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Guanidine hypoglycemic drug-polysaccharide conjugate, as well as preparation method and application thereof

A hypoglycemic agent and conjugate technology, which is applied in the field of diabetes treatment, can solve the problems of small target gene capacity, poor targeting specificity, and high immunogenicity, and achieves less reaction steps, high yield and simple synthesis method. Effect

Active Publication Date: 2014-08-13
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Viral vectors have high transfection efficiency, but there are disadvantages such as high immunogenicity, high toxicity, small target gene capacity, poor targeting specificity, complicated preparation and high cost, so people pay more and more attention to non-viral vectors for gene delivery Research

Method used

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  • Guanidine hypoglycemic drug-polysaccharide conjugate, as well as preparation method and application thereof
  • Guanidine hypoglycemic drug-polysaccharide conjugate, as well as preparation method and application thereof
  • Guanidine hypoglycemic drug-polysaccharide conjugate, as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061]

[0062] Synthesis of metformin-chitosan:

[0063]

[0064] 0.209g chitosan and 0.575g potassium periodate were dissolved in the acetate buffer of 25mL pH4.5 (respectively containing the chitosan monomer of 0.05mol / L and the sodium periodate of 0.1mol / L), After continuing to stir at 40°C for 1 h, add ethylene glycol equivalent to potassium periodate to terminate the reaction, and use a dialysis bag with a molecular weight cut-off of 3500 to dissolve the obtained product in pH 4.5 acetate buffer containing 0.2M NaCl and to remove Dialyzed in deionized water, freeze-dried. Weigh a certain amount of oxidized chitosan, dissolve it in 1M sodium hydroxide solution, then add a certain amount of metformin (the molar weight is twice the molar weight of the oxidized chitosan monomer), stir and react for 48 hours at 4°C , dialyzed in deionized water with a dialysis bag with a molecular weight cut-off of 3500, freeze-dried, and stored the final product at -20°C for future us...

Embodiment 2

[0066] Structure identification and molecular weight characterization of metformin-chitosan

[0067] Such as figure 1 As shown, the structure of metformin-chitosan conjugate was identified by H-NMR. Compared with the proton signal peak on the 2-carbon of chitosan (marked by the dotted line), the proton signal peak on the 2-carbon of chitosan in the chitosan-metformin structure basically disappears (δ H =3.2ppm), indicating that the C-C bond on the chitosan in the structure was successfully oxidized and broken by potassium periodate, and the chitosan-metformin 1 H NMR spectrum, showing metformin (δ H =3.0ppm; -N(CH 3 ) 2 ) and chitosan (δ H =2.0ppm; -COCH 3 ), further indicating the formation of chitosan-metformin.

[0068] The molecular weight of chitosan-metformin was detected by gel permeation chromatography: the column temperature was 25°C, the flow rate was 0.5mL / min, and the mobile phase was 0.5M ammonium acetate solution. The chitosan raw material has a molecular...

Embodiment 3

[0071] Study on Cytotoxicity of Metformin-Chitosan

[0072] The cytotoxicity of metformin-chitosan synthesized according to Example 1 was evaluated using L02 and HepG2 cell lines. L02 and HepG2 cells are normal human liver cells and human liver cancer cells, respectively. These two cells were divided into 1×10 4 The amount of cells / well was seeded in a 96-well flat-bottomed plate at 37°C, 5% CO 2 In the incubator, after incubating with DMEM medium for 18 hours, after treating with different concentrations of polymers for 24 hours, and after treating with 20 μL of MTS solution for 4 hours, the absorbance value at 490 nm was detected with a microplate reader. Such as figure 2 As shown, in the concentration range of 0-100 μg / ml, metformin-chitosan has no cytotoxicity to L02 and HepG2.

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Abstract

The invention discloses a guanidine hypoglycemic drug-polysaccharide conjugate, as well as a preparation method and application thereof. The conjugate is formed by connecting primary amine on a guanidine drug and the aldehyde group on oxidative polysaccharide through a schiff base bond. Compared with an existing guandine hypoglycemic drug, on the one hand, the conjugate can be used as a polymeric prodrug for reducing blood glucose, so that the pharmacologic action is strengthened, few adverse responses exist, and the safety is higher; on the other hand, the conjugate can be combined with therapeutic genes for treating diabetes mellitus, in particular obese diabetic, and the curative effect of the conjugate on cellular level and animal pattern are better than those of active compounds and therapeutic gene. The results prove that the guanidine hypoglycemic drug-polysaccharide conjugate has tremendous potential in the aspect of drug combined gene therapy of diabetes mellitus due to the excellent biocompatibility and effective gene transfer efficiency; the synthesizing and preparing method is simple, the process is mature, and the yield is high.

Description

technical field [0001] The invention relates to a guanidine hypoglycemic drug-polysaccharide conjugate, in particular to a guanidine hypoglycemic drug-polysaccharide conjugate with good physiological activity and biodegradability as a polymer prodrug used as a gene carrier, The invention also relates to the preparation method of the conjugate and the gene loading of the conjugate for the treatment of diabetes, belonging to the field of medicine and gene technology. Background technique [0002] According to the latest research in "Journal of the American Medical Association" (JAMA), China has become a country with a large population of diabetes, and the number of adult diabetic patients is estimated to exceed 100 million, of which type II diabetes accounts for more than 90%. With the improvement of living standards, people's dietary structure and lifestyle have changed, resulting in an increase in obesity patients. Studies have shown that more than 80% of type II diabetes pa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K9/19A61K31/155A61K48/00A61P3/06
CPCA61K31/155A61K47/50A61K48/00
Inventor 姜虎林王凤珍邢磊
Owner CHINA PHARM UNIV
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