhydryl group to trigger and release fluorescence, so that the phthalocyanine fluorescent molecular compound can be used for capturing albumin, can be combined with the albumin to trigger and release fluorescence, can be circulated in organisms for a long time, can be gathered in cancer cells through the high permeability and retention effect of solid tumors, and can generate singlet oxygen after being irradiated by illumination with a specific excitation wavelength to achieve the purpose of photodynamic therapy on superficial tumors.
According to the embodiment of the invention, the structure of the fluorescent molecular compound is shown as formula (I):
the formula (I), wherein,
represents a bioreactive group, n =4 or 8.
According to an embodiment of the present invention, the bio-reactive group includes: any one of the structures described by formula (II), formula (III), formula (IV) and formula (V):
in the embodiment of the invention, the biological reaction firewood group can be used as a targeting group to capture polypeptide or protein motif containing sulfydryl to trigger and release fluorescence, so that the phthalocyanine fluorescent molecular compound can be used for capturing albumin and triggering and release fluorescence by combining with the albumin.
According to an embodiment of the present invention, the hydrophilic polyethylene glycol segment includes tetraethylene glycol and octaethylene glycol.
As another aspect of the present invention, the present invention also provides a method for preparing the above fluorescent molecular compound, comprising:
reacting tetraethylene glycol and 4-nitrophthalonitrile in an anhydrous and oxygen-free environment to produce a phthalocyanine group precursor;
reacting the phthalocyanine group precursor with n-amyl alcohol, zinc acetate and diazabicyclo to generate a phthalocyanine group;
and reacting the phthalocyanine group with an isocyanate group to obtain the amphiphilic phthalocyanine fluorescent molecular compound.
According to an embodiment of the present invention, wherein the above tetraethylene glycol and 4-nitrophthalonitrile are reacted in an anhydrous and oxygen-free environment to produce a phthalocyanine group precursor, comprising:
mixing tetraethylene glycol, 4-nitrophthalonitrile and anhydrous K 2 CO 3 Stirring in N, N-dimethylformamide solvent at 40-80 deg.C, e.g. 40 deg.C, 50 deg.C, 70 deg.C for 24-56 h, e.g. 24h, 36h, 48h under nitrogen atmosphere, concentrating under reduced pressure, extracting, eluting, and vacuum drying to obtain phthalocyanine group precursor.
According to an embodiment of the present invention, the reacting the phthalocyanine group precursor with n-pentanol, zinc acetate, diazabicyclo to generate a phthalocyanine group includes:
adding the phthalocyanine group precursor into an n-amyl alcohol solvent, stirring for 10-60 min, for example, 10min,30min and 60min under the protection of nitrogen at 80-110 ℃, for example, 80 ℃, 90 ℃ and 110 ℃ to obtain a first mixed solution;
adding zinc acetate and diazabicyclo into the first mixed solution, reacting at 120-160 deg.C, e.g. 120 deg.C, 140 deg.C, 160 deg.C for 12-48 h, e.g. 12h,24h, 48h, removing n-amyl alcohol, adding tetrahydrofuran and silica gel, drying, separating and purifying by column chromatography, and using tetrahydrofuran and methanol as eluent to obtain phthalocyanine group.
According to an embodiment of the present invention, the above-mentioned reacting the phthalocyanine group and the isocyanate group to obtain the amphiphilic phthalocyanine fluorescent molecular compound includes:
mixing the phthalocyanine element and a catalyst in an organic solvent to obtain a second mixed solution;
the second mixed solution is added into isocyanate groups and reacts for 10 to 24 hours, such as 10h,12h and 24h under the protection of nitrogen gas, so that phthalocyanine fluorescent molecules are obtained.
According to an embodiment of the invention, wherein the catalyst comprises: dibutyl tin dilaurate.
According to an embodiment of the present invention, wherein the above tetraethylene glycol, 4-nitrophthalonitrile and anhydrous K 2 CO 3 Comprises the following components in percentage by mass: 2-5;
the mass ratio of the phthalocyanine group precursor, the zinc acetate and the diazabicyclo comprises: 1-2.
