A novel cationic lipid, a preparation method of the same and a delivery system comprising the same

A cationic lipid and delivery system technology, which can be used in other methods of inserting foreign genetic materials, endocrine system diseases, cardiovascular system diseases, etc., can solve the problems of reduced inherent physiological activity of proteins, and achieve increased intracellular delivery and enhanced Efficiency, cytotoxicity reduction effect

Active Publication Date: 2010-09-22
KOREA UNIV RES & BUSINESS FOUND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, said chemical conjugation results in a chemical modification of the physiologically active site of the protein, often resulting in a reduction in the intrinsic physiological activity of the protein

Method used

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  • A novel cationic lipid, a preparation method of the same and a delivery system comprising the same
  • A novel cationic lipid, a preparation method of the same and a delivery system comprising the same
  • A novel cationic lipid, a preparation method of the same and a delivery system comprising the same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Embodiment 1: the synthesis of dioleoyl glutamine (dioleoyl glutamide)

[0072] 1-1) 1 equivalent (1.47 g, 10 mmol) of glutamic acid was added to 5 mL of trifluoroacetic acid and 5 mL of dichloromethane, and the resulting mixture was stirred at 40° C. for 1 hour. Then, 3 equivalents (2.18mL, 30mmol) of SOCl 2 Slowly added dropwise to the reaction solution in an ice bath, followed by reaction at 0-40°C for 6 hours. After the reaction was completed, trifluoroacetic acid and dichloromethane were removed by concentration under reduced pressure, and the reaction was confirmed by thin layer chromatography (TLC).

[0073] 1-2) The reaction product obtained in Example 1-1 was dissolved in dichloromethane, and 1.5 equivalents (4.01 g, 15 mmol) of oleylamine dissolved in dichloromethane was slowly added dropwise thereto. The mixture was stirred in an ice bath for 1 hour, 3 mL of triethylamine was added dropwise thereto, followed by reaction at a temperature of 0-50° C. for 4 ...

Embodiment 2

[0082] Embodiment 2: the synthesis of dimyristoyl glutamine (dimyristoyl glutamide)

[0083] 2-1) Similar to Example 1-1, 2 equivalents of glutamic acid were used for reaction to obtain glutamic acid derivatives.

[0084] 2-2) The reaction product obtained in Example 2-1 was dissolved in dichloromethane. Similar to Example 1-2, 1.5 equivalents (3.20 g, 15 mmol) of myristylamine were subsequently used for the reaction. The product (3.22 g, yield: 85.7%) was obtained as a beige solid, which was subjected to structural analysis using a 1H NMR spectrophotometer.

[0085] 1H NMR (DMSO-d 6 , ppm): 8.0 (1H, -NH-CO of glutamic acid and tetradecylamine)

[0086] 2.0 (2H, -NH of glutamic acid 2 )

[0087] 1.29 (2H, -CH of tetradecylamine 2 -)

[0088] The reaction process of Example 2 is shown in Reaction Formula 2 below.

[0089] [Reaction 2]

[0090]

[0091] In Reaction 2, R 1 and R 2 independently is C 14 - saturated hydrocarbons.

Embodiment 3

[0092] Embodiment 3: the synthesis of dipalmitoyl glutamine (dipalmitoyl glutamide)

[0093] 3-1) Similar to Example 1-1, 2 equivalents of glutamic acid were used for reaction to obtain glutamic acid derivatives.

[0094] 3-2) The reaction product obtained in Example 3-1 was dissolved in dichloromethane. Similar to Example 1-2, 1.5 equivalents (3.62 g, 15 mmol) of palmitylamine were subsequently used for the reaction. The product (3.74 g, yield: 90.1%) was obtained as a beige solid, which was subjected to structural analysis using a 1H NMR spectrophotometer.

[0095] 1H NMR (DMSO-d 6 , ppm): 8.0 (1H, palmitamine / CH 2 Cl 2 Amine -NH-CO)

[0096] 2.0 (2H, -NH of glutamic acid 2 )

[0097] 1.29 (2H, -CH of palmitamine 2 -)

[0098] The reaction process of Example 3 is shown in Reaction Formula 3 below.

[0099] [reaction formula 3]

[0100]

[0101] In Equation 3, R 1 and R 2 independently is C 16 - saturated hydrocarbons.

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Abstract

The present invention provides a novel cationic lipid, a preparation method of the same and a delivery system comprising the same. The cationic lipid of the present invention is used for the preparation of delivery systems of nucleic acids or physiologically active anionic proteins. The cationic lipid of the present invention can be conveniently prepared and purified by a simple process and is therefore economically highly advantageous for industrial-scale production thereof. Further, a nucleic acid or protein delivery system comprising the cationic lipid of the present invention not only significantly improves the intracellular delivery efficiency of desired nucleic acid drugs (such as DNAs, RNAs, siRNAs, antisense oligonucleotides, and nucleic acid aptamers) or anionic proteins having physiological activity, but also is usefully used to augment therapeutic efficacy of nucleic acid or protein drugs due to attenuated cytotoxicity of the delivery system.

Description

technical field [0001] The present invention relates to novel cationic lipids, methods for their preparation and delivery systems comprising them. Background technique [0002] With the elaboration of medical applications of various nucleic acids such as plasmid DNA, small interfering RNA (siRNA), microRNA, and antisense oligonucleotides in recent years, nucleic acid delivery materials for providing efficient intracellular delivery of nucleic acids have been recognized and the importance of the system. [0003] Nucleic acid delivery systems that deliver nucleic acid material within cells can be broadly classified into viral and non-viral vector systems. [0004] Exemplary non-viral vector systems may comprise various types of formulations such as liposomes, cationic polymers, micelles, emulsions, nanoparticles, and the like. Among the components of these formulations, cationic lipids provide electrostatic binding to negatively charged nucleic acids and are therefore critic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/04
CPCC07C237/06C12N15/88A61P19/02A61P35/00A61P43/00A61P5/00A61P9/00C07C237/04C07C237/12C07C237/02
Inventor 吴裕耕徐玟成辛惠贞沈嘉蓉
Owner KOREA UNIV RES & BUSINESS FOUND
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