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Endostatin conjugate and its preparation method

An endostatin and conjugate technology, applied in the field of biomedicine, can solve problems such as unfavorable clinical application, and achieve the effects of long half-life, low antigenicity and high stability

Inactive Publication Date: 2006-12-13
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In view of the deficiencies in the prior art, the purpose of the present invention is to overcome the unfavorable shortcomings of the above-mentioned existing endostatin in clinical application, and propose a new ideal endostatin conjugate and its preparation method to solve the existing problems. Problems Existing in Clinical Application of Endostatin

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Embodiment 1: Preparation of polyethylene glycol-endostatin conjugate

[0029] (1) Activation of polyethylene glycol

[0030] Add 18g of polyethylene glycol (molecular weight: 6000 Daltons), 2.2g of anhydrous sodium carbonate, and 2.75g of cyanuric chloride into 75mL of anhydrous benzene, stir overnight at room temperature, filter, and precipitate the product with anhydrous ether. Dissolve in anhydrous benzene, and repeat this process several times until no cyanuric chloride is absorbed as detected by ultraviolet scanning, and then vacuum-dry to obtain a white solid powder, which is activated polyethylene glycol, which is sealed and stored in a refrigerator at 4°C.

[0031] (2) Modification of endostatin by activated polyethylene glycol

[0032] Dissolve the activated polyethylene glycol and endostatin (based on endostatin protein content) in a molar ratio of 40:1 in a sodium tetraborate buffer solution with a pH of 9.0 and 10 mmol / L, and react with slow stirring at 4°...

Embodiment 2

[0035] Embodiment 2: Preparation of monomethoxy polyethylene glycol-endostatin conjugate

[0036] (1) Activation of monomethoxypolyethylene glycol

[0037] Dissolve 50g of monomethoxypolyethylene glycol (molecular weight: 5000 Daltons), 5.5g of cyanuric chloride, 10g of anhydrous anhydrous sodium carbonate, and 5g of molecular sieve 5A in 400mL of anhydrous benzene, stir overnight at room temperature, and remove by centrifugation. Suspended matter such as sodium carbonate and molecular sieve 5A, the product was precipitated with anhydrous ether, and then dissolved in 400 mL of anhydrous benzene. Repeat this many times until no cyanuric chloride is absorbed by the UV scan. Vacuum-dried to obtain a white solid powder, that is, activated monomethoxypolyethylene glycol, which was placed in a refrigerator at 4°C and sealed for storage.

[0038] (2) Modification of endostatin by activated monomethoxypolyethylene glycol

[0039] Dissolve the activated monomethoxypolyethylene glyco...

Embodiment 3

[0042] Example 3: Preparation of Heparin-Endostatin Conjugate

[0043] (1) Activation of heparin (sodium periodate activation method)

[0044] Weigh 0.3 g of heparin (average molecular weight: 15,000 Daltons) and dissolve it in 4.5 mL of double distilled water, and add 0.5 mL of 12% sodium periodate solution dropwise under slight stirring. At this time, the pH value of the solution was measured to be about 5.40, and the pH of the solution was adjusted to about 5.0 with 0.1 mol / L hydrochloric acid, and activated by stirring slowly in the dark at 4°C for 20 hours.

[0045] Take out the solution of activation reaction for 20 hours from the dark place, add 5% sodium bisulfite solution dropwise under slow stirring to terminate the activation reaction of low molecular weight heparin, the color of the solution changes from colorless and clear to turbid purple-red to colorless during the process of terminating the reaction After clarification, adjust the pH of the solution to 9.0±0.2...

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Abstract

The disclosed endotheliochalone compound is prepared as: the free amino with modified rate as 1.22~54.13% to combine 1-8 heparins and salt, and other amino with modified rate as 23.78~76.92% to combine 1-8 carbowaxs and derivative. Compared with natural product, this invention has low antigenicity, long half-life, and high stability, and fit to application in clinic.

Description

technical field [0001] The invention relates to an angiogenesis inhibitor conjugate and a preparation method thereof, in particular to an endostatin conjugate and a preparation method thereof, and belongs to the field of biomedicine. Background technique [0002] Endostatin (Endostatin, ES), also known as endostatin, is an endogenous angiogenesis inhibitor discovered in recent years. Its mechanism of action is to inhibit tumor angiogenesis and block its nutrient supply. new antitumor drugs. Since endostatin has a specific effect on vascular endothelial cells, it will not cause obvious effects on blood vessels in normal tissues. Therefore, compared with traditional treatment methods (such as chemotherapy, radiotherapy, etc.), it has advantages such as no drug resistance, no Cytotoxicity and many other advantages. However, the results of its phase I clinical trials show that the effective dose of endostatin applied to humans is 300mg / m2 per day. 2 , this dose is very large ...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K47/34A61K47/36A61K38/17A61P35/00A61P3/10A61P27/02A61K47/54A61K47/60
Inventor 王凤山杨盛林王晓燕曹吉超马春红孙汶生谭海宁
Owner SHANDONG UNIV
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