CN117327098A - Preparation method and application of AIE type photosensitizer mainly used for type I photodynamic therapy - Google Patents
Preparation method and application of AIE type photosensitizer mainly used for type I photodynamic therapy Download PDFInfo
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- CN117327098A CN117327098A CN202311272063.8A CN202311272063A CN117327098A CN 117327098 A CN117327098 A CN 117327098A CN 202311272063 A CN202311272063 A CN 202311272063A CN 117327098 A CN117327098 A CN 117327098A
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- 239000003504 photosensitizing agent Substances 0.000 title claims abstract description 79
- 238000002428 photodynamic therapy Methods 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 238000000746 purification Methods 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 38
- -1 n-octyl Chemical group 0.000 claims description 24
- PDQRQJVPEFGVRK-UHFFFAOYSA-N 2,1,3-benzothiadiazole Chemical compound C1=CC=CC2=NSN=C21 PDQRQJVPEFGVRK-UHFFFAOYSA-N 0.000 claims description 23
- 206010028980 Neoplasm Diseases 0.000 claims description 21
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 20
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- ANSXAPJVJOKRDJ-UHFFFAOYSA-N furo[3,4-f][2]benzofuran-1,3,5,7-tetrone Chemical compound C1=C2C(=O)OC(=O)C2=CC2=C1C(=O)OC2=O ANSXAPJVJOKRDJ-UHFFFAOYSA-N 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 229940125898 compound 5 Drugs 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- UKHQRARQNZOXRL-UHFFFAOYSA-N trimethyltin Chemical compound C[SnH](C)C UKHQRARQNZOXRL-UHFFFAOYSA-N 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 2
- 238000005893 bromination reaction Methods 0.000 claims description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 2
- 150000004867 thiadiazoles Chemical class 0.000 claims 2
- 230000000694 effects Effects 0.000 abstract description 15
- 239000001301 oxygen Substances 0.000 abstract description 10
- 229910052760 oxygen Inorganic materials 0.000 abstract description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 9
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- 125000004434 sulfur atom Chemical group 0.000 abstract description 3
- JLZUZNKTTIRERF-UHFFFAOYSA-N tetraphenylethylene Chemical class C1=CC=CC=C1C(C=1C=CC=CC=1)=C(C=1C=CC=CC=1)C1=CC=CC=C1 JLZUZNKTTIRERF-UHFFFAOYSA-N 0.000 abstract description 3
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- 229940041181 antineoplastic drug Drugs 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
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- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 5
- 206010021143 Hypoxia Diseases 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
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- 229910021642 ultra pure water Inorganic materials 0.000 description 3
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
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- OZNXIGFAKCITRZ-UHFFFAOYSA-N (4-hexylthiophen-2-yl)-trimethylstannane Chemical compound CCCCCCC1=CSC([Sn](C)(C)C)=C1 OZNXIGFAKCITRZ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- AOYYVOMPLAJFEK-UHFFFAOYSA-N 3-[(2-carboxyacetyl)oxymethoxy]-3-oxopropanoic acid Chemical compound OC(=O)CC(=O)OCOC(=O)CC(O)=O AOYYVOMPLAJFEK-UHFFFAOYSA-N 0.000 description 1
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
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- SRLOHQKOADWDBV-NRONOFSHSA-M sodium;[(2r)-2,3-di(octadecanoyloxy)propyl] 2-(2-methoxyethoxycarbonylamino)ethyl phosphate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCCNC(=O)OCCOC)OC(=O)CCCCCCCCCCCCCCCCC SRLOHQKOADWDBV-NRONOFSHSA-M 0.000 description 1
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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
- C07D513/12—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 three hetero rings
- C07D513/14—Ortho-condensed systems
-
- 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
-
- 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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- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
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- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
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- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
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- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1003—Carbocyclic compounds
- C09K2211/1007—Non-condensed systems
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- 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
- C09K2211/1044—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms
- C09K2211/1051—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms with sulfur
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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
- 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
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- Chemical & Material Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
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- Biochemistry (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of antitumor drugs, and particularly discloses a preparation method and application of an AIE type photosensitizer mainly used for type I photodynamic therapy. The chemical structure of the AIE photosensitizer is shown as a formula (I):the photosensitizer of the invention can improve the coupling constant due to the heavy atomic effect of sulfur atoms, is favorable for intersystem crossing of excitons, improves the yield of active oxygen generated by the photosensitizer TM, and has good photodynamic therapy effect. The photosensitizer TM skeleton contains R 1 The group-substituted tetraphenyl ethylene unit shows obvious aggregation inductionLight emitting (AIE) performance. AIE photosensitizers are capable of rapidly generating cytotoxic superoxide anion radicals (. O) by electron transfer 2 ‑ ) Killing tumor cells and achieving the purpose of inhibiting tumor growth. The preparation method of the photosensitizer has the advantages of easily available raw materials, mild synthesis conditions, simple preparation method, convenient purification and easy realization, and has great application prospect.
Description
Technical Field
The invention belongs to the technical field of antitumor drugs, and particularly relates to a preparation method and application of an AIE type photosensitizer mainly used for type I photodynamic therapy.
