WO2025199302A1 - Lipides cationiques sensibles au ph, nanoparticules lipidiques les comprenant et procédés d'administration d'acides nucléiques - Google Patents

Lipides cationiques sensibles au ph, nanoparticules lipidiques les comprenant et procédés d'administration d'acides nucléiques

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Publication number
WO2025199302A1
WO2025199302A1 PCT/US2025/020674 US2025020674W WO2025199302A1 WO 2025199302 A1 WO2025199302 A1 WO 2025199302A1 US 2025020674 W US2025020674 W US 2025020674W WO 2025199302 A1 WO2025199302 A1 WO 2025199302A1
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group
compound
lipid
lipid nanoparticle
pharmaceutically acceptable
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Masamitsu TAGUCHI
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Nitto Denko Corp
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Nitto Denko Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers

Definitions

  • the present disclosure relates to a pH-sensitive cationic lipid, a lipid nanoparticle comprising the pH-sensitive lipid, and a method of delivering a nucleic acid encapsulated in the lipid nanoparticle to a cell or a subject.
  • Lipid nanoparticles are used as carriers to encapsulate lipophilic drugs and nucleic acids such as siRNA (short interfering RNA) and mRNAto deliver to target cells and organs.
  • nucleic acids such as siRNA (short interfering RNA) and mRNAto deliver to target cells and organs.
  • lipid nanoparticles comprising pH-sensitive cationic lipids as constituent lipids, which are electrically neutral at physiological pH and change to cationic in a weakly acidic pH environment such as endosome, are reported as lipid nanoparticles which serve as carriers to efficiently deliver nucleic acids such as siRNA into target cells (See, PCT publication No. WO 2018/230710, and Sato et al., Journal of controlled Release, 2019, vol.295, p.140-152).
  • PCT publication No. WO 2022/071582 discloses pH-sensitive cationic lipids, such as CL15F6, CL4F6, and CL4F 10-8 listed below as components of lipid nanoparticles which are useful for delivering nucleic acids to target cells and organs.
  • the present disclosure relates to a pH-sensitive cationic lipid that is useful for preparing nanoparticles that have favorable transfection property to target cells.
  • the present disclosure includes the following embodiments (1) to (15).
  • Embodiment (1) A compound represented by general formula (I) or pharmaceutically acceptable salt thereof:
  • R 1 and R 2 each independently represent a group represented by general formula (A):
  • R 11 and R 12 each independently represent a C5-15 alkoxy group; each c independently represents 0 or 1; each v independently represents an integer of 4-12; each w independently represents an integer of 0-3 ; and
  • X represents a 5- to 7-membered non-aromatic heterocyclic group, wherein a carbon atom of said heterocyclic group is bound to (O-CO)b- and one or two hydrogen atoms of said heterocyclic group may optionally be replaced with a Ci-4 alkyl group or C2-4 alkenyl group, or a group represented by general formula (B):
  • R 3 and R 4 each independently represent a Ci-4 alkyl group or C2-4 alkenyl group, or
  • R 3 and R 4 are bound to each other to form a 5- to 7-membered non-aromatic heterocyclic group, wherein one or two hydrogen atoms of said heterocyclic group may optionally be replaced with a Ci-4 alkyl group or C2-4 alkenyl group.
  • Embodiment (2) The compound of Embodiment (1) or pharmaceutically acceptable salt thereof, wherein c is 1.
  • Embodiment (3) The compound of Embodiment (1) or (2), or pharmaceutically acceptable salt thereof, wherein w is 1 or 2.
  • Embodiment (4) The compound of any one of Embodiments (1) to (3), or pharmaceutically acceptable salt thereof, wherein b is 0 and X is the group represented by the general formula (B).
  • Embodiment (5) The compound of any one of Embodiments (1) to (4), or pharmaceutically acceptable salt thereof, wherein b is 0, X is the group represented by the general formula (B), d is 0, and R 3 and R 4 are each independently a Ci-4 alkyl group.
  • Embodiment (6) The compound of any one of Embodiments (1) to (4), or pharmaceutically acceptable salt thereof, wherein b is 1 and X is a 5- to 7-membered non-aromatic heterocyclic group.
  • Embodiment (7) The compound of any one of Embodiments (1) to (6), or pharmaceutically acceptable salt thereof, wherein the compound is represented by general formula (la):
  • a represents an integer of 3 -5 ; each R 13 independently represents a C5-15 alkoxy group; b represents 0 or 1; each v independently represents an integer of 4-12; each w independently represents an integer of 1 -3 ;
  • X represents a 5- to 7-membered non-aromatic heterocyclic group, wherein a carbon atom of said heterocyclic group is bound to (O-CO)b- , and one or two hydrogen atoms of said heterocyclic group may optionally be replaced with a Ci-4 alkyl group or C2-4 alkenyl group, or a group represented by general formula (B):
  • R 3 and R 4 each independently represent a Ci-4 alkyl group or C2-4 alkenyl group, or
  • R 3 and R 4 are bound to each other to form a 5- to 7-membered non-aromatic heterocyclic group, wherein one or two hydrogen atoms of said heterocyclic group may optionally be replaced with Ci-4 alkyl group or C2-4 alkenyl group.
  • Embodiment (8) The compound of any one of Embodiments (1) to (7), or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of Compounds Nos. 1 to 9 as shown in the following Table 1.
  • Embodiment 9 A lipid nanoparticle comprising the compound of any one of Embodiments (1) to (8), or pharmaceutically acceptable salt thereof.
  • Embodiment (10) The lipid nanoparticle of Embodiment (9), further comprising a sterol, a phospholipid, and a polyalkylene glycol-modified lipid.
