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RGD-peptide-type cationic lipid compound, preparation method thereof, and application of compound to medicine and gene transportation

A technology of cationic lipids and compounds, which is applied in the field of RGD peptide cationic lipids, can solve the problems that cannot meet the requirements of clinical research, monovalent cationic lipids cannot be effective, and the transfection efficiency cannot meet the requirements of treatment, etc., and achieve cell toxicity Low, improve transfection efficiency, and reduce cytotoxicity

Inactive Publication Date: 2016-06-08
DALIAN NATIONALITIES UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Since monovalent cationic lipids cannot efficiently compact genes, transfection efficiency cannot meet therapeutic requirements
Therefore, people have developed a series of multivalent cationic lipids, such as DOGS, DPPES and DOSPA, etc. The transfection efficiency of these compounds is higher than that of monovalent cationic lipids such as DOTMA, but they cannot meet the requirements of clinical research.

Method used

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  • RGD-peptide-type cationic lipid compound, preparation method thereof, and application of compound to medicine and gene transportation
  • RGD-peptide-type cationic lipid compound, preparation method thereof, and application of compound to medicine and gene transportation
  • RGD-peptide-type cationic lipid compound, preparation method thereof, and application of compound to medicine and gene transportation

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Experimental program
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preparation example Construction

[0053] The present invention provides the preparation method of described a kind of RGD peptide cationic lipid compound, and described method comprises the following steps:

[0054] (1) Using a polypeptide solid-phase synthesis instrument, Fmoc-Asp-Wang resin, Fmoc-Gly-OH, and Fmoc-Arg-OH react according to the molar ratio of 1:1:1~1:4:4 to prepare the compound of formula i:

[0055]

[0056] The reaction temperature is 10~40°C, and the reaction solvent is DMF;

[0057] In a preferred embodiment, the reaction temperature is 10~30°C, the reaction solvent is DMF, Fmoc-Asp-Wang resin, Fmoc-Gly-OH, Fmoc-Arg-OH according to the molar ratio of 1:1:1~1: 3:3 response.

[0058] In a more preferred embodiment, the reaction temperature is 15~25°C, the reaction solvent is DMF, Fmoc-Asp-Wang resin, Fmoc-Gly-OH, Fmoc-Arg-OH according to the molar ratio of 1:1:1~1 :2:2 Response.

[0059] (2) Under alkaline conditions, 3-amino-1,2-propanediol and Fmoc-OSu were reacted according to the m...

Embodiment 1

[0091] The preparation of embodiment 1 compound RGDA14

[0092] ⑴ Synthesis of Fmoc-RGD tripeptide

[0093] Using a peptide solid-phase synthesis instrument, put the Fmoc-protected aspartic acid king resin into the reaction kettle, and then prepare the glycine and arginine that need to be connected into a solution, and then prepare the same concentration of HBTU and HOBt and DIEA are added to the container, and the instrument is operated through a computer program to control the reaction. After the reaction was completed, the resin was cut with trifluoroacetic acid, and the pure Fmoc-RGD tripeptide was obtained after purification. The characterization results are as follows: 1 HNMR (400MHz, CDCl 3 ) δ: 8.56 (s, 2H, NH 2 ), 7.28-7.87 (m, 8H, 2×CCHHCHCC), 4.76 (m, 1H, CHCOOH), 4.53 (m, 1H, CHCO), 2.90 (d, 2H, CH 2 COOH).IR, (KBr)υ / cm -1 :3331.15 (υ N-H ), 3054.95 (υ 芳环不饱和C-H ), 2939.33 (υ 饱和C-H ), 1691.52 (υ C=O ), 1614.3, 1537.08 (υ 芳环C=C ), 794.54 (δ 芳环C-H ); ESI-M...

Embodiment 2

[0100] The preparation of embodiment 2 cationic liposomes

[0101] The RGD peptide-type cationic lipid compound (RGDA14) obtained in the above-mentioned Example 1 was irradiated under ultraviolet light for 1 h, and 1 mg of the cationic lipid was weighed, respectively added to 1 ml of chloroform / methanol (v / v=2:1) ​​fully dissolved, uniformly blown dry with nitrogen to form a thin film, dried in vacuum for 10h, and removed the organic solvent. Add 1ml of sterile ultrapure water, sonicate at a constant temperature of 50°C for 1-3h to make it transparent and clear, and the final concentration is 1.00mM cationic liposome.

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Abstract

Disclosed are a RGD-peptide-type cationic lipid compound and a preparation method. The compound has a general formula shown in the description. In the formula, X- is one of F-, Cl-, Br-, I-, H2PO4-, HCO3-, NO3-, HSO3-, CH3COO-, gluconate, glucuronate, galactonate, galacturonate, propionate, and methanesulfonate, and R1 is one of a C1-20 alkyl group, octadecenyl, and a cholesterol group. The invention further relates to a composition prepared through mixing and interaction of the compound and a lipid auxiliary agent, and a compound prepared from the composition and a medicine or a genetic material. The compound in the invention is reduced in cytotoxicity and high in transfection efficiency, and can meet the high-efficiency-and-low-toxicity requirement of a carrying medicine including the genetic material and related materials.

Description

technical field [0001] The present invention relates to a class of cationic lipids, the lipid composition and the composition complex, and their preparation methods, in particular to a RGD peptide cationic lipid, the lipid composition and the composition of the composition Composite, and preparation method and application. Background technique [0002] In recent years, people have invented many new methods for treating diseases, but there is no effective method for the treatment of diseases such as cancer. Intracellular therapy using drugs or genes is a new and revolutionary treatment method, its effectiveness has been verified by many studies, and it has become one of the most active research fields in chemistry, biology and medical engineering. with broadly application foreground. The targeted delivery of drugs or genes is one of the key technologies in intracellular therapy. During the transfer process, drugs or genes with therapeutic effects are transported into target...

Claims

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Application Information

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IPC IPC(8): C07K5/09C07K1/06C07K1/04C12N15/88A61K48/00A61K47/48A61K31/713
CPCC07K5/0817A61K31/407A61K31/513A61K31/704A61K31/713A61K38/08A61K38/21A61K48/0033C12N15/88
Inventor 张树彪付双田甜张琳徐宇虹张峻峰
Owner DALIAN NATIONALITIES UNIVERSITY
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