Ionizable lipid molecule, preparation method thereof and application of ionizable lipid molecule in preparation of lipid nanoparticles

An ionic and lipid-based technology, applied in the biological field, can solve the problems of not being able to fully exert the efficacy of mRNA-LNP preparations, achieve excellent mRNA carrier performance, and improve the effect of translation and expression levels

Pending Publication Date: 2022-01-28
IMMORNA (HANGZHOU) BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The existing LNP component scheme cannot fully exert the effectiveness of the mRNA-LNP preparation, and it is necessary to continuously adjust the structure of the ionizable lipid molecule and optimize the design of specific RNA. The present invention solves such problems

Method used

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  • Ionizable lipid molecule, preparation method thereof and application of ionizable lipid molecule in preparation of lipid nanoparticles
  • Ionizable lipid molecule, preparation method thereof and application of ionizable lipid molecule in preparation of lipid nanoparticles
  • Ionizable lipid molecule, preparation method thereof and application of ionizable lipid molecule in preparation of lipid nanoparticles

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0107] The synthesis of embodiment 1 compound one (code name: XH-04)

[0108] (Compound 1, code name: XH-04)

[0109] The preparation method of compound one is as figure 1 Shown; specifically include the following steps:

[0110] Step 1, compound 1 in DCM dichloromethane (100mL) (20.0g, 89.6mmol, 1.00 equiv) was added to the solution of compound 1A (14.2 g, 98.6 mmol, 1.10 equiv), DMAP4-dimethylaminopyridine (1.10 g, 8.96 mmol, 0.10 equiv), and TEA triethylamine (36.3 g, 358.6 mmol, 49.9 mL, 4.00 equiv). To the solution was added EDCI 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (22.3 g, 116.5 mmol, 1.30 equiv). The reaction was stirred at 25°C for 12 hours. TLC silica gel plate thin layer chromatography (petroleum ether:ethyl acetate=10:1, Rf=0.62) showed that the reaction was complete. The reaction solution was poured into H 2 O (100mL). The solution was extracted with dichloromethane (200 mL×2). The organic layer was washed with brine (100 mL). Th...

Embodiment 2

[0122] The synthesis of embodiment 2 compound two

[0123] Compound two:

[0124] Add triethylamine (40.8g) and dimethylaminopyridine (1.64g) and 1-ethyl-(3-di Methylaminopropyl) carbodiimide hydrochloride (25.7 g), stirred at room temperature for 12 h, then added hydrochloric acid (20 mL) solution to terminate the reaction. Extracted 3 times with ethyl acetate, and washed the filtrate with brine. Dry over anhydrous magnesium sulfate, filter and remove the solvent, and obtain 14 g of nonyl-8-bromooctanoic acid ethyl ester after purification by chromatography column.

[0125] Add triethylamine (68g) and dimethylaminopyridine (2.74g) and 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (94.5g), stirred at room temperature for 12h, then added hydrochloric acid solution to terminate the reaction, then extracted 3 times with ethyl acetate, And the filtrate was washed with brine. Dry over anhydrous magnesium sulfate, filter and remove the solvent, and obtain a colorl...

Embodiment 3

[0129] Embodiment 3: the synthesis of compound three

[0130] Compound three:

[0131] The synthesis of compound three refers to the synthetic method of compound two. The H NMR spectrum of compound three is as follows:

[0132] 1 H NMR: (400MHz, CDCl 3 )δ6.86(s,1H),6.79(s,2H),5.15(s,2H),4.86(t,J=6.2Hz,1H),4.06(t,J=6.6Hz,2H),3.91( td,J=6.4,9.0Hz,4H),3.09-2.91(m,2H),2.74(s,6H),2.52(t,J=6.6Hz,2H),2.32-2.27(m,4H),2.23 -2.10(m,2H),1.79-1.74(m,4H),1.65-1.58(m,6H),1.55-1.41(m,9H),1.41-1.34(m,9H),1.33-1.23(m, 34H), 0.93-0.83 (m, 9H).

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Abstract

The invention discloses an ionizable lipid molecule, a preparation method thereof, a composition containing the same, and application of the ionizable lipid molecule in preparation of a carrier for delivering nucleic acid to cells and application of the ionizable lipid molecule in preparation of lipid nano-particles LNP. The action efficacy of an mRNA-LNP preparation is improved by improving the structure of the ionizable lipid molecule and adjusting an LNP component scheme. The ionizable lipid molecule has a structure as shown in a formula (I): the ionizable lipid molecule, phospholipid, cholesterol and polyethylene glycol are subjected to microfluidic synthesis to obtain LNP, and the obtained LNP can improve the translation expression level of a load-mRNA in cells, improve the action efficacy of an mRNA-LNP preparation, and provide a theoretical basis for theoretical treatment of a personalized mRNA-LNP preparation.

Description

[0001] priority of reference [0002] This application claims the priority of CN202110159969.3, the entirety of which is incorporated herein by reference. technical field [0003] The invention relates to the field of biotechnology, in particular to an ionizable lipid molecule, its preparation method and its application in the preparation of lipid nanoparticles. Background technique [0004] Therapeutic nucleic acids include small interfering RNA (siRNA), microRNA (miRNA), messenger RNA (mRNA). Such nucleic acids function through a variety of mechanisms. In the case of siRNA or miRNA, the intracellular levels of specific proteins can be down-regulated by the method of RNA interference (RNAi). After the siRNA or miRNA is introduced into the cytoplasm, the siRNA or miRNA can bind to the RISC protein, and its sense strand is removed by the RISC complex, thereby providing an mRNA within the RISC that recognizes and binds to the sequence complementary to the bound siRNA or miRN...

Claims

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Application Information

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IPC IPC(8): C07C229/12C07D239/06C07D207/12C07C219/10C07C217/10C07C219/14C07C67/08C07C69/63C07C67/31C07C67/30C07C69/712C07C227/18C07F7/18A61K9/51A61K47/18A61K47/24A61K47/28A61K47/14A61K31/7105A61K31/713A61K39/00A61P43/00B82Y5/00B82Y40/00
CPCC07C229/12C07D239/06C07D207/12C07C219/10C07C217/10C07C219/14C07C67/08C07C67/31C07C67/30C07C227/18C07F7/1804C07F7/188A61K9/5123A61K9/5146A61K31/7105A61K31/713A61K39/00A61P43/00B82Y5/00B82Y40/00C07C2601/08C07C2601/14A61K31/7088C07C69/63C07C69/712C07C67/313A61K2039/55555A61K39/39A61K2039/53B82Y30/00C07C69/738C07C69/736C07C229/08
Inventor 王子豪
Owner IMMORNA (HANGZHOU) BIOTECHNOLOGY CO LTD
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