  • Embodiment (11) The lipid nanoparticle of Embodiment (10), wherein the phospholipid is selected from the group consisting of l,2-distearoyl-sn-glycero-3- phosphocholine (DSPC), l,2-dioleoyl-sn-glycero-3 -phosphocholine (DOPC), and 1,2- dioleoyl-sn-glycero-3 -phosphoethanolamine (DOPE), wherein the polyalkylene glycol-modified lipid is l,2-dimyristoyl-rac-glycero-3- methoxypolyethylene glycol (DMG-PEG).
  • DSPC l,2-distearoyl-sn-glycero-3- phosphocholine
  • DOPC l,2-dioleoyl-sn-glycero-3 -phosphocholine
  • DOPE 1,2- dioleoyl-sn-glycero-3 -phosphoethanolamine
  • Embodiment (12) The lipid nanoparticle of Embodiment (10) or (11), wherein the lipid nanoparticle comprises:
  • Embodiment (13) The lipid nanoparticle of any one of Embodiments (9) to (12), further comprising a nucleic acid encapsulated in the lipid nanoparticle.
  • Embodiment (14) A method of delivering a nucleic acid to a cell, comprising contacting the cell with the lipid nanoparticle of Embodiment (13).
  • Embodiment 15 Amethod of delivering a nucleic acid to a subject in need thereof, comprising administering to the subject the lipid nanoparticle of Embodiment (13).
  • X1-X2 (where XI and X2 are real numbers satisfying XI ⁇ X2) means "XI or more and X2 or less”.
  • the present disclosure relates to a pH-sensitive cationic lipid that is a compound represented by the following general formula (I) or pharmaceutically acceptable salt thereof (hereinafter may be referred to as “pH-sensitive cationic lipids of the present disclosure”):
  • R 1 and R 2 each independently represent a group represented by general formula (A):
  • R 11 and R 12 each independently represent a C5-15 alkoxy group; each c independently represents 0 or 1; each v independently represents an integer of 4-12; each w independently represents an integer of 0-3 ; and
  • X represents a 5- to 7-membered non-aromatic heterocyclic group, wherein a carbon atom of said heterocyclic group is bound to (O-CO)b- , and one or two hydrogen atoms of said heterocyclic group may optionally be replaced with a Ci-4 alkyl group or C2-4 alkenyl group, or a group represented by general formula (B):
  • R 3 and R 4 each independently represent a Ci-4 alkyl group or C2-4 alkenyl group, or R 3 and R 4 are bound to each other to form a 5- to 7-membered non-aromatic heterocyclic group, wherein one or two hydrogen atoms of said heterocyclic group may optionally be replaced with a Ci-4 alkyl group or C2-4 alkenyl group.
  • alkyl refers to a linear or a branched hydrocarbyl radical of a saturated aliphatic group, which can be of any length unless otherwise specified.
  • alkenyl refers to a linear or a branched hydrocarbyl radical having at least one carbon-carbon double bond, which can be of any length unless otherwise specified.
  • alkoxy refers to a linear or a branched alkyl bound through a single, terminal ether linkage.
  • R 1 is the same as R 2 . In another embodiment, R 1 is different from R 2 .
  • R 11 is the same as R 12 . In another embodiment, R 11 is different from R 12 .
  • R 11 and R 12 are each independently a C5-14 alkoxy, C5-13 alkoxy, C5-12 alkoxy, C5-11 alkoxy, C5-10 alkoxy, C5-9 alkoxy, C5-8 alkoxy, or C5-7 alkoxy group.
  • R 11 and R 12 are each independently: n-pentyloxy group, 1 -methylbutyl oxy group, 2-methylbutyloxy group, 3- methylbutyloxy group, 1 -ethylpropoxy group, 1,1 -dimethylpropoxy group, or 2,2- dimethylpropoxy group; n-hexyloxy group, 1 -methylpentyl oxy group, 2-methylpentyloxy group, 3- methylpentyloxy group, 4-methylpentyloxy group, 1 -ethylbutyl oxy group, 1,1 -dimethylbutyl oxy group, 2,2-dimethylbutyloxy group, 3, 3 -dimethylbutyl oxy group, 1,2-dimethylbutyloxy group, or 1 -methyl -2,2-dimethylbutyloxy group; n-heptyloxy group, 1 -methylhexyl oxy group, 2-methylhexyloxy group, 3- methylhex
  • 9.9-dimethyldecyloxy group 5-methyl-9,9-dimethyldecyloxy group, 6-methyl-9,9- dimethyldecyloxy group, 7-methyl-9,9-dimethyldecyloxy group, or 8-methyl-9,9- dimethyldecyloxy group; n-tetradecyloxy group, 1 -methyltri decyl oxy group, 2-methyltri decyl oxy group, 3- methyltridecyloxy group, 4-methyltridecyloxy group, 5-methyltridecyloxy group, 6- methyltridecyloxy group, 7-methyltridecyloxy group, 8-methyltridecyloxy group, 9- methyltridecyloxy group, 10-methyltri decyl oxy group, 11 -methyltri decyloxy group, 12- methyltri decyloxy group, 1 -ethyldodecyl oxy group, 1,1 -dimethyl dodecyl oxy
  • R 11 and R 12 are each independently n-pentyloxy, n-hexyloxy, n- heptyloxy, n-octyloxy, n-nonyloxy , n-decyloxy, n-undecyloxy, n-dodecyloxy, n-tridecyloxy, n- tetradecyloxy, or n-pentadecyloxy.
  • both of R 11 and R 12 are n-pentyloxy, n- hexyloxy, n-heptyloxy, n-octyloxy, n-nonyloxy, n-decyloxy, n-undecyloxy, n-dodecyloxy, n- tridecyloxy, n-tetradecyloxy, or n-pentadecyloxy.
  • c is 0. In another embodiment, c is 1.