In the examples of the present invention, the above tetraethylene glycol, 4-nitrophthalonitrile and anhydrous K 2 CO 3 Comprises the following components in percentage by mass: 2 to 5, 0.5 to 2, for example, 2:0.5:1,3:1:1.5,5:2:2;
the mass ratio of the phthalocyanine group precursor, the zinc acetate and the diazabicyclo comprises: 1 to 2, 0.5 to 1.5, for example, 1:0.5:0.6,1.5:1:1,2:1.5;2.
as another aspect of the invention, the invention also provides the phthalocyanine fluorescent nano-material, which comprises an assembly formed by the fluorescent molecular compound.
In the embodiment of the invention, in an aqueous solution, the phthalocyanine fluorescent molecular compound forms an assembly to obtain the phthalocyanine nano material, so that the fluorophore is subjected to aggregate fluorescence quenching. When phthalocyanine nano-material enters into mouse body, under the action of albumin, it is prevented from being metabolized by glomerulus and captured by liver, and the enrichment of phthalocyanine nano-material in mouse tumor is enhanced, and after it enters into tumor, under the condition of existence of glutathione, albumin on the surface of phthalocyanine fluorescent molecular compound can be exchanged, and become completely water-soluble dye, and the dye is enhanced at tumor position where tumor in-situ generates fluorescent signal.
The present invention will be explained in further detail with reference to specific examples.
Example 1
The biological reactive group of the amphiphilic phthalocyanine fluorescent molecular compound, which is used as a capture group, can be modified through efficient reaction of hydroxyl and isocyanate groups, and for better understanding, phthalocyanine-tetraethyleneglycol-maleimide is taken as an example for illustration. The general reaction formula is shown as formula (VI):
the first step, synthesizing a phthalocyanine element precursor, wherein the reaction general formula is shown as a formula (VII):
the preparation method comprises the following steps: 2.24g of tetraethylene glycol, 1g of 4-nitrophthalonitrile and 1.6g of anhydrous K 2 CO 3 Dissolving in 30ml of N, N-Dimethylformamide (DMF), stirring at 50 deg.C for 48h under nitrogen atmosphere to obtain a first mixed solution,the first mixed solution was concentrated under reduced pressure, extracted three times with 60ml of ethyl acetate, and then eluted with petroleum ether-ethyl acetate volume ratio of 1.
Secondly, synthesizing phthalocyanine units containing hydrophilic chains, wherein the reaction general formula is shown as a formula (VIII):
dissolving 1.44g of phthalocyanine group precursor in 40mL of n-pentanol solvent to obtain a first mixed solution, reacting for 30min at 90 ℃ under a nitrogen atmosphere, adding 0.8g of zinc acetate and 1.0g of diazabicyclo (DBU, 1.5 mL) into the first mixed solution to obtain a second mixed solution, stirring the second mixed solution at 140 ℃, reacting for 48h, removing n-pentanol by spinning, adding tetrahydrofuran and silica gel by spinning, and purifying by column chromatography, wherein the solvent of the phthalocyanine group precursor is tetrahydrofuran: the (THF: methanol) volume ratio of methanol comprised 100:1 to 10:1 as eluent to obtain a green product which is a phthalocyanine group.
The third step: modifying a targeting group molecule through a mercapto-double bond Michael addition reaction, wherein the targeting group molecule is a biological reactive group, and the reaction general formula is shown as a formula (IX):
0.9g of maleimidobenzylacyl azide was taken in a dry round bottom flask, and 30mL of anhydrous toluene was taken and azeotropically removed by toluene. Then 20mL of anhydrous toluene is taken, heated to 90 ℃, reacted for four hours under the protection of nitrogen, and cooled to room temperature to become isocyanate group.
