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PH sensitive type liver-targeted compound nano drug delivery system based on sodium alginate and preparation method

A technology of sodium alginate and drug delivery system, applied in the field of biomedicine, can solve the problems of increasing the toxic and side effects of normal tissues, reducing the utilization rate of drugs, increasing the experimental risk, etc., achieving good application prospects, avoiding non-specific adsorption, and preparation method Simple and practical effects

Inactive Publication Date: 2012-12-26
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The self-assembly method can effectively improve the utilization rate of drugs and materials, but the preparation of the carrier material sulfate chitosan in this patent requires the use of a large amount of strong oxidant concentrated sulfuric acid and chlorosulfonic acid, which increases the risk of the experiment and is not conducive to scale-up production
At the same time, the system is prone to drug leakage during the transportation process in the body. When the pH=7.4, the cumulative release of the drug in 48 hours reaches 43%, which will increase the toxic and side effects on normal tissues and reduce the drug utilization (Tian Q., Wang XH. , et al. Self-Assembly and liver targeting of sulfated chitosan nanoparticles functionalized with glycyrrhetinic acid. Nanomedicine: Nanotechnology, Biology, and Medicine, 2012, 8(6):870-879)
Zhang et al. also prepared a glycyrrhetinic acid-modified sodium alginate liver-targeting nano drug delivery system by self-assembly, but the problem of drug leakage is still serious. At pH 7.4, 35% of the drug is still released.

Method used

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  • PH sensitive type liver-targeted compound nano drug delivery system based on sodium alginate and preparation method
  • PH sensitive type liver-targeted compound nano drug delivery system based on sodium alginate and preparation method
  • PH sensitive type liver-targeted compound nano drug delivery system based on sodium alginate and preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1: mPEG 550 Preparation of modified sodium alginate composite drug-loaded nanoparticles

[0042] 1) Preparation of tetrabutyl alginate

[0043] Dissolve sodium alginate with a molecular weight of 10000Da in double distilled water (2.5mg / mL), adjust the pH of the solution to 4.5 with 1mol / L hydrochloric acid, and dissolve this solution in a mixed solvent of ethanol and 12M hydrochloric acid (95 / 5v / v) Precipitated and collected the solid. Disperse the obtained solid in double-distilled water, neutralize it with tetrabutylammonium hydroxide, make the pH of the system 7.5, and freeze-dry to obtain tetrabutyl alginate.

[0044] 2), preparation of glycyrrhetinic acid-ethylenediamine

[0045] Dissolve 10.0mmol glycyrrhetinic acid in 20mL tetrahydrofuran, add 20mmol 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 20mmol N-hydroxysuccinimide, 30°C After reacting for 20 hours, add 2 mol of ethylenediamine to the system. After reacting for 24 hours, the...

Embodiment 2

[0054] Example 2: mPEG 5000 Preparation of modified sodium alginate composite drug-loaded nanoparticles

[0055] 1) Preparation of tetrabutyl alginate:

[0056] Dissolve sodium alginate with a molecular weight of 25000Da in double distilled water (2.5mg / mL), adjust the pH of the solution to 5 with 1mol / L hydrochloric acid, and dissolve this solution in a mixed solvent of ethanol and 12M hydrochloric acid (95 / 5v / v) Precipitated and collected the solid. Disperse the obtained solid in double-distilled water, neutralize it with tetrabutylammonium hydroxide, make the pH of the system 7.5, and freeze-dry to obtain tetrabutyl alginate.

[0057] 2), the preparation of glycyrrhetinic acid-ethylenediamine:

[0058] Dissolve 20mmol glycyrrhetinic acid in 40mL tetrahydrofuran, add 40mmol 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 40mmol N-hydroxysuccinimide, and react at 30°C After 24 hours, 4 mol of ethylenediamine was added to the system. After 24 hours of react...

Embodiment 3

[0067] Example 3: mPEG 2000 Preparation of modified sodium alginate composite drug-loaded nanoparticles

[0068] 1) Preparation of tetrabutyl alginate:

[0069] Dissolve sodium alginate with a molecular weight of 50000Da in double distilled water (2.5mg / mL), adjust the pH of the solution to 5 with 1mol / L hydrochloric acid, and dissolve this solution in a mixed solvent of ethanol and 12M hydrochloric acid (95 / 5v / v) Precipitated and collected the solid. Disperse the obtained solid in double-distilled water, neutralize it with tetrabutylammonium hydroxide, make the pH of the system 7.5, and freeze-dry to obtain tetrabutyl alginate.

[0070] 2), the preparation of glycyrrhetinic acid-ethylenediamine:

[0071] Dissolve 30.0mmol glycyrrhetinic acid in 60mL tetrahydrofuran, add 60mmol 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 60mmol N-hydroxysuccinimide, 30°C React for 24 hours, then add 6mol ethylenediamine to the system, react for 30h, the reaction solutio...

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Abstract

The invention relates to a pH sensitive type liver-targeted compound nano drug delivery system based on sodium alginate and a preparation method. The system is prepared by blending a liver-targeted carrier GA-ALG-mPEG or GA-ALG and a pH sensitive type drug carrier DOX-ALG-mPEG or DOX-ALG proportionally in a mode of dialysis through self assembly. The preparation of the material comprises a sodium alginate derivative (ALG-mPEG), the liver-targeted carrier and the pH sensitive type drug carrier. By the modification of the hydrophilic mPEG according to the compound nano drug delivery system, the non-specific adsorption with cells and protein can be effectively avoided. Meanwhile, the capabilities of drug loading and ligand targeting of the material are enhanced. The pH sensitive type liver-targeted compound nano drug delivery system based on the sodium alginate has the function of liver targeting. Meanwhile, the drug release of a fixed point at the part of a tumor can also be realized according to the difference of pH at normal tissues and the part of the tumor so as to enhance the curative effect and lower the side effect of drugs. The preparation method is simple, is easy to amplified production and has favorable application prospect.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to a sodium alginate-based pH-sensitive liver-targeting composite nano drug delivery system and a preparation method thereof. Background technique [0002] The liver-targeted nano drug delivery system can effectively deliver the drug to the liver lesion, reduce its systemic distribution and dosage, improve the utilization rate of the drug, and reduce the side effects. Therefore, the liver-targeted nano drug delivery system has a positive role in promoting the treatment of liver cancer. [0003] Since the discovery of a large number of glycyrrhetinic acid binding sites on the rat liver cell membrane (Negishi M., Irie A., Nagata N., et al. Specific binding of glycyrrhetinic acid to the rat liver membrane, Biochim. Biophys. Acta., 1991, 1066,77-82), scholars at home and abroad have developed a variety of liver-targeted nano drug delivery systems using glycyrrhetinic acid as the li...

Claims

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Application Information

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IPC IPC(8): A61K47/36A61K31/704A61P35/00C08B37/04
Inventor 袁直王蔚郭华张闯年吴玉昆
Owner NANKAI UNIV
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