  • v is an integer of 4-11, 4-10, 4-9, 4-8, 4-7, 4-6, 5-12, 5-11, 5-10, 5-9, 5-8, 5-7, 5-6, 6-12, 6-11, 6-10, 6-9, 6-8, or 6-7. In some embodiments, v is 6.
  • w is 1, 2 or 3. In some embodiments, w is 1 or 2.
  • a is 3 or 4. In some embodiments, a is 4 or 5. In some embodiments, a is 4.
  • b is 0. In some embodiments, b is 0 and X is the group represented by general formula (B). In some embodiments, b is 0, X is the group represented by general formula (B), d is 0, and R 3 and R 4 each independently a Ci-4 alkyl group. In some embodiments, b is 0, X is the group represented by general formula (B), d is 0, and R 3 and R 4 are n-propyl group.
  • d is 0, 1 or 2. In some embodiments, d is 0 or 1. In some embodiments, d is 0.
  • b is 1.
  • b is 1 and X is a 5- to 7- membered non-aromatic heterocyclic group, wherein a carbon atom of the heterocyclic group is bound to (O-CO)- and one or two hydrogen atoms of the heterocyclic group may be replaced with a Ci-4 alkyl group or C2-4 alkenyl group.
  • b is 1 and X is 1 -methyl -4- piperidinyl group.
  • R 3 and R 4 each independently represent a Ci-4 alkyl group or C2-4 alkenyl group.
  • the Ci-4 alkyl group of R 3 and/or R 4 is methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, or tert-butyl group.
  • the C2-4 alkenyl group of R 3 and/or R 4 is vinyl group, 1 -propenyl group, 2- propenyl group, 1-methylvinyl group, 2-methyl-l -propenyl group, 1-butenyl group, 2-butenyl group, or 3-butenyl group.
  • R 3 and R 4 are bound to each other to form a 5- to 7-membered non-aromatic heterocyclic group.
  • the 5- to 7-membered non-aromatic heterocyclic group formed by R 3 and R 4 bound to each other is, for example, 1-pyrrolidinyl group, 1 -piped dinyl group, 1-morpholinyl group, or 1-piperazinyl group.
  • one or two hydrogen atoms in the heterocyclic group may be replaced with a Ci-4 alkyl group or C2-4 alkenyl group.
  • two hydrogen atoms in said heterocyclic group are replaced with a Ci-4 alkyl group or C2-4 alkenyl group, they may be replaced with the same group or by different groups.
  • the hetero atom comprised in said heterocyclic group is nitrogen atom, oxygen atom, or sulfur atom.
  • the hetero atom(s) constituting the heterocycle in said heterocyclic group may be one, two, or more, and may be same or different.
  • the 5- to 7-membered non-aromatic heterocyclic group may be a saturated heterocycle and may comprise one or more double bonds, but the heterocycle is never an aromatic ring.
  • the pH-sensitive cationic lipid of the present disclosure is a compound represented by the following general formula (la) or pharmaceutically acceptable salt thereof: wherein: a represents an integer of 3 -5 ; each R 13 independently represents a C5-15 alkoxy group; b represents 0 or 1; each v independently represents an integer of 4-12; each w independently represents an integer of 1 -3 ;
  • X represents a 5- to 7-membered non-aromatic heterocyclic group, wherein a carbon atom of said heterocyclic group is bound to (O-CO)b- , and one or two hydrogen atoms of said heterocyclic group may optionally be replaced with a Ci-4 alkyl group or C2-4 alkenyl group, or a group represented by general formula (B): CH 2 )d-N(R 3 )(R 4 ) (B) wherein: d represents an integer of 0-3; and
  • R 3 and R 4 each independently represent a Ci-4 alkyl group or C2-4 alkenyl group, or R 3 and R 4 are bound to each other to form a 5- to 7-membered non-aromatic heterocyclic group, wherein one or two hydrogen atoms of said heterocyclic group may optionally be replaced with a Ci-4 alkyl group or C2-4 alkenyl group.
  • the pH-sensitive cationic lipid of the present disclosure is selected from the group consisting of Compounds Nos. 1 to 9 as shown in the following Table 1, or pharmaceutically acceptable salt thereof:
  • the term “pharmaceutically acceptable” refers to being compatible with use in subjects, for example, mammals such as human.
  • the pharmaceutically acceptable salt of the present disclosure includes, but is not limited to, salts containing a chloride, bromide, fluoride, iodide, nitrate, sulfate, methyl sulfate, phosphate, acetate, benzoate, citrate, glutamate and/or lactate.
  • the pharmaceutically acceptable salt of the compound of the general formula (I) of the present disclosure can be synthesized by conventional chemical methods.
  • the pharmaceutically acceptable salt of the compound of the general formula (I) of the present disclosure is prepared either by ion exchange chromatography or by reacting the free base in the compound with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
  • the compounds of the general formula (I) of the present disclosure may contain one or more chiral centers.
  • the compounds containing one or more chiral centers may include those described as an “isomef ’, a “stereoisomer”, a “diastereomer”, an “enantiomer”, an “optical isomer”, or a “racemic mixture”.
  • stereochemical nomenclature for example, the stereoisomer naming rules of Cahn, Ingold, and Prelog, as well as methods for the determination of stereochemistry and the separation of stereoisomers known in the art, see, for example, Michael B.
  • the pH-sensitive cationic lipids represented by the general formula (I) can be easily produced, for example, by the methods specifically shown in the examples herein. By referring to these production methods and appropriately selecting raw material compounds, reagents, and reaction conditions, one skilled in the art can easily produce any lipids included in the range of the general formula (I).
  • the present disclosure relates to a lipid nanoparticle comprising the pH- sensitive cationic lipids of the present disclosure (hereinafter may be referred to as “lipid nanoparticles according to the present disclosure”).
  • lipids which are generally used to form liposomes can generally be used as lipids other than the pH-sensitive cationic lipids of the present disclosure.
