Reduction/pH sensitive polysaccharide-based nano prodrug co-loaded with adriamycin and platinum type drug as well as preparation method and application of reduction/pH sensitive polysaccharide-based nano prodrug

A technology of platinum-based drugs and doxorubicin, which is applied in the field of reducing/pH-sensitive polysaccharide-based nano-prodrugs and its preparation, to achieve the effect of improving tumor treatment effects, rich sources of raw materials, and uniform particle size distribution

Active Publication Date: 2021-04-06
XI AN JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are very few polysaccharide polymer-based prodrugs that can simultaneously load two chemotherapeutic drugs and exhibit dual reduction / pH stimuli-responsive release behaviors.

Method used

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  • Reduction/pH sensitive polysaccharide-based nano prodrug co-loaded with adriamycin and platinum type drug as well as preparation method and application of reduction/pH sensitive polysaccharide-based nano prodrug
  • Reduction/pH sensitive polysaccharide-based nano prodrug co-loaded with adriamycin and platinum type drug as well as preparation method and application of reduction/pH sensitive polysaccharide-based nano prodrug
  • Reduction/pH sensitive polysaccharide-based nano prodrug co-loaded with adriamycin and platinum type drug as well as preparation method and application of reduction/pH sensitive polysaccharide-based nano prodrug

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preparation example Construction

[0032] A preparation method of reducing / pH-sensitive polysaccharide-based nano-prodrugs co-loaded with doxorubicin and platinum-based drugs. The main process is to prepare a hydrazide polysaccharide polymer by using the carbodiimide method, and then sequentially bond through hydrazone bonds. Connecting doxorubicin and coordination bonds to connect platinum drugs to obtain a reduced / pH-sensitive polysaccharide-based nano-prodrug that co-loads doxorubicin and platinum drugs. Specifically include the following steps:

[0033] (1) Preparation of hydrazide polysaccharide polymer: dissolving the carboxyl polysaccharide polymer in water to make a carboxyl polysaccharide polymer aqueous solution with a mass concentration of 0.1% to 10%, and then adding 5% to 60% of the carboxyl substance 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, in which 1-(3-dimethylaminopropyl)-3-ethane The molar ratio of carbodiimide hydrochloride and N-hydroxysuccinimid...

Embodiment 1

[0047] (1) Preparation of hyaluronic acid hydrazide: the molecular weight is 8kDa hyaluronic acid dissolved in water to make a mass concentration of 1.0% hyaluronic acid aqueous solution, adding 1-( 3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide; 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt The molar ratio of acid salt and N-hydroxysuccinimide is 1:1.5, adjust the pH value to 5.3 with dilute hydrochloric acid (1mol / L) and maintain it at 5.3, add 3,3' after stirring at room temperature for 1 hour -dithiodipropionyl hydrazide, after reacting for 36 hours, the reactant was placed in a dialysis bag with a molecular weight cut-off of 3500Da and dialyzed for 48 hours, and freeze-dried at minus 20 degrees Celsius to obtain hydrazide hyaluronic acid with a hydrazide degree of 40%; wherein , The molar ratio of 3,3'-dithiodipropionyl hydrazide to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is 5:1.

[0048] (2) Formation of doxoru...

Embodiment 2

[0058] (1) Preparation of hydrazidized hyaluronic acid: dissolve hyaluronic acid with a molecular weight of 8 kDa in water to make a hyaluronic acid aqueous solution with a mass concentration of 1.0%, add 1- (3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide; 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide The molar ratio of hydrochloride and N-hydroxysuccinimide is 1:1.5. Use dilute hydrochloric acid (1mol / L) to adjust the pH value to 5.0 and maintain it at 5.0. After stirring at room temperature for 0.5 hours, add 3,3 '-dithiodipropionyl hydrazide, after 48 hours of reaction, the reactant was placed in a dialysis bag with a molecular weight cut-off of 3500Da and dialyzed for 72 hours, and freeze-dried at minus 20 degrees Celsius to obtain hydrazide hyaluronic acid with a hydrazide degree of 20%; Wherein, the molar ratio of 3,3'-dithiodipropionyl hydrazide to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is 25:1.

[0059] (2) Forma...

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Abstract

The invention discloses a reduction/pH-sensitive polysaccharide-based nano prodrug co-loaded with adriamycin and a platinum type drug, and a preparation method and application of the prodrug. According to the preparation method, firstly 3,3'-dithiodipropionyl hydrazine is bonded to carboxyl of a polysaccharide polymer by using a carbodiimide method to obtain a hydrazide polysaccharide polymer, adriamycin is connected to the hydrazide polysaccharide polymer through a hydrazone bond, self-assembly is conducted to form nanoparticles, and finally the platinum type drug is loaded on the nanoparticles to form the reduction/pH sensitive polysaccharide-based nano prodrug co-loaded with doxorubicin and the platinum type drug. The nano prodrug has a core-shell structure, the particle size is adjustable within the range of 100-200 nm, quick release of the drug can be achieved in response to glutathione and pH dual stimulation, and the nano prodrug can be used for killing tumor cells. The preparation method of the nano prodrug has the characteristics of easily available raw materials, mild process conditions, simple purification process, easiness in large-scale preparation and the like, and has an application prospect in treatment of various tumors such as breast cancer, liver cancer and the like.

Description

technical field [0001] The invention belongs to the field of biological materials, and in particular relates to a reducing / pH sensitive polysaccharide-based nano-prodrug co-carrying doxorubicin and platinum drugs, a preparation method and application thereof. Background technique [0002] Cancer is one of the main causes of human death. In 2018, the number of deaths from cancer in the world was as high as 9.6 million. In recent years, new drug development and cellular immunotherapy have become research hotspots, but chemotherapy is still the basis of tumor treatment. As one of the most effective anti-cancer drugs, doxorubicin has a broad anti-tumor spectrum and has a good effect on various cancers including breast cancer, liver cancer, and lung cancer. At the same time, about 70%-80% of the cancer chemotherapy regimens in my country involve platinum-based antineoplastic drugs, mainly including cisplatin, carboplatin, nedaplatin, cycloplatin, oxaliplatin, lobaplatin, etc. . ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08B37/08C08B37/04C08B37/10C08B15/06C08B31/10A61K31/555A61K31/704A61K33/243A61K47/61A61K47/69A61P35/00
CPCC08B37/0072C08B37/0084C08B37/0075C08B37/003C08B31/10C08B15/06A61K31/704A61K33/243A61K31/555A61K47/61A61K47/6939A61P35/00A61K2300/00
Inventor 钱军民王亚萍胥伟军侯光晖
Owner XI AN JIAOTONG UNIV
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