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Intelligent hydrogel of podophyllotoxin derivative and preparation and application of intelligent hydrogel of podophyllotoxin derivative

A technology of podophyllotoxin and deoxypodophyllotoxin, which is applied in the field of biomedicine, can solve the problems of difficult control of colon targeting effect and high toxicity of degradation products.

Active Publication Date: 2019-09-20
LANZHOU INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the carrier research of flora-triggered drug delivery system mainly uses polysaccharides or azo polymer materials alone. Azo polymers have high targeting and accurate positioning, but their degradation products are highly toxic and polysaccharides Carbohydrate materials have good biocompatibility and unique pH-sensitive properties, but their colon-targeting effect is difficult to control

Method used

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  • Intelligent hydrogel of podophyllotoxin derivative and preparation and application of intelligent hydrogel of podophyllotoxin derivative
  • Intelligent hydrogel of podophyllotoxin derivative and preparation and application of intelligent hydrogel of podophyllotoxin derivative
  • Intelligent hydrogel of podophyllotoxin derivative and preparation and application of intelligent hydrogel of podophyllotoxin derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] 1. Preparation of aldylated dextran (AD)

[0051] Dextran (M n = 40000, 3.0 g), dissolved in 100 mL water, added sodium periodate (4.0 g), stirred at room temperature for 2 h, then added ethylene glycol (1.2 g), stirred at room temperature for 2 h, transferred to pure water for dialysis for 48 h , freeze-dried to obtain the target product (2.4 g, yield 80%).

[0052] 2, 4´- O -Nor-4 β - Preparation of p-diaminoazobenzene-4-deoxypodophyllotoxin (GL331-azo)

[0053] (1) Intermediate 4´- O -Nor-4 β -Synthesis of bromo-4-deoxypodophyllotoxin: Dissolve norepipodophyllotoxin (1.0 g, 2.4 mmol) in 25 mL of dry dichloromethane, cool to 0°C in an ice bath, pass through dry bromide Hydrogen gas for 45 min, followed by N 2 Remove excess hydrogen bromide, and concentrate under reduced pressure to obtain the target compound (1.1 g);

[0054] (2) 4´- O -Nor-4 β -Synthesis of p-diaminoazobenzene-4-deoxypodophyllotoxin (GL331-azo): take intermediate 4´- O -Nor-4 β -Bromo-4-...

Embodiment 2

[0060] 1. Preparation of aldylated dextran (AD): same as Example 1;

[0061] 2. Preparation of GL331-azo: Same as Example 1;

[0062]3. Preparation of aldylated dextran (AD-GL331) bonded with podophyllotoxin derivatives

[0063] Aldylated dextran AD (420 mg) was dissolved in 55 mL of dimethylformamide, then GL331-azo (110 mg) was added, stirred at 75 °C for 24 h, dialyzed in pure water for 72 h, and lyophilized. The target product (450 mg) was obtained with a yield of 84.9%;

[0064] 4. Preparation of podophyllotoxin derivatives loaded with 5-fluorouracil hydrogel

[0065] Dissolve AD-GL331 (30 mg) in 1 mL of water, add 5 mg of 5-fluorouracil, sonicate for 5 min, then add 1 mL of carboxymethyl chitosan aqueous solution (4wt%), sonicate for 2 min, let stand for 2 h, The multi-responsive hydrogel loaded with podophyllotoxin derivatives and 5-fluorouracil is obtained.

Embodiment 3

[0067] 1. Preparation of aldylated dextran (AD): same as Example 1;

[0068] 2. Preparation of GL331-azo: Same as Example 1;

[0069] 3. Preparation of aldylated dextran (AD-GL331) bonded with podophyllotoxin derivatives: same as Example 2;

[0070] 4. Preparation of podophyllotoxin derivative-loaded cisplatin hydrogel: Dissolve AD-GL331 (40 mg) in 1 mL water, add 3 mg cisplatin, sonicate for 5 min, then add 1 mL carboxymethyl chitosan Aqueous solution (2wt%), sonicated for 2 min, and left to stand for 2 h, the multi-responsive hydrogel loaded with podophyllotoxin derivatives and cisplatin was obtained.

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Abstract

The invention discloses a preparation method of intelligent hydrogel of a podophyllotoxin derivative. The method includes steps: preparing aldehyde glucan, bonding the podophyllotoxin derivative to a glucan chain through Schiff base reaction; subjecting to cross linking with carboxymethyl chitosan to form the intelligent hydrogel of the podophyllotoxin derivative. The hydrogel is capable of effectively improving water solubility of the podophyllotoxin derivative, and by a highly-hydrophilic internal structure of the hydrogel, a water-soluble anticancer drug can be further wrapped during hydrogel formation, and drug combination is realized. According to in-vitro drug release behaviors, the hydrogel has acid-base, reductant and enzyme sensitive multi-response drug release behaviors and is capable of releasing the podophyllotoxin derivative in a colon environment, thereby serving as a colon-targeted multi-drug controlled-release carrier for preparing colon-targeted controlled-release drugs.

Description

technical field [0001] The invention relates to a multi-responsive smart hydrogel, in particular to a podophyllotoxin derivative multi-responsive smart hydrogel and a preparation method thereof, which is mainly used as a drug carrier for the preparation of colon-targeted slow-release drugs, and belongs to Biomedical field. Background technique [0002] Podophyllotoxin is a lignan compound with excellent anti-tumor activity. Its derivatives are widely used in the treatment of cancers including small cell lung cancer, colon cancer, and lymphoma. Two drugs, poside, are used clinically. In view of the problems of poor water solubility and drug resistance of podophyllotoxin compounds, the current research on podophyllotoxin focuses on three aspects. One is to synthesize a large number of podophyllotoxin derivatives in order to discover the therapeutic effect Better podophyllotoxin derivatives. The second is to use podophyllotoxin derivatives with excellent activity as the rese...

Claims

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Application Information

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IPC IPC(8): A61K9/06A61K47/36A61K47/61A61K47/69A61K31/513A61K31/365A61P35/00
CPCA61K9/06A61K31/365A61K31/513A61K47/36A61K47/61A61K47/6903A61P35/00A61K2300/00
Inventor 哈伟师彦平赵晓博
Owner LANZHOU INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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