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Composition containing quaternary ammonium salt compound and siRNA and preparing method thereof

A technology of quaternary ammonium salts and compounds, applied in the field of medicine and biology, can solve the problems of short half-life, difficult to pass through the cell membrane, and strong inflammatory response, so as to change the biodistribution, improve pharmacokinetic characteristics, and reduce adverse reactions Effect

Inactive Publication Date: 2015-10-28
XIAMEN CHENGKUN BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Naked siRNA itself is negatively charged, has a large molecular weight, and strong polarity. It is difficult to pass through the cell membrane and vascular endothelium, and it is easy to stay in the spleen. It is easily degraded by nucleases in vivo, with a short half-life, low transfection efficiency, and even strong inflammation. reaction etc.

Method used

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  • Composition containing quaternary ammonium salt compound and siRNA and preparing method thereof
  • Composition containing quaternary ammonium salt compound and siRNA and preparing method thereof
  • Composition containing quaternary ammonium salt compound and siRNA and preparing method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] 1) Add 13.35g of linoleyl alcohol (cis-9,12-octadecadienol), 7.78g of triethylamine, and 0.732g of 4-dimethylaminopyridine into a 0.25L three-necked flask, and add dichloromethane 30ml, stir in -10°C low temperature circulation pump, drop below -5°C, dissolve 13.35g of p-toluenesulfonyl chloride in 20ml of dichloromethane and add dropwise in a constant pressure dropping funnel, keep the liquid temperature at -5°C, 90mins After dropping, rinse the constant-pressure dropping funnel with 5ml of dichloromethane, slowly heat up, and react at room temperature for 15 hours. TLC petroleum ether: ethyl acetate 5:1 monitors the absence of linoleyl alcohol, separates the organic phase, and extracts the water phase with dichloromethane twice , take the organic phase and dry it with anhydrous magnesium sulfate, and spin off the solvent to obtain a colorless oily substance 20.

[0040]2) Add 1.5 g of sodium hydride and 50 ml of tetrahydrofuran into a 500 ml four-neck flask, stir well...

Embodiment 2

[0044] Preparation formula (siRNA+T2C1+cholesterol-polyethylene glycol+DPPE+DOTMA 0.5:1:1:1:1)

[0045] Preparation of formulations: the trimethyl[2,3-(dilinoleyloxy)propyl]ammonium chloride synthesized in Example 1 was dissolved in ethanol, mixed with HBV siRNA to produce a water-insoluble precipitate, separated and After drying the precipitate, dissolve the precipitate in chloroform or similar solvent, and further mix with other lipids, phospholipid DPPE, cholesterol-polyethylene glycol cholesterol-polyethylene glycol, dissolve in chloroform in a glass container, in Chloroform was removed under vacuum. Then add 300ml of water, vortex and oscillate to dissolve in water, after homogenization treatment, the homogenization condition is 1000 bar, two cycles (ATS homogenizer). Trimethyl[2,3-(dilinoleyloxy)propyl]ammonium chloride:cholesterol-PEG:DPPE was (0.1:0.5:0.4) mixed in chloroform as described in (WO / 2010 / 135207) described process. After removing the organic solvent, the...

Embodiment 3

[0048] HBV siRNA:

[0049] Sense strand: [mC]CG[mU]GUG[mC]ACUUCGCUU[mC]A[dT][dT];

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Abstract

The invention belongs to the field of biological medicine and particularly relates to a composition containing a quaternary ammonium salt compound and siRNA and a preparing method thereof. The composition contains a siRNA sequence and the quaternary ammonium salt compound or lipid with the function of the quaternary ammonium salt compound and can also contain phopholipid, cholesterol and lipid-polyethylene glycol. The composition containing the quaternary ammonium salt compound and siRNA can improve the pharmacokinetics characteristic of siRNA treatment, change bio-distribution, intracellular intake, targeting and transfection efficiency, and reduce adverse reaction.

Description

technical field [0001] The invention belongs to the field of medicine and biology, and in particular relates to a composition comprising quaternary ammonium salt compounds and siRNA. Background technique [0002] Since the discovery of RNA interference (RNAi) technology more than 10 years ago, RNAi has become a key regulator of cytogenetics and a powerful tool for elucidating the growth, pathogenesis and aging of organisms. The siRNA binds to the associated protein to form RNA. RISC recognizes and degrades the messenger RNA (messenger RNA, mRNA) of the target gene through the guidance of siRNA, so that the expression of specific protein is inhibited, and then specifically leads to gene silencing. The key to the success of RNAi lies in whether siRNA can be completely transfected into target cells and combined with target gene mRNA, and the stability of siRNA in vivo is of great significance. Studies have shown that chemical modification of siRNA structure and carrier modifi...

Claims

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Application Information

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IPC IPC(8): A61K31/7088A61P31/20A61K31/14
Inventor 崔坤元郑志凌陈波
Owner XIAMEN CHENGKUN BIOTECH
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