Liver cancer targeting glycoside ligand molecule, preparation method thereof, and drug delivery system

A ligand molecule and drug-loading system technology, which is applied in the direction of pharmaceutical formulations, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., can solve problems such as lengthy steps, complicated reaction conditions, and low efficiency

Active Publication Date: 2017-04-26
SCHOOL OF MEDICINE JIAYING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In addition, according to literature reports, due to the presence of a large number of sugar hydroxyl groups in glycosyl ligand molecules, the chemical synthesis requires precise protection and deprotection measures for the hydroxyl groups at non-reactive sites, which makes the reaction conditions complex, lengthy steps, and low efficiency.

Method used

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  • Liver cancer targeting glycoside ligand molecule, preparation method thereof, and drug delivery system
  • Liver cancer targeting glycoside ligand molecule, preparation method thereof, and drug delivery system
  • Liver cancer targeting glycoside ligand molecule, preparation method thereof, and drug delivery system

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Example 1 Synthesis of GalNAc-C8-Chol

[0036] Method: Take 10mL stoppered vial, add CHS-SE (0.1mmol), GalNAc (0.05mmol), add 5mL dehydrated acetone, add enzyme TL IM 20mg, shake in an air bath constant temperature oscillator (45℃, 250r·min- 1), react for 24h. After the reaction is finished, the enzyme is filtered out, and the solvent is recovered to obtain the product. The reaction equation is shown in figure 1 shown. The product was purified by flash silica gel column chromatography, and the structure of the purified product was identified by infrared, ESI, 1H NMR, and 13C NMR.

[0037]

[0038] Identification of synthetic products

[0039] The structure of the product was identified as the target product by MS and NMR, and the specific data are as follows:

[0040] MS conditions: After the product is dissolved in an appropriate amount of methanol, it is analyzed by a mass spectrometer (MS), mass spectrometry parameters: triple quadrupole LC-MS / MS: electrospray...

Embodiment 2

[0045] Example 2 Preparation and Characterization of GalNAc Modified Nanoliposomes

[0046] Preparation method: Weigh phospholipids (PC), cholesterol (CHS), DSPG-Na, GalNAc ligand molecules, drugs, etc. according to a certain ratio (40:20:1:4:1) and mix and dissolve them in chloroform. Remove chloroform by rotary steaming at 55°C and 40rpm in an eggplant-shaped bottle to form a uniform lipid film, add pH 7.4 PBS buffer solution, hydrate at 55°C for 1 hour, and then squeeze and filter with 100nm and 50nm filter membranes in turn to obtain uniform nanoparticles.

[0047] And the particle size of the two ( Figure 6 ), zeta potential ( Figure 7 ), encapsulation efficiency, etc. Results Using this method, the nanoparticle size was smaller, the particle size distribution was uniform, the quality was stable, and the encapsulation efficiency was high (see Table 1), which met the requirements of subsequent tests.

[0048] The comparison (n=3) of table 1 common liposome and galacto...

Embodiment 3

[0050] Example 3 In vitro targeting studies of GalNAc-modified nanoliposomes

[0051] Experimental method: Human liver cancer HepG2 cells in the logarithmic growth phase were inoculated in a 24-well plate. After the cell confluence reached about 80% and the cell shape was plump, an appropriate amount of common fluorescent liposome (FL-LP) and GalNAc were added respectively. -LP-FL (adjust the lipid concentration to 1mmol·mL with medium -1 ). At 37°C, 5% CO 2 Incubate in the incubator for 1 hour, then use 1mL PBS (pH7.4) to wash away the fluorescent nanoliposomes that were not taken up by the cells, lyse the cells with 1% TriotnX-100PBS, and measure the uptake of FL-LP and GalNAc- by HepG2 cells with a microplate reader. The fluorescence intensity of LP-FL was evaluated in vitro for liver tumor targeting.

[0052] The liver targeting of GalNAc-modified fluorescent liposomes (GalNAc-LP-FL) was evaluated by human liver cancer HepG2 cells, and the results showed that the uptake...

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Abstract

The invention relates to a preparation method and of a liver cancer targeting glycoside ligand molecule and a preparation method of a liposome of the liver cancer targeting glycoside ligand molecule, and especially relates to a liver ASGPR target targeting glycoside ligand molecule and the liposome prepared by using the targeting glycoside ligand. The glycoside ligand molecule is formed by a liver targeting glycoside group, a lipophilic anchor and a substituted or non-substituted -(CH2)8 linear spacer arm for connecting the liver targeting glycoside group with the lipophilic anchor through an ester bond. The liver cancer targeting glycoside ligand molecule makes antitumor drugs in a drug delivery system maximally concentrated in liver tumor cells, improves the drug treatment index, reduces toxic and side effects on whole bodies, and improves patients' survival quality.

Description

technical field [0001] The present invention relates to a liver cancer targeting sugar ligand molecule and the preparation of liposome thereof, in particular to the liver cancer targeting sugar ligand molecule of the ASGPR receptor target, and the lipid prepared by using the targeting sugar ligand molecule body. 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 preferred treatment for early 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 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J41/00C12P33/20A61K31/58A61K47/69A61K47/54A61P35/00
CPCA61K9/127A61K31/337A61K31/4525A61K47/28A61P35/00C07J41/0055C12P33/20
Inventor 聂华张声源杨琪璿赵莹
Owner SCHOOL OF MEDICINE JIAYING UNIV
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