Background
The existing cancer treatment method mainly takes traditional surgical excision as a main part, and chemical drug treatment and radiation treatment are adopted as auxiliary parts. The traditional treatment method has certain effect, but also has limitations such as high possibility of recurrence, high toxic and side effects of the medicine and the like. Photodynamic therapy (PDT) is somewhat complementary to conventional methods. For example, photodynamic therapy has the advantages of good tissue selectivity, non-invasiveness, quick response, drug resistance, few systemic side effects, repeated treatment, and the like, and can cooperate with other therapeutic methods. Photosensitizers with AIE properties are highlighted in fluorescence-visualized photodynamic therapy of tumors, receiving extensive attention from researchers, thanks to their excellent optical properties and enhanced properties of aggregation-induced Reactive Oxygen Species (ROS) production. Photodynamic therapy is the conversion of an excited photosensitizer by singlet-triplet light, the energy gained by ground oxygen or by photooxidation to form singlet oxygen (Type II mechanism), or the reaction with other biomolecules to form numerous reactive oxygen species (reactive oxygen species, ROS, type I mechanism) for killing cancer cells, the mechanism schematic is shown in fig. 1 (yablon-base schematic).
Most of the AIE type photosensitizers reported at present are type II photosensitizers mainly generating singlet oxygen, however, the process of generating ROS by the type II photosensitizers has high dependence on oxygen, and the ROS generation efficiency is often limited by the hypoxia condition of tumor tissues. In contrast, type I photosensitizers proved to have better hypoxia tolerance properties, enabling full use of limited oxygen in the tumor microenvironment during photodynamic processes. And based on the important role played in maintaining cell growth, resisting cell death, activating invasion and metastasis of cancer cells, the nucleus is considered as the optimal target for photodynamic therapy. Therefore, the AIE type photosensitizer with I type photodynamic therapy is developed, the problem of hypoxia faced by the traditional high-oxygen dependent II type photosensitizer in the photodynamic therapy of tumors can be overcome, the photodynamic therapy efficacy of the I type photosensitizer is fully exerted, and the method has important significance for improving the therapy effect of the hypoxic solid tumor.
Disclosure of Invention
To overcome the above-mentioned drawbacks and disadvantages of the prior art, a primary object of the present invention is to provide an AIE-type photosensitizer based on use in type I photodynamic therapy.
It is another object of the present invention to provide a method for preparing the above-described AIE-type photosensitizers for use in type I photodynamic therapy.
It is still another object of the present invention to provide the use of the above AIE-type photosensitizers in the preparation of photosensitizers for photodynamic therapy of tumors, especially in the preparation of photosensitizers for photodynamic therapy of type I tumors.
The invention aims at realizing the following technical scheme:
an AIE type photosensitizer mainly used for type I photodynamic therapy, named TM, has a chemical structure shown in formula (I):
wherein R is a linear or branched alkyl group having 1 to 30 carbon atoms, R 1 Is hydrogen or straight-chain or branched alkyl with 1-30 carbon atoms, R 1 And taking and aligning.
Preferably, R is a straight or branched alkyl group having 1 to 12 carbon atoms, R 1 Is hydrogen or straight-chain or branched alkyl with 1-8 carbon atoms, R 1 And taking and aligning.
More preferably, R is a straight or branched alkyl group having 6 to 12 carbon atoms, R 1 Is hydrogen or straight-chain or branched alkyl with 1-4 carbon atoms, R 1 And taking and aligning.
More preferably, R is a linear or branched alkyl group having 6, 8 or 12 carbon atoms, R 1 Is hydrogen, methyl or tert-butyl, R 1 Taking para position, and the structural formula corresponding to the TM in the formula (I) is as follows:
most preferably, R is n-hexyl, n-octyl, isooctyl or 2-butyloctyl, R 1 Is hydrogen, methyl or tert-butyl, R 1 And taking and aligning.
The preparation method of the AIE type photosensitizer mainly used for type I photodynamic therapy comprises the following steps:
(1) 5, 8-dibromodithioeno [3',2':3,4; 2', 3', 5,6] benzo [1,2-c ] [1,2,5] thiadiazole and (4-R-base thiophene-2-base) trimethyl stannane are dissolved in toluene solvent, tetra (triphenylphosphine) palladium is used as a catalyst, the reaction is carried out for 8 hours at 80 ℃, and the compound 5, 8-bis (4-R-base thiophene-2-base) dithieno [3',2':3,4 is obtained after purification; 2",3":5,6] benzo [1,2-c ] [1,2,5] thiadiazole (compound 1);
(2) 5, 8-bis (4-R-ylthiophene-2-yl) dithieno [3',2':3,4; 2', 3':5, 6] benzo [1,2-c ] [1,2,5] thiadiazole (compound 1) is subjected to bromination reaction under the action of N-bromosuccinimide (NBS), and the compound 5, 8-bis (5-bromo-4-R-base thiophene-2-yl) dithieno [3',2':3,4 is obtained after purification; 2",3":5,6] benzo [1,2-c ] [1,2,5] thiadiazole (compound 2);
(3) 5, 8-bis (5-bromo-4-R-ylthiophene-2-yl) dithieno [3',2':3,4;2",3":5,6]Benzo [1,2-c][1,2,5]Thiadiazole (Compound 2) and 4, 5-tetramethyl-2- (4- (1, 2-tri R) 1 The phenyl) -1,3, 2-dioxaborane takes toluene as solvent to carry out Suzuki coupling reaction under the action of catalyst tetra (triphenylphosphine) palladium and potassium carbonate, and the reaction is carried out for 12 hours at 80 ℃, and the compound 5, 8-bis (4-R-group-5- (4- (1, 2-tri R) is obtained after purification 1 -phenylvinyl) phenyl) thiophen-2-yl) dithieno [3',2':3,4;2",3':5,6]Benzo [1,2-c][1,2,5]Thiadiazole (TM).
