Low molecular weight heparin-glycyrrhetinic acid polymer and its synthesis method and application

A low-molecular-weight heparin and glycyrrhetinic acid technology, which is applied in the preparation of anti-tumor drug nano-micelle preparations, the synthesis of nano-polymer self-assembled micellar materials, and the synthesis of low-molecular-weight heparin-glycyrrhetinic acid polymers. The effect of small size, round shape and excellent biocompatibility

Inactive Publication Date: 2017-01-11
SHANDONG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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  • Low molecular weight heparin-glycyrrhetinic acid polymer and its synthesis method and application
  • Low molecular weight heparin-glycyrrhetinic acid polymer and its synthesis method and application
  • Low molecular weight heparin-glycyrrhetinic acid polymer and its synthesis method and application

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Embodiment 1

[0035] Embodiment 1: Synthesis of low molecular weight heparin-glycyrrhetinic acid polymer

[0036] (1) Synthesis of low-molecular-weight heparin-adipate dihydrazide: Weigh 0.5g low-molecular-weight heparin and dissolve it in 100mL distilled water, stir to make it fully swell and dissolve, and then add 6.53g adipic acid dihydrazide to the solution in turn. Hydrazide, 0.96g 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.68g 1-hydroxybenzotriazole, adjust the reaction system pH value with sodium hydroxide 6.8, react at room temperature for 24 hours, dialyze with distilled water for three days, and freeze-dry to obtain the intermediate product low molecular weight heparin-adipate dihydrazide.

[0037] (2) Synthesis of glycyrrhetinic acid succinate: Weigh 200 mg of glycyrrhetinic acid and ultrasonically dissolve it in 5 mL of anhydrous tetrahydrofuran, add 4 times the molar amount of succinic anhydride and 0.1 times the molar amount of 4-dimethylaminopyridine, ...

Embodiment 2

[0041] Embodiment 2: Synthesis of low molecular weight heparin-glycyrrhetinic acid polymer

[0042] (1) Synthesis of low-molecular-weight heparin-adipate dihydrazide: Weigh 0.5g low-molecular-weight heparin and dissolve it in 100mL distilled water, stir to make it fully swell and dissolve, and then add 6.53g adipic acid dihydrazide to the solution in turn. Hydrazide, 0.96g 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.68g 1-hydroxybenzotriazole, adjust the reaction system pH value with sodium hydroxide 6.8, react at room temperature for 24 hours, dialyze with distilled water for three days, and freeze-dry to obtain the intermediate product low molecular weight heparin-adipate dihydrazide.

[0043] (2) Synthesis of glycyrrhetinic acid succinate: Weigh 200 mg of glycyrrhetinic acid and ultrasonically dissolve it in 5 mL of anhydrous tetrahydrofuran, add 4 times the molar amount of succinic anhydride and 0.1 times the molar amount of 4-dimethylaminopyridine, ...

Embodiment 3

[0046] Example 3: Preparation of paclitaxel-loaded low molecular weight heparin-glycyrrhetinic acid polymer nanomicelles

[0047] Disperse 50 mg of low-molecular-weight heparin-glycyrrhetinic acid (prepared in Example 1) ultrasonically in 5 mL of deionized water, and set aside; another 20 mg of paclitaxel was dissolved in 1 mL of tetrahydrofuran, and slowly added dropwise to the above-mentioned low-molecular-weight heparin under vigorous stirring. -In the aqueous solution of glycyrrhetinic acid polymer, after continuing to stir vigorously at room temperature for 4 hours, use probe ultrasonic treatment at 120W power for three times, each time for 2 minutes, keep the temperature at 4°C-8°C, pulse on for 2s and stop for 4s, after the ultrasonication is completed The solution was transferred to a dialysis bag and dialyzed against water for 24 hours, and then the resulting solution was centrifuged at 4000 r / min for 20 minutes to remove unencapsulated drugs. Then, the supernatant wa...

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Abstract

The invention relates to a low molecular heparin-glycyrrhetinic acid polymer and its synthetic method and application. The synthetic method comprises the following steps: firstly synthesizing low molecular heparin-adipodihydrazide; synthesizing glycyrrhetinic acid succinate; preparing an active ester solution of glycyrrhetinic acid succinate; and finally synthesizing the low molecular heparin-glycyrrhetinic acid polymer. According to the invention, heparin is used as a water-soluble skeleton material, and glycyrrhetinic acid is used to carry out lyophobic modification on the water-soluble skeleton through succinic anhydride and adipodihydrazide used as linkers so as to prepare a glycyrrhetinic acid-mediated nano-carrier material with targeting capability. The heparin-glycyrrhetinic acid polymer has good biocompatibility, biodegradability and non-immunogenicity. Prepared hepatocyte-targeted drug-loaded nano-micelles have high entrapment rate and drug loading capacity, have excellent slow-release property, can enhance drug treatment efficacy and reduce non-specific toxic and side effect, and have a good application prospect.

Description

technical field [0001] The present invention relates to the synthesis of a nano-polymer self-assembled micelle material (low molecular weight heparin-glycyrrhetinic acid polymer), in particular to the synthesis of low molecular weight heparin-glycyrrhetinic acid polymer and the preparation of the polymer as a biological material Application method of antitumor drug nano-micelle preparation. The invention belongs to the fields of biomedical materials and nano drug preparations. Background technique [0002] Over the past few decades, the incidence and mortality of malignant tumors have shown an obvious upward trend, becoming one of the frequently-occurring diseases that seriously threaten human life and health. Some studies predict that by 2050, the number of new cases and deaths of malignant tumors in the Asia-Pacific region alone will reach 7.3 million and 5.5 million, which is more than twice that of 2000. Among them, liver cancer is called "the king of cancers", with a ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08B37/10A61K47/36A61K9/51A61P35/00
Inventor 翟光喜杜洪亮刘梦锐
Owner SHANDONG UNIV
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