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RU-2861293-C1 - CATIONIC LIPID COMPOUND, COMPOSITION CONTAINING SAME AND USE THEREOF

RU2861293C1RU 2861293 C1RU2861293 C1RU 2861293C1RU-2861293-C1

Abstract

FIELD: chemistry; pharmaceuticals. SUBSTANCE: group of inventions relates to a compound characterised by one of the structures ; to a composition for delivering a nucleic acid, containing said compound as a cationic lipid; to the use of the proposed composition in the manufacture of a medicament for treating a disease or condition characterised by dysfunctional or abnormal activity of a protein or polypeptide. EFFECT: improved delivery to cells of therapeutic and/or prophylactic agents, such as nucleic acids, with high intracellular transfection efficiency, low cytotoxicity, as well as increased and prolonged expression. 12 cl, 10 dwg, 8 tbl, 7 ex

Inventors

  • SONG, Gengshen
  • WANG, Huanyu
  • ZHANG, HONGLEI
  • CHEN, Xichao
  • YU, XIAOWEN
  • HUANG, DAWEI

Dates

Publication Date
20260504
Application Date
20250703
Priority Date
20220113

Claims (20)

  1. 1. A compound characterized by one of the following structures:
  2. ,
  3. ,
  4. ,
  5. ,
  6. .
  7. 2. A composition for delivering a nucleic acid, comprising a nucleic acid as a therapeutic or prophylactic agent and a carrier, wherein the carrier comprises a cationic lipid, a neutral lipid, a structured lipid and a lipid conjugated with polyethylene glycol (PEG); wherein the cationic lipid is a compound according to claim 1;
  8. the molar content of cationic lipid in the carrier ranges from 30% to 70%;
  9. the molar ratio of cationic lipid to neutral lipid ranges from 1:1 to 10:1;
  10. the molar content of PEG-conjugated lipid in the carrier ranges from 0.5% to 5%;
  11. the mass ratio of carrier to therapeutic or prophylactic agent ranges from 10:1 to 30:1.
  12. 3. The composition of claim 2, wherein the neutral lipid is selected from one or more of phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, ceramide, sterol and derivatives thereof; Preferably, the neutral lipid is selected from one or more of 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 DietherPC), 1-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 LysoPC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2-Didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), dipalmitoylphosphatidylglycerol (DPPG), palmitoyl oleoyl phosphatidylethanolamine (POPE), distearoyl-phosphatidyl-ethanolamine (DSPE), dipalmitoylphosphatidylethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), 1-stearyl-2-oleoyl-stearoylethanolamine (SOPE), 1-stearoyl-2-oleoyl-phosphatidylcholine (SOPC), sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, palmitoyl oleoyl phosphatidylcholine, lysophosphatidylcholine, lysophosphatidylethanolamine (LPE), and mixtures thereof; more preferably, the neutral lipid is DOPE or DSPC.
  13. 4. The composition according to claim 2 or 3, wherein the molar ratio of cationic lipid to structured lipid is from 1:1 to 5:1.
  14. 5. The composition of claim 4, wherein the structured lipid is selected from one or more of cholesterol, nonsterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatine, ursolic acid, alpha-tocopherol and a corticosteroid; preferably, the structured lipid is cholesterol.
  15. 6. The composition of claim 5, wherein the PEG-conjugated lipid is selected from one or more of PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, and PEG-modified dialkylglycerol; preferably, the PEG-conjugated lipid is selected from one or more of distearoylphosphatidylethanolamine polyethyleneglycol 2000 (DSPE-PEG2000), dimyristoylglycero-3-methoxypolyethyleneglycol 2000 (DMG-PEG2000), and methoxypolyethyleneglycol ditetradecylacetamide (ALC-0159).
  16. 7. The composition according to any one of claims 2 to 6, wherein the carrier comprises a cationic lipid, a neutral lipid, a structured lipid and a lipid conjugated with PEG, and the molar ratio of the cationic lipid, neutral lipid, structured lipid and lipid conjugated with PEG is (25-65):(5-25):(25-45):(0.5-5), preferably is 50:10:38.5:1.5.
  17. 8. The composition according to any one of claims 2 to 7, wherein the composition is in the form of nanoparticles with an average particle size from 10 nm to 210 nm and a polydispersity index less than or equal to 50%; preferably, the composition is in the form of nanoparticles with an average particle size from 100 nm to 205 nm and a polydispersity index less than or equal to 30%.
  18. 9. The composition of any one of claims 2 to 7, wherein the composition further comprises one or more other ionizable lipid compounds;
  19. or the composition further comprises one or more pharmaceutically acceptable excipients and diluents;
  20. or the weight ratio of the carrier to the therapeutic or prophylactic agent is from 15:1 to 25:1; preferably, the weight ratio of the carrier to the therapeutic or prophylactic agent is 16:1.