Further, in step (1), 5, 8-dibromodithioeno [3',2':3,4; 2', 3':5, 6] benzo [1,2-c ] [1,2,5] thiadiazole, (4-R-ylthiophene-2-yl) trimethylstannane, tetrakis (triphenylphosphine) palladium in a molar ratio of 1:2 to 4:0.03 to 0.07, preferably 1:3:0.05,5, 8-dibromodithiophene [3',2':3,4; 2', 3':5, 6] benzo [1,2-c ] [1,2,5] thiadiazole in a molar amount to toluene volume ratio of 1mmol (5-10) mL, preferably 1mmol:7.5mL;
further, in step (2), 5, 8-bis (4-R-ylthiophene-2-yl) dithieno [3',2':3,4; 2', 3':5, 6] benzo [1,2-c ] [1,2,5] thiadiazole, N-bromosuccinimide in a molar ratio of 1:0.3-0.7, preferably 1:0.5;
further, in step (3), 5, 8-bis (5-bromo-4-R-ylthiophene-2-yl) dithieno [3',2':3,4;2",3":5,6]Benzo [1,2-c][1,2,5]Thiadiazole, 4, 5-tetramethyl-2- (4- (1, 2-tri R) 1 The molar ratio of the phenyl vinyl) phenyl) -1,3, 2-dioxaborane, the tetra (triphenylphosphine) palladium and the potassium carbonate is 1:2-3:0.02-0.2:5-10, preferably 1:2.5:0.05:8,5, 8-bis (5-bromo-4-R-thiophen-2-yl) dithieno [3',2':3,4;2",3":5,6]Benzo [1,2-c][1,2,5]The molar quantity of thiadiazole to toluene volume ratio is 1mmol (15-30) mL, preferably 1mmol:20mL.
The specific preparation route of the AIE type photosensitizer mainly used for type I photodynamic therapy is as follows:
the AIE photosensitizer and the application of the AIE photosensitizer synthesized by the method in preparing the photosensitizer for photodynamic therapy of tumors, in particular to the application in preparing the photosensitizer mainly for photodynamic therapy of tumor type I.
When the water-soluble photosensitizer nanoparticle is specifically applied, the photosensitizer and the amphiphilic polymer are dissolved in an organic solvent, then ultrapure water is added into the system, ultrasound is carried out, the system is uniformly dispersed, and then the organic solvent is removed, so that the water-soluble photosensitizer nanoparticle is obtained, and the apparent concentration of the water-soluble photosensitizer nanoparticle is more than or equal to 210 mug/mL.
Further, the organic solvent is selected from one of tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide and ethyl acetate.
Further, the amphiphilic polymer is F127 (amphiphilic triblock polymer formed by ethoxy-propoxy), DSPE-mPEG2000 (distearoyl phosphatidylethanolamine-polyethylene glycol 2000) or DSPE-mPEG5000 (distearoyl phosphatidylethanolamine-polyethylene glycol 5000).
Further, the tumor is a subcutaneous tumor.
The AIE type photosensitizer mainly used for type I photodynamic therapy can improve the coupling constant due to the heavy atomic effect of sulfur atoms, is favorable for intersystem crossing of excitons, improves the yield of active oxygen generated by the photosensitizer TM, and has good photodynamic therapy effect. The photosensitizer TM skeleton contains R 1 The group substituted tetraphenyl ethylene unit showed significant Aggregation Induced Emission (AIE) properties. Under the illumination condition, AIE type photosensitizer rapidly generates cytotoxic superoxide anion free radical (O) through photochemical route of electron transfer 2 - ) Killing tumor cells and achieving the purpose of inhibiting tumor growth. The preparation method of the photosensitizer has the advantages of easily available raw materials, mild synthesis conditions, simple preparation method, convenient purification and easy realization, and has great application prospect.
Compared with the prior art, the invention has the following advantages:
1. the photosensitizer TM can enlarge the spin orbit coupling constant between the singlet state and the triplet state due to the heavy atom effect of sulfur atoms, is favorable for intersystem crossing of excitons, improves the yield of active oxygen generated by the photosensitizer TM, and has good photodynamic therapy effect.
2. Photosensitizer TM contains R 1 The group-substituted tetraphenyl ethylene units have typical aggregation-induced emission (AIE) properties.
3. The photosensitizer TM is a photosensitizer which can be used for photodynamic therapy of tumors, has no toxicity to cancer cells in a normal cultivation environment and has good biocompatibility; the fluorescent dye has the characteristic of high injury effect on cancer cells under the illumination action of a xenon lamp (the wavelength range is 300-750 nm); the cells are cancer cells, especially Hela cells.
