Biodegradable aminolipid compound, preparation method and application thereof

A technology of amino lipids and compounds, applied in the field of organic biological functional materials, can solve the problems of large toxicity and poor biodegradation performance

Active Publication Date: 2019-08-23
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, although these aminolipid compounds exhibit good siRNA delivery ability, due to the poor biodegradability of these aminolipid compounds, they show greater toxicity than their precursors. A potential problem in citing

Method used

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  • Biodegradable aminolipid compound, preparation method and application thereof
  • Biodegradable aminolipid compound, preparation method and application thereof
  • Biodegradable aminolipid compound, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0123] Embodiment 1 Synthesis of aminolipid compound

[0124] 1. Synthesis of Lipid Acrylates Containing Disulfide Bonds

[0125] Prepared according to the following synthetic route 1:

[0126]

[0127] (1) Preparation of compound 4a:

[0128] Preparation of intermediate 2-(octyldisulfanyl)pyridine (2a): 2,2'-dithiobipyridine (12g, 54.55mmol, 2eq) was dissolved in 150mL ethanol, octylthiol (4.7mL, 27.37 mmol, 1eq) was dissolved in 20mL of dichloromethane. Under the protection of nitrogen, n-octyl mercaptan was slowly added dropwise to the solution of dithiobipyridine. The reaction was carried out for 24-48 hours, and the progress of the reaction was followed by TLC. After the octyl mercaptan reaction was completed, the reaction solution was concentrated, separated by gradient elution of column chromatography, and using 5%-10% ethyl acetate in petroleum ether as the mobile phase to obtain product 2a as a light yellow liquid with a yield of 67 %.

[0129] Preparation of ...

Embodiment 2

[0162] Example 2 Preparation of Polymer-siRNA Complex

[0163] Prepare the siRNA stock solution (20 μM) with RNase-free water (ribonuclease-free), then dilute it to a predetermined concentration with HEPES buffer (pH=6.8, 50 mM), and adjust the aqueous solution of the amino lipid compound with hydrochloric acid pH to 7-8, then dilute with the same buffer solution according to the predetermined nitrogen-phosphorus ratio, add an equal volume of the amino lipid compound solution to the siRNA solution, vortex for 2-3 seconds, and then incubate at 37°C After 20-30 minutes, the polymer-siRNA complex is obtained.

Embodiment 3

[0164] Example 3 siRNA binding ability test

[0165] 20 pmol siRNA was dissolved in 5 μL of HEPES buffer (pH=6.8, 50 mM), and an equal volume of amino lipid compound solution with gradient concentration was added. After incubating at 37°C for 30 minutes, add 2 μL of 6× loading buffer (40% glycerol, 0.05% xylene cyanol FF, 30 mM EDTA disodium, 1:1000 SYBR Gold stain), mix well, and 2% agarose gel Load the sample, add TBE buffer (trizma base 5.4g, boric acid 2.75g, EDTA disodium 0.375g and 1L deionized water), perform electrophoresis at 120V for 10 minutes, and obtain the fluorescence picture of siRNA after UV exposure.

[0166] The result is as Figure 6 As shown, all aminolipid compounds can fully bind siRNA at the ratio of nitrogen to phosphorus ratio less than or equal to 2.

[0167] In order to further verify the binding ability of aminolipid compounds to siRNA after degradation, the bPEI 600 - After incubation of C12-8 in 50Mm DTT for 1 hour, the purpose is to break the...

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Abstract

The invention discloses a biodegradable amino lipid compound and a preparation method and applications thereof, and belongs to the technical field of organic biological functional materials. The amino lipid compound is selected from compounds represented by the formula II and pharmaceutically acceptable salts thereof. The biodegradable amino lipid compound can form nano particles, micelles and liposome under proper conditions, can carry bioactive substances into cells or bodies, can be broken in cells due to the degradable disulfide bonds in the amino lip compound, and has good biocompatibility and low toxicity. The amino lipid compound is suitable for a drug delivering system, such as a polynucleotide delivering system.

Description

technical field [0001] The invention relates to the technical field of organic biological functional materials, in particular to a biodegradable amino lipid compound with amino and lipid structures and its preparation method and application. Background technique [0002] Some biologically active substances are difficult to enter cells or target tissues, such as proteins, polypeptides, DNA, RNA, insoluble molecules, etc. Therefore, delivery vehicles are designed and used to deliver various biologically active substances to cells or the body. Among them, amphiphilic molecules containing lipids can assemble in water to form particles of different sizes and shapes, and can effectively bind biologically active substances, and their complexes can enhance the interaction with cells so that they can enter cells and then release biologically active substances . This allows some biologically active substances to enter cells to regulate physiological processes, thus making it possible...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C319/22C07C323/12C08G73/04A61K47/18A61K47/34
CPCA61K47/18A61K47/34C07C319/22C07C319/24C07D213/71C08G73/02C07C323/12Y02P20/55
Inventor 郭高阳张必良米其·托尔托雷
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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