CN-121627601-B - Cationic lipid compound, lipid nanoparticle constructed by same, pharmaceutical composition and application

CN121627601BCN 121627601 BCN121627601 BCN 121627601BCN-121627601-B

Abstract

The invention discloses a cationic lipid compound, a lipid nanoparticle constructed by the cationic lipid compound, a pharmaceutical composition and application thereof, wherein the lipid nanoparticle constructed by the cationic lipid compound (formula I) has smaller particle size and lower polymorphic index, has extremely high encapsulation efficiency on drug molecules, can accurately deliver mRNA drugs loaded in the lipid nanoparticle to the liver on the premise of keeping high expression intensity, is hardly expressed in other organs such as the lung, the heart and the kidney, has little expression in the spleen, and has important clinical application significance in cancer treatment.

Inventors

Yang Zhenhuang
LIANG XIAOYU
WANG NENG
HUANG SHIYUN

Assignees

深圳市艾迪贝克生物医药有限公司

Dates

Publication Date: 20260508
Application Date: 20260130

Claims (6)

1. A cationic lipid compound, or a pharmaceutically acceptable salt thereof, selected from any one of the following: 。
2. A lipid nanoparticle is characterized by comprising the cationic lipid compound, phospholipid, steroid and polyethylene glycol lipid according to the molar ratio of (20-70): (0-30): (10-80): (0-5).
3. A pharmaceutical composition comprising the lipid nanoparticle-loaded drug of claim 2.
4. The pharmaceutical composition of claim 3, wherein the drug is selected from one or more of nucleic acids, small molecule compounds, bioactive lipids.
5. The pharmaceutical composition of claim 4, wherein the nucleic acid is messenger RNA.
6. Use of the cationic lipid compound of claim 1 or a pharmaceutically acceptable salt thereof, the lipid nanoparticle of claim 2 or the pharmaceutical composition of any one of claims 3-5 in the preparation of a nucleic acid drug.

Description

Cationic lipid compound, lipid nanoparticle constructed by same, pharmaceutical composition and application Technical Field The invention relates to a cationic lipid compound, a lipid nanoparticle constructed by the cationic lipid compound, a pharmaceutical composition and application thereof, in particular to a cationic lipid compound with liver targeting characteristics, a lipid nanoparticle constructed by the cationic lipid compound, a pharmaceutical composition and application of the lipid nanoparticle. Background Liver cancer, a common malignant tumor, is one of the medical problems that needs to be overcome in the global scope because of its high malignancy and mortality. Traditional treatment methods such as surgical excision, chemotherapy and radiotherapy bring hopes to patients to a certain extent, but also have various limitations such as large side effects, easy recurrence, limited treatment range and the like. With the rapid development of medical science and technology, messenger RNA (mRNA) therapy is an emerging treatment means, which lights new hopes for liver cancer patients, and has an extremely important role in comprehensive treatment of liver cancer. Messenger RNA (mRNA) therapy is a subverted technology with broad application prospects, and its success depends largely on efficient and safe delivery systems. Lipid Nanoparticles (LNPs) are currently the most developed non-viral delivery system in clinical progress, and are generally composed of cationic or ionizable lipids, phospholipids, steroids and polyethylene glycol (PEG) lipids, wherein the cationic or ionizable lipids are the core of the LNP delivery system and play a key role in encapsulating nucleic acids, cellular uptake and intracellular release, and even in targeting and the like. Efficient delivery of nucleic acid drugs is still challenging today, mainly because different types of nucleic acid drugs have different requirements for the delivery system, while existing traditional commercial lipid-based delivery systems still have limitations in efficiency and applicable scenarios. For example, the commercialized MC3 lipids are optimized primarily for liver-targeted delivery of small nucleic acid drugs, and SM-102 and ALC-0315 are designed for low dose mRNA vaccines (e.g., neocrown vaccines), which generally achieve higher delivery efficiencies in these applications. However, in emerging therapeutic scenarios such as mRNA-based gene editing therapies, not only does the required nucleic acid dose increase significantly, but also higher demands are placed on the targeting accuracy of the delivery system, and the delivery efficiency of conventional lipid nanoparticles in such high dose, high accuracy scenarios is often inadequate, limiting their therapeutic efficacy. Disclosure of Invention The first object of the invention is to provide a cationic lipid compound with high liver targeting property, the second object of the invention is to provide a lipid nanoparticle constructed by the cationic lipid compound and other lipid components together, the third object of the invention is to provide a pharmaceutical composition constructed by the lipid nanoparticle and capable of efficiently delivering nucleic acid molecules to the liver, and the fourth object of the invention is to provide a pharmaceutical use of the cationic lipid compound, the lipid nanoparticle constructed by the cationic lipid compound and the pharmaceutical composition. The cationic lipid compound or pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof has the structure shown in formula I: , Wherein, the X 1、X2 and X 3 are each independently selected from -C-、-O-、-C(O)-、-C(O)O-、-OC(O)-、-OC(O)O-、-S-、-S(O)-、-C(O)S-、-SC(O)-、-OC(S)-、-C(S)O-、-SC(O)O-、-OC(O)S-、-S-S-、-S(O)2-; R 1 and R 2 are each independently selected from C 2~16 linear or branched alkyl, C 2~16 linear or branched alkenyl, C 2~16 linear or branched alkynyl, or wherein optionally one or more methylene units are independently replaced by one or more R 'or-NR'; r 'is independently selected from H, C 1~14 straight or branched alkyl, -L a-ORa-、-La-SRa-、-La-NRa' -; R ', L a、Ra and R a' are each independently selected from H, C 1~14 linear or branched alkyl; R 3 is independently selected from-OH, -NC 2H6, or-NC 4H10; n 1、n6 is independently selected from 1 to 6, n 2、n3 is independently selected from 1 to 10, and n 4、n5 is independently selected from 1 to 5. The term "pharmaceutically acceptable" in the context of the present invention means that the compound or composition is chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or with the human or mammal with which the disease or condition is to be prevented or treated. The term "pharmaceutically acceptable salt" refers to the relatively non-toxic, inorganic or organic acid addition salts of the compounds of the present invention. It is further understood that the compound of form