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Fructose and RGD peptide co-modified dual-targeting triple-negative breast cancer lipid material

A dual-targeting technology for triple-negative breast cancer, applied in liposome delivery, organic active ingredients, medical preparations of non-active ingredients, etc., can solve problems such as limited targeting ability

Inactive Publication Date: 2019-12-03
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But only through the mediation of a single receptor or transporter, its targeting ability is limited, and the introduction of two targeting molecules seems to be able to further improve the targeting of drugs on the basis of a single targeting molecule

Method used

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  • Fructose and RGD peptide co-modified dual-targeting triple-negative breast cancer lipid material
  • Fructose and RGD peptide co-modified dual-targeting triple-negative breast cancer lipid material
  • Fructose and RGD peptide co-modified dual-targeting triple-negative breast cancer lipid material

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Preparation of compound 2

[0036]

[0037] Under argon protection, fructose-free 2 (2.00 g, 11.10 mmol) was added to a mixed solution of 39 mL of anhydrous acetone and 1.95 mL of sulfuric acid at 0 °C. The reaction solution was moved to room temperature and reacted for 2 h. The completion of the reaction was monitored by TLC, and 0 °C aqueous sodium hydroxide solution (6.10 g, 152.50 mmol, 55 mL) was slowly added to the reaction solution under an ice bath. Suction filtration, distill off the solvent in the filtrate under reduced pressure, dissolve the residue in dichloromethane (50 mL), wash with water (100 mL × 2), saturated brine (100 mL × 2) successively, anhydrous sodium sulfate Dry, filter, remove excess solvent under reduced pressure, recrystallize petroleum ether to obtain 2.10 g of white solid, yield 72.66%. Mp: 94-96°C (Literature Mp: 95-96°C).

Embodiment 2

[0039] Preparation of compound 3

[0040]

[0041] Under argon protection, compound 2 (2.00 g, 7.68 mmol), succinic anhydride (923 mg, 9.23 mmol) and 4-dimethylaminopyridine (DMAP, 94 mg, 0.77 mmol) were dissolved in anhydrous toluene and anhydrous In a mixed solution of triethylamine (30 mL:1 mL), the reaction solution was refluxed in an oil bath at 110 °C for 2.5 h. The completion of the reaction was monitored by TLC, the toluene was distilled off under reduced pressure, the residue was dissolved in a mixed solution of 38 mL of dichloromethane and 54 mL of water, and the pH was adjusted to neutral with acetic acid. The aqueous layer was extracted with dichloromethane (40mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 2.69 g of a colorless oil with a yield of 97.11%. The product was directly carried on to the next step without purification. 1 H-NMR (600 MHz, CDCl 3 , ppm)δ: 1.34...

Embodiment 3

[0043] Preparation of Compound 6

[0044]

[0045] Compound 4 (1.14 g, 6.51 mmol) was dissolved in 30 mL of tetrahydrofuran, N-methylmorpholine (NMM, 0.717 mL, 6.51 mmol) was added, and isobutyl chloroformate (IBCF, 0.823 mL, 6.51 mmol), after the dropwise addition, continue to activate at -10 ℃ for 30 min. Compound 5 (3.16 g, 6.51 mmol) was dissolved in a mixed solution of tetrahydrofuran (10 mL) and N-methylmorpholine (0.717 mL), and added dropwise to the activation solution above. After the dropwise addition was completed, the reaction was carried out at room temperature for 4 h, and the completion of the reaction was monitored by TLC. The solvent in the reaction solution was removed under reduced pressure, and the residue was dissolved in 30 mL of dichloromethane, followed by dilute hydrochloric acid (1 N, 50 mL × 2), saturated sodium bicarbonate solution (50 mL × 2) and saturated sodium chloride solution (50 mL × 2) for washing. The organic phase was dried over anhy...

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Abstract

The present invention discloses a novel lipid material for realizing transfer of triple negative breast cancer targeted drugs. The novel lipid material takes lysine as a connecting group to respectively connect a cholesteric part, a fructose part and an RGD part. Affinities between fructose in the novel lipid material and a fructose transporter GLUT5, and between RGD in the novel lipid material and an integrin receptor alpha v beta 3 are respectively utilized to realize double targeting functions of the triple negative breast cancer and exert stronger targeted treatment effects on the triple negative breast cancer. The novel liquid material can be sued for different dosages of liposomes, nanoparticles, micelle, etc. A prepared paclitaxel-loaded liposome has obvious triple negative breast cancer targeting property and a wide application prospect.

Description

technical field [0001] The present invention relates to a class of novel lipid materials and their applications in drug delivery systems, specifically referring to the fructose-modified lipid materials and RGD peptide-modified lipid materials on the basis of their reference substances, fructose and RGD It is used to co-modify lipid materials so that it has the function of dual targeting triple-negative breast cancer, and it is expected to further improve the targeting ability of drugs to triple-negative breast cancer. The invention includes the preparation and characterization of the material, and its application as a drug carrier in drug delivery, and belongs to the technical field of medicine. Background technique [0002] Breast cancer, as a malignant tumor that seriously affects women's survival and life, is known as the number one killer of women; in January 2019, the National Cancer Center released the latest national cancer statistics, among which, the incidence of ma...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/69A61K47/62A61K47/54A61K31/337A61P35/00
CPCA61K31/337A61K47/549A61K47/62A61K47/6911A61P35/00
Inventor 吴勇海俐管玫郭丽彭瑶蒲妍池
Owner SICHUAN UNIV
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