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

AI Technical Summary

Problems solved by technology

However, there are no literature or patent reports on the preparation of redox-sensitive cross-linked nanoparticles

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
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Example Embodiment

[0061] Example 1: Synthesis of Folic Acid-Pululan-Lipoic Acid Conjugates

[0062] Lipoic acid (117.5 mgg, 0.57 mmol) was dissolved in DMSO (2 mL) and added to a 50 mL sealed reactor under hydrogen protection. EDCI (165 mg, 0.86 mmol) and DMAP (69.5 mg, 0.57 mmol) dissolved in DMSO (2 mL) were added to the sealed reactor and activated with stirring for 30 min at room temperature. Another pullulan polysaccharide (250mg, 1.55mmol) was dissolved in DMSO (19mL, the concentration was 0.08M), magnetic stirring for 20min, so that it was completely dissolved, added to the activated lipoic acid, at room temperature, under nitrogen protection The reaction was stirred for 24 hours. Separately, folic acid (50 mg, 0.11 mmol) was dissolved in DMSO (5 ml), EDCI (54 mg, 0.28 mmol) and DMAP (14 mg, 0.11 mmol) were added respectively, and activated in the dark at 25°C for 1 h. In the Lulan polysaccharide-lipoic acid reaction solution, the reaction was protected from light for 12 hours. After t...

Example Embodiment

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

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

Example Embodiment

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

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

[0068] Take a certain amount of cross-linked and uncross-linked drug-loaded nanoparticle solutions, first remove the water in the solution by freeze-drying, then accurately weigh an appropriate amount of freeze-dried solids, add 0.3 ml of water to dissolv...

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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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