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Redox-sensitive core-crosslinked Pulullan nano particle having dual-targeting property and preparation method thereof

A pullulan polysaccharide and dual-targeting technology, which is applied in the field of double-targeted redox-sensitive nuclear cross-linked pullulan nanoparticles and its preparation, to achieve structural stability, improve bioavailability, and condition mild effect

Inactive Publication Date: 2017-05-31
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are no literature or patent reports on the preparation of redox-sensitive cross-linked nanoparticles with dual targeting properties as anti-tumor drug carriers through chemical synthesis of these three safe materials.

Method used

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  • Redox-sensitive core-crosslinked Pulullan nano particle having dual-targeting property and preparation method thereof
  • Redox-sensitive core-crosslinked Pulullan nano particle having dual-targeting property and preparation method thereof
  • Redox-sensitive core-crosslinked Pulullan nano particle having dual-targeting property and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Embodiment 1: Synthesis of folic acid-pullulan-lipoic acid conjugate

[0062] Under hydrogen protection, lipoic acid (117.5 mgg, 0.57 mmol) was dissolved in DMSO (2 mL) and added to a 50 mL sealed reactor. EDCI (165mg, 0.86mmol) and DMAP (69.5mg, 0.57mmol) dissolved in DMSO (2mL) were added into a sealed reactor, and stirred at room temperature for 30min to activate. Another pullulan (250mg, 1.55mmol) was dissolved in DMSO (19mL, concentration 0.08M), magnetically stirred for 20min to dissolve it completely, added to the activated lipoic acid, at room temperature, under the protection of nitrogen The reaction was stirred for 24 hours. Another folic acid (50mg, 0.11mmol) was dissolved in DMSO (5ml), EDCI (54mg, 0.28mmol) and DMAP (14mg, 0.11mmol) were added respectively, activated at 25°C in the dark for 1h, and the above synthesized common Lulan polysaccharide-lipoic acid reaction liquid, react in the dark for 12 hours, after the reaction, put the solution in a dialys...

Embodiment 2

[0064] Embodiment 2: Preparation of paclitaxel-loaded nanoparticles

[0065] The polymer FA-Pull-LA and PTX were dissolved in DMSO respectively, and the DMSO solution of PTX was dropped into the DMSO solution of polymer FA-Pull-LA (5mg / mL polymer, the mass ratio of polymer / PTX was 10 / 1), drop twice the amount of distilled water under magnetic stirring, then put the solution into a dialysis bag (MWCO: 14000Da) and dialyze in the aqueous solution for 24h, remove the solvent DMSO and the drug not loaded into nanoparticles, and obtain uncrosslinked solution of drug-loaded nanoparticles.

Embodiment 3

[0066] Example 3: Cross-linking of drug-loaded nanoparticles

[0067] Take 3ml of the above uncrosslinked nanoparticle solution (5mg / ml) and adjust the pH value to 8.5 with 0.7M borate buffer solution, and pass nitrogen gas for 10 minutes to ensure that the air is purged, and add the crosslinking agent dithiothreose Alcohol (DTT, 226 μ g), the amount of cross-linking agent is 10% of the molar number of disulfide bonds in the pull-LA nanoparticles, then at room temperature, stirred and reacted for 22 hours under nitrogen protection conditions, after the reaction, the nanoparticle solution was packed Put it into a dialysis bag (MWCO: 14000Da), dialyze with a borate buffer solution of pH=8.5 for 24 hours, remove DMSO and excess DTT, and obtain a cross-linked drug-loaded nanoparticle solution.

[0068] Take a certain amount of cross-linked and non-cross-linked drug-loaded nanoparticle solution, first remove the water in the solution by freeze-drying, then accurately weigh an appro...

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Abstract

The invention discloses a redox-sensitive core-crosslinked Pulullan nano particle having dual-targeting property and a preparation method thereof, preparation of a drug carrying nano particle with the compound as a carrier, and in-vitro releasing researching of the drug carrying nano particle. The method includes the steps of: 1) performing esterification reaction to lipoic acid and Pulullan to convert the water-soluble Pulullan into a hydrophobic polymer, which is beneficial to preparation of nano particles and entrapment of a hydrophobic medicine; 2) conjugating the polymer with folic acid to form a folic acid-Pulullan-lipoic acid conjugate, and performing crosslinking to inner cores of the nano particles in DTT in catalytic quantity to prepare stable and reversible folic acid-Pulullan-lipoic acid (FA-Pull-LA) nano particles having dual-targeting property. The drug carrying nano particle is prepared with paclitaxel as a model medicine in a dialysis manner, wherein stability and reduction sensitivity of the drug carrying nano particle are inspected through an in-vitro releasing test. A result proves that the dialysis method for preparing the FA-Pull-LA nano particles is simple and has good repeatability, is easy to achieve expanded production and has high drug carrying rate. The nano particle is stable in vitro and can quickly release the drug in an intracellular reductive environment.

Description

technical field [0001] The present invention designs a redox-sensitive nuclear cross-linked pullulan nanoparticle with dual targeting properties and its preparation method, that is, the hydrophilic pullulan polysaccharide is hydrophobized and modified, and then connected with an inner disulfide small molecules of lipoic acid, and then coupled with folic acid to form folic acid-pullulan-lipoic acid conjugates, prepared folic acid-pullulan-lipoic acid nanoparticles by dialysis, and under the action of catalytic amount of DTT Make the hydrophobic core of the nanoparticles cross-linked by disulfide bonds, and the preparation method of the drug-loaded nanoparticles with the polymer as the carrier and the research on its release in vitro. Background technique [0002] Polymer smart material is a new sub-discipline in the field of materials, which refers to making inanimate organic materials "feeling" and "perception" through organic synthesis. An important development direction o...

Claims

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Application Information

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IPC IPC(8): A61K9/51A61K31/337A61K47/36A61K47/22A61P35/00
CPCA61K9/5161A61K9/5123A61K31/337
Inventor 涂家生黄丽萍孙春萌王慧敏李亚楠
Owner CHINA PHARM UNIV
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