4. Photosensitizer rapidly generates superoxide anion radical (.O) by electron transfer 2 - ) To kill tumor cellsThe therapeutic purpose of inhibiting the growth of tumor is achieved, and the type I photodynamic therapy is mainly used, so that the composition has better hypoxia tolerance.
5. The preparation method of the photosensitizer TM has the advantages of easily available raw materials, mild synthesis conditions, simple preparation method and convenient purification.
Drawings
Fig. 1: a jacobian schematic diagram.
Fig. 2: fluorescence emission spectra of TM1 nanoparticles in different water content systems.
Fig. 3: ultraviolet visible absorption spectrum of ABDA under TM1 nanoparticles and light conditions.
Fig. 4: photo-dynamic therapeutic test results of photosensitizer TM1 nanoparticles on Hela cells.
Fig. 5: fluorescence emission spectrum of DHE under TM1 nanoparticles and illumination.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but embodiments of the present invention are not limited thereto.
Example one preparation of Compound TM1
(1) 5, 8-bis (4-hexylthiophen-2-yl) dithieno [3',2':3,4; synthesis of 2', 3':5, 6] benzo [1,2-c ] [1,2,5] thiadiazole (Compound 1)
5, 8-dibromodithioeno [3',2':3,4;2",3":5,6]Benzo [1,2-c][1,2,5]Thiadiazole (8.12 g,20 mmol), (4-hexylthiophen-2-yl) trimethylstannane (19.87 g,60 mmol), tetrakis (triphenylphosphine) palladium (1.16 g,1 mmol) and 150mL toluene were added to a 500mL two-necked flask, and reacted at 80℃for 8 hours under nitrogen protection. Stirring was stopped and cooled to room temperature, extracted with dichloromethane, washed with water and purified by column on silica gel (petroleum ether: dichloromethane=4:1, v/v) to give 9.36g of product in 81% yield. MS (APCI) (C) 30 H 32 N 2 S 5 ):580.90. MS results show that the obtained compound is a target product, and the chemical reaction equation in the preparation process is as follows:
(2) 5, 8-bis (5-bromo-4-hexylthiophen-2-yl) dithieno [3',2':3,4; synthesis of 2', 3':5, 6] benzo [1,2-c ] [1,2,5] thiadiazole (Compound 2)
5, 8-bis (4-hexylthiophen-2-yl) dithieno [3',2':3,4;2",3":5,6]Benzo [1,2-c][1,2,5]Thiadiazole (9.36 g,16.11 mmol) and N-bromosuccinimide (1.43 g,8.06 mmol), after 5 hours at normal temperature, the catalyst N-bromosuccinimide was quenched with ammonium chloride solution and purified by silica gel column (petroleum ether: dichloromethane=6:1, v/v); 6.53g of product was obtained in 70% yield. MS (APCI) (C) 30 H 30 Br 2 N 2 S 5 ):738.69. MS results show that the obtained compound is a target product, and the chemical reaction equation in the preparation process is as follows:
(3) Preparation of photosensitizer (TM 1)
5, 8-bis (5-bromo-4-hexylthiophen-2-yl) dithieno [3',2':3,4 ] was added to a 500mL two-necked flask under an argon atmosphere; 2', 3':5, 6] benzo [1,2-c ] [1,2,5] thiadiazole (6.53 g,8.84 mmol), 4, 5-tetramethyl-2- (4- (1, 2-triphenylvinyl) phenyl) -1,3, 2-dioxaborane (10.13 g,22.10 mmol), tetrakis (triphenylphosphine) palladium (0.51 g,0.44 mmol), potassium carbonate (9.77 g,70.72 mmol) and 176.80mL toluene were heated to 80℃and reacted for 12 hours. After stopping the reaction, quenching the reaction with water, extracting with dichloromethane, drying with anhydrous magnesium sulfate, concentrating the solution, purifying by silica gel column chromatography, using petroleum ether and dichloromethane mixed solvent (the volume ratio of petroleum ether to dichloromethane is 4:1) as leaching agent, and drying to obtain the compound TM1 with 75% yield. MS and elemental analysis results show that the obtained compound is a target product, and a chemical reaction equation in the preparation process is shown as follows:
TM1 (chemical structural formula C) 82 H 68 N 2 S 5 ) The theoretical molecular weight is 1241.78, and the result of the analysis by a matrix assisted laser desorption tandem time of flight mass spectrometer (MALDI-TOF) is 1240.40[ M+H ] + ]. The content of C, H, N element in TM1 is tested by a Perkinelmer element analyzer (model EA-2400 II), and the theoretical value is C79.24%; h5.47%; 2.25% of N; 12.88 percent of S. The measured value is C79.32%; h5.52%; 2.26% of N; s is 12.91 percent. The mass spectrum and elemental analysis test results are close to the theoretical values, and the synthesized product is proved to be the target product.
(4) Preparation of nanoparticles
In order to adapt to complex water environment in organisms, 10mg of oil-soluble photosensitizer TM1 and 100mg of amphiphilic polymer F127 (amphiphilic triblock polymer formed by ethoxy-propoxy) are completely dissolved in 1.5mL of tetrahydrofuran solution, under the condition of ultrasound, a mixed system is rapidly added into 20mL of ultrapure water, ultrasound is continued for 10min to uniformly disperse the system, nitrogen is blown into a sample to remove tetrahydrofuran, and finally the sample is stored in a refrigerator at 4 ℃ for standby.
