Chondroitin sulfate modifier of anti-angiogenic peptide ES2-AF and preparation method and application of cis-platinum loaded by chondroitin sulfate modifier

A technology of ES2-AF and chondroitin sulfate, applied in the field of biomedicine, can solve the problems of poor targeting, strong toxic and side effects, short half-life, etc., and achieve high stability, high stability and biological activity, good use effect and application value effect

Inactive Publication Date: 2021-09-17
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the shortcomings of short half-life and poor stability of these protein and polypeptide drugs have laid hidden dangers for their wide and long-term use.
At the same time, due to the disadvantages of strong toxic and side effects and poor targeting of chemical drugs, their further use is limited.

Method used

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  • Chondroitin sulfate modifier of anti-angiogenic peptide ES2-AF and preparation method and application of cis-platinum loaded by chondroitin sulfate modifier
  • Chondroitin sulfate modifier of anti-angiogenic peptide ES2-AF and preparation method and application of cis-platinum loaded by chondroitin sulfate modifier
  • Chondroitin sulfate modifier of anti-angiogenic peptide ES2-AF and preparation method and application of cis-platinum loaded by chondroitin sulfate modifier

Examples

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preparation example Construction

[0045] In yet another specific embodiment of the present invention, the preparation method of the chondroitin sulfated modification of the anti-angiogenic peptide ES2-AF includes:

[0046] When the chondroitin sulfate modification of the anti-angiogenic peptide ES2-AF is CS-Cys-ES2-AF, its preparation method is:

[0047] S1. Preparation of CS-Cys conjugate: use Cys as a linker to connect ES2-AF and CS, so that ES2-AF can be released rapidly from CS-Cys-ES2-AF in the tumor microenvironment and dissociate to the surrounding tumor Endothelial cells exert anti-angiogenic effects. The specific preparation method is: dissolve CS in water, add EDCI and NHS as catalysts to activate the carboxyl group in CS, add lye to adjust the pH to weak alkaline after activation, and then slowly add Cys solution for reaction. After the reaction is completed, the reaction product After purification, the CS-Cys conjugate is obtained;

[0048] S2. Preparation of CS-Cys-ES2-AF conjugate: Dissolve ES2...

Embodiment 1

[0073] Example 1: Preparation of the chondroitin sulfated modification of the anti-angiogenic peptide ES2-AF (CS-Cys-ES2-AF) The preparation steps are as follows:

[0074] (1) The anti-angiogenic peptide ES2-AF (IVRRADRAAVPGGGGGGNQWFI) was prepared by solid-phase synthesis (synthesized by Ningbo Kangbei Biochemical Co., Ltd.), and the purity of ES2-AF was analyzed by high performance liquid chromatography. The detection wavelength is 220nm, the chromatographic column is a SHIMADZU Inertsil ODS-SP (4.6×250mm, 5 μm) column, the mobile phase A is an aqueous solution containing 0.1% trifluoroacetic acid, and the mobile phase B is an acetonitrile solution containing 0.1% trifluoroacetic acid. The gradient elution was carried out with 15%-75% mobile phase B within 25min at 1.0mL / min.

[0075] (2) Weigh 71mg CS, dissolve it in 30mL double-distilled water, add 710mg EDCI and 70mg NHS after complete dissolution, and activate for 20min. Adjust the pH to 7.4 with 1mol / L NaOH, add 1.65g ...

Embodiment 2

[0077] Example 2: Preparation of chondroitin sulfate-modified anti-angiogenic peptide ES2-AF and cisplatin-loaded conjugate (CDDP-CS-Cys-ES2-AF)

[0078] The preparation process is as follows:

[0079] (1) The anti-angiogenic peptide ES2-AF (IVRRADRAAVPGGGGGGNQWFI) was prepared by solid-phase synthesis (synthesized by Ningbo Kangbei Biochemical Co., Ltd.), and the purity of ES2-AF was analyzed by high performance liquid chromatography. The detection wavelength is 220nm, the chromatographic column is a SHIMADZU Inertsil ODS-SP (4.6×250mm, 5 μm) column, the mobile phase A is an aqueous solution containing 0.1% trifluoroacetic acid, and the mobile phase B is an acetonitrile solution containing 0.1% trifluoroacetic acid. The gradient elution was carried out with 15%-75% mobile phase B within 25min at 1.0mL / min.

[0080] (2) Weigh 71mg CS, dissolve it in 30mL double-distilled water, add 710mg EDCI and 70mg NHS after complete dissolution, and activate for 20min. Adjust the pH to 7...

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Abstract

The invention provides a chondroitin sulfate modifier of anti-angiogenesis peptide ES2-AF and a preparation method and application of cis-platinum loaded by the chondroitin sulfate modifier, and belongs to the technical field of biological medicine. The chondroitin sulfate-cystamine-ES2-AF peptide conjugates and / or cis-platinum-chondroitin sulfate-cystamine-ES2-AF peptide conjugates with different binding degrees are prepared by controlling the conditions of the supply quantity of Cys, ES2-AF peptide and CDDP, the pH value of a reaction system, the reaction time and the like. Compared with the ES2-AF peptide, the chondroitin sulfate modified and cis-platinum entrapped conjugate of the anti-angiogenesis peptide ES2-AF retains the anti-angiogenesis and anti-tumor activity of the ES2-AF peptide, and integrates the anti-tumor effect of cis-platinum, so that the synthesized conjugate has higher stability, targeting property and biological activity. Therefore, the chondroitin sulfate modifier of the anti-angiogenic peptide ES2-AF and the preparation method and application of the cis-platinum loaded by the chondroitin sulfate modifier has better use effect and application value.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to a chondroitin sulfate modified product of anti-angiogenesis peptide ES2-AF and a preparation method and application thereof loaded with cisplatin. Background technique [0002] The information disclosed in this background section is only intended to increase the understanding of the general background of the present invention, and is not necessarily taken as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to those skilled in the art. [0003] ES2-AF peptide (IVRRADRAAVPGGGGGGNQWFI, SEQ ID NO.1) is an anti-neoplastic peptide obtained by linking ES2 peptide (IVRRADRAAVP) that inhibits endothelial cell proliferation and migration with Anti-Flt1 peptide (AF peptide, GNQWFI) that blocks angiogenesis Angiogenic peptides. Due to the presence of polypeptide enzymes in the body, polypeptide drugs have the disadvanta...

Claims

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Application Information

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IPC IPC(8): A61K47/61A61K38/16A61K33/243A61P35/00A61P9/00C08B37/08C07K19/00C07K1/107
CPCA61K47/61A61K38/16A61K33/243A61P35/00A61P9/00C08B37/0069C07K7/06C07K2319/00A61K2300/00
Inventor 谭海宁孙凤李妍侯慧文王洁唐雯卢鲁符家爱
Owner SHANDONG UNIV
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