  • lipids include, for example, phospholipid, sterol or sterol derivative, glycolipid, or saturated or unsaturated fatty acids, etc. These can be used in one type or a combination of two or more types.
  • the lipid nanoparticle comprises the pH-sensitive cationic lipid of the present disclosure, a phospholipid, a sterol, and a polyalkylene glycol-modified lipid.
  • the phospholipids can include glycerophospholipids such as phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, phosphatidylethanolamine, phosphorylcholine, cardiolipin, plasmalogen, ceramide phosphorylglycerol phosphate, phosphatidic acid; and sphingophospholipids such as sphingomyelin, ceramide phosphorylglycerol, ceramide phosphoryl ethanolamine; etc.
  • phospholipids derived from natural products such as egg yolk lecithin and soy lecithin can also be used.
  • Fatty acid residues in glycerophospholipids and sphingophospholipids are not particularly limited, but can include, for example, saturated or unsaturated fatty acid residues having carbon number of 12-24, saturated or unsaturated fatty acid residues having carbon number of 14-20 are preferable.
  • acyl groups derived from fatty acids such as lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidic acid, arachidonic acid, behenic acid, and lignoceric acid can be included.
  • glycerolipids or sphingolipids have two or more fatty acid residues
  • all fatty acid residues may be the same group or may be different group from each other.
  • the phospholipids includes diphytanoyl phosphatidyl ethanolamine (DPhPE), l,2-Diphytanoyl-.s//- Glycero-3 -Phosphocholine (DPhPC), l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2- dipalmitoyl-sn-glycero-3 -phosphocholine (DPPC), l,2-dioleoyl-sn-glycero-3 -phosphocholine (DOPC), 1,2- dipalmitoyl-sn-glycero-3 -phosphoethanolamine (DPPE), and 1,2-dioleoyl-sn- glycero-3 -phosphoethanolamine (DOPE).
  • DPhPE diphy
  • Sterols or sterol derivatives include, for example, animal-derived sterols such as cholesterol, cholesterol succinic acid, lanosterol, dihydrolanosterol, desmosterol, and dihydrocholesterol; plant-derived sterols (phytosterols) such as stigmasterol, sitosterol, P- sitosterol, campesterol, brassicasterol; and microorganism-derived sterols such as zymosterol and ergosterol, etc.
  • animal-derived sterols such as cholesterol, cholesterol succinic acid, lanosterol, dihydrolanosterol, desmosterol, and dihydrocholesterol
  • plant-derived sterols phytosterols
  • stigmasterol such as stigmasterol, sitosterol, P- sitosterol, campesterol, brassicasterol
  • microorganism-derived sterols such as zymosterol and ergosterol, etc.
  • Glycolipids include, for example, glyceroglycolipids such as sulfoxyribosylglyceride, diglycosyl diglyceride, digalactosyl diglyceride, galactosyl diglyceride, glycosyl diglyceride; sphingoglycolipids such as galactosylcerebroside, lactosylcerebroside, ganglioside; etc.
  • Saturated or unsaturated fatty acids include, for example, saturated or unsaturated fatty acids having carbon number of 12-20 such as palmitic acid, oleic acid, stearic acid, arachidonic acid, and myristic acid.
  • the constituent lipids of the lipid nanoparticles according to the present disclosure preferably comprise neutral lipid, more preferably comprise phospholipid or sterol, further preferably comprise sterol, and more further preferably comprise cholesterol.
  • the lipid nanoparticles according to the present disclosure preferably comprise polyalkylene glycol-modified lipids as a lipid component.
  • Polyalkylene glycol is a hydrophilic polymer, and, by constructing lipid nanoparticles using polyalkylene glycol-modified lipids as lipid membrane constituent lipids, surface of the lipid nanoparticles can be modified with polyalkylene glycol. Surface modification with polyalkylene glycol may be able to enhance the stability such as blood retention of lipid nanoparticles.
  • polyalkylene glycol for example, polyethylene glycol, polypropylene glycol, polytetramethylene glycol, polyhexamethylene glycol, etc. can be used.
  • the average molecular weight of polyalkylene glycol is, for example, approximately between 200 and 10,000, preferably approximately between 500 and 10,000, further preferably approximately between 1,000 and 5,000.
  • the molecular weight of polyalkylene glycol is about 200, 300, 350, 400, 500, 550, 750, 1000, 1500, 2000, 3000, 3500, 4000, 5000 or 10,000 Da.
  • stearylated polyethylene glycol e.g., PEG-45 stearate (STR-PEG45), etc.
  • polyethylene glycol derivatives such as N-[carbonyl -methoxypoly ethylene glycol]-l,2-dipalmitoyl-sn-glycero- 3 -phosphoethanolamine (DPPE-PEG), N-[carbonyl-methoxypolyethylene glycol]-l,2-distearoyl- sn-glycero-3-phosphoethanolamine (DSPE-PEG), and l,2-dimyristoyl-rac-glycero-3- methoxypolyethylene glycol (DMG-PEG) can be used.
  • DPPE-PEG N-[carbonyl -methoxypoly ethylene glycol]-l,2-dipalmitoyl-sn-glycero- 3 -phosphoethanolamine
  • DMG-PEG l,2-dimyristoyl-rac-glycero-3- methoxypolyethylene glycol
  • the lipid nanoparticles according to the present disclosure comprises any one of DSPC, DOPC and DOPE as the phospholipid and DMG-PEG as the polyalkylene glycol-modified lipid.
  • an embodiment of the lipid nanoparticles according to the present disclosure comprises 40-60 mol% of the pH-sensitive cationic lipids of the present disclosure to the total lipid amount of the lipid nanoparticle; 30-50 mol% of the sterol (such as cholesterol) to the total lipid amount of the lipid nanoparticle; 5-15 mol% of any one of DSPC, DOPC and DOPE to the total lipid amount of the lipid nanoparticle; and 1-5 mol% of DMG-PEG (such as DMG-PEG2000) to the total lipid amount of the lipid nanoparticle.
