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CN-121974813-A - Aromatic lipid compound, composition and application thereof

CN121974813ACN 121974813 ACN121974813 ACN 121974813ACN-121974813-A

Abstract

The invention belongs to the technical field of biological medicines, and relates to an aromatic lipid compound, a composition and application thereof. The invention aims to solve the technical problem that the existing Lipid Nanoparticle (LNPs) delivery system is insufficient in mRNA delivery efficiency. The invention discloses an aromatic lipid compound with a specific structural general formula, which structurally comprises an amine core, aromatic group residues and hydrophobic molecule residues. The mechanism research shows that the introduced aromatic ring group obviously improves the binding affinity and encapsulation efficiency of lipid and mRNA through cation-pi interaction, and simultaneously, the structural modification also improves the membrane fluidity of LNPs, and synergistically promotes the cell uptake and endosome escape. Membrane destabilization, LNPs simultaneously dissociates when the aromatic lipids interact with endosomal membranes, eventually achieving efficient release and delivery of mRNA. Compared with SM-102 LNPs approved by FDA, the aromatic lipid LNPs provided by the invention has obviously improved mRNA delivery efficiency and protein expression level in vitro and in vivo, and provides a high-efficiency and stable delivery platform for mRNA therapy.

Inventors

  • LIU SHUAI
  • LIN LIXIN
  • YAN XINXIN

Assignees

  • 浙江大学

Dates

Publication Date
20260505
Application Date
20251223

Claims (11)

