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Ionizable cationic lipid compounds and uses thereof

A technology of cationic lipids and compounds, applied in the field of gene therapy, can solve the problems of low efficiency and achieve the effects of reducing cytotoxicity, increasing stability in vivo, and effectively delivering

Active Publication Date: 2015-12-30
SHANGHAI JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] At present, cationic lipids as gene carriers have become the most widely used non-viral vectors due to their simple structure, easy operation, and high biological safety. However, the problems of low transfection efficiency and cytotoxicity caused by positive charges still need to be solved. , so the present invention attempts to design ionizable cationic lipids to solve the above problems, so as to achieve better gene therapy effect

Method used

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  • Ionizable cationic lipid compounds and uses thereof
  • Ionizable cationic lipid compounds and uses thereof
  • Ionizable cationic lipid compounds and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Embodiment 1, ionizable cationic lipid L1

[0048] Using lysine, linoleic acid, and oleyl alcohol as raw materials, L1 lipids were synthesized by Shanghai Maofu Chemical Technology Co., Ltd. according to related technologies; all were purified by HPLC and identified by mass spectrometry, with a purity greater than 95%, and a molecular weight consistent with the theoretical value;

[0049] Effect verification:

[0050] (1) figure 1 is the structural diagram of ionizable cationic lipid L1;

[0051] (2) figure 2 It is a schematic diagram of the synthesis method of ionizable cationic lipid L1;

[0052] (3) image 3 Carry out nuclear magnetic resonance spectrum result for ionizable cationic lipid L1;

[0053] (4) Figure 4 Mass spectrometry analysis was carried out for the ionizable cationic lipid L1, and the molecular weight of the obtained L1 lipid compound was close to the theoretical value, which was 658 g / mol.

Embodiment 2

[0054] Embodiment 2, ionizable cationic lipid L2

[0055] Lysine, linoleic acid, and dexamethasone were selected as raw materials, and L1 lipid was synthesized by Shanghai Maofu Chemical Technology Co., Ltd. according to related technologies. All were purified by HPLC and identified by mass spectrometry, the purity was greater than 95%, and the molecular weight was consistent with the theoretical value.

[0056] Effect verification:

[0057] (1) Figure 5 is the structure diagram of ionizable cationic lipid L2;

[0058] (2) Figure 6 Schematic diagram of the synthesis method for ionizable cationic lipid L2

[0059] (3) Figure 7 Carry out nuclear magnetic resonance spectrum result for ionizable cationic lipid L2;

[0060] (4) Figure 8 Mass spectrometry analysis was carried out for the ionizable cationic lipid L2, and the molecular weight of the obtained L2 lipid compound was close to the theoretical value, which was 797 g / mol.

Embodiment 3

[0061] Embodiment 3, L1 ionizable cationic liposome

[0062] In this example, ionizable cationic liposomes were prepared according to different ratios by using ionizable cationic lipid L1 and auxiliary lipid.

[0063] Its preparation method comprises the following steps:

[0064] 1. Preparation of Sample Solutions

[0065] Preparation of L1 ethanol solution, dipalmitoylphosphatidylcholine (DPPC) ethanol solution, and cholesterol (Cholesterol, CHOL) ethanol solution: Weigh a certain amount with an electronic balance, add absolute ethanol to make it 10mg / ml, and use it as stock solution;

[0066] Preparation of HEPES buffer (HEPES buffer): Weigh HEPES with an electronic balance, add deionized water, adjust the pH with hydrochloric acid solution to make it 20mMpH4.0, treat with diethylpyrocarbonate (DEPC), and after sterilization, use it as a stock solution;

[0067] 2. Preparation of liposomes:

[0068] 1) Take out L1 cationic lipid, cholesterol (CHOL), dipalmitoylphospha...

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Abstract

The invention relates to an ionizable cation lipid compound in the technical field of gene treatment and application thereof. The invention further relates to a lipid prepared from the ionizable cation lipid compound; and the application refers to that the lipid is used as a gene drug carrier transporting system. After the lipid prepared from the ionizable cation is compounded with the gene drug siRNA, a compound which is small in grain size and uniform in distribution can be formed. Meanwhile, the ionizable cation lipid compound is electroneutral in an environment with pH of 7.0, in-vivo stability of the lipid compound is increased, and cell toxicity caused by too many positive charges is reduced. The lipid provided by the invention can be modified by lipid polypeptides specifically combined by myeloid derived suppressor cells (MDSCs), and can transfer fluorescent gene drugs in vitro to enter MDSCs.

Description

technical field [0001] The invention belongs to the technical field of gene therapy, and specifically relates to an ionizable cationic lipid compound and its application. Background technique [0002] Gene therapy refers to the introduction of exogenous normal genes into target cells to correct or compensate diseases caused by gene defects and abnormalities, so as to achieve therapeutic purposes. In the past two decades, gene therapy has pushed the research from preclinical to clinical in many disease treatment fields, and has irreplaceable advantages for diseases caused by gene abnormalities that are difficult to solve in the medical field, such as tumors. Common gene medicines include plasmid DNA (plasmidDNA, pDNA), antisense oligonucleotide (antisenseODN), small interfering RNA (siRNA) and small hairpin RNA (shRNA). Among many gene medicines, in addition to the classic therapeutic method of introducing and expressing exogenous cDNA into the body, the idea of ​​using siRN...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/49C07C231/12C07J41/00A61K48/00A61K9/127A61K47/18A61K47/28A61P35/00
Inventor 徐宇虹张金平司晓菲刘君
Owner SHANGHAI JIAOTONG UNIV
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