  • DMG-PEG such as DMG-PEG2000
  • the molar ratio of the pH-sensitive cationic lipids of the present disclosure, the sterol, the phospholipid selected from the group consisting of DSPC, DOPC and DOPE, and DMG-PEG in the lipid nanoparticle according to the present disclosure includes, but not limited to, (60/31/8/1), (60/31/7.5/1.5), (60/31/7/2), (60/31/6.5/2.5), (60/31/6/3), (60/31/5.5/3.5), (60/31/5/4), (60/31/4.5/4.5), (60/31/4/5), (60/31.5/7.5/1), (60/30.5/7.5/2), (60/30/7.5/2.5), (60/29.5/7.5/3), (60/29/7.5/3.5), (60/28.5/7.5/4), (60/28/7.5/4.5), (60/27.5/7.5/5), (59/32/7.5/1.5), (58/33/7.5/1.5), (57/34/7.5/1.5
  • the lipid nanoparticle according to the present disclosure may comprise (1) Compound 1: cholesterol: DOPE: DMG-PEG, preferably in ratio 57.5:38.5:2.5:1.5 (mol%), or (2) Compound 1: cholesterol: DOPE: DMG-PEG, preferably in ratio 59:34:5.5:1.5 (mol%).
  • the lipid nanoparticles according to the present disclosure can be subjected to appropriate surface modification, as necessary.
  • the lipid nanoparticles according to the present disclosure can be modified on the surface with hydrophilic polymers, etc. to enhance blood retention. Surface modification may be able to be achieved by using lipids modified with these modifying groups as constituent lipid of the lipid nanoparticles.
  • lipid nanoparticles for example, glycophorin, ganglioside GM1, phosphatidylinositol, ganglioside GM3, glucuronic acid derivatives, glutamic acid derivatives, and polyglycerol phospholipid derivatives, etc. can be used as lipid derivatives to enhance blood retention.
  • dextran, pullulan, ficoll, polyvinyl alcohol, styrene-maleic anhydride alternating copolymer, divinyl ether-maleic anhydride alternating copolymer, amylose, amylopectin, chitosan, mannan, cyclodextrin, pectin and carrageenan, etc., other than polyalkylene glycol, can be used for surface modification, as hydrophilic polymers to enhance blood retention.
  • lipid nanoparticles can be surface-modified with oligosaccharide compounds with three or more saccharides.
  • the type of oligosaccharide compounds with three or more saccharides is not particularly limited, but for example, oligosaccharide compounds in which approximately between 3 and 10 saccharide units are bound can be used, preferably oligosaccharide compounds in which approximately between 3 and 6 saccharide units are bound can be used.
  • oligosaccharide compounds with trimer or hexamer of glucose can be used, and, further preferably, oligosaccharide compounds with trimer or tetramer of glucose can be used.
  • isomaltotriose, isopanose, maltotriose, maltotetraose, maltopentaose, or maltohexaose can be preferably used, among which maltotriose, maltotetraose, maltopentaose, or maltohexaose with a 1-4 bound glucose are further preferable.
  • maltotriose or maltotetraose is particularly preferred, and most preferred is maltotriose.
  • Surface modification amount of lipid nanoparticles by oligosaccharide compound is not particularly limited, but, for example, it is approximately between 1 and 30 mol%, preferably approximately between 2 and 20 mol%, and more preferably approximately between 5 and 10 mol% to the total lipid amount.
  • the method for surface modifying lipid nanoparticles with oligosaccharide compound is not particularly limited, but, for example, liposomes in which lipid nanoparticles are surface modified with monosaccharides such as galactose and mannose (PCT publication No. WO 2007/102481) are known, so the method for the surface modification described in the publication can be employed.
  • the surface modification method described in this publication can be adopted to the present disclosure. All of the disclosures in above publication shall be included by reference as the disclosures in the present application.
  • the lipid nanoparticles according to the present disclosure can also be imparted any one or more functions such as temperature change sensitive function, membrane permeability function, gene expression function, and pH-sensitive function. Adding these functions appropriately can improve the retention of lipid nanoparticles in the blood and allow the lipid nanoparticles to efficiently escape from endosomes after endocytosis in target cells.
  • functions such as temperature change sensitive function, membrane permeability function, gene expression function, and pH-sensitive function. Adding these functions appropriately can improve the retention of lipid nanoparticles in the blood and allow the lipid nanoparticles to efficiently escape from endosomes after endocytosis in target cells.
  • the lipid nanoparticles according to the present disclosure may comprise one or more substances selected from the group consisting of anti-oxidizing agents such as tocopherol, propyl gallate, ascorbyl palmitate, butylated hydroxytoluene, charged substances, and membrane polypeptides, etc.
  • Charged substances which impart positive charges can include, for example, saturated or unsaturated aliphatic amines such as stearylamine and oleylamine, and charged substances which impart negative charges can include, for example, dicetyl phosphate, cholesteryl hemi succinate, phosphatidylserine, phosphatidylinositol, phosphatidic acid, etc.
  • Membrane polypeptides include, for example, membrane extrinsic polypeptide or membrane intrinsic polypeptide, etc. The compounded amount of these substances is not particularly limited and can be appropriately selected according to the purpose.
  • the average particle size of the lipid nanoparticles according to the present disclosure is, for example, 400 nm or less, 300 nm or less, 200 nm or less, or 150 nm or less.
  • the “average particle size of the lipid nanoparticles” means the Z-average particle size measured by dynamic light scattering (DLS). Measurement by dynamic light scattering can be carried out by usual method using commercially available DLS equipment, etc.
