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Enzyme-sensitive polypeptide micelle type diagnosis and treatment agent and application thereof in preparation of antitumor drugs

An enzyme-sensitive, micellar technology, applied in the direction of antineoplastic drugs, drug combination, drug delivery, etc., to achieve high yield, biodegradability, functional diversification, and good biocompatibility

Active Publication Date: 2021-08-06
SOUTH CENTRAL UNIVERSITY FOR NATIONALITIES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no report on the specific diagnosis and treatment of tumors using amphiphilic small molecular functional peptides and linear triphenylamine donors-benzothiadiazole receptors-cyano acceptors.

Method used

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  • Enzyme-sensitive polypeptide micelle type diagnosis and treatment agent and application thereof in preparation of antitumor drugs
  • Enzyme-sensitive polypeptide micelle type diagnosis and treatment agent and application thereof in preparation of antitumor drugs
  • Enzyme-sensitive polypeptide micelle type diagnosis and treatment agent and application thereof in preparation of antitumor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Embodiment 1, the synthesis of AIEgens-1

[0052]

[0053] Add 1mol 4-bromo-7-(2,2-dicyanovinyl)benzo[C][1,2,5]thiadiazole, 2mol 4,4'-dimethoxy- 4 "-triphenylamine borate, 10mmol anhydrous sodium carbonate (1.06g), 0.04mmol tetrakis-(triphenylphosphine) palladium (50mg), pass into nitrogen to remove the oxygen in the flask completely. Under nitrogen atmosphere, to three-necked flask 20mL of toluene and 3mL of deionized water were added to it, and the reaction was refluxed at 110°C for 4h. After the reaction was completed, 40mL of dichloromethane and 4.0g of silica gel powder were added, and the obtained product was rotatably concentrated into a powder. Then it was placed in 60 ℃ vacuum drying oven, drying to obtain the crude product. The product is separated by silica gel column chromatography, and the mixed solvent of dichloromethane / petroleum ether with a volume ratio of 4:1 is used as the eluent, and finally purified and dried to obtain purple Black solid (yield:...

Embodiment 2

[0054] Embodiment two, amphiphilic small molecule peptide (FMOC 2 -K-GFLGG-R 8 Synthesis of GD)

[0055] FMOC was synthesized by standard Fmoc solid-phase peptide synthesis method 2 -K-GFLGG-R 8GD: Weigh 2-chloro-trityl chloride resin (0.8g, 0.97mmol / g) into the peptide solid-phase synthesis column, add 20mL N,N-dimethylformamide (DMF) to soak the resin for 30 minutes, and make After it was fully swollen, the DMF was removed by suction filtration. Prepare to insert the first amino acid and enter the amino acid condensation reaction. Then, a DMF solution in which Fmoc-Asp(OtBu)-OH (3 times the degree of substitution of the resin) and DIEA (6 equivalents of the degree of substitution of the resin) was dissolved was added to the polypeptide solid-phase synthesis column, and reacted for 2 hours. After the reaction, the filtrate was sucked away and washed 4 times with DMF. The peptide resin after condensation of the first amino acid protected by FMOC was obtained. Then add 2...

Embodiment 3

[0057] Embodiment three, the synthesis of AIEgens-1@MPA

[0058] 50mg AIEgens-1 (prepared in Example 1), 50mg FMOC 2 -K-GFLGG-R 8 GD (prepared in Example 2) and 20 mL of DMF were added into a single-necked round-bottomed flask, and the reaction was stirred at room temperature for 24 h. Subsequently, the above solution was added to a dialysis bag (MWCO 1000Da), dialyzed in ultrapure water for 24 hours, and the ultrapure water was changed every 4 hours. After the dialysis, the aqueous solution in the dialysis bag is frozen into a solid, and then placed in a lyophilizer to freeze-dry into a powder. Characterization of FMOC by Transmission Electron Microscopy (TEM) 2 -K-GFLGG-R 8 The morphology and size of micelles formed by self-assembly of GD small molecule peptides, such as Figure 5 shown. from Figure 5 It was observed in TEM that the micelles are spherical and have good dispersion. The dry state particle size of the micelles is 35nm±1nm, which proves that the amphiphi...

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Abstract

The invention belongs to the technical field of preparation of antitumor drugs, and particularly discloses an enzyme-sensitive polypeptide micelle type diagnosis and treatment agent (AIEgens-1@MPA) and application thereof in preparation of anti-tumor drugs. The agent is characterized by involving the following steps of by taking 4,4'-dimethoxy-4''-boric acid triphenylamine and 4-bromo-7-(2,2-dicyanovinyl) benzo [C] [1,2,5] thiadiazole as main raw materials, and carrying out Suzuki Coupling one-step reaction to synthesize an AIEgens-1 photosensitizer; synthesizing a water-soluble small molecular functional peptide (FMOC2-K-GFLGG-R8GD) by adopting a polypeptide solid-phase synthesis method; and carrying out self-assembly by utilizing an amphiphilic structure of a polypeptide in an aqueous solution to form a micelle, and then effectively embedding the hydrophobic AIEgens-1 photosensitizer, so that the enzyme-sensitive polypeptide micelle type diagnosis and treatment agent (AIEgens-1@ MPA) is constructed. According to the enzyme-sensitive polypeptide micelle type diagnosis and treatment agent, the diagnosis and treatment integrated functions of specificity enrichment of the AIEgens-1 photosensitizer in tumor cells, cathepsin stimulation responsive release and light stimulation induction are realized by utilizing the functional diversity of the polypeptide.

Description

technical field [0001] The invention belongs to the technical field of antitumor drug preparation, and in particular relates to an enzyme-sensitive polypeptide micellar diagnostic agent (AIEgens-1@MPA) and its application in the preparation of antitumor drugs. Background technique [0002] The integration of diagnosis and treatment of cancer combines diagnosis and treatment into one, through the integration of drugs and imaging reagents in nanocarriers, targeted delivery to tumor tissues and real-time monitoring of treatment effects, so as to achieve early cancer diagnosis and accurate treat. At present, the successful application of cancer therapeutic reagents largely depends on the design and rational use of multifunctional materials, and the development of efficient and low-toxic diagnostic drugs is of great significance to the precise diagnosis and treatment of cancer. [0003] Traditional organic fluorescent molecules often exhibit fluorescence quenching (ACQ) in high-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/107A61K41/00A61K47/42A61K49/00A61P35/00C07D285/14
CPCA61K9/1075A61K47/42A61K41/0057A61P35/00A61K49/0021A61K49/0056A61K49/0082C07D285/14
Inventor 程崟家黎永秀秦四勇张爱清
Owner SOUTH CENTRAL UNIVERSITY FOR NATIONALITIES
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