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CN-122005849-A - 4-BrPA/beta-CD supermolecule photosensitizer, preparation method and application thereof

CN122005849ACN 122005849 ACN122005849 ACN 122005849ACN-122005849-A

Abstract

The invention discloses a 4-BrPA/beta-CD supermolecule photosensitizer, a preparation method and application thereof, and belongs to the field of biomedical materials. The method takes beta-cyclodextrin as a main body, 4-bromophthalic anhydride as a guest, and a water-soluble photosensitizer is constructed through a supermolecule assembly strategy of chemical modification. The preparation method comprises the specific steps of reacting beta-cyclodextrin with p-toluenesulfonyl chloride to obtain mono- (6-O-p-toluenesulfonyl) -beta-cyclodextrin, reacting with ethylenediamine to obtain mono- (6-ethylenediamine-6-deoxy) -beta-cyclodextrin, reacting with 4-bromophthalic anhydride in N, N-dimethylformamide, precipitating and purifying by ethyl acetate to obtain a crude product, and finally carrying out ultrasonic treatment, centrifugal separation and freeze drying to obtain a pure product. The prepared 4-BrPA/beta-CD supermolecule photosensitizer has excellent water solubility, at least 7 excitation centers in a visible light region of 400-520 nm, at least 7 emission centers correspondingly generated in a range of 500-780 nm, a maximum excitation wavelength of about 460+/-10 nm and a maximum emission wavelength of about 620+/-10 nm, and extremely wide visible light response characteristics, and can be used for antibacterial photodynamic therapy.

Inventors

  • LI CHAOXIA
  • JIANG BO
  • XIAO RONG
  • WANG TIE
  • CUI ENTIAN
  • Cao Liurui
  • WANG JIN
  • WEI CHANG

Assignees

  • 盐城工学院
  • 盐城工学院技术转移中心有限公司

Dates

Publication Date
20260512
Application Date
20260224

Claims (10)

  1. 1. The preparation method of the 4-BrPA/beta-CD supermolecule photosensitizer is characterized by comprising the following steps: (1) Reacting beta-cyclodextrin with p-toluenesulfonyl chloride under alkaline conditions to obtain a pure product of mono- (6-O-p-toluenesulfonyl) -beta-cyclodextrin; (2) Reacting the mono- (6-O-p-toluenesulfonyl) -beta-cyclodextrin obtained in the step (1) with ethylenediamine to obtain a pure product of the mono- (6-ethylenediamine-6-deoxy) -beta-cyclodextrin; (3) Reacting the mono- (6-ethylenediamine-6-deoxy) -beta-cyclodextrin obtained in the step (2) with 4-bromophthalic anhydride in N, N-dimethylformamide, and precipitating and purifying with ethyl acetate to obtain a 4-BrPA/beta-CD crude product; (4) Dissolving the 4-BrPA/beta-CD crude product obtained in the step (3) in water, and carrying out ultrasonic treatment, centrifugal separation and freeze drying to obtain the 4-BrPA/beta-CD supermolecule photosensitizer pure product.
  2. 2. The process according to claim 1, wherein in the step (1), the mass ratio of the beta-cyclodextrin to the p-toluenesulfonyl chloride is (5-25): (5-15), the reaction temperature is 15-35 ℃ and the reaction time is 20-40mi, the alkaline condition is provided by an aqueous sodium hydroxide solution having a concentration of 0.3-0.5 mol/L, and the purification comprises a recrystallization step.
  3. 3. The preparation method according to claim 2, wherein in the step (1), the amount of beta-cyclodextrin is 20g, the amount of p-toluenesulfonyl chloride is 10g, the reaction temperature is 30 ℃ and the reaction time is 30min; The yield of mono- (6-O-p-toluenesulfonyl) - β -cyclodextrin under the conditions described was 6.791g.
  4. 4. The process according to claim 1, wherein in the step (2), the amount ratio of the mono- (6-O-p-toluenesulfonyl) - β -cyclodextrin to ethylenediamine is (1.5-7.5) g (20-40) mL, the reaction temperature is 65-85 ℃ and the reaction time is 4-8 hours, and the purification comprises a recrystallization step.
  5. 5. The process according to claim 4, wherein in the step (2), the amount of mono- (6-O-p-toluenesulfonyl) - β -cyclodextrin is 6.0g, the amount of ethylenediamine is 35mL, the reaction temperature is 75℃and the reaction time is 6 hours, and the yield of mono- (6-ethylenediamine-6-deoxy) - β -cyclodextrin is 4.637g.
  6. 6. The process according to claim 1, wherein in the step (3), the mass ratio of the mono- (6-ethylenediamine-6-deoxy) - β -cyclodextrin to the 4-bromophthalic anhydride is (3.6-6.0): (0.4-1.2), the ratio of N, N-dimethylformamide to the mono- (6-ethylenediamine-6-deoxy) - β -cyclodextrin is (15-35) mL (3.6-6.0), the reaction temperature is 70-90 ℃, the reaction time is 4-8 hours, and the ratio of ethyl acetate to the mono- (6-ethylenediamine-6-deoxy) - β -cyclodextrin is (50-250) mL (3.6-6.0) g.
  7. 7. The process according to claim 6, wherein in the step (3), the amount of mono- (6-ethylenediamine-6-deoxy) - β -cyclodextrin is 4.8g, the amount of 4-bromophthalic anhydride is 0.8g, the amount of N, N-dimethylformamide is 25mL, the reaction temperature is 80 ℃, the reaction time is 6 hours, the amount of ethyl acetate is 150mL, and the yield of 4-BrPA/β -CD crude product under the above conditions is 4.542g.
  8. 8. The preparation method of claim 1, wherein in the step (4), the ultrasonic-assisted dispersion is pulsed ultrasonic for 3-5 min, standing for 0.5-1 min, centrifuging for 8-15 min at 12000-16000 r/min and 4 ℃, and freeze-drying for 1.5-3 h at-80 ℃ and then freeze-drying for 24-36 h at-60 ℃.
  9. 9. A 4-BrPA/β -CD supramolecular photosensitizer characterized by being obtained by the preparation method of any one of claims 1-8 and having a characteristic emission peak at 610-630 nm at an excitation wavelength of 450-470 nm; At least 7 excitation centers are arranged in a visible light region of 400-520 nm, and at least 7 emission centers are arranged in a visible light to near infrared region of 500-780 nm; The maximum excitation wavelength is 460+ -10 nm, and the maximum emission wavelength is 620+ -10 nm.
  10. 10. Use of the 4-BrPA/beta-CD supermolecule photosensitizer according to claim 9 for the preparation of an antibacterial photodynamic therapy drug and for the preparation of a fluorescence imaging reagent.

