Amphiphilic block copolymer prodrug based on disulfiram as well as preparation method and application of amphiphilic block copolymer prodrug

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: 2021-11-23
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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  • Amphiphilic block copolymer prodrug based on disulfiram as well as preparation method and application of amphiphilic block copolymer prodrug
  • Amphiphilic block copolymer prodrug based on disulfiram as well as preparation method and application of amphiphilic block copolymer prodrug
  • Amphiphilic block copolymer prodrug based on disulfiram as well as preparation method and application of amphiphilic block copolymer prodrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] The synthesis of embodiment 1 disulfiram prodrug monomer DTCM

[0054] Weigh 2.19g of diethylamine (30.0mmol) and 2.34g of mercaptoethanol (30.0mmol) into a single-necked flask, add 30.0mL of anhydrous dichloromethane, and 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 in turn, and the reaction was stirred at room temperature for 2h. After the reaction, it was washed with water three times and dried overnight with anhydrous sodium sulfate. Concentrate by rotary evaporation, and then purify by column chromatography using n-hexane / ethyl acetate as eluent to obtain a yellow oily product named HDTC.

[0055] Weigh 1.0g HDTC (4.4mmol) and 0.44g triethylamine (4.4mmol) into a single-necked flask, add 20.0mL of anhydrous dichloromethane, and ice-bath. Add 0.46 g of methacryloyl chloride (4.4 mmol), and stir the reaction at room temperature for 12 h. After the reaction, it was washed th...

Embodiment 2

[0056] The synthesis of embodiment 2 disulfiram prodrug monomer DTCM

[0057] Weigh 2.19g of diethylamine (30.0mmol) and 2.34g of mercaptoethanol (30.0mmol) into a single-necked flask, add 30.0mL of anhydrous dichloromethane, and ice-bath. 2.28g of carbon disulfide (30.0mmol), 3.03g of triethylamine (30.0mmol) and 14.92g of carbon tetrabromide (45.0mmol) were successively added, and the reaction was stirred at room temperature for 2h. After the reaction, it was washed with water three times and dried overnight with anhydrous sodium sulfate. Concentrate by rotary evaporation, and then purify by column chromatography using n-hexane / ethyl acetate as eluent to obtain a yellow oily product named HDTC.

[0058] Weigh 1.0g HDTC (4.4mmol) and 0.67g triethylamine (6.6mmol) into a single-necked flask, add 20.0mL of anhydrous dichloromethane, and ice-bath. Add 0.69 g of methacryloyl chloride (6.6 mmol), and stir the reaction at room temperature for 12 h. After the reaction, it was was...

Embodiment 3

[0059] The synthesis of embodiment 3 disulfiram prodrug monomer DTCM

[0060] Weigh 2.19g of diethylamine (30.0mmol) and 2.34g of mercaptoethanol (30.0mmol) into a single-necked flask, add 30.0mL of anhydrous dichloromethane, and ice-bath. 2.28g of carbon disulfide (30.0mmol), 3.03g of triethylamine (30.0mmol) and 19.89g of carbon tetrabromide (60.0mmol) were added in turn, and the reaction was stirred at room temperature for 2h. After the reaction, it was washed with water three times and dried overnight with anhydrous sodium sulfate. Concentrate by rotary evaporation, and then purify by column chromatography using n-hexane / ethyl acetate as eluent to obtain a yellow oily product named HDTC.

[0061] Weigh 1.0g HDTC (4.4mmol) and 0.89g triethylamine (8.8mmol) into a single-necked flask, add 20.0mL of anhydrous dichloromethane, and ice-bath. Add 0.92 g of methacryloyl chloride (8.8 mmol), and stir the reaction at room temperature for 12 h. After the reaction, it was washed t...

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Abstract

The invention belongs to the field of nano medicines and new materials, and discloses a disulfiram prodrug monomer, an amphiphilic block copolymer prodrug synthesized on the basis of the disulfiram prodrug monomer, and a preparation method and application of the amphiphilic block copolymer prodrug. The preparation method comprises the following steps: firstly synthesizing the disulfiram prodrug monomer, then copolymerizing a hydrophilic polyethylene glycol methyl acrylate monomer (PEGA) and a hydrophobic disulfiram prodrug monomer (DTCM) through a reversible addition fragmentation transfer (RAFT) method to obtain an amphiphilic block copolymer prodrug (PPEGA-PDTCM), and further constructing a self-assembled polymer vesicle. The prepared polymer vesicle can improve the solubility and stability of disulfiram, premature release of disulfiram in vivo is avoided, the limitation of clinical treatment of disulfiram is overcome, the polymer vesicle can load another medicine at the same time, and combined treatment of the two medicines is achieved. The polymer vesicle has better reduction response drug release property and has the activity of inhibiting the growth of tumor cells.

Description

technical field [0001] The invention belongs to the field of nanomedicine and new materials, and relates to a disulfiram prodrug monomer, an amphiphilic block copolymer prodrug synthesized based on the disulfiram prodrug monomer, and an amphiphilic block copolymer prodrug based on the amphiphilic block copolymer Polymer vesicles prepared from drug prodrugs and the application of the polymer vesicles in drug carriers. Background technique [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 good anti-tumor effects on various cancers (Cvek B. Drug discovery today, 2012, 17(9-10): 409-412). The antitumor effect of disulfiram is copper ion dependent. Disulfiram is metabolized in vivo and converted to the disulfiram derivative diethyldithiocarbamate (DTC), which can chelate copper ions and form Cu(DTC) 2 Chelates (LIU P, et al. British Journal of Cancer, 2012, 107(9): 148...

Claims

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Application Information

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Patent Type & Authority Applications(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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