The apparent concentration of the prepared water-soluble TM1 nanoparticles (TM 1 NPs) was 500. Mu.g/mL. The size of the TM1NPs was measured using a Markov laser particle sizer (model Mastersizer 3000) and indicated a particle size of 86nm and a polydispersity PDI of 0.17.
EXAMPLE two preparation of Compound TM7
(1) 5, 8-bis (4- (2-butyl) octylthiophen-2-yl) dithieno [3',2':3,4; synthesis of 2', 3':5, 6] benzo [1,2-c ] [1,2,5] thiadiazole (Compound 1)
5, 8-dibromodithioeno [3',2':3,4;2",3":5,6]Benzo [1,2-c][1,2,5]Thiadiazole (8.12 g,20 mmol), (4- (2-butyl) octylthiophen-2-yl) trimethylstannane (24.92 g,60 mmol), tetrakis (triphenylphosphine) palladium (1.16 g,1 mmol) and 150mL toluene were added to a 500mL two-necked flask and reacted at 80℃for 8 hours under nitrogen protection. Stirring was stopped and cooled to room temperature, extracted with dichloromethane, washed with water, and purified by a silica gel column (elutionThe agent is petroleum ether: dichloromethane = 4:1, v/v) to give 11.94g of product in 80% yield. MS (APCI) (C) 42 H 56 N 2 S 5 ):749.22. MS results show that the obtained compound is a target product, and the chemical reaction equation in the preparation process is as follows:
(2) 5, 8-bis (5-bromo-4- (2-butyl) octylthiophen-2-yl) dithioeno [3',2':3,4; synthesis of 2', 3':5, 6] benzo [1,2-c ] [1,2,5] thiadiazole (Compound 2)
5, 8-bis (4- (2-butyl) octylthiophen-2-yl) dithieno [3',2':3,4;2",3":5,6]Benzo [1,2-c][1,2,5]Thiadiazole (11.94 g,15.94 mmol) and N-bromosuccinimide (1.42 g,7.97 mmol), after 5 hours at normal temperature, the catalyst N-bromosuccinimide was quenched with ammonium chloride solution and purified by silica gel column (petroleum ether: dichloromethane=6:1, v/v); 10.21g of product was obtained in 71% yield. MS (APCI) (C) 42 H 54 Br 2 N 2 S 5 ):907.02. MS results show that the obtained compound is a target product, and the chemical reaction equation in the preparation process is as follows:
(3) Preparation of photosensitizer (TM 7)
5, 8-bis (5-bromo-4- (2-butyl) octylthiophen-2-yl) dithieno [3',2':3,4 ] was added to a 500mL two-necked flask under an argon atmosphere; 2', 3':5, 6] benzo [1,2-c ] [1,2,5] thiadiazole (10.21 g,10.36 mmol), 4, 5-tetramethyl-2- (4- (1, 2-triphenylvinyl) phenyl) -1,3, 2-dioxaborane (11.87 g,25.90 mmol), tetrakis (triphenylphosphine) palladium (0.60 g,0.52 mmol), potassium carbonate (11.45 g,82.88 mmol) and 207.20mL toluene were heated to 80℃and reacted for 12 hours. After stopping the reaction, quenching the reaction with water, extracting with dichloromethane, drying with anhydrous magnesium sulfate, concentrating the solution, purifying by silica gel column chromatography, using petroleum ether and dichloromethane mixed solvent (the volume ratio of petroleum ether to dichloromethane is 4:1) as leaching agent, and drying to obtain the compound TM7 with the yield of 72%. MS and elemental analysis results show that the obtained compound is a target product, and a chemical reaction equation in the preparation process is shown as follows:
TM7 (chemical structural formula C) 94 H 92 N 2 S 5 ) The theoretical molecular weight is 1410.18, and the result of the analysis by a matrix assisted laser desorption tandem time of flight mass spectrometer (MALDI-TOF) is 1408.59[ M+H ] + ]. The content of C, H, N element in TM1 is tested by a Perkinelmer element analyzer (model EA-2400 II), and the theoretical value is C79.99%; h is 6.52%; 1.99% of N; s is 11.35 percent. The measured value is C80.07%; h is 6.58%; 1.99% of N; s is 11.37 percent. The mass spectrum and elemental analysis test results are close to the theoretical values, and the synthesized product is proved to be the target product.
(4) Preparation of nanoparticles
In order to adapt to complex water environment in organisms, 10mg of oil-soluble photosensitizer TM7 and 100mg of amphiphilic polymer F127 (amphiphilic triblock polymer formed by ethoxy-propoxy) are completely dissolved in 1.0mL of tetrahydrofuran solution, under the condition of ultrasound, a mixed system is rapidly added into 20mL of ultrapure water, ultrasound is continued for 10min to uniformly disperse the system, nitrogen is blown into a sample to remove tetrahydrofuran, and finally the sample is stored in a refrigerator at 4 ℃ for standby.