Description

4-BrPA/beta-CD supermolecule photosensitizer, preparation method and application thereof Technical Field The invention belongs to the technical field of biomedical materials and photodynamic therapy, and particularly relates to a 4-BrPA/beta-CD supermolecule photosensitizer which is constructed by taking 4-bromophthalic anhydride (4-Bromo phthalic anhydrus, 4-BrPA) as a photosensitive object, taking beta-cyclodextrin (beta-CD) as a main framework and through covalent amide bond connection, a preparation method and spectrum characterization thereof, and application in antibacterial photodynamic therapy and fluorescence imaging. Background 1. Description of the prior art The antibacterial photodynamic therapy (aPDT) utilizes a photoexcitation photosensitizer to generate Reactive Oxygen Species (ROS) to kill pathogens, and a nonspecific oxidative damage mechanism is not easy to induce bacterial drug resistance, so that a novel strategy with great prospect is provided for coping with the global antibiotic drug resistance crisis. However, the traditional photosensitizer always faces three key bottlenecks in practical application, namely (1) poor water solubility and easy aggregation in a physiological environment, (2) self-aggregation quenching caused by pi-pi accumulation, remarkably reduced singlet oxygen quantum yield, and (3) excitation wavelength in the ultraviolet region, limited tissue penetration depth and cytotoxicity of ultraviolet light. Beta-cyclodextrin (beta-CD) is widely used to construct supramolecular photosensitizers due to its unique "internal hydrophobic, external hydrophilic" cavity structure and good biocompatibility. In the prior art, hydrophobic photoactive molecules are physically embedded in a beta-CD cavity through a host-guest inclusion strategy, and although the water solubility can be improved, the inherent defects of low inclusion constant, easy dissociation in a physiological environment, uncontrollable drug loading, poor batch repeatability and the like exist. 2. Technical defects of the prior art Through searching, the prior patent and literature related to beta-CD modified photosensitizer mainly have the following technical defects: (1) The covalent modification strategy is incomplete, and the prior art mostly adopts physical inclusion or single-step modification, and lacks a complete, repeatable and transparent covalent synthesis process route from raw materials to finished products. (2) The synthesis process is not optimized, the yield is low, most of the existing reports are feasibility verification research, and the key parameters such as reactant proportion, temperature, time, precipitant dosage and the like are not optimized in a systematic single factor, so that the yield of the product is low, the process window is unclear, and the large-scale production cannot be guided. (3) Yield data do not disclose that most documents only report "successful synthesis" and do not disclose actual yields or yields, and those skilled in the art cannot evaluate the efficiency of the process and do not repeat or scale up. (4) The excitation wavelength is still in the ultraviolet region, the maximum excitation wavelength of most beta-CD-based photosensitizers is less than 400 nm, and the diagnosis and treatment integrated spectral characteristics of visible light excitation/near infrared emission are not provided. (5) The guest molecule structure is single, and the system process optimization and the yield maximization report of the beta-CD conjugated photosensitizer taking 4-bromophthalic anhydride (4-BrPA) as a photosensitizing guest are not seen. 3. Technical problem to be solved by the invention Aiming at the defects in the prior art, the invention aims to provide a 4-BrPA/beta-CD supermolecule photosensitizer which takes 4-BrPA as a photosensitizing object, takes ethylenediamine modified beta-CD as a main framework and is connected through covalent amide bonds, and solves the following technical problems: (1) Providing a set of 4-BrPA/beta-CD photosensitizer covalent synthesis process with complete steps, clear parameters, repeatability and amplification, and completely disclosing single-factor optimized data and yield maximization conditions of each step; (2) The product yield of each step is obviously improved, and the synthesis yield of the mono- (6-O-p-toluenesulfonyl) -beta-cyclodextrin (OTs-beta-CD), the mono- (6-ethylenediamine-6-deoxy) -beta-cyclodextrin (2N-beta-CD) and the 4-BrPA/beta-CD reach gram scale which is not disclosed in the prior art; (3) The prepared photosensitizer has the broad spectrum response characteristics of visible light excitation (460+/-10 nm)/near infrared emission (620+/-10 nm) and has the functions of fluorescence imaging and photodynamic therapy; (4) The specific application scheme of the photosensitizer in antibacterial photodynamic therapy and fluorescence imaging is provided. Disclosure of Invention Based on the problems existing in the backgrou