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Macrocyclic polyamine coupled chitosan gene vector, preparation method and uses thereof

A macrocyclic polyamine and gene carrier technology, which is applied in the field of macrocyclic polyamine-coupled chitosan gene carrier and its preparation, can solve the problems of reduced surface charge density and reduced cytotoxicity, and achieve improved water solubility and high transgenic transfection efficiency and low cytotoxicity

Inactive Publication Date: 2009-10-07
BEIJING UNIV OF CHEM TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Macrocyclic polyamines are similar to PEI structural units, but are small molecules with significantly lower surface charge density, and therefore, less cytotoxicity

Method used

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  • Macrocyclic polyamine coupled chitosan gene vector, preparation method and uses thereof
  • Macrocyclic polyamine coupled chitosan gene vector, preparation method and uses thereof
  • Macrocyclic polyamine coupled chitosan gene vector, preparation method and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Embodiment 1: the preparation of N-(1,4,7,10-tetraazacyclododecyl) acetylated chitosan

[0035] (1) 1.977g (3.33mmol) 4,7,10-tris(tert-butoxycarbonyl)-1,4,7,10-tetraazacyclododecylacetic acid with 20ml N,N,-dimethyl Dissolve formamide, add 0.313g (3.725mmol) NaHCO 3 ,Magnetic stirring.

[0036] (2) add dropwise 0.600g (1.49mmol amino) 6-O-triphenyl methyl etherified chitosan (Cs-Tr) N, N,-dimethylformamide solution 20ml in the last step reaction solution, Stir well, then add 0.715 g (3.725 mmol) of 1-ethyl(-3-dimethylaminopropyl) carbodiimide, and stir for 18 hours. The obtained solution was precipitated by adding diethyl ether, and the precipitate was washed with diethyl ether, dialyzed with deionized water in a dialysis bag for 3 days, and the product was freeze-dried. Obtain 6-O-triphenyl methyl etherified -N-(4,7,10-tris(tert-butoxycarbonyl)-1,4,7,10-tetraazacyclododecyl) acetylated shell polysaccharides.

[0037] (3) Add 20ml of trifluoroacetic acid to the pro...

Embodiment 2

[0043] Embodiment 2: the preparation of N-(1,4,7-triazacyclononyl) acetylated chitosan

[0044] (1) 0.9773g (2.52mmol) 4,7-bis(tert-butoxycarbonyl)-1,4,7-triazacyclononyl)acetic acid was dissolved in 10ml N,N,-dimethylformamide, Add 0.212g (2.525mmol) NaHCO 3 , magnetically stirred for 30 min.

[0045] (2) Add dropwise 0.403g (1.01mmol amino) 6-O-triphenylmethyl etherified chitosan (Cs-Tr) N, N,-dimethylformamide solution 15ml in the previous step reaction solution, Stir well, add 0.484 g (2.525 mmol) of 1-ethyl(-3-dimethylaminopropyl) carbodiimide, and stir for 12 hours. The obtained solution was precipitated by adding diethyl ether, and the precipitate was washed with diethyl ether, dialyzed in a dialysis bag with deionized water for 4 days, and the product was freeze-dried. 6-O-triphenylmethyl etherified-N-(4,7-bis(tert-butoxycarbonyl)-1,4,7-triazacyclononyl)acetylated chitosan was obtained.

[0046] (3) Add 15ml of trifluoroacetic acid to the product obtained in the ab...

Embodiment 3

[0052] Embodiment 3: Preparation of 6-O-(1,4,7,10-tetraazacyclododecyl) acetylated chitosan

[0053] (1) Under ice-bath conditions, add 2.054g (3.86mmol) 4,7,10-tris(tert-butoxycarbonyl)-1,4,7,10-tetraazacyclododecylacetic acid to 10ml N, N dimethylacetamide dissolved, add 1.1881g (4.25mmol, 1.1 times the equivalent) Carter condensing agent, 0.807ml diisopropylethylamine, stir to dissolve, remove the ice bath, continue to stir the reaction, TLC traces to the formation Activated ester; 1.126g (3.86mmol 6-hydroxyl) N-phthalylated chitosan (Cs-NPTh) was dissolved in 20ml N, N dimethylacetamide, and 4 times the equivalent of diisopropyl Ethylamine, stirred to obtain a phthalylated chitosan solution.

[0054] (2) Mix the activated ester and the phthalylated chitosan solution evenly, and stir for 12 hours. TLC tracked that the reaction of the generated activated ester was complete, and water was added to precipitate a solid. The obtained precipitate was washed with water and ethe...

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PUM

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Abstract

The present invention discloses a macrocyclic polyamine coupled chitosan gene vector, preparation method and uses thereof. General formula of the gene vector is as follows, wherein the R[1], R[2] represents macrocyclic polyamine compounds or H, the macrocyclic polyamine is coupled to second amidogen of the chitosan in amide linkage or coupled to sixth hydroxy of the chitosan in ester linkage. The invention is obtained by using EDAC as condensing agent to couple the macrocyclic polyamine at the second position of the chitosan macromolecular skeleton, or using BOP reagent as ester condensing agent to couple the macrocyclic polyamine at the sixth position. The macrocyclic polyamine coupled chitosan compounds can be used as non-viral gene vector for cell transfection to cure various genopathy. The invention applies gel electrophoresis method to study combination and protection effect of target compounds to DNA, and provides good basement and effective approach for obtaining non-viral gene vector with low cytotoxicity and high transfection efficiency.

Description

technical field [0001] The invention relates to the field of medicinal polymer materials, in particular to a macrocyclic polyamine-coupled chitosan gene carrier and a preparation method and application thereof. Background technique [0002] Gene therapy provides broad therapeutic prospects for many important human diseases such as genetic diseases, tumors, cardiovascular diseases and neurodegenerative diseases. Gene therapy is a means to treat diseases by introducing exogenous target genes into the body through vectors or other channels and displaying corresponding biological effects in target tissues and cells, and effective and safe therapeutic vectors are still The subject of hard work. In order to overcome the defects of viral vectors, a series of non-viral vectors are being recognized and utilized. [0003] Chitosan is the deacetylation product of natural chitin, which is a rare non-biologically toxic alkaline polysaccharide. It has excellent biocompatibility and biod...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08B37/08A61K47/40
Inventor 乔仁忠戎娜刘学娜
Owner BEIJING UNIV OF CHEM TECH
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