A kind of disulfiram-based amphiphilic block copolymer prodrug and its preparation method and application

A technology of amphiphilic block and disulfiram, which is applied in the direction of pharmaceutical formulations, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., can solve problems such as premature release, and avoid premature release , Improve the effect of tumor therapy, improve solubility and stability

Active Publication Date: 2022-05-24
SOUTH CHINA UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Aiming at the problems of poor water solubility, easy degradation and premature release of disulfiram, the object of the present invention is to provide a disulfiram prodrug monomer and an amphiphilic block copolymer prodrug synthesized based on the monomer, through which The amphiphilic block copolymer prodrug self-assembles to form polymersomes; this polymersome can improve the solubility and stability of disulfiram, avoid the premature release of disulfiram in the human body, and can be used as a drug Carrier realizes co-delivery of disulfiram and other drugs for combined anti-tumor

Method used

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  • A kind of disulfiram-based amphiphilic block copolymer prodrug and its preparation method and application
  • A kind of disulfiram-based amphiphilic block copolymer prodrug and its preparation method and application
  • A kind of disulfiram-based amphiphilic block copolymer prodrug and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1 Synthesis of disulfiram prodrug monomer DTCM

[0054] Weigh 2.19g diethylamine (30.0mmol) and 2.34g mercaptoethanol (30.0mmol) in a single flask, add 30.0mL of anhydrous dichloromethane, ice bath. 2.28g of carbon disulfide (30.0mmol), 3.03g of triethylamine (30.0mmol) and 9.94g of carbon tetrabromide (30.0mmol) were added sequentially, and the reaction was stirred at room temperature for 2 h. After the reaction is over, wash 3 times with water and dry overnight using anhydrous sodium sulfate. Rotary distillation concentration, and then n-hexane / ethyl acetate as an eluent, purified by column chromatography, to obtain a yellow oily product, named HDTC.

[0055] Weigh 1.0g HDTC (4.4mmol) and 0.44g triethylamine (4.4mmol) in a single-mouth flask and add 20.0mL of anhydrous dichloromethane to an ice bath. Add 0.46g of methacryloyl chloride (4.4mmol) and stir the reaction at room temperature for 12h. After the reaction, wash 3 times with saturated sodium chloride solu...

Embodiment 2

[0056] Example 2 Synthesis of disulfiram prodrug monomer DTCM

[0057] Weigh 2.19g diethylamine (30.0mmol) and 2.34g mercaptoethanol (30.0mmol) in a single flask, add 30.0mL of anhydrous dichloromethane, ice bath. 2.28g carbon disulfide (30.0mmol), 3.03g triethylamine (30.0mmol) and 14.92g carbon tetrabromide (45.0mmol) were added sequentially, and the reaction was stirred at room temperature for 2h. After the reaction is over, wash 3 times with water and dry overnight using anhydrous sodium sulfate. Rotary distillation concentration, and then n-hexane / ethyl acetate as an eluent, purified by column chromatography, to obtain a yellow oily product, named HDTC.

[0058]Weigh 1.0 g of HDTC (4.4 mmol) and 0.67 g of triethylamine (6.6 mmol) in a single flask and add 20.0 mL of anhydrous dichloromethane to an ice bath. Add 0.69g methacryloyl chloride (6.6mmol) and stir the reaction at room temperature for 12h. After the reaction, wash 3 times with saturated sodium chloride solution and...

Embodiment 3

[0059] Example 3 Synthesis of disulfiram prodrug monomer DTCM

[0060] Weigh 2.19g diethylamine (30.0mmol) and 2.34g mercaptoethanol (30.0mmol) in a single flask, add 30.0mL of anhydrous dichloromethane, ice bath. 2.28g carbon disulfide (30.0mmol), 3.03g triethylamine (30.0mmol) and 19.89g carbon tetrabromide (60.0mmol) were added sequentially, and the reaction was stirred at room temperature for 2h. After the reaction is over, wash 3 times with water and dry overnight using anhydrous sodium sulfate. Rotary distillation concentration, and then n-hexane / ethyl acetate as an eluent, purified by column chromatography, to obtain a yellow oily product, named HDTC.

[0061] Weigh 1.0 g of HDTC (4.4 mmol) and 0.89 g of triethylamine (8.8 mmol) in a single flask and add 20.0 mL of anhydrous dichloromethane to an ice bath. Add 0.92g of methacryloyl chloride (8.8mmol) and stir the reaction at room temperature for 12h. After the reaction, wash 3 times with saturated sodium chloride solution...

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Abstract

The invention belongs to the field of nano-medicine and new materials, and discloses a disulfiram prodrug monomer, an amphiphilic block copolymer prodrug synthesized based on the monomer, a preparation method and application thereof. The preparation method first synthesizes the disulfiram prodrug monomer, and then synthesizes the hydrophilic polyethylene glycol methyl acrylate monomer (PEGA) and the hydrophobic disulfiram prodrug by the reversible addition-fragmentation transfer (RAFT) method. The monomer (DTCM) is copolymerized to obtain the amphiphilic block copolymer prodrug (PPEGA-PDTCM), and then construct its self-assembled polymer vesicle. The polymersomes prepared by the present invention can improve the solubility and stability of disulfiram, avoid the premature release of disulfiram in vivo, so as to overcome the limitation of clinical treatment of disulfiram, and the polymersomes can simultaneously Another drug is loaded to realize the combined treatment of two drugs. The polymer vesicle has good reduction response drug release property and has the activity of inhibiting the growth of tumor cells.

Description

Technical field [0001] The present invention belongs to the field of nanomedicine and new materials, relates to a disulfiram prodrug monomer, based on the disulfiram prodrug monomer synthesis of amphiphilic block copolymer prodrug prodrug, based on the amphiphilic block copolymer prodrug prepared polymer vesicles and the application of the polymer vesicle in the drug carrier. Background [0002] Disulfiram is an FDA-approved drug for the treatment of alcoholism. Since the 1970s, a large number of clinical studies have found that disulfiram has shown good anti-tumor effects on a variety of cancers (Cvek B. Drugdiscovery today, 2012, 17(9-10): 409-412). The antitumor effect of disulfiram is copper ion-dependent. Disulfiram is metabolized in vivo and converted to disulfiram derivative diethyl dithiocarbamic acid (DTC), which can be combined with copper ion chelating to form Cu (DTC). 2 Chelates (LIU P,et al. British Journal of Cancer,2012,107(9):1488-97)。 It is currently widely beli...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C333/30C07C333/32C08F293/00A61K9/127A61K31/145A61K45/06A61K47/60A61P35/00
CPCC07C333/30C07C333/32C08F293/005A61K31/145A61K47/60A61K9/1273A61K45/06A61P35/00
Inventor 王林格方宇煌于倩倩徐蒙蒙
Owner SOUTH CHINA UNIV OF TECH
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