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P(hpma)-nitrogen mustard polymer with antitumor activity and its preparation method and application

A high-molecular polymer and anti-tumor activity technology, applied in the field of high-molecular chemistry, can solve the problems of high toxicity and side effects, and achieve the effects of reducing toxicity, promoting inhibition, and reducing damage

Active Publication Date: 2020-09-22
甘肃新风中药材科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to its high toxicity and side effects, there are certain limitations in clinical application. Therefore, it is currently a research hotspot to link small molecular nitrogen mustards to polymers with good biocompatibility to prepare high molecular weight anticancer drugs.

Method used

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  • P(hpma)-nitrogen mustard polymer with antitumor activity and its preparation method and application
  • P(hpma)-nitrogen mustard polymer with antitumor activity and its preparation method and application
  • P(hpma)-nitrogen mustard polymer with antitumor activity and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] A kind of preparation method of the P(HPMA)-nitrogen mustard polymer with antitumor activity, specifically comprises the steps:

[0030] Step (1) N, the synthesis of N-bis-(2-chloroethyl)-4-phenylmethylacrylamide: the step N,N-bis-(2-chloroethyl)-1,4-benzene The hydrochloride (2.7g, 0.01mol) of the amine was first separated and purified with 30% cold NaOH (15ml) solution, then extracted with chloroform (15ml×3), and transferred to the extracted organic solution with pipette Add methacryloyl chloride (0.9678ml, 0.01mol) into the gun, then add triethylamine (1.3899ml, 0.01mol) in trichloromethane solution (5.0ml) dropwise under stirring at 0°C, and control the rate of dropping for 1h The dropwise addition was completed. After the dropwise addition was completed, the ice-water bath was removed, and the reaction was stirred at room temperature for 24 hours. After the reaction was complete, it was washed with distilled water three times (30mL×3), dried overnight with anhydro...

Embodiment 2

[0034] A kind of preparation method of the P(HPMA)-nitrogen mustard polymer with antitumor activity, specifically comprises the steps:

[0035]Step (1) Synthesis of N,N-bis-(2-chloroethyl)-4-benzyl acrylamide: same as Example 1.

[0036] Step (2) Preparation of P(HPMA)-nitrogen mustard polymer with antitumor activity: N, N-bis-(2-chloroethyl)-4-phenylmethylacrylamide (0.0333g) and N-(2-hydroxypropyl) methacrylamide (0.14g) was dissolved with solvent dimethyl sulfoxide (0.3mL), and the initiator azobisisobutyronitrile (0.009g) was added, under nitrogen protection at 65 React at ℃ for 24 hours to polymerize, precipitate with a mixed solution of acetone and ether, and finally centrifuge with an ultrafiltration concentration centrifuge tube with a molecular weight of 3000 to obtain the target polymer.

[0037] Mn=2.1×10 4 , Mw / Mn=1.98. 1 H-NMR (400MHz, d 6 -DMSO, δ, ppm): 3.68(-CH(OH)-ofHPMA,-(CH 2 ) 2 N-),1.33-1.80(-CH 2 -of HPMA), 7.45 (CH of benzene), 7.66 (CH of benzene...

Embodiment 3

[0039] A kind of preparation method of the P(HPMA)-nitrogen mustard polymer with antitumor activity, specifically comprises the steps:

[0040] Step (1) Synthesis of N,N-bis-(2-chloroethyl)-4-benzyl acrylamide: same as Example 1.

[0041] Step (2) Preparation of P(HPMA)-nitrogen mustard polymer with antitumor activity: N, N-bis-(2-chloroethyl)-4-phenylmethylacrylamide (0.0666g) and N-(2-hydroxypropyl) methacrylamide (0.14g) was dissolved with solvent dimethyl sulfoxide (0.3mL), and the initiator azobisisobutyronitrile (0.012g) was added, under nitrogen protection at 65 React at ℃ for 24 hours to polymerize, precipitate with a mixed solution of acetone and ether, and finally centrifuge with an ultrafiltration concentration centrifuge tube with a molecular weight of 3000 to obtain the target polymer.

[0042] Mn=2.6×10 4 , Mw / Mn=2.08. 1 H-NMR (400MHz, d 6 -DMSO, δ, ppm): 3.68(-CH(OH)-ofHPMA,-(CH 2 ) 2 N-),1.33-1.80(-CH 2 -of HPMA), 7.45 (CH of benzene), 7.66 (CH of benzen...

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Abstract

The invention relates to a P(HPMA)-nitrogen mustard high-molecular polymer with antitumor activity and a preparation method and application thereof. The P(HPMA)-nitrogen mustard high-molecular polymeris a high-molecular polymer which is formed by connecting N,N-di-(2-chloroethyl)-4-phenmethacrylamide to N-(2-hydroxypropyl)methacrylamide through a covalent bond. According to the invention, by superposition of activities of N,N-di-(2-chloroethyl)-4-phenmethacrylamide and HPMA, the tumor inhibiting effect of the polymer is further promoted, and the residence time of an anticancer drug in cancercells can be prolonged; with the unique chemical bond in the copolymer, the drug reaches the tumor site and then the chemical bond is broken, thus reducing drug toxicity and intelligently releasing the anticancer drug in the tumor cells; with the HPMA, the copolymer shows good biocompatibility and toxicity of the anticancer drug is reduced, thus reducing damage to normal tissues. Therefore, the high-molecular polymer of the invention has a good application prospect in the preparation of antitumor drugs.

Description

technical field [0001] The invention belongs to the field of polymer chemistry, and in particular relates to a P(HPMA)-nitrogen mustard polymer with antitumor activity, a preparation method and application thereof. Background technique [0002] Cancer has become one of the main threats to human health, and the number of people who die from cancer every year is on the rise. The current main methods of treating cancer include radiotherapy, chemotherapy, surgical therapy and gene therapy. Among them, chemotherapy is an extremely important non-surgical therapy. Nitrogen mustard compounds are alkylating agent antineoplastic drugs, and are currently mainly used for the treatment of malignant lymphoma. According to the parent structure, the compounds can be divided into benzoate mustard, chlorambucil, benzaldehyde mustard and methyl mustard. However, due to its high toxicity and side effects, there are certain limitations in clinical application. Therefore, the preparation of sma...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08F220/58C08F220/60A61K47/58A61K31/785A61P35/00
CPCA61K31/785A61K47/58A61P35/00C08F220/58C08F220/606
Inventor 许卫兵龙海涛蒲陆梅
Owner 甘肃新风中药材科技有限公司