0.6g of phthalocyanine moiety was added to a dry round-bottom flask, 1 drop of dibutyltin Dilaurate (DBTL) was added, and 30mL of anhydrous toluene was taken and azeotropically removed with toluene. After water is removed, 30mL of anhydrous tetrahydrofuran is added into the round-bottom flask to obtain a first mixed solution, the first mixed solution is transferred into the isocyanate group by a syringe, and the reaction is carried out for 12 hours under the protection of nitrogen, so as to obtain the phthalocyanine fluorescent molecular compound.
Fig. 1 schematically shows a nuclear magnetic hydrogen spectrum of a phthalocyanine fluorescent molecular compound.
1H NMR (300MHz, DMSO-d 6)): δ =9.39-9.64 (m, 4H), 9.18-9.21 (m, 4H), 8.79-8.85 (m, 4H), 7.74-7.78 (m, 4H), 7.34-7.49 (m, 8H), 7.10-7.22 (m, 8H), 6.94-7.07 (m, 8H)), 4.55-4.70 (m, 8H), 3.57-4.20 (m, 64H).
Fig. 2 schematically shows a mass spectrum of a phthalocyanine fluorescent molecular compound.
As shown in FIG. 2, the molecular weight of the phthalocyanine fluorescent molecule compound is 2266.28.
The ultraviolet spectrum and the fluorescence spectrum of the phthalocyanine fluorescent molecular compound are shown in fig. 3 and fig. 4.
FIG. 3 schematically shows the infrared spectra of phthalocyanine fluorescent molecular compounds in aqueous solution and in dimethyl sulfoxide (dissolved state).
Fig. 4 schematically shows a fluorescence spectrum of a phthalocyanine fluorescent molecular compound in an aqueous solution and in dimethyl sulfoxide (dissolved state).
Example 2
2mg of the phthalocyanine fluorescent molecule compound prepared in example 1 is dissolved in 1mL of dimethyl sulfoxide (DMSO), and then 8mL of water is slowly added under magnetic stirring at 500rpm, wherein the water addition rate is 1mL/h. After the water is added, a dialysis bag with the molecular weight cut-off of 14000Da is used for dialysis in deionized water to remove the organic solvent in the system, water is changed every 6 hours for 3 times in total, and the dialysis is finished. The system is supplemented to 10mL, and the final phthalocyanine nano-particle has an assembly concentration of 0.2mg/mL.
The particle size of the prepared assembly was characterized by light scattering and transmission electron microscopy, and the results are shown in fig. 5A and 5B. Fig. 5A schematically shows an ALV light scattering particle size test result and a TEM electron micrograph of the side group post-modified phthalocyanine fluorescent nanomaterial forming an assembly in an aqueous solution.
Fig. 5B schematically shows a TEM electron micrograph of the assembly formed by the phthalocyanine fluorescent nanomaterial after side group post-modification in aqueous solution.
The results of the change of fluorescence spectra of phthalocyanine fluorescent nano-materials with different times in the presence of dichlorofluorescein and under the irradiation of 660nm laser are shown in fig. 6A and 6B.
FIG. 6A schematically shows the results of the fluorescence spectra of phthalocyanine fluorescent nanomaterial with different times in the presence of dichlorofluorescein and irradiation with 660nm laser.
Fig. 6B schematically shows the result of the change of the fluorescence spectrum with different times under the condition of irradiation of 660nm laser of phthalocyanine fluorescent nanomaterial.
FIG. 6A shows fluorescence excitation wavelength on the abscissa and fluorescence absorption intensity on the ordinate, indicating the efficiency of generation of Reactive Oxygen Species (ROS) in the phthalocyanine fluorescent nanomaterial under 660nm excitation light irradiation by the nanoparticles, and it can be seen from FIG. 6A that the fluorescence absorption is multiplied under 660nm wavelength laser irradiation of 20s,40s,60s,120s,240s with 2, 7-Dichlorofluorescein (DCFH) added, demonstrating that the efficiency of generation of reactive oxygen species in the nanoparticles is extremely high.
