Targeting ligand molecule, preparation method thereof and drug delivery system

A ligand molecule and liver-targeting technology, which is applied in the direction of pharmaceutical formulations, medical preparations with non-active ingredients, and medical preparations containing active ingredients. Balance, reduced efficiency of liver targeting, etc.

Active Publication Date: 2021-05-11
JIAYING UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Further studies have found that arbitrarily extending or shortening the length of the carbon bridge between the galactose target head and cholesterol will significantly affect the liver targeting efficiency of the ligand molecule, such as reducing the carbon bridge from 8 CH2 to 4 or increasing it to 13 , the liver targeting efficiency is significantly reduced, which may be related to the influence of the carbon bridge length on the hydrophilic / hydrophobic balance of the ligand molecule, which in turn affects the distribution of the target head on the liposome surface

Method used

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  • Targeting ligand molecule, preparation method thereof and drug delivery system
  • Targeting ligand molecule, preparation method thereof and drug delivery system
  • Targeting ligand molecule, preparation method thereof and drug delivery system

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] The chemical synthesis route of embodiment 1CHS-DIO-SA-GalNAc

[0079] The synthesis steps are as follows:

[0080]

[0081] Synthesis of step 1 intermediate 1,3,6-dioxa-(divinyl suberate) (3,6-dioxa-(divinyloctanedioate))

[0082] Weigh 28mol of 3,6-dioxaoctandioic acid, 5.6mol of vinyl acetate, 0.028mol of mercury acetate and a small amount of copper acetate into a 1000mL three-necked flask. Heat and stir the three-necked flask containing the above substances in a constant temperature water bath at 50°C, add 0.5 mL of concentrated sulfuric acid dropwise after 10 min, and react for 8 h. After the reaction was completed, about 4g of sodium acetate was added to fully shake to neutralize the sulfuric acid. After the excess vinyl acetate was distilled off by water pump under reduced pressure, the remaining blue liquid was chromatographed on a silica gel column and eluted isocratically with petroleum ether-ethyl acetate (9: 1), and the pure product was isolated with a ...

Embodiment 3

[0099] The preparation of embodiment 3 drug-carrying system liposome

[0100] 3.1 Preparation of doxorubicin liposomes

[0101] Preparation of Doxorubicin Liposomes by Gradient Loading Method [18] . Mix HSPC and CHS according to a certain ratio (see Table 1), dissolve in chloroform, place in a water bath rotary evaporator at 55°C, evaporate the chloroform to dryness until a layer of lipid film is formed on the inner wall of the bottle, and dry overnight in a vacuum desiccator (12 h), then add ammonium sulfate solution (300 mmol / L) for hydration, stir slowly at 55 ° C, incubate for 1 h, and then use a high-pressure extruder to pass through 0.1 and 0.05 μm polycarbonate membranes 10 times each to obtain the blank lipid body. Then pass the blank liposomes through a Sephadex G-50 column to remove unencapsulated ammonium sulfate, and finally add DOX solution, and incubate at 65°C for 1 hour to obtain DOX-loaded ordinary liposomes (CL-LP DOX).

[0102] Table 1 Common lipid doxor...

Embodiment 4

[0110] The characterization of embodiment 4 liposome

[0111] 4.1 Liposome particle size and Zeta potential measurement

[0112] Take 100 μL of the above liposome solution, dilute to 2 mL with normal saline, mix well, and analyze its particle size distribution, Zeta potential, and polymer dispersion index (PDI) using a laser scattering particle size analyzer. The experimental data are expressed as Statistical software SPSS 22.0 was used for data analysis, and the mean comparison of particle size, PDI and Zeta potential among the groups was performed by analysis of variance. The results are shown in Table 4.

[0113] Table 4 liposome characterization ( n=3)

[0114]

[0115]

[0116] (-) represents anionic liposomes containing DSPG-Na. Leakage rate < 3%

[0117] ** indicates that the particle size of GalNAc-DIO-LP DOX group is significantly different from that of GalNAc-LP DOX group (P<0.01); *** indicates CL-LP DOX, GalNAc-LP DOX, Gal-LP DOX, Lac-LP DOX , GalNAc...

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Abstract

The invention relates to a novel targeting sugar ligand molecule and a preparation method of a liposome thereof, in particular to a targeting sugar ligand molecule of a liver ASGPR (Accelerated Solvent Growth Protein Receptor) target spot and a liposome prepared by applying the targeting sugar ligand molecule. The liver targeting sugar ligand molecule is composed of three parts: a liver targeting sugar group, a lipophilic anchor structure and a connecting arm for adjusting hydrophilic/ hydrophobic balance. The sugar ligand molecule is specifically loaded to the nano drug delivery system, so that after the drug delivery system is absorbed by a body, parenchymal hepatic cells can be accurately locked, an anti-tumor drug is concentrated at a liver tumor part to the maximum extent, the toxic and side effects of the whole body are reduced, and the life quality of a patient is improved.

Description

technical field [0001] The present invention relates to a novel targeting sugar ligand molecule and the preparation of liposome thereof, especially the targeting sugar ligand molecule related to liver ASGPR receptor target, and the liposome prepared by using the targeting sugar ligand molecule plastid. Background technique [0002] Primary liver cancer (PLC) is one of the most common digestive tract malignancies clinically, and 90% of them are hepatocellular carcinoma (HCC). my country is a country with a high incidence of HCC, accounting for about 70% of the total number of HCC in the world, ranking third in domestic tumor mortality [Chen, W., et al., Cancer statistics in China, 2015. CA Cancer J Clin, 2016.66 (2): p.115-32]. The treatment of choice for early-stage HCC includes surgical resection and liver transplantation. However, most patients are already in the middle and advanced stages when they are diagnosed, and they are often combined with hepatitis B / C virus and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J9/00C12P33/20A61K9/127A61K31/704A61K47/28A61P35/00
CPCC07J9/00C12P33/20A61K31/704A61K9/127A61K47/28A61P35/00
Inventor 聂华周铭张声源刘小敏杨琪璿
Owner JIAYING UNIV
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