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Ionizable cation lipid compound and application thereof

A technology of cationic lipids and compounds, applied in the field of gene therapy, can solve problems such as low efficiency, and achieve the effect of reducing cytotoxicity, easy degradation and effective delivery

Active Publication Date: 2014-06-11
SHANGHAI JIAO TONG 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 cation lipid compound and application thereof
  • Ionizable cation lipid compound and application thereof
  • Ionizable cation lipid compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1. Ionizable cationic lipid L1

[0048] Lysine, linoleic acid and oleyl alcohol were selected as raw materials, and L1 lipid was synthesized by Shanghai Maofu Chemical Technology Co., Ltd. according to the relevant technology; all of which 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;

[0049] Effect verification:

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

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

Embodiment 2

[0054] Example 2, ionizable cationic lipid L2

[0055] Using lysine, linoleic acid, and dexamethasone as raw materials, L1 lipid was synthesized by Shanghai Maofu Chemical Technology Co., Ltd. according to the relevant technology. All of them have been purified by HPLC and identified by mass spectrometry. The purity is greater than 95%, and the molecular weight is consistent with the theoretical value.

[0056] Effect verification:

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

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

[0059] (3) Figure 7 NMR spectrum results for ionizable cationic lipid L2;

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

Embodiment 3

[0061] Example 3, L1 ionizable cationic liposomes

[0062] In this example, ionizable cationic liposomes were prepared according to different ratios 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, dipalmitoyl phosphatidyl choline (DPPC) ethanol solution, and cholesterol (Cholesterol, CHOL) ethanol solution: Weigh a certain amount with an electronic balance, add absolute ethanol to make it 10 mg / ml, and use it as stock solution;

[0066] Preparation of HEPES buffer (HEPES buffer): Weigh HEPES with an electronic balance, add deionized water, adjust pH with hydrochloric acid solution to make it 20mM pH 4.0, treat with diethyl pyrocarbonate (DEPC), and sterilize, use it as a stock solution;

[0067] 2. Preparation of liposomes:

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

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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 in particular relates to an ionizable cationic lipid compound and use thereof. Background technique [0002] Gene therapy refers to the introduction of exogenous normal genes into target cells to correct or compensate for diseases caused by gene defects and abnormalities to achieve therapeutic purposes. In the past two decades, gene therapy has pushed research from preclinical to clinical in many disease treatment fields. Common gene drugs include plasmid DNA (plasmid DNA, pDNA), antisense oligonucleotide (antisense ODN), small interfering RNA (siRNA) and small hairpin RNA (shRNA). Among the many gene drugs, in addition to the classic treatment method of introducing exogenous cDNA into the body and expressing it, the idea of ​​using siRNA as a gene drug based on the principle of RNA interference has attracted great attention once it was put forward. [0003] siRNA (Small interfering RN...

Claims

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Application Information

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Patent Type & Authority Applications(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 JIAO TONG UNIV
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