The abscissa of fig. 6B represents different times and the ordinate represents the fluorescence coefficient, and as can be seen from fig. 6B, fig. 6B is a normalized constant representing the fold increase in fluorescence coefficient from the initial fluorescence value over time.
Example 3
The fluorescence emission of albumin in mice in combination with amphiphilic phthalocyanine nanomaterials was simulated.
In mice, there are many thiol-containing proteins that can efficiently react with the double bond of maleimide to make the fluorescent nanoparticles water-soluble. For this, 1mL of the assembly at a concentration of 0.2mg/mL was taken in a 10mL sample bottle, and 1mL of phosphate buffer solution (pH =6.0, 200mm) was added. (1) 0.2mL of aqueous solution of Glutathione (GSH) with concentration of 100mM is added, then the mixed system is incubated at 37 ℃, samples are taken at fixed time points for monitoring, and the fluorescence emission of the phthalocyanine fluorescent molecule is tracked through fluorescence spectrum, as shown in FIGS. 8A-8B.
Fig. 8A-8B schematically show the results of the change in fluorescence spectrum of the glutathione triggered phthalocyanine fluorescent nanomaterial implemented according to the present invention.
The abscissa of fig. 8A represents the fluorescence excitation wavelength, and the ordinate represents the fluorescence absorption intensity, and it can be seen from fig. 8A that the fluorescence absorption of the assembled nano-cyanine fluorescent nanomaterial is also enhanced immediately after the Glutathione (GSH) is added, and the fluorescence intensity is continuously enhanced along with the time changes from 5min,10min and 30min, and the intensity of the fluorescence spectrum does not change any more around 60 minutes, so that the fluorescence spectrum is kept balanced.
The abscissa of fig. 8B represents time, and the ordinate represents fluorescence coefficient, and normalized constants from fig. 8B represent the fold increase of fluorescence coefficient with time after starting the addition of albumin.
(2) 10mg/mL of bovine serum albumin aqueous solution was added, and the mixed system was incubated at 37 ℃ and sampled and monitored at fixed time points.
The fluorescence emission of the phthalocyanine fluorescent molecule was followed by fluorescence spectroscopy, as shown in fig. 7A-7B.
Fig. 7A and 7B schematically show the result of the change of the fluorescence spectrum of the bovine serum albumin triggered phthalocyanine fluorescent nanomaterial according to the embodiment of the present invention.
The abscissa of fig. 7A represents the fluorescence excitation wavelength, and the ordinate represents the fluorescence absorption intensity, and it can be seen from fig. 7A that the fluorescence absorption of the aqueous solution of the assembled phthalocyanine nano-material is enhanced immediately after the bovine serum albumin is added, and the fluorescence intensity is continuously enhanced with the time from 5min,10min,30min, and the intensity of the fluorescence spectrum is not changed for about 30 minutes, and at this time, the nanoparticles are fully combined with the albumin.
The abscissa of fig. 7B represents time, and the ordinate represents the fluorescence coefficient, and normalized constants from fig. 7B represent the fold increase of the fluorescence coefficient with time after the start of albumin addition.
The particle size change of the phthalocyanine fluorescent molecular assembly is tracked by ALV, as shown in FIGS. 9A-9D.
Fig. 9A, 9B, 9C and 9D schematically show the results of bovine serum albumin triggering the change of the particle size of the phthalocyanine fluorescent nanomaterial ALV implemented according to the present invention.
The abscissa of fig. 9A to 9D represents the particle diameter and the ordinate represents the dispersion constant, and as can be seen from fig. 9A to 9D, the particle diameters of the phthalocyanine fluorescent nanomaterial tested at 5min,10min,30min,60min are gradually shifted to the left as can be seen from fig. 9A to 9D, that is: the particle size becomes smaller.
