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Preparation and application of glucose and triphenylphosphonium modified brain tumor targeting liposome

A technology targeting liposomes and triphenylphosphonium, applied in liposome delivery, anti-tumor drugs, medical preparations of non-active ingredients, etc., can solve problems such as increased toxicity

Active Publication Date: 2021-08-10
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, triphenylphosphonium-modified liposomes will have a strong positive charge, which will increase toxicity to both normal and tumor cells and be easily cleared by the reticuloendothelial system

Method used

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  • Preparation and application of glucose and triphenylphosphonium modified brain tumor targeting liposome
  • Preparation and application of glucose and triphenylphosphonium modified brain tumor targeting liposome
  • Preparation and application of glucose and triphenylphosphonium modified brain tumor targeting liposome

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Preparation of compound 3

[0029]

[0030] At -5 °C, 3,3'-dithiodipropionic acid (4.054 g, 19.28 mmol) CH 2 Cl 2 (30 mL) solution was added EDCI (4.75 g, 24.1 mmol), DMAP (2.95 g, 24.1 mmol), and DIPEA (3.74 g, 28.92 mmol), and stirred for 30 minutes. Then, CH 2 Cl 2 (30 mL) solution and react overnight at room temperature. The reaction solution was washed sequentially with aqueous HCl (1N, 100 mL×2) and saturated NaCl (100 mL×3). The organic phase was further treated with anhydrous Na 2 SO 4 Dry and remove solvent. Finally, by silica gel column chromatography (CH 2 Cl 2 / CH 3 OH=300 / 1) to obtain light yellow semi-solid (5.067 g), yield 74.06%. 1H-NMR (400 MHz, CDCl3, ppm) δ: 0.67 (s, 3H), 0.86 (dd, 6H, J 1 = 6.6Hz, J 2 = 1.6 Hz), 0.91 (d, 3H, J =6.4 Hz), 0.99 (s, 3H), 0.85-2.39 (remaining cholesterol protons), 2.75-2.79(m, 4H), 2.93 -2.97 (m, 4H), 3.15-3.24 (m, 1H), 3.64- 3.68 (m, 8H), 3.72-3.74(m, 2H), 4.26-4.28 (m, 2H), 5.34 (s, 1H). HRMS (ESI) ...

Embodiment 2

[0032] Preparation of Compound 4

[0033]

[0034] At -5 °C, CH 2 Cl 2 (10 mL) solution, add DCC (257 mg, 1.247 mmol) and DMAP (25 mg, 0.208 mmol) and stir for 30 minutes. Then, PEG (1.039 g, 1.04 mmol) in CH 2 Cl 2(10 mL) solution, stirred overnight at room temperature. After filtering off by-products (DCU), the reaction solution was concentrated. Finally, by silica gel column chromatography (CH 2 Cl 2 / CH 3 OH=70 / 1) to obtain light yellow oil (898 mg), yield 51.05%. 1 H-NMR (400 MHz, CDCl 3 , ppm)δ: 0.67 (s, 3H), 0.86 (dd, 6H, J 1 = 6.8Hz, J 2 = 1.2 Hz), 0.91 (d, 3H, J = 6.4 Hz), 0.99 (s, 3H), 0.85-2.38 (remainingcholesterol protons), 2.75-2.79 (m, 4H), 2.91 -2.94 (m, 4H), 3.10-3.22 (m,2H), 3.47-3.83 (m, 85H), 4.25-4.27 (m, 4H), 5.34 (s, 1H).

Embodiment 3

[0036] Preparation of compound 5

[0037]

[0038] CH 2 Cl 2 (10 mL) solution, DCC (84 mg, 0.41 mmol), DMAP (8 mg, 0.065 mmol) were added and stirred for 30 minutes. Then, compound 4 (200 mg, 0.34 mmol) in CH was added dropwise to the mixture 2 Cl 2 (10 mL), stirred overnight at room temperature. After filtering off DCU, the reaction solution was concentrated. Finally, by silica gel column chromatography (CH 2 Cl 2 / CH 3 OH=100 / 1) to obtain light yellow oil (158 mg), yield 61.24%. 1H-NMR (400 MHz, CDCl 3 , ppm)δ:0.14-0.15 (m, 36H), 0.68 (s, 3H), 0.86 (d, 6H, J = 6.6 Hz), 0.91 (d, 3H, J =6.0 Hz), 0.99 (s, 3H), 0.85-2.39 (remaining cholesterol protons), 2.66-2.67(m, 4H), 2.75-2.79 (m, 4H), 2.91-2.94 (m, 4H), 3.10- 3.21 (m, 2H), 3.64-3.92(m, 95H), 4.03-4.07 (m, 2H) 4.25-4.27 (m, 6H), 4.35-4.38 (m, 1H), 4.42-4.50(m, 1H ), 5.00 (d, 1H, J =2.4 Hz), 5.34 (s, 1H).

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Abstract

The invention discloses preparation and application of glucose and triphenylphosphonium co-modified reduction-sensitive brain tumor targeting lipidosome, which are used for realizing efficient transmission of brain tumor targeting drugs. The novel liposome is jointly modified by glucose and triphenylphosphonium, can respectively recognize a glucose transporter GLUT1 highly expressed on the surface of a blood brain barrier and a brain tumor cell, and can generate electrostatic interaction with mitochondria in the tumor cell, and from two levels of cells and organelles, the multi-targeting function on blood-brain barriers, tumor tissues and mitochondria is realized, and a stronger brain tumor targeting treatment effect is achieved. The novel liposome can be used for combined entrapment of chemotherapy drugs and chemotherapy sensitizers acting on mitochondria, is used for synergistic treatment of brain tumors, has more accurate brain tumor targeting, can improve chemotherapy effects and reduce toxic and side effects, and has a wide application prospect.

Description

technical field [0001] The invention relates to a new type of liposome and its application in drug delivery system, specifically refers to using glucose as a dual targeting ligand for blood-brain barrier and brain tumor, and triphenylphosphonium as a mitochondrial targeting ligand for Co-modify liposomes, and introduce disulfide bonds as reduction-sensitive bonds and make liposomes PEGylated to achieve long-term circulation. This new multifunctional liposome is used to co-encapsulate chemotherapeutic drugs and chemosensitizers. Further improve the targeted therapeutic effect of drugs on brain tumors. 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] Glioma is the most common and deadly brain tumor, with a life expectancy of only 12-18 months after diagnosis. However, traditional therapies such as chemotherapy still...

Claims

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Application Information

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IPC IPC(8): A61K47/69A61K47/54A61K47/60A61K45/06A61K47/24A61K47/28A61P35/00
CPCA61K47/6911A61K47/549A61K47/54A61K47/60A61K45/06A61K47/24A61K47/28A61P35/00
Inventor 吴勇海俐彭瑶郭丽李茹卢嘉琪
Owner SICHUAN UNIV
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