Hepatocellular carcinoma-targeted paclitaxel galactosamine conjugate, nanoparticles as well as preparation method and application thereof

A technology of galactosamine and paclitaxel, applied in the preparation of sugar derivatives, sugar derivatives, sugar derivatives, etc., can solve the problems of limiting the clinical transformation and wide application of nano-drugs, avoid toxic side effects, and achieve good in vivo tumor inhibition effect. , uniform size effect

Active Publication Date: 2021-06-04
SHANDONG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

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

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  • Hepatocellular carcinoma-targeted paclitaxel galactosamine conjugate, nanoparticles as well as preparation method and application thereof
  • Hepatocellular carcinoma-targeted paclitaxel galactosamine conjugate, nanoparticles as well as preparation method and application thereof
  • Hepatocellular carcinoma-targeted paclitaxel galactosamine conjugate, nanoparticles as well as preparation method and application thereof

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preparation example Construction

[0047] In yet another specific embodiment of the present invention, a preparation method of the above paclitaxel-galactosamine conjugate is provided, the preparation method comprising: using pentaerythritol as the basis, and linking the liver-targeting ligand and the 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 Carrying out deprotection and succinic anhydride reaction to introduce carboxyl groups, and finally undergoing amidation reaction with two galactosamines to obtain paclitaxel galactosamine conjugate shown in formula 1;

[0048] A hydroxyl group of pentaerythritol undergoes an esterification reaction with succinyl-paclitaxel, then reacts with succinic anhydride to introduce a 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

[0095] Embodiment 1. Preparation of intermediate formula 3 compound

[0096] Succinyl paclitaxel (0.477g, 0.50mmol) and pentaerythritol monobenzaldehyde (0.113g, 0.50mmol), DMAP (12.2mg, 0.1mmol) and EDC (0.192g, 1mmol) were dissolved in 15ml of dichloromethane, room temperature The reaction was stirred for 20 hours, and the solvent was distilled off under reduced pressure. The resulting 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

[0097] Embodiment 2. Preparation of intermediate formula 4 compound

[0098] Formula 3 compound (0.232g, 0.2mmol) and 0.16g triethylamine are dissolved in 4 milliliters of dichloromethane, dropwise add the dichloromethane solution of 2 milliliters of stearyl chloride (0.3mmol), react at room temperature for 20 hours, remove by distillation under reduced pressure Solvent, the resulting 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 hepatocellular carcinoma-targeted paclitaxel galactosamine conjugate, nanoparticles as well as a preparation method and application thereof, and belongs to the technical field of biomedical materials and pharmaceutical preparations. The prepared paclitaxel galactosamine conjugate has a hydrophilic and hydrophobic structure, can be self-assembled into nanoparticles, and has the effects of actively and passively targeting hepatocellular carcinoma. The drug is adopted as a carrier,the drug loading capacity is high, the quality is controllable, the metabolism difficulty and the toxic-side effect caused by the auxiliary material are avoided, and the experiment results prove that the paclitaxel galactosamine conjugate has good anti-hepatocellular carcinoma effect in vivo and in vitro. Meanwhile, the paclitaxel galactosamine conjugate is relatively cheap in raw material, simple in preparation method, free of complex and expensive equipment, mild in reaction condition, relatively high in operability and capable of promoting clinical application and industrial production, so that the paclitaxel galactosamine conjugate 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, nanoparticles and a preparation method and application thereof. Background technique [0002] The information disclosed in this background section is only intended to increase the understanding of the general background of the present invention, and is not necessarily taken as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to those skilled 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 conventional treatment methods. Due to the disadvantages of low resection rate, high recurrence rate, and uneconomical effects of surgery...

Claims

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Application Information

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Patent Type & Authority Applications(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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