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Cationic lipid

a lipid and cationic technology, applied in the field of cationic lipids, can solve the problems of affecting the nucleic acid delivery efficiency of the cytoplasm, the difficulty of nucleic acid delivery into cells, and the achievement of nucleic acid delivery efficiency into the cytoplasm, so as to promote the release of the encapsulated substance (nucleic acid), suppress the degradation of nucleic acid by serum components, and promote the effect of encapsulation

Active Publication Date: 2019-08-20
NOF CORP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about a chemical called cationic lipid which can form a structure like a membrane and can be used to carry nucleic acids into cells. This chemical is stable in blood and accumulates in tumors, promoting the release of the nucleic acid inside cells. It also prevents the nucleic acid from breaking down in the blood. This invention results in a high efficiency of delivering nucleic acids into the cytoplasm of cells. Additionally, it reduces the degradation of nucleic acids by serum components, making it useful for nucleic acid introduction in the presence of serum or in vivo.

Problems solved by technology

However, delivery of nucleic acid into cells is difficult, since nucleic acid is rapidly degraded when used alone by enzymes in the blood.
On the other hand, they are associated with problems such as formation of tumor caused by insertion of the viral vector into the genome and nonspecific influence on cells other than the target cells.
However, since the electrostatic interaction between DOTAP having a quaternary amine and nucleic acid is too strong, release of the nucleic acid from the carrier is problematically difficult (non-patent document 2).
However, despite the technical progress in this field, the nucleic acid delivery efficiency into the cytoplasm, which is achieved by a lipid membrane structure using cationic lipid, is not fully satisfactory.
Therefore, improvement of nucleic acid delivery efficiency cannot be expected.

Method used

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Examples

Experimental program
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Effect test

example 1

[Example 1] Synthesis of TS-PZ4C2

[0176]Acetonitrile (143 ml) was added to bis(2-hydroxyethyl) disulfide (15 g, manufactured by Tokyo Chemical Industry Co., Ltd.) (97 mmol), and the mixture was dissolved at 20-25° C. Triethylamine (33.3 g, manufactured by KANTO CHEMICAL CO., INC.) (328 mmol) was added, and the mixture was cooled to 10° C. with stirring. Methanesulfonyl chloride (34.5 g, manufactured by KANTO CHEMICAL CO., INC.) (300 mmol) was added dropwise over 1 hr to set the temperature to 20° C. or below. After the completion of the dropwise addition, the mixture was reacted at 20-25° C. for 3 hr. The disappearance of the spot of bis(2-hydroxyethyl) disulfide was confirmed by TLC analysis (eluent: chloroform, iodine color development), and the reaction was completed. Ethanol (29 mL) was added to the reaction solution to discontinue the reaction, and insoluble materials were removed by filtration. 10% Sodium bicarbonate water (150 g) was added to the filtrate, and the mixture was ...

example 2

[Example 2] Synthesis of L-PZ4C2

[0185]di-PZ4C2 form (2.5 g, 7 mmol) and linoleic acid (3.7 g, manufactured by NOF CORPORATION) (13 mmol) were dissolved in chloroform (25 mL) at 20-25° C. Thereafter, 4-dimethylaminopyridine (0.3 g, 3 mmol) and EDC (3.8 g, 20 mmol) were added and the mixture was reacted at 30° C. for 4 hr. The disappearance of the spot of linoleic acid was confirmed by TLC analysis (eluent: chloroform / methanol=9 / 1 (v / v), phosphoric acid copper sulfate color development), and the reaction was completed. The reaction solvent was distilled off by an evaporator, and hexane (57 mL) was added. Thereafter, acetonitrile (24 mL) was added, and the mixture was stirred for 5 min. After standing for 10 min, the hexane layer was recovered, and the solvent was distilled off by an evaporator to give a pale-yellow liquid (4.9 g). The liquid (4.9 g) was purified by silica gel column chromatography (eluent: chloroform / methanol=99 / 1-97 / 3 (v / v)) to give the object product L-PZ4C2 (3.1 g)...

example 3

[Example 3] Synthesis of O-PZ4C2

[0188]di-PZ4C2 form (0.8 g, 2 mmol) and oleic acid (1.2 g, manufactured by NOF CORPORATION) (4 mmol) were dissolved in chloroform (8 mL) at 20-25° C. Thereafter, 4-dimethylaminopyridine (0.1 g, 1 mmol) and EDC (1.2 g, 6 mmol) were added and the mixture was reacted at 30° C. for 3 hr. The disappearance of the spot of oleic acid was confirmed by TLC analysis (eluent: chloroform / methanol=9 / 1 (v / v), phosphoric acid copper sulfate color development), and the reaction was completed. The reaction solvent was distilled off by an evaporator, and hexane (12 mL) was added. Thereafter, acetonitrile (5 mL) was added, and the mixture was stirred for 5 min. After standing for 10 min, the hexane layer was recovered, and the solvent was distilled off by an evaporator to give a pale-yellow liquid (1.8 g). The liquid (1.7 g) was purified by silica gel column chromatography (eluent: chloroform / methanol=99 / 1-97 / 3 (v / v)) to give the object product, O-PZ4C2 (1.1 g).

1H-NMR S...

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Abstract

The present invention aims to provide a cationic lipid that can be used as a nucleic acid delivery carrier, a lipid membrane structure using a cationic lipid, a nucleic acid-introducing agent using a cationic lipid, and a method of achieving nucleic acid introduction by using a nucleic acid-introducing agent containing a cationic lipid. A lipid membrane structure containing a cationic lipid represented by the formula (1)wherein each symbol is as defined in the DESCRIPTION, is superior in the stability in blood and tumor accumulation property. A nucleic acid-introducing agent using the cationic lipid can achieve high nucleic acid delivery efficiency of nucleic acid to be delivered into the cytoplasm.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This patent application is the U.S. national phase of International Patent Application No. PCT / JP2016 / 052690, filed on Jan. 29, 2016, which claims the benefit of Japanese Patent Application No. 2015-016786, filed Jan. 30, 2015, the disclosures of which are incorporated herein by reference in their entireties for all purposes.TECHNICAL FIELD[0002]The present invention relates to a cationic lipid having improved nucleic acid delivery efficiency, a lipid membrane structure containing same, and use thereof.BACKGROUND ART[0003]Nucleic acid treatment is a therapeutic method for suppressing expression of a pathogenic protein by delivering the nucleic acid (RNA) into the cytoplasm, and gene therapy is a therapeutic method for promoting expression of a protein useful for the treatment by delivering the nucleic acid (DNA) into the nucleus. In these treatment methods, delivery of the nucleic acid into cells is important. However, delivery of nucleic...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D295/088A61K48/00C07D311/72A61K45/00A61K47/22A61K9/127C12N15/64A61K31/7088C07D311/00A61P29/00A61K31/573A61K31/713
CPCC07D295/088A61K9/127A61K9/1272A61K31/573A61K31/7088A61K31/713C12N15/64A61K47/22A61K48/00A61P29/00C07D311/00C07D311/72A61K45/00A61P35/00A61P43/00
Inventor NAKAI, YUTATANGE, KOTAAKITA, HIDETAKAHARASHIMA, HIDEYOSHITOGASHI, RYOHEIMIURA, NAOYAMAETA, MIO
Owner NOF CORP
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