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A kind of hepatocellular carcinoma-targeted paclitaxel-galactosamine conjugate, nanoparticle and preparation method and application thereof

A technology of galactosamine and paclitaxel, which is applied in the preparation of sugar derivatives, sugar derivatives, sugar derivatives, etc., can solve the problems that limit the clinical transformation and wide application of nano-medicines, and achieve good application prospects, cheap raw materials, and good anti-inflammatory properties. proliferative effect

Active Publication Date: 2022-08-09
SHANDONG UNIV
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

These factors greatly limit the clinical translation and wide application of nanomedicines.

Method used

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  • A kind of hepatocellular carcinoma-targeted paclitaxel-galactosamine conjugate, nanoparticle and preparation method and application thereof
  • A kind of hepatocellular carcinoma-targeted paclitaxel-galactosamine conjugate, nanoparticle and preparation method and application thereof
  • A kind of hepatocellular carcinoma-targeted paclitaxel-galactosamine conjugate, nanoparticle and preparation method and application thereof

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preparation example Construction

[0046] In yet another specific embodiment of the present invention, there is provided a preparation method of the above-mentioned paclitaxel-galactosamine conjugate, the preparation method comprising: based on pentaerythritol, connecting a liver targeting ligand and an anticancer drug with a succinyl structural unit. Benzaldehyde protects the two hydroxyl groups of pentaerythritol, and then introduces succinyl paclitaxel and stearic acid, followed by FeCl 3 Carry out deprotection and succinic anhydride reaction to introduce carboxyl group, and finally undergo an amidation reaction with two galactosamines to obtain the paclitaxel-galactosamine conjugate shown in formula 1;

[0047] One hydroxyl group of pentaerythritol undergoes esterification reaction with succinyl paclitaxel, then reacts with succinic anhydride to introduce carboxyl group, and finally undergoes amidation reaction with three galactosamines to obtain the paclitaxel-galactosamine conjugate shown in formula 2.

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Embodiment 1

[0093] Example 1. Preparation of intermediate compound of formula 3

[0094] Succinyl paclitaxel (0.477 g, 0.50 mmol) and pentaerythritol monobenzaldehyde (0.113 g, 0.50 mmol), DMAP (12.2 mg, 0.1 mmol) and EDC (0.192 g, 1 mmol) were dissolved in 15 mL of dichloromethane, room temperature The reaction was stirred for 20 hours, the solvent was distilled off under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography to obtain 0.278 g of the compound of formula 3 with a yield of 48%. ESI-MSm / z: 1195.48[M+Cl] - .

Embodiment 2

[0095] Example 2. Preparation of intermediate compound of formula 4

[0096] The compound of formula 3 (0.232 g, 0.2 mmol) and 0.16 g of triethylamine were dissolved in 4 ml of dichloromethane, and a solution of 2 ml of stearoyl chloride (0.3 mmol) in dichloromethane was added dropwise to react at room temperature for 20 hours, and then distilled under reduced pressure to remove solvent, and the obtained crude product was separated and purified by silica gel column chromatography to obtain 0.151 g of the compound of formula 4 with a yield of 53%. ESI-MS m / z: 1448.74[M+Na] + .

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Abstract

The invention provides a paclitaxel-galactosamine conjugate targeting hepatocellular carcinoma, a nanoparticle and a preparation method and application thereof, belonging to the technical field of biomedical materials and pharmaceutical preparations. In the present invention, the paclitaxel-galactosamine conjugate is prepared by preparing the conjugate, which has a hydrophilic and hydrophobic structure and can be self-assembled into nanoparticles, and has the functions of active and passive targeting of hepatocellular carcinoma. Using the drug itself as a carrier, the drug has a high drug load, controllable quality, and avoids the metabolic difficulties and toxic side effects caused by excipients. Experiments have shown that it has a good anti-hepatocellular carcinoma effect in vitro and in vivo. At the same time, the paclitaxel-galactosamine conjugate has relatively cheap raw materials, simple preparation method, no complicated and expensive equipment, mild reaction conditions, strong operability, and promotes clinical application and industrial production, so it has good practical application value. .

Description

technical field [0001] The invention belongs to the technical field of biomedical materials and pharmaceutical preparations, and in particular relates to a paclitaxel-galactosamine conjugate targeting hepatocellular carcinoma, a nanoparticle, and a preparation method and application thereof. Background technique [0002] The disclosure of information in this Background section is only for enhancement of understanding of the general background of the invention and should not necessarily be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person of ordinary skill in the art. [0003] Hepatocellular carcinoma is one of the most common primary malignant tumors of the liver, and its mortality rate ranks second among malignant tumors. Surgery, radiotherapy and chemotherapy are the three major conventional treatments. Due to the disadvantages of surgery and radiotherapy, such as low resection rate, high recurrence r...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/54A61K31/337A61K9/51A61P35/00C07H1/00C07H5/06
CPCA61K47/549A61K31/337A61K9/5123A61P35/00C07H1/00C07H5/06Y02P20/55
Inventor 刘兆鹏李莎莎刘超
Owner SHANDONG UNIV
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