  1. 1. An aromatic lipid compound characterized by a compound represented by formula I, or a stereoisomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof: (I) wherein An is An aliphatic amine nucleus or An aromatic amine nucleus containing 1, 2, 3, 4 or 5 nitrogen atoms, R is connected to nitrogen in the structure of An, R is independently substituted or unsubstituted C1-C26 alkyl, any one group selected from-O-, -OH, -C (=O) O-, -OC (=O) C (=O) O-, -C (=O) -, -OC (=O) O-, or 8 can be inserted or connected between any two carbon-carbon single bonds in the C1-C26 alkyl or on the carbon atoms, and n is 1, 2, 3, 4, 5, 6, 7 or 8; Is An aromatic structure with aromatic groups, which is connected with nitrogen in An structure, ar is selected from any one of phenyl, 4-methoxyphenyl, trityl and 9-anthryl; R 1 is any one of-OH, -H and-CH 3 ; R 2 is any one of-O-, -CH 2 O-、-CH 2 -、-CH 2 OC (=o) -, -OC (=o) -, and-C (=o) -; R 3 is any one of-O-, -CH 2 O-、-CH 2 -; m1 is 0 or 1, m2 is 0 or 1;m is 1 or 2; Preferably, each R is independently a substituted or unsubstituted C1-C20 alkyl group, and any two carbon-carbon single bonds in the C1-C20 alkyl group or a group selected from the group consisting of-O-, -OH, -C (=o) O-, -OC (=o) C (=o) O-, -C (=o) -, -OC (=o) O-may be inserted or bonded between or to the carbon atoms.
  2. 2. The aromatic lipid compound of claim 1, wherein An is selected from one of the following structures: 、 、 、 、 、 、 、 、 、 、 。
  3. 3. the aromatic lipid compound according to claim 1, wherein the aromatic lipid compound comprises Selected from one of the following structures: 、 、 、 、 、 、 。
  4. 4. A fragrant lipid compound according to any one of claims 1-3, wherein each R is independently an EP residue or an Ac residue, wherein EP and Ac each represent an epoxy, acrylate hydrophobic tail of different carbon chain length; Preferably, the EP residue is selected from one of the following structures: 、 、 、 、 、 、 ; Preferably, the Ac residue is selected from one of the following structures: 、 、 、 、 。
  5. 5. The aromatic lipid compound according to claim 1, wherein the compound is selected from the group consisting of: 、 、 、 。
  6. 6. a lipid nanoparticle, characterized in that it comprises a lipid compound according to any one of claims 1-5, preferably the lipid nanoparticle further comprises a helper lipid.
  7. 7. The lipid nanoparticle of claim 6, wherein the helper lipid is selected from any one or more of a phospholipid, a steroid, a polymer conjugated lipid, and a modifiable lipid; Preferably, the phospholipid is selected from any one or a combination of dioleoyl phosphatidylethanolamine (DOPE), distearoyl phosphatidylcholine (DSPC), ‌ dipalmitoyl phosphatidylcholine (DPPC), dimyristoyl phosphatidylcholine (DMPC), dioleoyl phosphatidylcholine (DOPC), palmitoyl Oleoyl Phosphatidylcholine (POPC), sphingomyelin (SM), and/or the steroid is selected from one or more of cholesterol, sitosterol, stigmasterol, and ergosterol, and/or the polymer conjugated lipid is selected from polyethylene glycol, polylactic acid, polyamide, cationic polymer, polymyosine, polylactic acid-glycolic acid copolymer, polyamino acid, polypeptide, clustered peptide conjugated lipid, and/or the modifiable lipid is selected from lipid that can be modified by small molecule compounds, carbohydrates, peptides, proteins, nucleic acids, lipopolysaccharides, inorganic molecules, metal ions, and combinations thereof; More preferably, the phospholipid is dioleoyl phosphatidylethanolamine (DOPE) or distearoyl phosphatidylcholine (DSPC), and/or the steroid is cholesterol and/or sitosterol, and/or the polymer conjugated lipid is a polyethylene glycol conjugated lipid selected from one or more of 2- [ (polyethylene glycol) -2000] -N, N-tetracosylacetamide (ALC-0159), 1, 2-dimyristoyl-rac-glycerol-3-methoxypolyethylene glycol 1000 (DMG-PEG 1000), 1, 2-dimyristoyl-rac-glycerol-3-methoxypolyethylene glycol 5000 (DMG-PEG 5000), 1, 2-dimyristoyl-rac-glycerol-3-methoxypolyethylene glycol 2000 (DMG-PEG 2000), and phospholipid-methoxypolyethylene glycol 2000 (DSPE-PEG 2000); Most preferably, the phospholipid is dioleoyl phosphatidylethanolamine (DOPE), and/or the steroid is cholesterol, and/or the polymer conjugated lipid is a polyethylene glycol conjugated lipid selected from 1, 2-dimyristoyl-rac-glycerol-3-methoxypolyethylene glycol 2000 (DMG-PEG 2000).
  8. 8. The lipid nanoparticle of claim 6 or 7, wherein the molar ratio of the aromatic lipid compound to the helper lipid is from 1:1 to 80; preferably, the molar ratio of the aromatic lipid compound to the auxiliary lipid is 1:1-20; More preferably, the molar ratio of the aromatic lipid compound to the auxiliary lipid is 1:2-10.
  9. 9. Use of an aromatic lipid compound according to any one of claims 1-5 or a lipid nanoparticle according to any one of claims 6-8 for the preparation of a drug delivery vehicle; preferably, the medicament is a therapeutic or prophylactic agent; preferably, the therapeutic or prophylactic agent is a nucleic acid; Preferably, the nucleic acid is selected from the group consisting of single stranded DNA, double stranded DNA, single stranded RNA, double stranded RNA, short isoforms, plasmid DNA, complementary DNA, antisense nucleic acid molecules, small interfering nucleic acids, small activating nucleic acids, asymmetric interfering nucleic acids, small nucleic acid agonists (agomir), small nucleic acid antagonists (antagomir), dicer enzyme substrate nucleic acids, small hairpin nucleic acids, preferably the nucleic acid is selected from the group consisting of single stranded RNA, more preferably the nucleic acid is selected from the group consisting of transfer RNA, messenger RNA, circular RNA, and most preferably the nucleic acid is messenger RNA.
  10. 10. A pharmaceutical composition comprising an aromatic lipid compound according to any one of claims 1-5 or a lipid nanoparticle according to any one of claims 6-8, and a therapeutic or prophylactic agent.
  11. 11. A formulation comprising the pharmaceutical composition of claim 10 and a pharmaceutically acceptable adjuvant.

