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Application of chitosan reduction-sensitive system as gene drug delivery carrier

A technology of gene carrier and chitosan derivative, which is applied in the field of preparation of the carrier, achieves the effects of high safety, low toxicity and side effects, and good biocompatibility

Inactive Publication Date: 2016-08-24
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Introducing an anti-tumor non-viral gene carrier rich in amino compounds on chitosan through a linker containing a disulfide bond has not yet been reported in any literature or patents

Method used

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  • Application of chitosan reduction-sensitive system as gene drug delivery carrier
  • Application of chitosan reduction-sensitive system as gene drug delivery carrier
  • Application of chitosan reduction-sensitive system as gene drug delivery carrier

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1: the preparation of hydroxyethyl chitosan-histidine reduction sensitive copolymer

[0047] Dissolve 1g of chitosan in isopropanol solution, add 10ml of 50% NaOH solution, after alkalization, add 10ml of ethylene oxide to the reaction solution, and stir magnetically for 2-24 hours under the condition of 35-50°C oil bath, Adjust the pH of the reaction solution to 7, dialyze and freeze-dry to obtain water-soluble hydroxyethyl chitosan.

[0048] 0.3g hydroxyethyl chitosan is dissolved in the mixed solvent of water and methanol (v / v=1:1), add 0.6g S-aminoethyl-3,4-dithiopropionic acid, 0.547g EDC React with 0.328g NHS for 12h, remove methanol by rotary evaporation, dialyze (MWCO=14000) for 2-3 days, and lyophilize to obtain a chitosan intermediate whose free segment is an amino group.

[0049] React 0.25g of chitosan intermediate, 0.22g of histidine, 1.36g of EDC and 0.818g of NHS for 12 hours. After the reaction, use excess acetone to precipitate the polysacch...

Embodiment 2

[0050] Embodiment 2: the preparation of hydroxyethyl chitosan-spermine reduction sensitive copolymer

[0051] Dissolve 1g of chitosan in acetic acid solution, add 10ml of 50% NaOH solution, after alkalization, add 10ml of ethylene oxide to the reaction solution, stir magnetically for 2-24 hours under the condition of 35-50°C oil bath, and put the reaction The pH of the solution was adjusted to 7, and the water-soluble hydroxyethyl chitosan was obtained by dialysis and freeze-drying.

[0052] 0.3g hydroxyethyl chitosan is dissolved in the mixed solvent of water and methanol (v / v=1: 1), add 0.6g3,3'-dithiodipropionic acid, 0.547g EDC and 0.328g NHS, React for 12 hours, remove methanol by rotary evaporation, dialyze (MWCO=14000) for 2-3 days, and lyophilize to obtain a chitosan intermediate with a carboxyl group as the free segment.

[0053] 0.3g chitosan intermediate, 0.1337g spermine, 0.1785g EDC and 0.1065g NHS were reacted for 24 hours, dialyzed (MW=14000) for 3 days, and fr...

Embodiment 3

[0054] Embodiment 3: the preparation of hydroxyethyl chitosan-arginine reduction sensitive copolymer

[0055] Dissolve 1g of chitosan in acetic acid solution, add 10ml of 50% NaOH solution, after alkalization is completed, add 10ml of ethylene oxide to the reaction solution, stir magnetically for 2-24h under the condition of 35-50°C oil bath, and put the reaction The pH of the solution was adjusted to 7, and the water-soluble hydroxyethyl chitosan was obtained by dialysis and freeze-drying.

[0056] 0.3g hydroxyethyl chitosan is dissolved in the mixed solvent of water and methanol (v / v=1:1), add 0.6g S-aminoethyl-3,4-dithiopropionic acid, 0.547g EDC React with 0.328g NHS for 12h, remove methanol by rotary evaporation, dialyze (MWCO=14000) for 2-3 days, and lyophilize to obtain a chitosan intermediate whose free segment is an amino group.

[0057] 0.3g chitosan intermediate, 0.115g arginine, 0.154g EDC and 0.092g NHS were reacted for 12h, dialyzed (MW=14000) for 3 days, and fr...

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Abstract

The invention relates to a reduction-sensitive anti-tumor chitosan derivative gene carrier, which is characterized in that a compound, which is rich in amino groups, is introduced to a chitosan skeleton by virtue of a specifically degradable truss arm which contains a disulfide bond; under the action of electrostatic adsorption, negatively charged siRNA is tightly compressed, so that nanoparticles are formed, and the nanoparticles can escape from the interior of an endosome through a proton sponge effect; and after the nanoparticles reach cytoplasm, the disulfide bond truss arm can be specifically degraded by a high-concentration reducing substance, namely glutathione, in focus cells, and the loaded siRNA is rapidly released and acts on a target, so that the silencing effect of a gene medicine is obviously improved. The adjuvant material, when applied to such administration modes as intravascular injection, intramuscular injection, external application, oral administration and the like as the gene carrier, is high in safety. The preparation method disclosed by the invention is simple and mature in process, and the preparation method is suitable for continuous large-scale production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical preparations, and designs a reduction-sensitive chitosan derivative as a gene drug carrier. The invention also relates to a preparation method and application of the carrier. Background technique [0002] Chitosan is a deacetylated derivative of chitin, the only alkaline natural polysaccharide in nature, and has a wide range of sources. Chitosan is a polycation with good biocompatibility, nontoxicity and low immunogenicity. Chitosan is an excellent gene carrier material. It can combine with negatively charged gene drugs through electrostatic adsorption and hydrogen bonding to protect gene drugs from degradation by nucleases, and the size of the gene type carried is not limited. In order to improve the water solubility of chitosan and increase the charge density to improve its ability to compress genes, there are currently a variety of reports of chitosan-amino compound grafts, such as: chitosan-PEI ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K48/00A61K47/36A61P35/00C08B37/08
CPCA61K48/0025A61K47/36C08B37/003
Inventor 霍美蓉周建平秦晨
Owner CHINA PHARM UNIV
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