The experimental result shows that the fluorescence spectrum of the amphiphilic phthalocyanine molecular compound is converted under the condition of the existence of bovine serum albumin. As can be seen from the fluorescence spectrum, almost no fluorescence emission occurs before albumin is added, and after bovine serum albumin is added, the fluorescence of the phthalocyanine fluorescent nano-material assembly aqueous solution is reversed and changes along with the change of time, and finally the aqueous solution is balanced. As can be seen from ALV light scattering, the particle size of the assemblies became smaller after albumin addition, also indicating that the assemblies became water soluble over time.
FIG. 10 schematically shows the result of the change of the tumor-selective fluorescence signal amplification phthalocyanine fluorescent nano-material in the small animal living body imaging according to the invention.
As shown in fig. 10, fig. 10 is the fluorescence imaging effect of nanoparticles injected into mice at different times: pc-4OH is an unlinked bioreactive group (reference group) and Pc-4OH-4MI is an attached bioreactive group (experimental group).
The above-mentioned embodiments, objects, technical solutions and advantages of the present invention are further described in detail, it should be understood that the above-mentioned embodiments are only examples of the present invention, and should not be construed as limiting the present invention, and any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (5)
1. A phthalocyanine fluorescent molecule compound comprising:
a hydrophobic phthalocyanine group, a hydrophilic polyethylene glycol segment, and a bioreactive group;
the biological reactive group can be used as a targeting group to capture polypeptide or protein motif containing sulfydryl to trigger and release fluorescence;
wherein the structure of the fluorescent molecular compound is shown as the formula (I):
wherein, the first and the second end of the pipe are connected with each other,
represents a bioreactive group, n =4 or 8;
wherein the bioreactive group is of the formula (II):
2. a method of preparing the fluorescent molecular compound of claim 1, comprising:
reacting tetraethylene glycol and 4-nitrophthalonitrile in an anhydrous and oxygen-free environment to produce a phthalocyanine group precursor;
reacting the phthalocyanine group precursor with n-amyl alcohol, zinc acetate and diazabicyclo to generate a phthalocyanine group;
reacting the phthalocyanine group with an isocyanate group to obtain an amphiphilic phthalocyanine fluorescent molecular compound;
wherein the tetraethylene glycol and 4-nitrophthalonitrile are reacted in an anhydrous and oxygen-free environment to produce a phthalocyanine group precursor comprising:
reacting tetraethylene glycol, 4-nitrophthalonitrile and anhydrous K 2 CO 3 Reacting for 24-56 h in N, N-dimethylformamide solvent at 40-80 ℃ in nitrogen atmosphere to obtain phthalocyanine group precursor;
wherein the reaction of the phthalocyanine group precursor with n-pentanol, zinc acetate, diazabicyclo to generate a phthalocyanine group comprises:
adding the phthalocyanine group precursor into an n-amyl alcohol solvent, and stirring for 10-60 min at 80-110 ℃ under the protection of nitrogen to obtain a first mixed solution;
adding zinc acetate and diazabicyclo into the first mixed solution, and reacting for 12-48 h at 120-160 ℃ to obtain phthalocyanine groups;
wherein, the phthalocyanine group and the isocyanate group are reacted to obtain the amphiphilic phthalocyanine fluorescent molecular compound, which comprises the following steps:
mixing the phthalocyanine group and a catalyst in an organic solution to obtain a second mixed solution;
and adding the second mixed solution into isocyanate, and reacting for 10-24 h under the protection of nitrogen to obtain the phthalocyanine fluorescent molecule.
3. The production method according to claim 2, wherein the catalyst comprises dibutyltin dilaurate.
4. The production method according to claim 2, wherein the tetraethylene glycol, 4-nitrophthalonitrile and anhydrous K 2 CO 3 The mass ratio of (1) to (2) is (2-5);
the mass ratio of the phthalocyanine group precursor to the zinc acetate to the diazabicyclo is 1-2.
5. A phthalocyanine fluorescent nanomaterial comprising an assembly formed from the fluorescent molecular compound of claim 1.
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