Description

Aromatic lipid compound, composition and application thereof Technical Field The invention belongs to the field of medicines, and relates to an aromatic lipid compound, a composition and application thereof. Background Messenger ribonucleic acid (mRNA) therapy has become a revolutionary biomedical approach, and its application range covers the fields of vaccine, cancer immunotherapy, protein substitution therapy, gene editing, etc., successfully breaking through many limitations of traditional drug development. However, the lack of an efficient, stable delivery system in the prior art remains a key factor that prevents this therapy from achieving a broad clinical transition. Lipid Nanoparticles (LNPs) have been widely used as the most advanced mRNA delivery platform today in a variety of approved mRNA vaccines and clinical tumor treatment protocols, but their delivery efficiency has not yet reached the ideal level for the development of next generation therapeutic modalities. To improve mRNA delivery efficiency, current research has focused mainly on modification of the chemical structure of ionizable lipids, but there are still significant limitations to current research. First, most studies focused on performance verification, and lack of in-depth exploration of the mechanism of action behind. Second, achieving efficient mRNA delivery requires multiple steps to co-operate, including mRNA encapsulation, nanoparticle endocytosis, LNPs endosomal escape, and mRNA release into the cytoplasm for protein expression. The introduction of most chemical groups can only facilitate a single step therein. Thus, there is an urgent need to explore the delivery mechanism in depth, thereby obtaining a vector that can improve mRNA delivery efficiency from multiple mechanisms of synergy simultaneously. At present, in the structural design of most delivery vehicles, the mRNA delivery performance of LNPs is improved by introducing functional groups such as hydroxyl groups, imidazolyl groups, disulfide bonds, carbonate groups, ester groups and the like, but the research on the mechanism aspect is relatively deficient, and the delivery efficiency is limited. To sum up, in the prior art, the modification of lipid compounds lacks systematic studies, which makes their delivery efficacy low, and the requirement of novel mRNA therapies for efficient delivery systems cannot be met. Disclosure of Invention In order to overcome the defects in the prior art, the invention provides an aromatic lipid compound, a composition and application thereof. The invention specifically designs an aromatic ring group introduction strategy, which introduces specific aromatic ring functional groups into specific lipid chemical structures to form specific molecular structures, and based on the specific molecular structures, novel aromatic derivative Lipid Nano Particles (LNPs) are constructed. Through the integral synergy of the aromatic structure and the lipid compound core structure, on one hand, the cation-pi interaction of the aromatic structure and the electrostatic action of the lipid compound core structure are synergistic, the binding affinity of the lipid compound integral and LNPs to mRNA is greatly enhanced, so that the encapsulation efficiency is remarkably improved, and on the other hand, the fluidity and the membrane fusion capability of a lipid membrane are synergistically improved, so that the cell uptake and endosome escape are synergistically promoted. And membrane destabilization is carried out when the aromatic lipid interacts with an endosomal membrane, LNPs is dissociated simultaneously, and finally the efficient release of mRNA is realized. This design balances the encapsulation and release of mRNA, ultimately achieving a significant increase in mRNA delivery efficiency, which is nearly an order of magnitude greater than FDA approved SM-102 LNPs. In the invention, each specific structure is connected in a specific way to form a specific lipid compound molecule, and the specific connection way enables the aromatic structure and the amine core (An) to exert the integral synergistic effect on the structure, so that the remarkable improvement of the performance is realized on a plurality of delivery key links such as mRNA binding (through cation-pi interaction), membrane fluidity, cell uptake, endosomal escape, mRNA release and the like. In the invention, polyamine chain (An) is adopted as a core skeleton in the design of a molecular skeleton, and An aromatic structure with An aromatic group at the tail end is used as a functional branch to be connected to the core. The special molecular structure makes the lipid compound different from the lipid compound in the prior art in spatial structure, molecular stacking and conformational freedom degree, and further improves the performance of the lipid compound in a plurality of delivery links such as mRNA binding force, membrane fluidity, cell uptake, endosome escape, mRNA release and the li