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Application of quaternized natural polymer material as virus vector delivery enhancing material

A technology of natural polymers and viral vectors, which is applied in the application field of quaternized natural polymer materials as viral vector delivery enhancement materials, and can solve the problem of difficult balance between high nucleic acid delivery efficiency and high biocompatibility of viral vectors. Normalize the problems of delivery efficiency and poor biocompatibility, and achieve the effect of improving nucleic acid delivery efficiency and biocompatibility, improving nucleic acid delivery efficiency, and improving delivery efficiency

Active Publication Date: 2020-08-18
BEIJING UNIV OF CHEM TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, although the existing viral vectors have high delivery efficiency, they are strongly dependent on high doses, resulting in two serious drawbacks
One, high dose (titer) viral vectors are often more toxic to cells, so it is difficult to balance the high nucleic acid delivery efficiency and high biocompatibility of viral vectors; two, due to their strong immunogenicity, viral vectors, although The delivery effect is better in cell experiments, but in human experiments, viral vectors such as adenovirus vectors (common and typical viral vectors) are particularly limited by the body's own pre-existing immune response, and are easily absorbed by the human body during body fluid / blood delivery. Self-immune response clearance, unable to exert its delivery efficiency normally
At the same time, positively charged amino polymer materials in aqueous solution have been developed for the delivery of non-viral nucleic acid materials, but there is a problem of low efficiency, and most amino polymer materials such as PEI, lipo2K, PAMAM have high toxicity, The disadvantage of poor biocompatibility

Method used

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  • Application of quaternized natural polymer material as virus vector delivery enhancing material
  • Application of quaternized natural polymer material as virus vector delivery enhancing material
  • Application of quaternized natural polymer material as virus vector delivery enhancing material

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] 1) Add 2.0g of epichlorohydrin dropwise to 3.0g of N,N-dimethylethylamine, stir at 50°C for 8 hours, after the end, precipitate and wash with diethyl ether and n-hexane twice, and dry under reduced pressure to obtain cyclo Oxygen quaternary ammonium salt A, molecular formula is

[0021] 2) Add 2.0 g of chitosan citrate (degree of deacetylation: 95%, average molecular weight: 6000) into 200 mL of deionized water, and heat to dissolve at 50° C. Afterwards, 2.5 g of epoxy quaternary ammonium salt A was dissolved in 20 mL of deionized water and added to the chitosan citrate solution, and reacted at 50° C. for 48 hours.

[0022] 3) After the reaction, wash with ethanol precipitation for 3 times, and dry under reduced pressure to obtain the quaternized natural polymer delivery material 1.

Embodiment 2

[0024] 1) Add 10g of epichlorohydrin dropwise to 30g of N,N-dimethylpropylamine, stir at 35°C for 24 hours, after the end, precipitate and wash with petroleum ether and n-hexane for 3 times, dry under reduced pressure to obtain epoxy quaternary ammonium salt B, the molecular formula is

[0025] 2) Add 3.0 g of chitosan hydrochloride (degree of deacetylation: 90%, average molecular weight: 20000) into 200 mL of deionized water, and heat to dissolve at 45° C. Then 1.0 g of epoxy quaternary ammonium salt B was dissolved in 10 mL of deionized water and added to the chitosan hydrochloride solution, and reacted at 40° C. for 24 hours.

[0026] 3) After the reaction, wash twice with ethanol precipitation, dialyze and freeze-dry to obtain the quaternized natural polymer delivery material 2.

Embodiment 3

[0028] 1) Dissolve 5.0g of hydroxypropyl cellulose (average molecular weight: 18000) in 40mL of N,N-dimethylformamide, add 1.5g of phenyl p-nitrochloroformate and 10mL of pyridine, and stir at 0°C for 4 hours. It was then precipitated 3 times with anhydrous ether.

[0029] 2) Add the product purified in step 1) into 30 mL of N,N-dimethylformamide, add 4.5 g of ethylenediamine, and stir for 24 hours at 25°C under a nitrogen atmosphere.

[0030] 3) Precipitate in ether for 3 times, and dry in vacuum to obtain hydroxypropyl cellulose with primary amino groups.

[0031] 4) Dissolve 2.0g aminohydroxypropyl cellulose in 200mL deionized water; add 0.4g 3-chloro-2-hydroxypropyltrimethylammonium chloride and 0.4g sodium hydroxide in 20mL deionized water, React at 30°C for 24 hours.

[0032] 5) After the reaction, wash with ethanol precipitation for 3 times, and dry under reduced pressure to obtain the quaternized natural polymer delivery material 3.

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Abstract

The invention discloses application of a quaternized natural polymer material as a virus vector delivery enhancing material. The quaternized natural polymer material can be used for virus vector delivery, and the preparation method comprises the following steps of: 1) preparing an aqueous solution of a natural polymer with a primary amine group; 2) adding epoxy alkyl short alkyl chain quaternary ammonium salt or chlorohydroxypropyl short alkyl quaternary ammonium salt with short alkyl carbon atom number X for reaction, wherein X is equal to 1-6; and 3) precipitating, washing and drying to obtain the quaternized natural polymer delivery material. The virus vector delivery enhancing material disclosed by the invention can reduce the toxicity of a high-dose (titer) virus vector to cells, improve the nucleic acid delivery efficiency and biocompatibility, weaken the inhibition effect of a neutralizing antibody on the virus vector infection efficiency under a pre-stored immune condition, andimprove the nucleic acid delivery efficiency of the virus vector.

Description

technical field [0001] The invention belongs to the field of delivery vectors, and relates to the application of a quaternized natural polymer material as a delivery enhancement material for virus vectors. Background technique [0002] Viral vectors are widely used in the fields of gene therapy (using the ability of viruses to infect cells to deliver nucleic acid fragments that target somatic cells or tumor cells that lack delivery) and immunotherapy (as a vaccine, delivering nucleic acid fragments that can express antigens to targeted immunity). However, although the delivery efficiency of existing viral vectors is relatively high, they are strongly dependent on high doses, resulting in two serious drawbacks. One, high dose (titer) viral vectors are often more toxic to cells, so it is difficult to balance the high nucleic acid delivery efficiency and high biocompatibility of viral vectors; two, due to their strong immunogenicity, viral vectors, although The delivery effect...

Claims

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Application Information

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IPC IPC(8): A61K48/00A61K47/36A61K47/38A61K47/28A61K47/22
CPCA61K48/0025A61K47/36A61K47/38A61K47/28A61K47/22
Inventor 徐福建胡杨汪超范亚倩
Owner BEIJING UNIV OF CHEM TECH
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