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All-solid-phase synthesis method for high-polymer materials with tumor site enzyme sensitive characteristics for constructing vesicae

A polymer material and solid-phase synthesis technology, which is applied in the direction of non-active ingredients of polymer compounds, pharmaceutical formulations, medical preparations of non-active ingredients, etc. The steps are cumbersome and other problems, and the effect of high product yield, simple operation and short synthesis cycle is achieved

Inactive Publication Date: 2017-05-10
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since the liquid-phase synthesis steps involve centrifugation, repeated dialysis and freeze-drying, the steps are cumbersome, the operation is complicated, and the time is long. In addition, the liquid-phase synthesis reaction also has the problems of low efficiency and many by-products
Foreign patent US08314060 discloses a method of synthesizing protease-sensitive polypeptides by solid-phase synthesis, and coupling drugs on the polypeptides to prepare prodrugs to exert drug effects on tumor sites. Polypeptide drug conjugates, but none of them involve the method of coupling high molecular weight polymers at both ends of the polypeptide by solid-phase synthesis

Method used

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  • All-solid-phase synthesis method for high-polymer materials with tumor site enzyme sensitive characteristics for constructing vesicae

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Experimental program
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Effect test

Embodiment 1

[0030] Take 0.5mmol of 2-chlorotrityl chloride resin to swell in N,N-dimethylformamide solution, and connect the peptide sequence Ala-Met-Gly-Leu-Lys-Ser-Lys sequentially with amino-terminal Fmoc -Protected and side chain protected amino acids, the amount of amino acids used is 2.5 mmol. During this period, the Fmoc protecting group was removed with a mixture of piperidine and N,N-dimethylformamide at a volume ratio of 1:4, and the resin was detected to be dark blue by the ninhydrin method. Take the condensing agent HOBt 0.46g, HBTU 1.14g, and DIEA 0.87ml to activate the amino acid in turn, and carry out the peptide-grafting reaction. Use the ninhydrin method to detect that the resin is yellow, that is, the reaction is complete, and Ala-Met-Gly-Leu-Lys-Ser-Lys is obtained. -2-Chlorotrityl chloride resin. Remove the Fmoc-protecting group of the amino acid at the amino terminal of the polypeptide, retain the resin, take 3.13g of the hydrophobic segment PCL-COOH (molecular weigh...

Embodiment 2

[0034] Take 0.8mmol of 2-chlorotrityl chloride resin to swell in N,N-dimethylformamide solution, and connect the peptide sequence Gly-Ser-Gly-Leu-Lys-Ala-Lys sequentially with amino terminal Fmoc -Protected and side chain protected amino acids, the amount of amino acid used is 4mmol. During this period, the Fmoc protecting group was removed with a mixture of piperidine and N,N-dimethylformamide at a volume ratio of 1:4, and the resin was detected to be dark blue by the ninhydrin method. After adding 0.74g of condensing agent HOBt, 1.82g of HBTU and 1.4ml of DIEA to activate the amino acid, the peptide grafting reaction was carried out, and the resin was detected to be yellow by the ninhydrin method, indicating that the reaction was complete, and Gly-Ser-Gly-Leu-Lys-Ala- Lys-2-chlorotrityl chloride resin. Remove the Fmoc-protecting group of the amino acid at the amino terminal of the polypeptide, retain the resin, take 6g of the hydrophobic segment PLA-COOH (molecular weight 6...

Embodiment 3

[0038] Take 1mmol of 2-chlorotrityl chloride resin to swell in dichloromethane solution, according to the polypeptide sequence Lys-Val-Gly-Leu-Arg-Thr-Lys, sequentially connect to the amino-terminal Fmoc-protected and side chain protected Amino acid, the consumption of amino acid is 5mmol. During this period, the Fmoc protecting group was removed with a mixture of piperidine and N,N-dimethylformamide at a volume ratio of 1:4, and the resin was detected to be dark blue by the ninhydrin method. Take the condensing agent HOBt 0.92g, HBTU 2.27g and DIEA 1.75ml to activate the amino acid in turn, carry out the peptide reaction, use the ninhydrin method to detect that the resin is yellow, that is, the reaction is complete, and Lys-Val-Gly-Leu-Arg-Thr-Lys is obtained -2-Chlorotrityl chloride resin. Remove the Fmoc-protecting group of the amino acid at the amino terminal of the polypeptide, retain the resin, take 12.5g of the hydrophobic segment PS-COOH (molecular weight 10,000) and ...

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Abstract

The invention relates to the field of synthesis of high-polymer materials, in particular to an all-solid-phase synthesis method for high-polymer materials with tumor site enzyme sensitive characteristics for constructing vesicae. The all-solid-phase synthesis method has the advantages that the high-polymer materials are synthesized by the aid of the all-solid-phase synthesis method, the all-solid-phase synthesis method is easy to implement, short in synthesis period and high in product yields, and only few byproducts can be generated; the high-polymer materials can be subjected to self-assembly to form the vesicae, water-soluble medicines are encapsulated in internal water phases and can be degraded by high-expression MMP-9 enzymes at tumor sites after being targeted to tumor tissues, accordingly, the vesicae can be broken, and antitumor medicines can be instantly released; the tumor tissue targeting ability of the medicines can be improved by vesica medicine delivery systems constructed by the aid of the high-polymer materials, the medicines can be released in a responsive manner, the concentration of the medicines at the tumor sites can be increased, and the toxicity of the antitumor medicines on normal tissues and cells can be reduced.

Description

technical field [0001] The invention relates to the field of polymer material synthesis, in particular to an all-solid-phase synthesis method of a polymer material with tumor site enzyme-sensitive properties used to construct vesicles. Background technique [0002] In recent years, the incidence of tumors in various countries in the world has nearly doubled compared with 10 years ago. Cancer is a serious threat to human health and has become an urgent problem in the current medical field. Chemotherapy is currently the commonly used clinical tumor treatment method. However, anticancer drugs are different from ordinary drugs. Due to their lack of selectivity, they not only have a killing effect on diseased cells, but also produce toxicity to rapidly proliferating normal tissue cells (such as bone marrow cells or gastrointestinal tract cells), bring serious adverse reactions and side effects to patients. Therefore, how to use pharmaceutical preparations to effectively and exc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G81/00C08G81/02A61K9/127A61K47/10A61K47/32A61K47/34A61K47/42
Inventor 张文丽刘建平金雅周卫赛
Owner CHINA PHARM UNIV
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