Search

CN-121991129-A - Phosphatidylglycerol skeleton compound containing dithiolane structure and application of phosphatidylglycerol skeleton compound and lipid nanoparticles in biological medicine

CN121991129ACN 121991129 ACN121991129 ACN 121991129ACN-121991129-A

Abstract

The invention provides a phosphatidylglycerol skeleton compound containing a dithiolane structure and application of lipid nano particles thereof in biological medicine, belonging to the technical field of nucleic acid drug delivery. The structural formula of the compound provided by the invention is shown as formula I. The phosphatidylglycerol skeleton compound containing the dithiolane structure provided by the invention takes phosphatidylglycerol as a skeleton, and the molecular structure is mainly formed by connecting glycerol, phosphoric acid, fatty acid and fatty acid containing the dithiolane structure by ester bonds, so that the degradability is stronger, the number of dithiolane in the molecule is more, the efficiency and the safety are higher in nucleic acid delivery, and the phosphatidylglycerol skeleton compound can be used as a functional lipid material for preparing lipid nano particles, so that the surface of the prepared lipid nano particles has the dithiolane structure and can be subjected to chemical reaction with mercapto on the surface of cells, thereby being beneficial to the ingestion of LNP by NK cells and improving the capability of nucleic acid drugs entering cells.

Inventors

  • XUE SONG
  • CHEN QIANQIAN
  • ZHANG CONG
  • CHEN DONGSHAN
  • ZHANG HONGQIAN
  • ZHANG DAIZHOU
  • TANG XUAN
  • LI DAWEI
  • YANG XUEHUA
  • Li Shuolei

Assignees

  • 山东省药学科学院

Dates

Publication Date
20260508
Application Date
20260130

Claims (10)

  1. 1. A phosphatidylglycerol backbone compound containing a dithiolane structure or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate or non-covalent complex thereof, wherein the structural formula of the phosphatidylglycerol backbone compound containing the dithiolane structure is shown as formula I: A formula I; In the formula I, R 1 and R 2 are independently one of C 1-24 alkyl and C 1-24 alkenyl, A 1 and A 2 are independently methylene, 1, 2-ethanediyl, 1, 3-propanediyl, 1-methyl-1, 2-ethanediyl, 1, 2-isopropyl, 1-methyl-1, 3-propanediyl, 2-methyl-1, 3-propanediyl, 1, 4-butanediyl, 1, 5-pentanediyl, 1-methyl-1, 4-butanediyl, 2-methyl-1, 4-butanediyl, 3-methyl-1, 4-butanediyl, 2-dimethyl-1, 3-butanediyl, 1, 6-hexanediyl, 1-methyl-1, 5-pentanediyl, 2-methyl-1, 5-pentanediyl, 3-methyl-1, 5-pentanediyl, 1-ethyl-1, 4-butanediyl or 2-ethyl-1, 4-butanediyl.
  2. 2. The method for preparing a phosphatidylglycerol backbone compound containing a dithiolane structure according to claim 1, comprising the steps of mixing an acid compound, an organic solvent, carbonyl diimidazole and a lipid compound, and performing an esterification reaction to obtain the phosphatidylglycerol backbone compound containing the dithiolane structure.
  3. 3. A lipid nanoparticle comprising an ionizable or cationic lipid, a cholesterol compound, an amphiphilic lipid, and a phosphatidylglycerol compound, wherein the phosphatidylglycerol compound is the phosphatidylglycerol skeleton compound containing a dithiolane structure of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate or non-covalent complex thereof.
  4. 4. The lipid nanoparticle of claim 3, wherein the ionizable or cationic lipid comprises one or more of SM-102, ALC-0315, DLin-MC3-DMA, DLinDMA, DODMA, DOTMA, DLin-KC2-DMA, DOTAP, C-200, and DC-Chol, and the cholesterol-based compound comprises one or more of cholesterol, stigmasterol, beta-sitosterol, campesterol, ergosterol, 11-dehydroergosterol, and brassicasterol.
  5. 5. The lipid nanoparticle of claim 3, wherein the amphiphilic lipid comprises one or more of PEG-DSPE, PEG-PE, PEG-DMG, PEG-C14, PEG-C-DMA, PEG-modified ceramide, tween-20, tween-80, PEG-DPG, PEG-s-DMG, and PEG-C-DOMG.
  6. 6. The lipid nanoparticle of claim 3, wherein the ratio of the amounts of the phosphatidylglycerol compound, the ionizable or cationic lipid, the cholesterol compound, and the amphiphilic lipid is (3-15): 15-60): 20-55): 0.2-10.
  7. 7. A nucleic acid drug-loaded lipid nanoparticle comprising the lipid nanoparticle of any one of claims 3-6 and a nucleic acid drug.
  8. 8. The nucleic acid drug-loaded lipid nanoparticle of claim 7, wherein the nucleic acid drug comprises one or more of DNA, siRNA, mRNA, dsRNA, antisense nucleic acid, microrna, antisense micro RNA, antagomir, microrna inhibitor, microrna activator, and immunostimulatory nucleic acid.
  9. 9. A nucleic acid drug formulation comprising the nucleic acid drug-loaded lipid nanoparticle of claim 7 or 8, a buffer salt, an osmotic pressure regulator, a suspending agent, and a solvent.
  10. 10. The nucleic acid pharmaceutical formulation of claim 9, wherein the buffer salt comprises one of a boric acid buffer salt, a phosphoric acid buffer salt, a citric acid buffer salt, an acetic acid buffer salt, a 4-hydroxyethylpiperazine ethane sulfonic acid buffer salt, and a tris (hydroxymethyl) aminomethane buffer salt, the osmotic pressure regulator comprises one or more of sodium chloride, potassium chloride, glycerol, and glucose, and the suspending agent comprises one or more of polyvinylpyrrolidone, polyvinyl alcohol, hyaluronic acid, sodium hyaluronate, ethylcellulose, and hydroxypropyl methylcellulose.

