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Lipid nanoparticles and use thereof in nucleic acid delivery

A technology of lipid nanoparticles and lipids, which can be used in medical preparations of non-active ingredients, other methods of inserting foreign genetic materials, capsule delivery, etc., and can solve problems such as limiting LNP transfection ability and pDNA immobilization

Active Publication Date: 2022-05-27
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, pDNA is almost immobile in the viscous cytoplasm, which is one of the main reasons for limiting the transfection ability of LNP.

Method used

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  • Lipid nanoparticles and use thereof in nucleic acid delivery
  • Lipid nanoparticles and use thereof in nucleic acid delivery
  • Lipid nanoparticles and use thereof in nucleic acid delivery

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Preparation of glutamic acid dilinolenic acid ester (LA 2 -NH 2 ), the chemical structure is as follows:

[0083]

[0084] L-glutamic acid (3.00g, 20.60mmol), p-toluenesulfonic acid (4.30g, 22.66mmol) and anhydrous toluene (150mL) were added to the 250mL reaction flask, then the reaction solution was heated to 140°C, and the reaction was refluxed for 3h . After the heating was stopped, the mixed solution was cooled to room temperature, linolenic alcohol (11.53 g, 43.25 mmol) was added in batches, and the reaction was carried out at 140° C. overnight. After the reaction, the toluene was removed by rotary evaporation to obtain a dark brown oil. The crude product was dissolved in dichloromethane, washed twice with an appropriate amount of water, twice with saturated aqueous sodium bicarbonate solution, once with saturated brine, dried over anhydrous sodium sulfate, and concentrated by suction filtration to obtain a dark yellow oil. Purified by column chromatography ...

Embodiment 2

[0086] Preparation of carboxylated glutamic acid bislinolenol ester (LA 2 -COOH), the chemical structural formula is as follows:

[0087]

[0088] will LA 2 -NH 2 (1.21 g, 1.88 mmol) was dissolved in dichloromethane, triethylamine (1.04 mL, 7.51 mmol) and succinic anhydride (188 mg, 1.88 mmol) were successively added thereto under stirring, and the reaction was carried out at room temperature overnight. After the reaction, the solvent was removed by rotary evaporation to obtain a light yellow oily crude product, which was purified by column chromatography (dichloromethane:methanol=50:1) to obtain 1.20 g of a light yellow oily product, yield: 85.7%. 1 H NMR (300MHz, CDCl 3 ):δ(ppm)7.53(d,J=8.7Hz,1H,CONHCH),5.43-5.26(m,8H,CHCH),4.51(d,J=5.4Hz,1H,CONHCH),4.11(t,J =6.7Hz, 2H, COOCH 2 ),4.05(t,J=6.8Hz,2H,COOCH 2 ),2.96(s,2H,CH 2 COOH), 2.83(s, 2H, NHCOCH 2 ), 2.75(t, J=6.6Hz, 4H, CHCH 2 CH),2.39(dd,J=16.3,8.4Hz,2H,CHCH 2 CH 2 ,2H,OCOCH 2 ),2.05(m,8H,CHCHCH 2 ),1.62(...

Embodiment 3

[0090] The compound LA1 is prepared, and the chemical structural formula is as follows:

[0091]

[0092] will LA 2 -COOH (500 mg, 0.67 mmol) was dissolved in dichloromethane, EDCI (206 mg, 1.08 mmol) and HOBt (145 mg, 1.08 mmol) were sequentially added at 0°C and stirred for 5 min, then the mixed solution was moved to room temperature for 3 h to obtain Reaction solution A; 1-(3-aminopropyl)pyrrolidine (85 μL, 0.67 mmol) was dissolved in dichloromethane, triethylamine (280 μL, 2.02 mmol) was added at room temperature, and the reaction was stirred for 1 h to obtain reaction solution B . The reaction solution B was slowly added dropwise to the reaction solution A, and the mixture was stirred at room temperature overnight. After the reaction, the reaction solution was washed twice with an appropriate amount of water, twice with a 10% aqueous citric acid solution, once with saturated brine, dried over anhydrous sodium sulfate, and concentrated by suction filtration to obtain ...

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Abstract

The invention discloses lipid nanoparticles and application thereof in nucleic acid delivery. The functional lipid provided by the invention takes tertiary amine or a PEG fragment as a hydrophilic part, amino acid as a skeleton, an ester bond as a connecting bond and an alkane chain as a hydrophobic part, and has the advantages of good biocompatibility, high safety, simple and rapid synthesis method and the like. The lipid nanoparticles prepared based on the functional lipid designed by the invention can stably load nucleic acid drugs, and the transfection effect on primary cells and tumor cells is remarkable. The invention provides a novel lipid material capable of effectively transfecting cells, and provides a safe and effective non-viral vector platform for cell transfection.

Description

technical field [0001] The present invention relates to the field of chemistry and formulation, in particular to lipid nanoparticles and their application in nucleic acid delivery. Background technique [0002] Nucleic acid drugs refer to various ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) with different functions, which can directly act on pathogenic target genes or target mRNAs, and play a role in treating diseases at the gene level. Because nucleic acid drugs have the characteristics of strong negative charge, strong hydrophilicity, and easy degradation, they cannot directly penetrate the biofilm barrier, and cannot be effectively taken up by cells and reach the target organelles to function. Therefore, how to safely and efficiently deliver nucleic acid drugs into cells and successfully function has become the core issue for the further development of nucleic acid drugs. [0003] The most widely studied nucleic acid delivery vectors include viral and non-viral ...

Claims

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Application Information

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IPC IPC(8): C07C229/24C07C233/47C07C237/12C07C271/22C07D207/09C07D207/14C07D207/408C07D211/26C07D295/13C07H13/12C08G65/333C12N15/88A61K9/51A61K47/18A61K47/22A61K47/26A61K48/00A61P35/00A61P37/02A61P43/00
CPCC07C229/24C07C233/47C07C237/12C07C271/22C07D295/13C07D211/26C07D207/09C07D207/14C07D207/408C07H13/12C12N15/88A61K47/18A61K47/22A61K47/26A61K48/005A61K9/5146A61K9/5123A61P35/00A61P37/02A61P43/00C08G65/33306Y02A50/30
Inventor 张灿鞠曹云黄滢霜陶雨薛玲静龙秋林
Owner CHINA PHARM UNIV
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