The apparent concentration of the prepared water-soluble TM7 nanoparticles (TM 7 NPs) was 500. Mu.g/mL. The size of the TM7NPs was measured using a Markov laser particle sizer (model Mastersizer 3000) and indicated a particle size of 75nm and a polydispersity PDI of 0.18.
Compared with the photosensitizers TM1 and TM7, the conjugated skeletons of the photosensitizers TM1 and TM7 are the same, the photophysical properties are the same, the solubility of the side chain alkyl chain is different, the process is slightly different in the process of preparing the nano particles, and the specific embodiment is that the volume of the dissolved photosensitizers is different.
Photosensitizer TM contains R1 groups substituted tetraphenyl ethylene units with typical aggregation-induced emission (AIE) properties. Experiments prove that: configuration 10 -3 The mother solution (TM 1 as solute and acetonitrile as solvent) of mol/L is diluted to a concentration of 10 -5 The absorption wavelength of the solution with the water content of 0%, 20%, 40%, 60%, 80% and 99% is measured by fluorescence emission spectrum after the solution is placed in an ultrasonic instrument for ultrasonic treatment for 30s, and the test result is shown in figure 2. As can be seen from FIG. 2, the fluorescence emission wavelength of TM1 with different water contents is about 560 nm. And as the water content increases, the fluorescence emission wavelength of TM1 increases first and then decreases, which indicates that the photosensitizer TM has good AIE performance.
The photodynamic properties of TM1 nanoparticles are measured by the yield of active oxygen. 9, 10-Anthranediyl-bis (methylene) dimalonate (ABDA) is a commonly used singlet oxygen (one of the active oxygen) probe, and TM1 nanoparticles generate singlet oxygen under light conditions, which can oxidize ABDA. Thus, the amount of ABDA in the system is consumed and the absorbance decreases accordingly. If the TM1NPs cannot generate singlet oxygen under the illumination condition, the absorbance of the ABDA remains unchanged. 3mL of the test sample was prepared, wherein the concentration of TM1NPs was 60. Mu.g/mL and the concentration of ABDA was 50. Mu. Mol/L. FIG. 3 is an ultraviolet-visible absorption spectrum of the ABDA of the TM1NPs under illumination (xenon lamp) with an illumination wavelength of 300-450 nm and an illumination power of 80mW cm -2 . As can be seen from the graph, the absorbance of the characteristic peak of ABDA at 399nm gradually decreased with the change in light irradiation time, showing time dependence. After 300s of illumination, the absorbance of 0.791 was reduced to 0.507 at no illumination, with a reduction of 36%. The photosensitizer TM1 is II type photosensitizer, can efficiently generate active oxygen through illumination, and can be used for photodynamic therapy.
The cytotoxicity of TM1 and photodynamic therapy effect on HeLa cells were examined by CCK-8 method, and the specific experimental procedure was as follows:
1) Nanoparticle stock solutions at 500. Mu.g/mL were diluted to 10. Mu.g/mL, 30. Mu.g/mL, 50. Mu.g/mL, 70. Mu.g/mL, 90. Mu.g/mL with complete medium (DMEM, containing 10% fetal calf serum, 100U/mL penicillin and 100. Mu.g/mL streptomycin).
2) HeLa cells (human cervical cancer cells, ATCC) in logarithmic growth phase were digested with 0.25% trypsin and the cells were diluted uniformly to a concentration of 5X 10 4 Individual cells/mL.
3) Adding the cell solution into 96-well plate with 100 μl of each well, slightly shaking, and adding 5% CO at 37deg.C 2 Is cultivated for 24 hours.
4) Complete medium containing TM1 nanoparticles at different concentrations was added to 96-well plates at 100 μl per well, 10 wells were set per concentration, one group per 5 wells, and 2 groups total, i.e. illuminated and non-illuminated. Wherein 0. Mu.g/mL was set as the control group. And the 96-well plates were placed in an incubator for 12h incubation.
5) The illuminating group 96-well plate was taken out, and a xenon lamp (power 80W/cm was used 2 ) After 5.0min of irradiation, the cells were placed in an incubator and incubated for a further 12h. No light treatment was required for the non-light group 96-well plates. Directly culturing for 24h.
6) The spent medium in the 96-well plates of the light and non-light groups was washed out, 100. Mu.L of complete medium containing 10% CCK-8 was added to each well, and the medium was returned to the incubator for 1 hour.
7) And (3) placing the 96-well plates of the light group and the non-light group into an enzyme-labeling instrument, testing the absorbance of an absorption peak of each well at 450nm, averaging the absorbance of 5 wells of each group and calculating the standard deviation, and calculating the survival rate of the cancer cells. The CCK-8 test results are shown in FIG. 4.
As can be seen from FIG. 4, the viability of Hela cells was maintained at 94% or more at different concentrations of TM1NPs in the absence of light. The TM1NPs are demonstrated to exhibit excellent biocompatibility under light conditions without a xenon lamp. Whereas, in the light conditions, the viability of the cells is related to the concentration of TM1NPs, the greater the concentration of TM1NPs, the lower the viability of the cells, i.e. the greater the killing power of the cells in the case of xenon lamp illumination. At a concentration of 10. Mu.g/mL, TM1NPs can kill 14.4% of HeLa cells; at a concentration of 30 μg/mL, TM1NPs can kill 28.7% of Hela cells; at a concentration of 50. Mu.g/mL, TM1NPs can kill 41.5% of HeLa cells; at a concentration of 70. Mu.g/mL, TM1NPs can kill 54.4% of Hela cells; at a concentration of 90. Mu.g/mL, TM1NPs can kill 66.8% of HeLa cells. The TM1NPs were demonstrated to have excellent photodynamic therapy effect on HeLa cells.
