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Copolymer nucleic acid carrier containing metal coordination pyridine derivative ligand, preparation method and application thereof

A metal coordination and nucleic acid carrier technology, which is applied in the field of preparation of copolymer nucleic acid carriers, can solve the problems of low charge density, high cytotoxicity, and high positive charge density, and achieve low cytotoxicity, high endocytosis efficiency, and high transfection efficiency effect

Active Publication Date: 2018-12-07
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The purpose of the present invention is to provide a low charge density, multifunctional copolymer containing metal-coordinated pyridine derivative ligands in view of the high positive charge density of current polycationic nucleic acid carriers and the high cytotoxicity of in vivo applications. Nucleic acid carrier preparation method and application

Method used

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  • Copolymer nucleic acid carrier containing metal coordination pyridine derivative ligand, preparation method and application thereof
  • Copolymer nucleic acid carrier containing metal coordination pyridine derivative ligand, preparation method and application thereof
  • Copolymer nucleic acid carrier containing metal coordination pyridine derivative ligand, preparation method and application thereof

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Embodiment 1

[0019] A kind of copolymer nucleic acid carrier material containing metal coordinated pyridine derivative ligands. It consists of coordination unit dimethylpyridine amine group and stimulus response unit containing disulfide bond monomer N,N'-bis(acryloyl)cysteine A functional monomer containing a pyridine derivative ligand composed of amine (CBA), which is formed by controlled free radical polymerization with the hydrophilic monomer hydroxyethyl methacrylate (HEMA) and the hydrophobic monomer n-butyl methacrylate The structural formula of the copolymer nucleic acid carrier material with the coordination metal being zinc (Zn) ion and zinc-coordinated pyridine derivative ligand is as follows:

[0020]

[0021] The preparation method of the metal-coordinated pyridine derivative ligand-containing copolymer nucleic acid carrier material shown in the above structural formula includes the following steps:

[0022] 1) Preparation of metal ligand functional monomer DPASS

[0023] Dissolve 1...

Embodiment 2

[0028] A metal-coordinated pyridine derivative ligand-containing copolymer nucleic acid carrier material, which is composed of a coordination metal, a coordination unit, and a stimulus response unit. It is a functional monomer containing a pyridine derivative ligand, a hydrophilic monomer and a hydrophobic monomer. Monomer composition, the coordination metal is magnesium (Mg), the coordination unit is a dimethylpyridine amine group, and the stimulus response unit is a disulfide bond monomer bis(2-propylene)ethoxydisulfide (DSDA) ); The hydrophilic monomer is hydroxyethyl methacrylate; the hydrophobic monomer is isopropylacrylamide.

[0029] A preparation method of the metal-coordinated pyridine derivative ligand-containing copolymer carrier Mg-HDN includes the following steps:

[0030] 1) Preparation of DDAD, a functional monomer of metal ligands

[0031] Dissolve 20mmol 1,4-p-dichlorobenzyl (Dx) in 20mL dichloromethane, add 10mmol dimethylpyridine amine (DPA) and 45mmol anhydrous p...

Embodiment 3

[0035] The application of the prepared copolymer containing metal-coordinating pyridine derivative ligands is used in nucleic acid carriers to deliver deoxyribonucleic acid (DNA) to cells. The method is as follows: the metal-containing coordinating pyridine derivative prepared in Example 1 Ligand copolymer Zn-HDB was mixed with DNA in equal volume and left standing at room temperature for 15 minutes to prepare DNA complexes with mass ratios of 20, 40 and 60:1 respectively; the prepared complexes were used to transfect different cells Department, the method is as follows:

[0036] Cell transfection steps

[0037] 1) Preparation of DNA complex:

[0038] The DNA used is the green fluorescent protein plasmid pCMV-GFP and the luciferase plasmid pCMV-GLuc. The metal-coordinated pyridine derivative ligand-containing copolymer Zn-HDB and DNA prepared in Example 1 were separately dissolved in an acetate buffer of pH 5.2, mixed in equal volumes, and allowed to stand at room temperature for 1...

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Abstract

A copolymer nucleic acid carrier containing a metal coordination pyridine derivative ligand, a preparation method and application thereof are disclosed. The carrier is composed of a ligand functionalmonomer composed of a coordinated metal, a coordination unit and a stimulus-response unit, a hydrophilic functional monomer, and a hydrophobic functional monomer. The copolymer non-viral carrier material containing the metal coordination pyridine derivative ligand that is prepared by a controllable polymerization mode has strong DNA binding ability and interaction with a cell membrane, and the obtained DNA complex has high endocytosis efficiency. After the complex enters cells, due to the stimulus-response, the metal ion ligand unit is disconnected from the copolymer backbone, and the DNA is released and expressed, thus exhibiting high transfection efficiency. Meanwhile, due to the small amount of cations in the copolymer system, the positive charge density of the copolymer and the nucleicacid complex is low, and cytotoxicity of the complex is low. Therefore, the metal-containing coordination pyridine derivative ligand copolymer is a novel low-charge-density non-viral nucleic acid carrier material with good clinical potential.

Description

Technical field [0001] The invention belongs to the field of gene therapy and new materials, and specifically relates to a preparation method and application of a copolymer nucleic acid carrier containing a metal coordinated pyridine derivative ligand. Background technique [0002] Gene therapy achieves the purpose of treating diseases by delivering therapeutic functional nucleic acid molecules to specific cells of patients. It is currently a major disease that cannot be cured, such as cancer, genetic diseases (such as hemophilia), and infectious diseases (such as , AIDS, rheumatoid disease, etc.) and cardiovascular diseases, etc., bring hope. The key to successful gene therapy is how to construct a safe and efficient nucleic acid delivery system to deliver the therapeutic gene to the treatment site and efficiently transfect it. Currently, viral vectors are mainly used in clinical practice. Although viral vectors exhibit very considerable transfection efficiency, their potential...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08F220/18C08F220/20C08F230/04C08F220/54C12N15/87
CPCC08F220/18C08F220/54C12N15/87C08F220/1804C08F220/20C08F230/04
Inventor 郭天瑛刘帅贾惠婷潘建萍
Owner NANKAI UNIV
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