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Blood vessel blocking agent bond joint fluorine-boron pyrrole derivative and preparation method and application thereof

A blood vessel blocking agent, a technology connected with fluborapyr, which is applied in the field of near-infrared dyes and nanomedicine, can solve the problems of photodynamic effect decline and hinder clinical application, etc., and achieve the advantages of simple synthesis method, precise tumor treatment and high yield Effect

Active Publication Date: 2020-05-01
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the generation of singlet oxygen is closely related to the oxygen concentration, and when the oxygen concentration inside the tumor decreases during treatment, the photodynamic effect drops sharply, hindering its clinical application.

Method used

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  • Blood vessel blocking agent bond joint fluorine-boron pyrrole derivative and preparation method and application thereof
  • Blood vessel blocking agent bond joint fluorine-boron pyrrole derivative and preparation method and application thereof
  • Blood vessel blocking agent bond joint fluorine-boron pyrrole derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Vasoblocker-linked BDPVDA synthesis

[0056] (1) In a 500mL flask, dissolve 4-methoxybenzaldehyde (0.37g, 3.0mmol) and 2,4-dimethylpyrrole (0.63g, 6.6mmol) in 90mL tetrahydrofuran, add 0.1mL three Fluoroacetic acid, stirring at room temperature for 12 hours; adding 12 ml of 2,3-dichloro-dicyano-p-benzoquinone (0.68 g, 3.0 mmol) tetrahydrofuran solution to the reaction solution, and continuing the reaction at room temperature for 4 hours; , add 18mL triethylamine and 18mL boron trifluoride diethyl ether dropwise to the reaction liquid, and continue to react for 12 hours; V / V) to obtain an orange solid product (compound 1, 0.459g, about 45% yield), the structural formula is as follows:

[0057]

[0058] The chemical name of compound 1 is: 4-(5,5-difluoro-1,3,7,9-tetramethyl-5H-4λ 4 , 5λ 4 -dipyrrole[1,2-c:2',1'-f][1,3,2]diazaboron)-phenol.

[0059] (2), in a 50mL round bottom flask, dissolve compound 1 (0.34g, 1.0mmol) and 4-dimethylaminobenzaldehyde (0.33g, 2.4mmo...

Embodiment 2

[0067] Preparation of mPEG-PPDA-coated BDPVDA nanoparticles (PBV NPs)

[0068] Dissolve 100mg of mPEG-PPDA (the molecular weight of mPEG is 2000, and the degree of polymerization of PPDA is 80) and 4mg of BDPVDA in 5mL of tetrahydrofuran, stir for 5 minutes, drop it into 80mL of deionized water under ultrasonic conditions (200W), and continue to sonicate for 30 minute. The tetrahydrofuran was removed by vacuum rotary evaporation, and PBV NPs were obtained by filtration with a 220 nm filter head.

[0069] Such as Figure 4 As shown, in the ultraviolet-visible absorption spectrum of PBV NPs, there are strong absorption peaks in the wavelength range of 570nm-850nm, and the highest absorption peak is at 733nm, indicating that PBV NPs have excellent near-infrared absorption properties. At the same time, if Figure 5 As shown, the particle size distribution test showed that the particle size distribution of PBV NPs was 60.7 ± 5.1 nm.

Embodiment 3

[0071] Acid Stimulus-Responsive Release Properties of Vasoblocker DMXAA

[0072] 20 mL of phosphate buffer solution containing PBV NPs (50 μg / mL) was placed in a dialysis bag (molecular weight cut-off: 1000), and placed in phosphate buffer with different pH values ​​(5.0, 6.5, 7.4) for slow release. Record the absorption value of DMXAA at different time points to detect the release amount. Such as Image 6 As shown, the cumulative release rate of DMXAA increased with the decrease of pH value, indicating that PBVNPs have good acid stimulation responsiveness, which will be beneficial to realize the drug release stimulated by tumor micro acid.

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Abstract

The invention discloses a blood vessel blocking agent bond joint fluorine-boron pyrrole derivative. The blood vessel blocking agent bond joint fluorine-boron pyrrole derivative is prepared through covalent bond joint of a near-infrared photosensitizer namely fluorine-boron pyrrole and a blood vessel blocking agent namely 2,5-pentoxifylline. Besides, the invention also discloses a nanometer diagnosis and treatment reagent obtained through self-assembling of the derivative and electron-enriched amphiphilic polymer namely methoxy-poly(ethanediol)-poly(2-diisopropylamine) methyl methacrylate, andan application of the nanometer diagnosis and treatment reagent to tumor treatment through synergism of I type photodynamic therapy and a blood vessel blocking treatment method. The blood vessel blocking agent bond joint fluorine-boron pyrrole derivative disclosed by the invention is clear in the structure of objective products, and simple in synthesis technology; the diagnosis and treatment reagent based on the objective products concurrently has I type photodynamic and pH responsiveness blood vessel blocking agent releasing properties, under passive targeting effects and fluorescence imagingmediating, the nanometer diagnosis and treatment reagent can accurately reach tumor positions, block tumor blood vessels and kill tumor cells, so that recurrence and transfer of tumors can be effectively prevented.

Description

technical field [0001] The invention belongs to the field of near-infrared dyes and nanomedicine, and specifically relates to a blood vessel blocking agent-bonded flubororpyrrole derivative and a preparation method thereof, and the preparation of the blood vessel blocking agent-bonded flubororpyrrole derivative in the preparation of fluorescence imaging mediation Application of type I photodynamic / vascular blockade synergistic drugs in tumor therapy. Background technique [0002] In the process of cancer development, when the tumor diameter reaches 2-3 mm, the oxygen and nutrients in the tumor are not enough to support the further growth of the tumor, which induces the upregulation of vascular endothelial growth factor (VEGF) in the tumor microenvironment, and generates new blood vessels to provide tumor support. oxygen and nutrients. When the tumor develops to a certain extent, the surrounding immune system is attacked, and a large number of free cancer cells and exosomes ...

Claims

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Application Information

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IPC IPC(8): A61K41/00A61K9/51A61K47/55A61P35/00C07F5/02A61K31/352
CPCA61K41/0057C07F5/022A61P35/00A61K31/352A61K47/55A61K9/5146A61K9/0019
Inventor 董晓臣陈大鹏邵进军司伟丽张琪黄维
Owner NANJING UNIV OF TECH
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