The photodynamic therapy effect of TM7NPs was evaluated by the same method as described above, except that the complete medium containing different concentrations of TM1NPs in step 4) was changed to a complete medium containing different concentrations of TM7 NPs. The results show that the survival rate of Hela cells can be maintained to be more than 90% under the condition of no illumination by the TM7NPs with different concentrations. The TM7NPs are free from cytotoxicity under the condition of no illumination and have good biocompatibility. While the viability of cells under light conditions is also related to the concentration of TM7NPs, the greater the concentration of TM7NPs, the lower the cell viability, i.e., the greater the killing of cells under xenon lamp light. At a concentration of 10. Mu.g/mL, TM7NPs can kill 13.4% of HeLa cells; at a concentration of 30 μg/mL, TM7NPs can kill 26.3% of Hela cells; at a concentration of 50. Mu.g/mL, TM7NPs can kill 34.2% of Hela cells; at a concentration of 70. Mu.g/mL, TM7NPs can kill 52.9% of Hela cells; at a concentration of 90. Mu.g/mL, TM7NPs can kill 67.5% of Hela cells. The TM7NPs are also shown to have excellent photodynamic therapy effect on Hela cells, and are equivalent to the photodynamic therapy effect of TM1 NPs.
AIE photosensitizers are capable of rapidly generating cytotoxic superoxide anion radicals (. O) by electron transfer 2 (-), kill tumor cells, and achieve the treatment purpose of inhibiting tumor growth.
DHE (Dihydroethidium) is itself a blue probe of cell membrane permeability (λEx/λEm:370/420 nm) and can be used to detect superoxide anion radical (. Degree.O) 2 (-), the amount and change of the ROS content of the cells can be judged according to the condition of fluorescence reduction. To verify that TM1 is a type I photosensitizer for photodynamic therapy, 100. Mu.L of DHE (10 umol/L) was added to a solution of TM1NPs at a concentration of 40. Mu.g/mL in a volume of 3.0mL, and the sample was tested using a fluorescence spectrometer, with a specific absorption spectrum as shown in FIG. 5. The sample responded very fast after addition of DHE and fluorescence decreased in the 380-500nm range compared to the no DHE group. TM1 is illustrated with a type I photosensitizer for photodynamic therapy. FIG. 3 Experimental determination of photosensitizer TM1 as a type II photosensitizer using an ABDA indicatorThe test response time of the indicator is long and is 300s; while the experimental DHE indicator of fig. 5 measures photosensitizer TM1 as a type I photosensitizer, the test response time is only 5s. The photosensitizer TM1 is described as an AIE type fluorescent molecule that is primarily useful in type I photodynamic therapy.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (10)
1. An AIE type photosensitizer mainly used for type I photodynamic therapy, which has a chemical structure as shown in formula (I):
wherein R is a linear or branched alkyl group having 1 to 30 carbon atoms, R 1 Is hydrogen or straight-chain or branched alkyl with 1-30 carbon atoms, R 1 And taking and aligning.
2. The AIE-type photosensitizer predominantly for photodynamic therapy type I according to claim 1, characterized in that: in the formula (I), R is a straight-chain or branched-chain alkyl group with 1-12 carbon atoms, R 1 Is hydrogen or straight-chain or branched alkyl with 1-8 carbon atoms, R 1 And taking and aligning.
3. The AIE-type photosensitizer predominantly for photodynamic therapy type I according to claim 1, characterized in that: in the formula (I), R is a straight-chain or branched-chain alkyl group with 6-12 carbon atoms, R 1 Is hydrogen or straight-chain or branched alkyl with 1-4 carbon atoms, R 1 And taking and aligning.
4. The AIE-type photosensitizer predominantly for photodynamic therapy type I according to claim 1, characterized in that: the structural formula of the TM is as follows:
5. the AIE-type photosensitizer predominantly for photodynamic therapy type I according to claim 1, characterized in that: in the formula (I), R is n-hexyl, n-octyl, isooctyl or 2-butyloctyl, R 1 Is hydrogen, methyl or tert-butyl, R 1 And taking and aligning.
6. A process for the preparation of AIE-type photosensitizers for use in type I photodynamic therapy as claimed in any one of claims 1 to 5, characterized in that the TM of formula (I) is prepared by the following route:
therein, R, R 1 The radicals are as defined in the corresponding claims 1 to 5.