Description

[0001] This application claims the benefit of Chinese Patent Application No. 202210034449.4, filed on January 13, 2022, the contents of which are incorporated herein by reference as part of this application. AREA OF TECHNOLOGY [0002] The present invention relates to the field of medicine. The present invention specifically relates to a cationic lipid compound, compositions containing the same, and the use thereof. LEVEL OF TECHNOLOGY [0003] Effective targeted delivery of biologically active substances such as small molecule drugs, peptides, proteins, and nucleic acids, particularly nucleic acids, is an ongoing medical challenge. Nucleic acid therapy faces significant challenges due to the low cellular permeability and high susceptibility to degradation of certain nucleic acid molecules, including RNA. [0004] Compositions, liposomes, and liposomal complexes (lipoplexes) containing cationic lipid have been demonstrated as delivery vehicles for the efficient delivery of biologically active substances, such as small molecule drugs, polypeptides, proteins, and nucleic acids, into cells and/or intracellular compartments. These compositions typically contain one or more "cationic" and/or amino (ionizable) lipids, and also contain a neutral lipid, a structured lipid, and a lipid conjugated to a polymer. Cationic and/or ionizable lipids include, for example, amine-containing lipids that are readily protonated. Although a variety of such lipid-containing nanoparticle compositions have been demonstrated, safety, efficacy, and specificity remain to be improved. Notably, the increased complexity of lipid The complexity of RNAi nanoparticles (LNPs) complicates their production and can increase their toxicity, a serious issue that may limit their clinical application. For example, siRNA LNPs such as patisiran require pre-treatment with steroids and antihistamines to eliminate unwanted immune responses (T. Coelho, D. Adams, A. Silva, et al., Safety and efficacy of RNAi therapy for transthyretin amyloidosis, N Engl J Med, 369 (2013) 819–829). Accordingly, there is a need to develop improved cationic lipid compounds and compositions containing them that facilitate the delivery of therapeutic and/or prophylactic agents such as nucleic acids to cells. ESSENCE OF THE INVENTION [0005] The present invention is based at least on the discovery that there is no clear correspondence between the structure of cationic lipid compounds and the efficiency of intracellular transfection, cytotoxicity, and high and prolonged expression in animals. Compounds with small structural differences can have very large differences in the efficiency of transfection and/or cytotoxicity and high expression in cells. For example, the compounds YK-009 and YK-010 of the present application have a nearly 60-fold difference in the efficiency of cell transfection and a 25% or more difference in toxicity to transfected cells. As another example, the difference in expression and prolonged expression of compounds YK-003 and YK-010 in mice can be 50-fold. [0006] Therefore, it is very difficult to select suitable cationic lipid compounds that can simultaneously have high transfection efficiency and low cytotoxicity, and high expression and prolonged expression in mice. Through the unique design, the present invention has found some compounds such as YK-009, YK-003, YK-006, YK-008 and YK-011, which can deliver nucleic acids with high cell transfection efficiency, low or no cytotoxicity and high and prolonged expression in animals compared with other compounds of the prior art, and achieve unexpected technical effects. [0007] In a first aspect of the present invention, there is provided a compound characterized by one of the following structures: [0008] In a second aspect of the present invention, there is provided a composition for delivering a nucleic acid, comprising a nucleic acid as a therapeutic or prophylactic agent and a carrier, wherein the carrier comprises a cationic lipid, a neutral lipid, a structured lipid and a lipid conjugated with polyethylene glycol (PEG); wherein the cationic lipid is the above compound; the molar content of cationic lipid in the carrier ranges from 30% to 70%; the molar ratio of cationic lipid to neutral lipid ranges from 1:1 to 10:1; the molar content of PEG-conjugated lipid in the carrier ranges from 0.5% to 5%; the mass ratio of carrier to therapeutic agent or prophylactic agent is from 10:1 to 30:1. [0009] In a preferred embodiment, the neutral lipid is selected from one or more of phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, ceramide, sterol and derivatives thereof; Preferably, the neutral lipid is selected from one or more of 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-diundecanoyl-sn-glycero-phos