Amphiphilic derivatives of 3-((2-(dimethylamino)ethyl)(methyl)amino)propionic acid and uses thereof

A technology based on dimethylamino and ethyl groups, which is applied in the field of gene therapy, can solve the problems of complex preparation process and difficulty in scale-up production, and achieve the effects of increasing loading capacity, effective delivery, and increasing in vivo stability

Active Publication Date: 2017-12-15
SHANGHAI JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] 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, most of the preparation processes are complicated and difficult to scale up.

Method used

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  • Amphiphilic derivatives of 3-((2-(dimethylamino)ethyl)(methyl)amino)propionic acid and uses thereof
  • Amphiphilic derivatives of 3-((2-(dimethylamino)ethyl)(methyl)amino)propionic acid and uses thereof
  • Amphiphilic derivatives of 3-((2-(dimethylamino)ethyl)(methyl)amino)propionic acid and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Example 1, 3-((2-(dimethylamino) ethyl) (methyl) amino) propionic acid amphiphilic derivative TMEA

[0072] figure 1 It is the structural diagram of the amphiphilic compound TMEA; its preparation is as follows figure 2 As shown, specifically: choose N, N, N'-ethylenediamine, linoleic acid, etc. as raw materials, according to the reaction process figure 2 Synthesized to obtain TMEA lipids. image 3 NMR spectrum results for the amphiphilic compound TMAEA, Figure 4 Its mass spectrum results.

[0073] Reaction materials:

[0074] Linoleic acid, tetrahydrofuran (THF), red aluminum solution (vitride), toluene (toluene), anhydrous sodium sulfate, ethyl acetate, pure water, dichloromethane, triethylamine, DMAP (4-dimethylaminopyridine) , EDC·HCl (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride), methanesulfonic anhydride, PMA (propylene glycol methyl ether acetate), hydrochloric acid, sulfuric acid, chlorination Sodium, DMF (dimethylformamide), lithium br...

Embodiment 2

[0097] Example 2, 3-((2-(dimethylamino) ethyl) (methyl) amino) propionic acid amphiphilic derivative T1

[0098] Figure 5 It is the structural diagram of 3-((2-(dimethylamino)ethyl)(methyl)amino)propionic acid amphiphilic derivative T1; its preparation is as follows: select N, N, N'-ethylenediamine , palmitic acid, etc. as raw materials, synthesized according to the synthesis method of Example 1, the difference is: in step 1, reactant 1 is palmitic acid, and other synthesis steps, synthesis principles and raw materials are exactly the same. T1 lipids were obtained; 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.

Embodiment 3

[0099] Example 3, 3-((2-(dimethylamino) ethyl) (methyl) amino) propionic acid amphiphilic derivative T2

[0100] Image 6 It is the structural diagram of 3-((2-(dimethylamino)ethyl)(methyl)amino)propionic acid amphiphilic derivative T2; its preparation is specifically as follows: select N, N, N'-ethylenediamine, Oleic acid etc. are used as raw materials, synthesized according to the synthesis method of Example 1, the difference is: in step 1, the reactant 1 is oleic acid, and other synthesis steps, synthesis principles and raw materials are exactly the same. Obtain T2 lipid. All 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.

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Abstract

The present invention relates to a kind of amphiphilic derivative of 3-((2-(dimethylamino) ethyl) (methyl) amino) propionic acid and its use; Prepared liposome; the use is the use of liposome as a drug carrier delivery system. The liposome prepared from the amphiphilic compound of the present invention can carry more positive charges at acidic pH, can better compound gene drug siRNA, and form a complex with smaller particle size and uniform particle size distribution. At the same time, it is electrically neutral under the pH7.4 environment, which increases the stability of the lipoplex in vivo and reduces the cytotoxicity caused by excessive positive charges. The liposome provided by the invention can specifically inhibit gene expression in human non-small cell lung cancer H1299‑Pgl3 cells in vitro, and can specifically transfer fluorescent gene drugs into normal mouse liver cells in vivo.

Description

technical field [0001] The invention belongs to the technical field of gene therapy, and in particular relates to an amphiphilic derivative of 3-((2-(dimethylamino)ethyl)(methyl)amino)propionic acid 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 (plasmid DNA, pDNA), antisense oligonucleotide (antisense ODN), small interfering RNA (siRNA) and small hairpin RNA (shRNA). siRNA that has RNAi interference effect and can specifically silence the target gene is the focus of curre...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C229/16C07C227/06A61K9/127A61K48/00A61K47/18A61P35/00A61P1/16
Inventor 徐宇虹张金平刘君司晓菲吴烈宜
Owner SHANGHAI JIAOTONG UNIV
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