  • the poly dispersity index (PDI) of the lipid nanoparticles according to the present disclosure is, for example, approximately between 0.01 and 0.7, preferably approximately between 0.01 and 0.6, further preferably approximately between 0.03 and 0.3.
  • the zeta potential at pH 7.4 can be in the range of -50 mV-5 mV, preferably -45 mV- 5 mV.
  • the morphology of the lipid nanoparticles according to the present disclosure is not particularly limited, but can include, for example, unilamellar liposome, multilayer liposome, spherical micelle, or unshaped layered structure as morphology dispersed in aqueous solvent.
  • the lipid nanoparticles according to the present disclosure are preferably unilamellar liposome or multilayer liposome.
  • the lipid nanoparticles according to the present disclosure preferably encapsulate components for the purpose of being delivered into the target cells inside the particle covered with lipid membranes.
  • the components which the lipid nanoparticles according to the present disclosure encapsulate inside the particles are not limited as long as they are sized available to be encapsulated.
  • the lipid nanoparticles according to the present disclosure can encapsulate any component such as nucleic acids, saccharides, peptides, low molecular weight compounds, and metallic compounds. In some embodiments, the component is an active pharmaceutical ingredient.
  • the component encapsulated in the lipid nanoparticles according to the present disclosure is preferably nucleic acid.
  • the nucleic acid may be DNA, or may be RNA, or also may be analogs or derivatives thereof (e.g., peptide nucleic acid (PNA) or phosphorothioate DNA, etc.).
  • PNA peptide nucleic acid
  • the nucleic acids to be encapsulated in the lipid nanoparticles according to the present disclosure may be single-stranded nucleic acids, may be double-stranded nucleic acids, also may be linear, or cyclic.
  • the nucleic acids to be encapsulated in the lipid nanoparticles according to the present disclosure comprise a foreign gene to be expressed in the target cell, preferably they are nucleic acids which function to express the foreign gene in the cell by being taken up into the cell.
  • the foreign genes may be genes originally comprised in the genomic DNA of the target cells, or they may be genes not comprised in the genomic DNA.
  • Such nucleic acids include gene expression vectors comprising nucleic acids consisting of base sequences encoding genes of interest to be expressed.
  • the gene expression vectors may be present as extrachromosomal genes in the introduced cell, or it may be taken up into the genomic DNA by homologous recombination.
  • the gene expression vectors to be encapsulated in the lipid nanoparticles according to the present disclosure are not particularly limited, and vectors generally used in gene therapy, etc. can be used.
  • the gene expression vectors to be encapsulated in the lipid nanoparticles according to the present disclosure are preferably nucleic acid vectors such as plasmid vectors.
  • the plasmid vectors may remain in a circular form or may be encapsulated in the lipid nanoparticles according to the present disclosure in a pre-cut linear form.
  • the gene expression vectors can be designed by usual method using commonly used molecular biological tools based on the base sequence information of the gene of the target to be expressed, and can be produced by various known methods.
  • the nucleic acids to be encapsulated in the lipid nanoparticles according to the present disclosure are also preferably functional nucleic acids which control the expression of target genes present in the target cells.
  • the functional nucleic acids include antisense oligonucleotide, antisense oligonucleotide (including antisense DNA and antisense RNA), siRNA, microRNA(miRNA), and mRNA, etc. Also, they may be plasmid DNA (pDNA) becoming siRNA expression vectors which express siRNA in the cells.
  • the siRNA expression vectors can be prepared from commercially available siRNA expression vectors, also which may be appropriately modified.
  • the lipid nanoparticles according to the present disclosure comprise pH-sensitive cationic lipids of the present disclosure and mRNA.
  • the “N/P ratio” is the ratio of the number of cationic nitrogen atoms (N) of the pH-sensitive cationic lipids of the present disclosure to the number of phosphate residues (P) of the nucleic acids encapsulated in the lipid nanoparticles according to the present disclosure.
  • the N/P ratio may be, for example, in the range of 3.0 to 12.0.
  • lipid nanoparticles according to the present disclosure is not particularly limited, and any method available to those skilled in the art can be adopted. As an example, they can be produced by, after forming a lipid film by dissolving all lipid components in an organic solvent such as chloroform and then drying under reduced pressure by an evaporator or spray drying by a spray dryer, adding components to be encapsulated into the lipid nanoparticles (for example, aqueous solvent comprising nucleic acids, etc. to dried above mixture, then emulsifying by emulsifier such as homogenizer, ultrasonic emulsifier, or high pressure jet spray emulsifier, etc.
  • emulsifier such as homogenizer, ultrasonic emulsifier, or high pressure jet spray emulsifier, etc.
  • lipid nanoparticles can also be produced by a well-known method for producing liposomes, for example, reversed-phase evaporation method. If the size of the lipid nanoparticles is to be controlled, extrusion (extruding filtration) may be carried out under high pressure using membrane filter with uniform pore size, etc.
  • composition of the aqueous solvents is not particularly limited, but can include, for example, buffer solutions such as phosphate buffer solution, citrate buffer solution, and phosphate buffered physiological saline, physiological saline, and culture media for cell culture.
  • buffer solutions such as phosphate buffer solution, citrate buffer solution, and phosphate buffered physiological saline, physiological saline, and culture media for cell culture.
  • aqueous solvents can stably disperse lipid nanoparticles, but they may furthermore be added saccharides (aqueous solution) such as: monosaccharides such as glucose, galactose, mannose, fructose, inositol, ribose, and xylose; disaccharides such as lactose, sucrose, cellobiose, trehalose, and maltose; tri saccharides such as raffinose and meredinose; polysaccharides such as cyclodextrin; sugar alcohols such as erythritol, xylitol, sorbitol, mannitol, and maltitol; and polyalcohols (aqueous solution) such as glycerin, diglycerin, polyglycerin, propylene glycol, polypropylene glycol, ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol,
  • saccharides
  • the lipid nanoparticles according to the present disclosure also can be produced by alcohol dilution method using flow channel.