Description

Phosphatidylglycerol skeleton compound containing dithiolane structure and application of phosphatidylglycerol skeleton compound and lipid nanoparticles in biological medicine Technical Field The invention belongs to the technical field of nucleic acid drug delivery, and in particular relates to a phosphatidylglycerol skeleton compound containing a dithiolane structure and application of lipid nanoparticles thereof in biological medicine. Background CAR-T therapy opens a new way for immune cell therapy to treat tumors, and is accompanied by various side effects such as Cytokine Release Syndrome (CRS), immune effector cell-related neurotoxic syndrome, oncolytic syndrome, hypoimmunoglobulin syndrome, and other diseases caused by immune system changes while the treatment of hematological tumors makes breakthrough progress. At the same time, CAR-T therapy may impair the immune system, increasing the risk of bacterial, viral or fungal infection. Unlike CAR-T therapy, NK cells, which are congenital lymphocytes present in the peripheral circulation, have nonspecific targeting and killing mechanisms, unlike T cells' killing mechanisms for tumors, can kill tumor cells in a non-MHC restricted manner, do not require antigen pre-sensitization, have strong immune monitoring and killing functions, and have multiple cytotoxic mechanisms of action, can regulate immune responses by producing cytokines, and play a key role in both innate and adaptive immune responses. Although CAR-NK therapy has unique advantages, NK cells are difficult to transfect, resulting in difficult construction of CAR-NK, and the key technology for efficient transfection of NK cells limits further development of CAR-NK therapy. At present, three technologies are mainly used for NK cell transfection, the highest transfection efficiency is the electrotransfection technology, the transfection efficiency can reach more than 90 percent, even 100 percent, but the electrotransfection needs to use high-voltage current to open cell membranes, and instantaneous cavity introduction exogenous genes are formed, so that the damage to NK cells is larger, and the survival rate of cells is lower. Secondly, virus-based transfection techniques, which, although more mature and widely used in the construction of CAR-T, are less efficient than NK cell transfection and potentially toxic. Finally, LNP transfection technique is the most safe technique, but there is also a problem of low transfection efficiency. Disclosure of Invention The invention aims to provide a phosphatidylglycerol skeleton compound containing a dithiolane structure and application of lipid nanoparticles thereof in biological medicines. The phosphatidylglycerol skeleton compound containing the dithiolane structure provided by the invention is used as a functional component of LNP, can improve the capability of LNP for transfecting NK cells, and is used for efficient construction of CAR-NK. In order to achieve the above object, the present invention provides the following technical solutions: The invention provides a phosphatidylglycerol skeleton compound containing a dithiolane structure or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, chelates or non-covalent complexes thereof, wherein the structural formula of the phosphatidylglycerol skeleton compound containing the dithiolane structure is shown as formula I: A formula I; In the formula I, R 1 and R 2 are independently one of C 1-24 alkyl and C 1-24 alkenyl, A 1 and A 2 are independently methylene, 1, 2-ethanediyl, 1, 3-propanediyl, 1-methyl-1, 2-ethanediyl, 1, 2-isopropyl, 1-methyl-1, 3-propanediyl, 2-methyl-1, 3-propanediyl, 1, 4-butanediyl, 1, 5-pentanediyl, 1-methyl-1, 4-butanediyl, 2-methyl-1, 4-butanediyl, 3-methyl-1, 4-butanediyl, 2-dimethyl-1, 3-butanediyl, 1, 6-hexanediyl, 1-methyl-1, 5-pentanediyl, 2-methyl-1, 5-pentanediyl, 3-methyl-1, 5-pentanediyl, 1-ethyl-1, 4-butanediyl or 2-ethyl-1, 4-butanediyl. The invention also provides a preparation method of the phosphatidyl glycerol skeleton compound containing the dithiolane structure, which comprises the steps of mixing an acid compound, an organic solvent, carbonyl diimidazole and a lipid compound, and carrying out esterification reaction to obtain the phosphatidyl glycerol skeleton compound containing the dithiolane structure. The invention also provides a lipid nanoparticle, which comprises ionizable or cationic lipid, cholesterol compounds, amphiphilic lipid and phosphatidylglycerol compounds, wherein the phosphatidylglycerol compounds are phosphatidylglycerol skeleton compounds containing dithiolane structures or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, chelates or noncovalent complexes thereof. Preferably, the ionizable or cationic lipid comprises one or more of SM-102, ALC-0315, DLin-MC3-DMA, DLinDMA, DODMA, DOTMA, DLin-KC2-DMA, DOTAP, C-200 and DC-Chol, and the cholesterol-based compound comprises one or more of cholesterol, stigm