7. The method for preparing AIE-type photosensitizers mainly for type I photodynamic therapy according to claim 6, comprising the steps of:
(1) 5, 8-dibromodithioeno [3',2':3,4; 2', 3', 5,6] benzo [1,2-c ] [1,2,5] thiadiazole and (4-R-base thiophene-2-base) trimethyl stannane are dissolved in toluene solvent, tetra (triphenylphosphine) palladium is used as a catalyst, the reaction is carried out for 8 hours at 80 ℃, and the compound 5, 8-bis (4-R-base thiophene-2-base) dithieno [3',2':3,4 is obtained after purification; 2', 3':5, 6] benzo [1,2-c ] [1,2,5] thiadiazole; wherein the R groups are as defined in the corresponding claims 1 to 5;
(2) 5, 8-bis (4-R-ylthiophene-2-yl) dithieno [3',2':3,4; 2', 3', 5,6] benzo [1,2-c ] [1,2,5] thiadiazole undergoes bromination reaction under the action of N-bromosuccinimide, and the compound 5, 8-bis (5-bromo-4-R-yl thiophene-2-yl) dithieno [3',2':3,4 is obtained after purification; 2', 3':5, 6] benzo [1,2-c ] [1,2,5] thiadiazole;
(3) 5, 8-bis (5-bromo-4-R-ylthiophene-2-yl) dithieno [3',2':3,4;2",3":5,6]Benzo [1,2-c][1,2,5]Thiadiazoles and 4, 5-tetramethyl-2- (4- (1, 2-tri R) 1 The phenyl) -1,3, 2-dioxaborane takes toluene as solvent to carry out Suzuki coupling reaction under the action of catalyst tetra (triphenylphosphine) palladium and potassium carbonate, and the reaction is carried out for 12 hours at 80 ℃, and the compound 5, 8-bis (4-R-group-5- (4- (1, 2-tri R) is obtained after purification 1 -phenylvinyl) phenyl) thiophen-2-yl) dithieno [3',2':3,4;2",3":5,6]Benzo [1,2-c][1,2,5]Thiadiazoles; wherein R is 1 The radicals are as defined in the corresponding claims 1 to 5.
8. The method of preparing AIE-type photosensitizers for use in type I photodynamic therapy according to claim 7, wherein:
in step (1), 5, 8-dibromodithioeno [3',2':3,4; 2', 3':5, 6] benzo [1,2-c ] [1,2,5] thiadiazole, (4-R-base thiophene-2-base) trimethyl stannane and tetra (triphenylphosphine) palladium in a molar ratio of 1:2-4:0.03-0.07,5,8-dibromodithiophene [3',2':3,4; 2', 3':5, 6] benzo [1,2-c ] [1,2,5] thiadiazole with a volume ratio of 1mmol (5-10) mL to toluene;
in step (2), 5, 8-bis (4-R-ylthiophene-2-yl) dithieno [3',2':3,4; 2', 3':5, 6] benzo [1,2-c ] [1,2,5] thiadiazole and N-bromosuccinimide in a molar ratio of 1:0.3-0.7;
in step (3), 5, 8-bis (5-bromo-4-R-ylthiophene-2-yl) dithieno [3',2':3,4;2",3":5,6]Benzo [1,2-c][1,2,5]Thiadiazole, 4, 5-tetramethyl-2- (4- (1, 2-tri R) 1 The molar ratio of the phenyl) -1,3, 2-dioxaborane, the tetra (triphenylphosphine) palladium and the potassium carbonate is 1:2-3:0.02-0.2:5-10,5,8-bis (5-bromo-4-R-thiophen-2-yl) dithieno [3',2':3,4;2",3":5,6]Benzo [1,2-c][1,2,5]Moles of thiadiazoleThe volume ratio of the amount to toluene is 1mmol (15-30) mL.
9. The method of preparing AIE-type photosensitizers for use in type I photodynamic therapy according to claim 8, wherein:
in step (1), 5, 8-dibromodithioeno [3',2':3,4; 2', 3':5, 6] benzo [1,2-c ] [1,2,5] thiadiazole, (4-R-ylthiophene-2-yl) trimethylstannane, tetrakis (triphenylphosphine) palladium in a molar ratio of 1:3:0.05,5, 8-dibromodithiophene [3',2':3,4; 2', 3':5, 6] benzo [1,2-c ] [1,2,5] thiadiazole in a 1 mmol/7.5 mL volume ratio to toluene;
in step (2), 5, 8-bis (4-R-ylthiophene-2-yl) dithieno [3',2':3,4; 2', 3':5, 6] benzo [1,2-c ] [1,2,5] thiadiazole and N-bromosuccinimide in a molar ratio of 1:0.5;
in step (3), 5, 8-bis (5-bromo-4-R-ylthiophene-2-yl) dithieno [3',2':3,4;2",3":5,6]Benzo [1,2-c][1,2,5]Thiadiazole, 4, 5-tetramethyl-2- (4- (1, 2-tri R) 1 The molar ratio of the phenyl) -1,3, 2-dioxaborane, the tetra (triphenylphosphine) palladium and the potassium carbonate is 1:2.5:0.05:8,5, 8-bis (5-bromo-4-R-base thiophene-2-yl) dithieno [3',2':3,4;2",3":5,6]Benzo [1,2-c][1,2,5]The molar amount of thiadiazole to toluene was 1 mmol/20 mL.
10. Use of an AIE-type photosensitizer according to any one of claims 1 to 5 or prepared by a preparation method according to any one of claims 6 to 9 for the preparation of a photodynamic tumour therapeutic photosensitizer; in particular to the application in preparing photosensitizer mainly for the type I photodynamic therapy of tumor.
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