  • the method is a method for producing lipid nanoparticles by introducing a solution in which lipid components are dissolved in alcohol solvent and a solution in which water-soluble components to be included in lipid nanoparticles are dissolved in aqueous solvent from different flow channels and merging them together.
  • microchannel with built-in three-dimensional micromixer which can achieve instantaneous mixing of two liquids, lipid nanoparticles with a diameter of about 30 nm can be produced at high reproducibility (See, Leung et al., Journal of Physical Chemistry C Nanomater Interfaces, 2012, vol.116(34), p.18440-18450).
  • the stability may be able to be improved using, for example, saccharide (aqueous solution) such as: monosaccharides such as glucose, galactose, mannose, fructose, inositol, ribose, and xylose; disaccharides such as lactose, sucrose, cellobiose, trehalose, and maltose; trisaccharides such as raffinose and meredinose; polysaccharides such as cyclodextrin; sugar alcohols such as erythritol, xylitol, sorbitol, mannitol, and maltitol.
  • saccharide aqueous solution
  • monosaccharides such as glucose, galactose, mannose, fructose, inositol, ribose, and xylose
  • disaccharides such as lactose, sucrose, cellobiose, trehalose, and mal
  • the stability when freezing above aqueous dispersions, the stability may be able to be improved using, for example, aforementioned saccharides and polyalcohols (aqueous solutions) such as glycerin, diglycerin, poly glycerin, propylene glycol, polypropylene glycol, ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, ethylene glycol monoalkyl ether, diethylene glycol monoalkyl ether, and 1,3-butylene glycol.
  • aforementioned saccharides and polyalcohols aqueous solutions
  • the lipid nanoparticles according to the present disclosure are lyophilized.
  • the lipid nanoparticles according to the present disclosure are synthesized by injecting ethanol solution of lipids into a buffer solution including a nucleic acid in the same manner as described in U.S. publication No. 2013-0022665, PCT publication No. W02019/090359, and PCT publication No. W02020/102668.
  • the lipid nanoparticles according to the present disclosure are synthesized by combining a lipid solution with a nucleic acid using a microfluidic mixing device such as NanoAssemblr TM (Precision Nano Systems).
  • the lipid nanoparticles according to the present disclosure have excellent stability.
  • the lipid nanoparticles of the disclosure are, for example, stable for at least 1 week when kept at -80°C.
  • An apparent pKa values of the lipid nanoparticles according to the present disclosure is not particularly limited, but can be selected, for example, in the range of approximately between 4.0 and 9.0, preferably approximately between 4.5 and 8.5.
  • the pKa values can be determined by using 2-(p-toluidino)-6-napthalene sulfonic acid (TNS) (for example, see PCT publication No. WO2022/071582)
  • the present disclosure relates to a method of delivering a nucleic acid to a cell, comprising contacting the lipid nanoparticle according to the present disclosure that encapsulates the nucleic acid with the cell.
  • the cell is in vitro.
  • the cell is in vivo.
  • the cell is ex vivo.
  • the present disclosure relates to a method of delivering a nucleic acid to a subject in need thereof, comprising administering the lipid nanoparticle according to the present disclosure that encapsulates the nucleic acid to the subject.
  • the subject may be human or nonhuman animals.
  • the non-human animals include mammals such as cattle, pig, horse, sheep, goat, monkey, dog, cat, rabbit, mouse, rat, hamster, and guinea pig, and birds such as chicken, quail, and duck, etc.
  • the lipid nanoparticle may be administered by any means known in the art including, but not limited to, oral or parenteral routes, including intravenous, intramuscular, subcutaneous, transdermal, or airway (aerosol) administration.
  • Compound (iv) can be produced according to or in analogy to methods known in the art.
  • test compounds are Compounds Nos. 1 to 8, CL15F6, CL4F6, and CL4F 10-8.
  • CL15F6, CL4F6, and CL4F 10-8 were prepared according to PCT publication No.
  • LNP formulations were prepared by injecting ethanol solution of lipids into a Flue mRNA (TriLink, 5moU) buffer solution, in the same manner as described in U.S. publication No. 2013-0022665, PCT publication No. W02019/090359, and PCT publication No. W02020/102668, which are hereby expressly incorporated by reference in their entirety.
  • the average particle size (PS), the polydispersity index (PDI), the encapsulation efficiency for mRNA (%EE), and the yield of each LNP formulation obtained is shown in the following Table 2.
  • PS and PDI were obtained by using Malvern Zetasizer Nano-ZS ZEN 3600.
  • %EE was obtained by the Ribogreen fluorescence assay following GenVoy-ILMTM User Guide by Precision NanoSystems.
  • A549, Hep3B, and Panc-1 cell lines were cultured in media supplemented with 10%
  • HI-FBS Gibco Ref# 10082-147.
  • F-12K media ATCC Ref# 30-2004
  • EMEM media ATCC Ref # 30-2003
  • DMEM media Gibco Ref # 11965-092.
  • cells were plated in white opaque 96-well TC-treated plates (Greiner Ref # 655083) at a density of 5000 cells/well using 90pL of cell mixture per well. The plates were placed in a 37°C incubator with 5% CO2 overnight to allow cell attachment.
  • the mRNA/LNP complex was equilibrated to room temperature, then diluted with DPBS (Gibco Ref # 14190-144) to create a dose-response curve and added to plates at a volume of lOpL/well. The plates were placed back in the 37°C incubator with 5% CO2 for 24 hours.
  • the Promega Luciferase Assay System (Ref # E1501) buffer and substrate were equilibrated to room temperature and combined, then added to the SpectraMax L Luminometer (Molecular Devices) injectors.
