Novel aza-crown ether compound as well as cationic liposome, preparation method and application thereof

A cationic liposome and azacrown ether technology, applied in the field of biomedicine, can solve problems such as clinical difficulties, high cytotoxicity, and unsatisfactory cell transfection efficiency, and achieve broad application range, low cytotoxicity, and reduction of multidrugs The effect of drug resistance

Active Publication Date: 2022-06-24
CHONGQING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Generally, viral vectors have higher transfection efficiency, but there are certain problems, such as higher cytotoxicity and clinical difficulties; non-viral transfection vectors have high safety, but cell transfection efficiency is not ideal

Method used

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  • Novel aza-crown ether compound as well as cationic liposome, preparation method and application thereof
  • Novel aza-crown ether compound as well as cationic liposome, preparation method and application thereof
  • Novel aza-crown ether compound as well as cationic liposome, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1: Preparation and detection of novel azacrown ether compounds

[0045] 1. Experimental method

[0046] 1) Preparation of 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane, the synthetic route is as follows figure 1 shown

[0047] 1,2-bis(2-chloroethoxy)ethane (19.03g, 101.7mmol) and sodium iodide (33.4g, 222.8mmol) were added to acetone (50mL), stirred and refluxed for 72h; cooled to room temperature and extracted The filtrate was filtered, and the filtrate was spin-dried to obtain a light yellow oily viscous residue. The above residue was dissolved in methyl tert-butyl ether (MTBE), and anhydrous sodium sulfate (60.3 g, 240 mL) was used as the aqueous phase, and the residue was left alone. Set the liquid separation, take the MTBE phase of the upper layer, spin the MTBE phase to dryness, and obtain the intermediate product, 1,2-bis(2-iodoethoxy)ethane as a colorless oily liquid;

[0048] 1,8-Diamino-3,6-dioxoctane (32.46 g, 219.0 mmol) was dissolved in acetonitri...

Embodiment 2

[0072] Example 2: Preparation of Cationic Liposomes

[0073] The neutral lipid dioleoylphosphatidylethanolamine (0.005mmol) was combined with the novel azacrown ether compounds, namely 5a, 5b, and 5c, respectively, in chloroform, dried under reduced pressure with nitrogen, and the chloroform solvent was removed. MnSO for lipid membrane 4 ·H 2 O(5mL, 1mM) and Cu(NO 3 ) 2 ·3H 2 The O (5 mL, 1 mM) solution was hydrated to a final lipid concentration of 1 mM. The mixture was stirred until the film was completely resuspended and then sonicated (60°C) in a cell disintegrator to give cationic liposome lipid 1-M (1=1a, 1b, 1c, M=Mn 2+ and Cu 2+ ), stored at 4°C.

Embodiment 3

[0074] Example 3: Preparation of cationic liposome / pDNA complexes (lipoplexes)

[0075] 0ul, 1.050ul, 1.125ul, 1.875ul, 2.625ul, 3.375ul and 4.125ul of cationic lipid were thoroughly mixed with 0.125ug of DNA at N / P ratios of 0, 1, 3, 5, 7, 9 and 11, respectively , and incubated at room temperature for 30 min to obtain lipid complexes. The theoretical N / P ratio represents the charge ratio (molar ratio) of cationic lipid to nucleotide base, and takes into account an average nucleotide mass of 330 g / mol.

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Abstract

The invention discloses a novel aza-crown ether compound and a cationic liposome, a preparation method and application thereof, and the cationic liposome is prepared by taking diaza 18-crown ether-6 as a raw material, carrying out nucleophilic substitution reaction and hydrolysis reaction, and carrying out HBTU condensation reaction with alkylamine with different carbon chains to obtain the novel aza-crown ether compound. The novel aza-crown ether compound and dienoyl phosphatidyl ethanolamine (DOPE) are assembled to obtain a stable cationic liposome lipid 1-M, and then the cationic liposome and pDNA are subjected to electrostatic interaction to obtain the cationic liposome / pDNA compound. Can be used as a virus vector. Along with the increase of a carbon chain, the cytotoxicity is gradually reduced, and the cell transfection efficiency is gradually improved. A new thought is provided for research of gene vectors, and the application range of the aza-crown ether structure derivative is widened.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to a novel azacrown ether compound and its cationic liposome, a preparation method and application. Background technique [0002] Cancer has always been the biggest health problem. The general treatment strategies for cancer include chemotherapy, radiotherapy, tumor resection and killing of cancer cells, etc., which reduces the immunity of the human body and causes great harm. Cells like melanoma, however, cannot be removed surgically, and new treatments need to be found. In recent years, gene therapy is still a promising therapeutic strategy for the treatment of inherited and acquired diseases. Therefore, the development of gene vectors with high transfection efficiency and low cytotoxicity is the most critical part of gene therapy. [0003] The ideal gene carrier is able to target cells to successfully release and express nucleic acid drugs. Generally, viral vect...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D273/08A61K47/54A61K47/69
CPCC07D273/08A61K47/6911A61K47/544A61K47/545
Inventor 李硕侯梦琪程倩万山可
Owner CHONGQING UNIV OF TECH
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