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Cationic polymer as well as preparation method and application thereof

A cationic polymer and polymer technology, applied in the direction of using vectors to introduce foreign genetic material, recombinant DNA technology, etc., can solve problems such as transfection failure and cytotoxicity

Inactive Publication Date: 2012-05-23
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But polymers with high charge density, especially non-degradable polymers, can be extremely toxic to cells
In addition, when the nanocomplex enters the cell, the DNA must be effectively dissociated from the complex to function, so too tight compression of the DNA will cause the DNA to fail to dissociate from the complex and cause transfection failure

Method used

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  • Cationic polymer as well as preparation method and application thereof
  • Cationic polymer as well as preparation method and application thereof
  • Cationic polymer as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Embodiment 1 contains the synthesis of the alkynylated triethylenetetramine monomer (numbering A) of Boc

[0073] Triethylenetetramine (1.46g, 10mmol) was dissolved in DCM (50mL) solution, and after cooling in an ice bath, ethyl trifluoroacetate (2.95g, 21mmol) was added dropwise, and stirred for 1h under ice bath. After the temperature of the reaction solution rose to room temperature and then stirred for 1 h, Boc dissolved in an appropriate amount of DCM was added dropwise. 2 O (5.68g, 26mmol) solution and TEA (2.63g, 26mmol) solution were stirred at room temperature overnight. with saturated NaHCO 3 Washed with saturated brine, anhydrous Na 2 SO 4 dry. After concentration, it was recrystallized with DCM / n-hexane system.

[0074] The above-mentioned recrystallized product (2.00g) was mixed with K 2 CO 3 (1.80 g) was refluxed in methanol / water (volume ratio 20:1) system for 4 h, methanol was spin-dried, and the residue was extracted with DCM (3×100 mL). The com...

Embodiment 2

[0077] Synthesis of embodiment 2 azide diethylene glycol monomer (numbering 1)

[0078] Diethylene glycol (2.12 g, 20 mmol) was dissolved in DCM (250 mL) and cooled in an ice bath. Add p-toluenesulfonyl chloride (7.62g, 42mmol), TEA (4.25g, 42mmol) and 4-dimethylaminopyridine DMAP (0.12g, 0.1mmol) in sequence, stir in ice bath for 1h, and then stir at room temperature for 12h. The reaction solution was sequentially washed with saturated NaHCO3 (2×300mL) and saturated brine (300mL) for washing, anhydrous Na 2 SO 4 dry. After concentration, it was recrystallized with DCM / n-hexane system. Dissolve the recrystallized product (4.1 g, 10 mmol) in acetone, add sodium azide (1.9 g, 30 mmol), and reflux for 48 h. The solvent was concentrated, separated by silica gel column chromatography, and eluted with petroleum ether / ethyl acetate (volume ratio 2:1) to obtain monomer 1 ( 1 HNMR (DMSO-d 6 ): 2.87(s, 4H), 2.70(s, 4H)). The structural formula of monomer 1 is as follows:

[0079...

Embodiment 3

[0080] Synthesis of embodiment 3 azide-containing disulfide bond-containing monomer (numbering b)

[0081] Dissolve propylamine chloride (1.30 g, 10 mmol) in water, add sodium azide (1.95 g, 30 mmol), and react at 80° C. for 15 h. After removing most of the water under reduced pressure, the reaction solution was cooled in an ice bath, and sodium hydroxide (4 g) was added to neutralize the hydrochloric acid. The aqueous solution was extracted with diethyl ether and washed with diethyl ether (3×100 mL), the combined organic phases were washed with anhydrous K 2 CO 3 Drying; Concentrate to obtain azidopropylamine;

[0082] Dissolve 3,3'-dithiodipropionic acid (2.10g, 10mmol) in water (100mL), and add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride respectively (EDC, 4.34g, 22mmol) and N-hydroxysuccinimide (NHS, 2.53g, 22mmol), reacted for 2h, added azidopropylamine (2.20g, 22mmol), and continued to react at room temperature for 24h. The reaction solution was extract...

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Abstract

The invention discloses a novel cationic polymer used as a non-viral gene carrier as well as a preparation method and application thereof. The cationic polymer provided by the invention has a structure shown as the following formula I. The cationic polymer has a 1,2,3-triazole group structure and a disulfide bond structure and is generated by an alkynylation monomer and an azide monomer (an azide-diethylene glycol monomer and an azide monomer containing a disulfide bond) through cycloaddition and polymerization of alkynyl-azide catalyzed by single-charge copper ions. The polymer provided by the invention has a structure in which triazole is adjacent to amide, and the structure has specific binding ability with nucleic acid, thus, the stability of genes in the transmission process can be improved; and the disulfide bond contained in the structure also has reduction responsiveness and can be degraded in a cell to further increase the transfection efficiency and lower the toxicity, therefore, the non-viral gene carrier prepared by using the polymer has the characteristics of high biocompatibility, low toxicity, high transfection efficiency and the like.

Description

technical field [0001] The present invention relates to a novel cationic polymer, its preparation method and use, and also relates to the nanocomposite composed of the novel cationic polymer and nucleic acid, its preparation method and use. Background technique [0002] Gene therapy refers to the introduction of normal genes or genes with therapeutic effects into target cells in a certain way to correct gene defects or exert therapeutic effects. To be precise, it is the transfer of specific nucleic acid sequences related to genetic information. It is a comprehensive Sexually difficult biotechnology. Therefore, the key issue of gene therapy is to find highly efficient and low-toxic gene carriers. The gene vectors researched and developed so far mainly include viral vectors and non-viral vectors. Among them, viral vectors, such as various retroviruses, adenoviruses, herpes viruses, and adeno-associated viruses, have high transfection efficiency, but there are There are many ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G73/08C12N15/63C12N15/65
Inventor 高瑜李亚平张志文顾王文
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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