  • the plates were prepared according to Promega kit guidelines by first removing the media in each well, then gently rinsing the well with DPBS, and finally adding 20pL of IX reporter lysis buffer (Ref # E397A) to each well.
  • the plates were placed in the Luminometer and injected with 100 pL of luciferase buffer/ substrate mixture per well while luminescence values were obtained.
  • ECso values were determined by fitting dose-response curve with 4-parameter logistic model using GraphPad/Prism.
  • ECso values of the LNP formulation including any one of Compounds 1 to 3 were determined according to the protocol 1.
  • A549, Hep3B, and Panc-1 cell lines were cultured in media supplemented with 10%
  • HI-FBS Gibco Ref# 10082-147.
  • F-12K media ATCC Ref# 30-2004
  • EMEM media ATCC Ref # 30-2003
  • DMEM media Gibco Ref # 11965-092.
  • cells were plated in white opaque 384-well TC-treated plates (USA Scientific Ref # 5678-1080) at a density of 1500 cells/well using the Multidrop Combi+ (Thermo Scientific) by adding 30pL of cell mixture per well. The plates were placed in a 37°C incubator with 5% CO2 overnight to allow cell attachment.
  • the mRNA/LNP complex was equilibrated to room temperature, then diluted with DPBS (Gibco Ref # 14190-144) to create a dose-response curve and added to plates at a volume of 3.3pL/well. The plates were placed back in the 37°C incubator with 5% CO2 for 24 hours.
  • the ONE-Glo EX Luciferase Assay System (Promega Ref # E8130) was equilibrated to room temperature and combined. The plates were prepared according to Promega kit guidelines by adding 33.3pL of reagent mixture to each well. The plates were placed on a plate shaker for 3 minutes to assure cell lysis.
  • LNP formulations containing the pH-sensitive cationic lipids of the present disclosure showed high transfection property to the target cells as seen in Table 3 above.
  • the ECso value was about 22 to 51 -fold lower than when any one of the control LNPs (LNP Rl, LNP R2, and LNP R3) was applied to the same cells.
  • the ECso value was about 7.3 to 16.8-fold lower than when any one of the control LNPs was applied to the same cells.
  • LNP 3a was applied to A549 cells
  • the ECso value was about 24 to 36-fold lower than when any one of the control LNPs was applied to the same cells.
  • the EC 50 value was about 1.8 to 4.2-fold lower than when any one of the control LNPs was applied to the same cells.
  • the EC50 value was about 12 to 19-fold lower than when any one of the control LNPs was applied to the same cells.
  • the EC50 value was about 1.8 to 4.2-fold lower than when any one of the control LNPs was applied to the same cells.
  • LNP8a was applied to A549 cells, the EC50 value was about 3.4 to 5.1 -fold lower than when any one of the control LNPs was applied to the same cells.
  • LNP formulations with Flue mRNA were prepared according to the same procedure as explained in Example 1 except thatN/P ratio varied. PS, PDI, %EE, and the yield of representative LNP formulations are shown in the following Table 4.
  • LNP with CleanCap® FLuc mRNA (5moU) (from TriLink) was delivered and transfected into Balb/c mice.
  • the animals were intravenously given a single injection with one of LNP lb and 2b at a dose of 0.5 mg/kg.
  • Mice were anesthetized 6 hours after mRNA injection and then sacrificed immediately, and different organs were harvested and saved under -80° C until further analysis.
  • the organs were homogenized in Reporter Lysis Buffer (Promega Ref # E3971) and the content of luciferase was quantified with the Promega Luciferase Assay System (Ref # El 501 ).
  • the total luminescence value (RLU) per organ was determined by the SpectraMax L Luminometer (Molecular Devices). The experimental results obtained are shown in Table 5 below.

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Abstract

L'invention concerne un lipide cationique sensible au pH, une nanoparticule lipidique comprenant le lipide sensible au pH, et un procédé d'administration d'un acide nucléique encapsulé dans la nanoparticule lipidique à une cellule ou à un sujet. La nanoparticule lipidique peut comporter un composé représenté par la formule générale (I) ou un sel pharmaceutiquement acceptable de celui-ci : (R1)(R2)C(OH) –(CH2)a–(O–CO)b–X (I) dans laquelle a représente un nombre entier de 3 à 5 ; b représente 0 ou 1 ; R1 et R2 représentent chacun indépendamment un groupe représenté par la formule générale (A) : (R11)(R12) – CH–(CH2)w – (CO–O)c – (CH2)v – (A), dans laquelle R11 et R12 représentent chacun indépendamment un groupe alcoxy en C5-15 ; chaque c représente indépendamment 0 ou 1 ; chaque v représente indépendamment un nombre entier de 4 à 12 ; chaque w représente indépendamment un nombre entier de 0 à 3 ; et X représente un groupe hétérocyclique non aromatique à 5 à 7 chaînons, un atome de carbone du groupe hétérocyclique étant lié à (O-CO)b- et un ou deux atomes d'hydrogène du groupe hétérocyclique pouvant éventuellement être remplacés par un groupe alkyle en C1-4 ou un groupe alcényle en C2-4.
PCT/US2025/020674 2024-03-21 2025-03-20 Lipides cationiques sensibles au ph, nanoparticules lipidiques les comprenant et procédés d'administration d'acides nucléiques Pending WO2025199302A1 (fr)

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Citations (3)

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US10125092B2 (en) * 2014-09-05 2018-11-13 Novartis Ag Lipids and lipid compositions for the delivery of active agents
US20200129431A1 (en) * 2017-06-15 2020-04-30 National University Corporation Hokkaido University LIPID MEMBRANE STRUCTURE FOR DELIVERY INTO siRNA CELL
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