Squalene chidamide prodrug self-assembled nanoparticles, and preparation method and application thereof

A technology of self-assembled nanoparticles and chidamide, applied in the field of medicine, can solve the problems of low tumor microenvironment permeability, poor targeting, etc. Effect

Active Publication Date: 2021-12-24
ZHEJIANG CHINESE MEDICAL UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The object of the present invention is to provide a kind of squalene for the disadvantages of chidamide in the treatment of solid tumors, such as p

Method used

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  • Squalene chidamide prodrug self-assembled nanoparticles, and preparation method and application thereof
  • Squalene chidamide prodrug self-assembled nanoparticles, and preparation method and application thereof
  • Squalene chidamide prodrug self-assembled nanoparticles, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] The preparation process of squalene-based chidamide prodrug molecule (SQ-CHI) comprises the following steps:

[0058] Weigh 1,1',2-Tris-norsqualenoyl acid (1,1',2-Tris-norsqualenoyl acid, SQ-COOH) 100mg and add 1mL DMF to dissolve evenly, and gradually add N-hydroxysuccinimide ( NHS) 30 mg and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) 100 mg were reacted at room temperature for 30 min under nitrogen protection. Accurately weigh 100 mg of Chidaniline and dissolve it in 1 mL of DMF, add it dropwise to the above reaction system, continue to stir and react at room temperature under nitrogen protection for 48 h, and adopt flash column chromatography (eluent is dichloromethane:methanol = 99:1; 95:5) for purification. Results The SQ-CHI prodrug molecule was successfully prepared.

Embodiment 2

[0060] The preparation process of squalene-based chidamide prodrug molecule (SQ-CHI) comprises the following steps:

[0061] Weigh 1,1',2-Tris-norsqualenoyl acid (1,1',2-Tris-norsqualenoyl acid, SQ-COOH) 200mg and add 1mL DMF to dissolve evenly, and gradually add N-hydroxysuccinimide ( NHS) 60 mg and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) 50 mg, reacted for 120 min at room temperature under nitrogen protection. Accurately weigh 100 mg of Chidaniline and dissolve it in 1 mL of DMF, add it dropwise to the above reaction system, continue to stir and react at room temperature under nitrogen protection for 96 h, and adopt flash column chromatography (eluent is dichloromethane:methanol = 95:5; 85:5) for purification. Results The SQ-CHI prodrug molecule was successfully prepared.

[0062] Both Example 1 and Example 2 successfully prepared SQ-CHI prodrug molecules, and the prodrug molecules prepared in Example 1 were preferred for subsequent research.

Embodiment 3

[0064] The preparation process of folic acid-polyethylene glycol-squalene (FA-PEG-SQ) small molecule ligand comprises the following steps:

[0065] Accurately weigh 100mg of SQ-COOH and add 100μLDMF to dissolve evenly, gradually add 30mg of NHS and 100mg of EDCI to the reaction system, and react for 30min at room temperature under nitrogen protection. Accurately weigh FA-PEG-NH 2 100 mg of the powder was dissolved in 100 μL of DMF, and added dropwise to the above reaction system, and the reaction was continued with stirring at room temperature for 48 h under nitrogen. At the end of the reaction, use an ultrafiltration centrifuge tube (molecular cut-off 3KDa), and centrifuge at a high speed of 10000rpm for 30min. Results The SQ-PEG-FA complex was successfully prepared.

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Abstract

The invention discloses squalene chidamide prodrug self-assembled nanoparticles, and a preparation method and application thereof; firstly, squalene acid and chidamide are dissolved in methylformamide respectively; N-hydroxysuccinimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloric acid are used as catalysts; the two are mixed and react to prepare squalene chidamide prodrug molecules; then, squalene acid and folic acid-polyethylene glycol-amino or p-methoxybenzamide-polyethylene glycol-amino are dissolved in methylformamide respectively; N-hydroxysuccinimide (NHS) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) are used as catalysts; the two are mixed and react to obtain a small molecule ligand; and the small molecule ligand, arginine-glycine-aspartic acid and the squalene chidamide prodrug molecules are self-assembled in water to form the nanoparticles. According to the invention, the defects of low permeability, poor targeting property and large toxic and side effects of chidamide in the aspect of solid tumour treatment can be effectively overcome.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a self-assembled nanoparticle of squalene-based chidamide prodrug, its preparation method and application. Background technique [0002] Pancreatic cancer is a malignant gastrointestinal tumor with a mortality rate of 94% and high tumor heterogeneity. Due to the lack of early diagnostic markers, the prognosis is extremely poor, and the current 5-year survival rate is only 8-9%. Pancreatic cancer has a very complex tumor microenvironment, including many types of inflammatory cells. In addition, tumor-associated fibroblasts form a dense extracellular matrix, which hinders drug delivery and compresses the space of blood vessels, making it difficult for small molecule drugs to enter the tumor to play a role in killing tumor cells. At present, the treatment of pancreatic cancer is still dominated by traditional surgical resection, but the proportion of patients eligible for surgery...

Claims

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Application Information

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IPC IPC(8): A61K31/4406A61K31/01A61K47/55A61K47/60A61K9/51A61P35/00
CPCA61K31/4406A61K31/01A61K47/55A61K9/5146A61P35/00A61K2300/00A61K47/551A61K47/60A61K47/64A61K47/6929
Inventor 谷满仓陈凯迪赵山石燕
Owner ZHEJIANG CHINESE MEDICAL UNIVERSITY
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