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Quercetin-low molecular heparin-paclitaxel conjugate as well as preparation method and application thereof

A low-molecular-weight heparin and quercetin technology, which can be applied to medical preparations without active ingredients, medical preparations containing active ingredients, and drug combinations, etc., can solve the problems of instability, limitation, and low water solubility of quercetin. , to achieve the effect of mild conditions and good versatility

Inactive Publication Date: 2020-12-29
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, quercetin has extremely low water solubility (solubility in water is 1 μg / mL), is unstable in the gastrointestinal tract, and has low oral bioavailability, which greatly limits its clinical application.

Method used

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  • Quercetin-low molecular heparin-paclitaxel conjugate as well as preparation method and application thereof
  • Quercetin-low molecular heparin-paclitaxel conjugate as well as preparation method and application thereof
  • Quercetin-low molecular heparin-paclitaxel conjugate as well as preparation method and application thereof

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preparation example Construction

[0031] The second aspect of the present invention provides the preparation method of the paclitaxel-low molecular weight heparin-quercetin conjugate described in the first aspect, the preparation method comprising the following steps: respectively synthesizing adipate dihydrazide modified low molecular weight heparin (LWMH- ADH), quercetin-NHS ester (QT-NHS) and carboxylated paclitaxel (PTX-COOH), using adipate dihydrazide modified low molecular weight heparin and quercetin-NHS ester as raw materials to synthesize low molecular weight heparin-quercetin Cortex (LWMH-QT); the paclitaxel-low molecular weight heparin-quercetin conjugate (PTX-LWMH-QT) is obtained by mixing and reacting low molecular weight heparin-quercetin and carboxylated paclitaxel.

[0032] Preferably, the synthesis method of adipate dihydrazide modified low-molecular-weight heparin is as follows: add adipamide (ADH), EDCI, HOBt to the aqueous solution of low-molecular-weight heparin, add lye to adjust the pH va...

Embodiment 1

[0098] The preparation of embodiment 1 PTX-LWMH-QT

[0099]1. Synthesis of LWMH-QT

[0100] (1) Weigh 0.25g of LWMH and dissolve it in 50mL of distilled water, stir to dissolve it fully, then add 4g of ADH, 0.48g of EDCI, and 0.48g of HOBt. Adjust the pH of the system to 6.8 with 0.1M NaOH solution, stir and react at room temperature for 24 hours to obtain a crude product, dialyze against water for 3 days, change the water every 6 hours, filter the dialysate and freeze-dry to obtain LWMH-ADH.

[0101] (2) Weigh 302 mg of QT and 200 mg of succinic anhydride, dissolve them together in 10 mL of tetrahydrofuran, add 805 μL of pyridine, and react under nitrogen protection for 3 days. The solvent in the reaction solution was removed by rotary evaporation, washed with alkali and saturated brine, dried, and passed through a silica gel column to obtain the intermediate quercetin hemisuccinic acid.

[0102] (3) Dissolve 1.15g of N-hydroxysuccinimide in 6mL of dichloromethane, add 1.4m...

Embodiment 2

[0108] Example 2 Preparation of PTX-LWMH-QT self-assembled nanoparticles

[0109] Weigh 5 mg of PTX-LWMH-QT, disperse it in 3 mL of PBS (pH=7.4, 10 mM), stir well and then ultrasonicate the sample (40 W, 2 s on / 4 s off, 4 min in total). After the ultrasonic sample is filtered through a 0.8 μm microporous membrane, the PTX-LWMH-QT self-assembled nanoparticle solution can be obtained.

[0110] Weigh 10mg PTX-LWMH-QT, use d 6 -DMSO / D 2 O mixed solvent to dissolve it, carry out 1 H-NMR analysis, get figure 2 As shown in the spectrum, the characteristic absorption peaks of PTX and QT appeared, proving that the polymer was successfully synthesized.

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Abstract

The invention particularly relates to a quercetin-low molecular heparin-paclitaxel conjugate as well as a preparation method and application thereof. Quercetin and paclitaxel have good anti-tumor activity, but the quercetin and the paclitaxel are poor in water solubility and low in bioavailability, so that the clinical application condition is not ideal. The invention provides a paclitaxel-low molecular heparin-quercetin conjugate. Low-molecular heparin sodium is taken as a skeleton and the paclitaxel and the quercetin are connected through covalent bonds. As an anti-tumor active component, the conjugate effectively improves the defect of poor solubility of the paclitaxel and the quercetin. The conjugate obtained according to the preparation method basically does not destroy the active structures of the paclitaxel and the quercetin, well retains the pharmacological activity of the paclitaxel and the quercetin, is applied to anti-tumor drugs, is expected to achieve the treatment effectof the paclitaxel and the quercetin, and has important clinical treatment significance.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a quercetin-low molecular weight heparin-paclitaxel conjugate. The preparation method of the conjugate records the application in the preparation of antitumor drugs. 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] Paclitaxel (PTX), a diterpene alkaloid compound isolated and purified from the bark of the gymnosperm yew, is mainly used clinically for the treatment of ovarian cancer, small cell lung cancer and breast cancer; for other types of cancer, Such as prostate cancer, nasopharyngeal cancer, etc. also have certain curative effect. However, ...

Claims

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Application Information

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IPC IPC(8): A61K31/352A61K31/337A61K47/61A61K9/51A61P35/00
CPCA61K31/352A61K31/337A61K47/61A61K9/5161A61P35/00A61K2300/00
Inventor 翟光喜杨小叶程慧玲
Owner SHANDONG UNIV
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