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Gene targeting delivery system aiming at CD44 high expression type tumors and application

A high-expression, systematic technology, applied in the field of medicine, can solve the problems of long stirring reaction time, small mass concentration range, high reaction temperature, etc., and achieve the effects of huge market application prospects, positive social effects, and rich economic benefits

Inactive Publication Date: 2018-05-15
THE AFFILIATED HOSPITAL OF QINGDAO UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Yet, there is following problem in the method described in this application: (1) reaction temperature is high, is 40-70 ℃, easily causes the reduction of chitosan molecular weight; (2) the mass concentration range of hyaluronic acid in aqueous solution is little, only 1-5%, thereby limiting the amount of reaction; (3) after the completion of the reaction, repeated dialysis and washing treatments are required to obtain modified hyaluronic acid, and the operation is complicated; (4) the stirring reaction time is as long as 3-24h, resulting in The whole operation process takes a long time, which will easily lead to a decrease in the activity of the aldehyde group after the reaction
[0006] In addition, there is no report on the combination of oxidized hyaluronic acid and chitosan nanoparticles as a gene-targeted delivery system for tumors with high CD44 expression

Method used

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  • Gene targeting delivery system aiming at CD44 high expression type tumors and application
  • Gene targeting delivery system aiming at CD44 high expression type tumors and application
  • Gene targeting delivery system aiming at CD44 high expression type tumors and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] A gene-targeted delivery system for tumors with high CD44 expression, the gene-targeted delivery system is a coupling shell obtained by covalently cross-linking dialdehyde-based modified hyaluronic acid HAD to chitosan nanoparticles CSNPs Glycan targeting nanoparticles. Wherein, the chitosan nanoparticles CSNPs are chitosan nanoparticles wrapped with siRNA, that is, CSNps-siRNA. The structural formula of the HAD is as follows:

[0029]

[0030] The gene-targeted delivery system for tumors with high CD44 expression was prepared by the following method:

[0031] (1) The oxidized hyaluronic acid HA is reacted with alcohol to obtain hyaluronic acid HAD with two aldehyde groups:

[0032] (a) Weigh 2g of hyaluronic acid (HA), and add it into 95% (v / v) ethanol under stirring to obtain an ethanol solution of 9% (w / v) hyaluronic acid; (b) avoid light Weigh 0.5310g NaIO 4 (M HA :M NaIO4 =4:1), it was completely dissolved in water to obtain 0.5M NaIO 4 Aqueous solution; ...

Embodiment 2

[0058] Different from Example 1,

[0059] The gene-targeted delivery system for tumors with high CD44 expression was prepared by the following method:

[0060] (1) The oxidized hyaluronic acid HA is reacted with alcohol to obtain hyaluronic acid HAD with two aldehyde groups:

[0061] (a) take by weighing 1g hyaluronic acid (HA), add in 60% ethanol under stirring, obtain the ethanolic solution of the hyaluronic acid that concentration is 5% (w / v); (b) avoid light and take by weighing 0.5310g NaIO 4 (M HA :M NaIO4 =2:1), it was completely dissolved in water to obtain 0.1M NaIO 4 Aqueous solution; at 25°C the dissolved NaIO 4 The solution was slowly added to the HA solution drop by drop, and the reaction was stirred at a constant speed in the dark until the oxidation reaction was completed. (c) The reacted solution was added to three times the volume of absolute ethanol for precipitation, washed and dried to obtain oxidized hyaluronic acid HAD.

[0062] (2) Preparation of c...

Embodiment 3

[0067] Different from Example 1,

[0068] The gene-targeted delivery system for tumors with high CD44 expression was prepared by the following method:

[0069] (1) The oxidized hyaluronic acid HA is reacted with alcohol to obtain hyaluronic acid HAD with two aldehyde groups:

[0070] (a) take by weighing 3g hyaluronic acid (HA), add in 85% ethanol under stirring, obtain the ethanol solution of the hyaluronic acid that concentration is 6% (w / v); (b) avoid light and take by weighing 0.5310g NaIO 4 , which was completely dissolved in water to obtain 1M NaIO 4 Aqueous solution; at 22°C the dissolved NaIO 4 The solution was slowly added to the HA solution drop by drop, and the reaction was stirred at a constant speed in the dark until the oxidation reaction was completed.

[0071] (2) Preparation of chitosan nanoparticles CSNps-siRNA wrapped with siRNA:

[0072] The mass ratio of CS and TPP is 6:1; the stirring time is 40min.

[0073] (3) Preparation of CSNps-siRNA-HAD targeti...

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Abstract

The invention provides a gene targeting delivery system aiming at CD44 high expression type tumors and application thereof, based on a current situation of a gene targeting delivery technology adopting chitosan (CS) nanoparticles at present. The gene targeting delivery system is composed of coupled chitosan targeting nanoparticles which are obtained by covalently crosslinking dual-aldehyde-group modified hyaluronic acid HAD to the chitosan nanoparticles CSNPs. The chitosan nanoparticles CSNPs are chitosan nanoparticles covered with siRNA, i.e., CSNPs-siRNA. The quantity of aldehyde groups in oxidized hyaluronic acid HAD is 2. The oxidized hyaluronic acid HAD is prepared by adopting alcohol phase reaction. The alcohol phase reaction adopted by the gene targeting delivery system can be carried out at room temperature and heating is not needed; the hyaluronic acid HA has a swelling state in an ethanol solution, but not a dissolved state, so that the concentration can be remained to be 5 to 10 percent (w / v) and the reaction amount of one step is greatly increased.

Description

technical field [0001] The invention belongs to the field of medicine and relates to a gene carrier, in particular to a targeting gene carrier obtained by modifying chitosan nanoparticles with modified hyaluronic acid. Background technique [0002] Modern molecular biology studies have shown that the occurrence and development of tumors is a complex evolution process with multiple genes, multiple stages, and multiple steps. The root cause may be abnormal changes in gene structure and expression inside cells, involving the abnormality and accumulation of various proto-oncogenes, tumor suppressor genes, growth factors and their receptors, cell adhesion factors, and DNA repair genes. For example, Bcl2 is a proto-oncogene and one of the most important genes that inhibit tumor cell apoptosis. Studies have shown that the translocation and high expression of Bcl2 gene are closely related to the occurrence, development and poor prognosis of tumors. Reducing or eliminating the overe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/69A61K47/61A61K31/713A61K48/00A61P35/00C08B37/08
CPCA61K31/713A61K48/0041C08B37/0072
Inventor 牛海涛梁晔王丽萍李丹梁志娟陈元斌张文华
Owner THE AFFILIATED HOSPITAL OF QINGDAO UNIV
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