Preparation method of galactose derivative cationic liposome nanoparticles

A cationic liposome and nanoparticle technology, applied in liposome delivery, genetic material components, medical preparations of non-active ingredients, etc., can solve the problem of low transfection efficiency

Active Publication Date: 2019-05-28
湖南远泰生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, a common disadvantage of cationic liposomes as gene carriers is the low transfection efficiency

Method used

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  • Preparation method of galactose derivative cationic liposome nanoparticles
  • Preparation method of galactose derivative cationic liposome nanoparticles
  • Preparation method of galactose derivative cationic liposome nanoparticles

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Embodiment 1. Galactose derivative cationic liposome di -C 12 - Preparation of Gal-TMA nanoparticles:

[0034] Acetic anhydride (393.5 mL, 4.2 mol) was added into a 1.0 L round bottom flask, stirred by magnetic force, and cooled to 0 in an ice bath. o C, add HClO dropwise 4 (2.0 mL). Control temperature is less than 20 o C, add galactose (100.0 g, 0.56 mol) in batches. After the addition, it was naturally raised to room temperature, and was analyzed by TLC (V 石油醚 : V 乙酸乙酯 = 1 : 1) Monitor the reaction. After the reaction is complete, add DCM (200.0 mL) to dilute, wash with water and dichloromethane successively, combine the organic phases, wash with anhydrous MgSO 4 Dry, filter and concentrate to give a white solid. Vacuum drying at room temperature yields 1,2,3,4,6-penta- O - Acetyl-α,β-D-galactopyranose (208.7 g, 96.4%).

[0035] In a 1.0 L round bottom flask add 1,2,3,4,6-penta- O -Acetyl-α,β-D-galactopyranose (79.0 g, 202.4 mmol), mixed with methanol ...

Embodiment 2

[0046] Example 2. Galactose derivative cationic liposomes di -C 14 - Preparation of Gal-TMA nanoparticles:

[0047] In a 100.0 mL round bottom flask, add the compound 3'-azidopropyl 3,4- O -Isopropylidene-β-D-galactopyranoside (1.2 g, 3.9 mmol), was dissolved in anhydrous DMF (30.0 mL), NaH (1.0 g, 23.4 mmol) was added under magnetic stirring, and bromo Tetradecane (4.3 mL, 15.6 mmol). Normal temperature reaction, TLC (V 石油醚 : V 乙酸乙酯 =8:1) Monitor the reaction until the starting material disappears. Extract with water and dichloromethane, combine the organic phases, wash with anhydrous MgSO 4 Dry, filter and concentrate. Through column chromatography (eluent: V 石油醚 : V 乙酸乙酯 = 20: 1) separation and purification to obtain a colorless viscous compound 3'-azidopropyl 2,6-two- O -n-tetradecyl-3,4- O - Isopropylidene-β-D-galactopyranoside (1.5 g, 55.6%). 1 H NMR (500MHz, CDCl 3 ):δ (ppm): 4.19 (d, 1 H, J 1,2 = 8.0 Hz, H-1), 4.11 (dd, 1 H, J 4,3 = J 4,5 = 6....

Embodiment 3

[0052] Example 3. Galactose derivative cationic liposomes di -C 16 - Preparation of Gal-TMA nanoparticles:

[0053] In a 100.0 mL round bottom flask, add the compound 3'-azidopropyl 3,4- O -Isopropylidene-β-D-galactopyranoside (1.2 g, 3.9 mmol), was dissolved in anhydrous DMF (30.0 mL), NaH (1.0 g, 23.4 mmol) was added under magnetic stirring, and bromo Hexadecane (4.8 mL, 15.6 mmol). Normal temperature reaction, TLC (V 石油醚 : V 乙酸乙酯 =8:1) Monitor the reaction until the starting material disappears. Extract with water and dichloromethane, combine the organic phases, wash with anhydrous MgSO 4 Dry, filter and concentrate. Through column chromatography (eluent: V 石油醚 : V 乙酸乙酯 = 20: 1) separation and purification to obtain white solid compound 3'-azidopropyl 2,6-two- O -n-hexadecyl-3,4- O - Isopropylidene-β-D-galactopyranoside (1.9 g, 63.3%). 1 H NMR (500MHz, CDCl 3 ):δ (ppm): 4.21 (d, 1 H, J 1,2 = 8.0 Hz, H-1), 4.12 (dd, 1 H, J 4,3 =6.0 Hz, H-4), 4.06 (t,1 ...

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Abstract

The invention discloses a method for preparing galactose derivative cationic liposome nanoparticles. Galactose as a raw material is subjected to total acetylation, 1-O-acetyl removal, trichloroacetic imine esterification, glycosylation, azidation and all acetyl removal reactions to obtain an intermediate, the intermediate is subjected to 3,4-O-isopropylidene formation, etherification, isopropylidene removal, reductive amination, quaternary ammonium salinization and reductive ammoniation, tertiary amination and quaternary ammonium salinization reactions, and two series of galactose derivative cationic liposomes with different physical structures are synthesized; after water dispersion, the corresponding cationic liposome nanoparticles are obtained, have the advantages of good stability, moderate particle size and surface charges, low preparation cost and the like, and can meet basic requirements required for nucleic acid drug transporters.

Description

technical field [0001] The invention relates to a preparation method of a series of galactose derivative cationic liposome nanoparticles. Background technique [0002] With the in-depth development of clinical medicine and biomolecular theoretical research, gene therapy has increasingly become one of the research hotspots in the medical field. Gene therapy refers to introducing exogenous normal genes into target cells, compensating for missing or defective genes, and expressing corresponding proteins, fundamentally eliminating the internal factors of the resulting disease, so as to achieve the purpose of treating the disease. However, during the process of introducing exogenous genes into cells, DNA will be degraded by nucleases in the body, and will be degraded into small molecule nucleotides when it does not enter the target cells or even reach the target organs, thus losing its therapeutic effect. In order to better protect the therapeutic gene during in vivo transportat...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/54A61K47/26A61K9/127A61K48/00
Inventor 曾佑林郭婉蓉刘美艳
Owner 湖南远泰生物技术有限公司
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