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Reductively-responsive paclitaxel prodrug and preparation method for nano-micelle carrier

A nanomicelle, paclitaxel technology, which is applied in pharmaceutical formulations, medical preparations with non-active ingredients, and medical preparations containing active ingredients, etc., can solve the problems of limited drug encapsulation efficiency and drug loading, and achieve drug release. Significantly rapid, increased drug loading, and improved stability

Inactive Publication Date: 2016-11-09
NANJING MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most of them still construct carrier materials first, and then carry out drug entrapment, and the encapsulation efficiency and drug loading capacity of drugs are still very limited.

Method used

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  • Reductively-responsive paclitaxel prodrug and preparation method for nano-micelle carrier
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  • Reductively-responsive paclitaxel prodrug and preparation method for nano-micelle carrier

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] According to the following synthetic route, 11.7 mg of dithioglycolic acid, 5 mL of dichloromethane, and 55.5 mg of HBTU (O-benzotriazole-tetramethylurea) were added to a 50-ml round-bottomed flask, stirred magnetically, and in an ice-water bath. Fluorophosphate 0.146mmol), 58μL DIPEA (N,N-diisopropylethylamine, 0.351mmol) was slowly added dropwise, after 20 minutes of reaction, 100mg PTX (0.117mmol) was added, nitrogen protection, dark, stirred at room temperature for 20 After hours, the reaction was monitored by thin layer chromatography (TLC:chloroform:methanol=15:1, Rf=0.6). 55 ml of dichloromethane was added to the reaction solution, washed with 10 mL of 5% aqueous sodium bicarbonate solution, 10 mL of 5% glacial acetic acid, and 10 mL of water. The organic layer was dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to obtain the crude product . The reduction-sensitive paclitaxel prodrug PTX-SS-PTX was obtained aft...

Embodiment 2

[0028] According to the synthetic route, 20 mg of dithiodibenzoic acid and 60 mg of HBTU were dissolved in 6 ml of dichloromethane, and 60 μL of DIPEA was slowly added dropwise in an ice bath. After 20 minutes of reaction, 90 mg of docetaxel was added, nitrogen protection, and dark , stirred at room temperature for 20 hours, and monitored the reaction by thin layer chromatography (TLC:chloroform:methanol=15:1). 55 ml of dichloromethane was added to the reaction solution, washed with 10 mL of 5% aqueous sodium bicarbonate solution, 10 mL of 5% glacial acetic acid, and 10 mL of water. The organic layer was dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to obtain the crude product . The reduction-sensitive docetaxel prodrug PTX-SS-PTX was obtained after purification by silica gel column chromatography with chloroform:methanol=100:1.

Embodiment 3

[0029] Example 3: Preparation of Nanomicellar Carrier

[0030] Using the solvent evaporation method, 30mg PTX-SS-PTX and 10mg MePEG-DSPE were dissolved in 10mL of absolute ethanol, slowly added dropwise to 100mL of deionized water, stirred, and the ethanol was removed by rotary evaporation at 65 °C, respectively, after passing 0.8 μm and 0.45 μm The microporous filter membrane was obtained to obtain the nanomicelle carrier.

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Abstract

The invention discloses a reductively-responsive paclitaxel prodrug. The reductively-responsive paclitaxel prodrug is synthesized from paclitaxel (PTX) and dithiodicarboxylic acid in a mol ratio of 2: 1 through covalent combination via an ester bond, and the molecular structure of the synthesized paclitaxel prodrug is PTX-SS-PTX. A PTX prodrug nano-micelle carrier is mainly composed of PTX-SS-PTX and distearoyl-phosphatidylethanolamine-polyethylene glycol (DSPE-PEG). According to the PTX-SS-PTX prodrug in the invention, a disulfide bond can rotate freely; and on the condition that the paclitaxel prodrug and a paclitaxel prodrug nano-micelle drug delivery system provided by the invent are stimulated by a high-concentration glutathione reductive environment in tumor cells, the disulfide bond breaks, and a parent drug is released. The reductively-responsive paclitaxel prodrug can obviously improve the drug loading capacity and encapsulation efficiency of PTX and improves stability of a PTX nanometer drug delivery system.

Description

technical field [0001] The present invention relates to the construction of an anti-tumor taxol prodrug with reduction response and its nano-micellar carrier. Background technique [0002] Paclitaxel is a new broad-spectrum anticancer drug that has been widely used in clinic in recent years, and can be widely used in the treatment of various tumors. Paclitaxel has good antitumor activity, but its solubility in water is low and oral bioavailability is poor. Therefore, in clinical use, surfactant polyoxyethylene castor oil (Cremophor EL) should be added to the injection to improve the solubility of paclitaxel in water. . However, Cremophor EL releases histamine when it is degraded in the body, which can lead to severe allergic reactions; it can also form tiny particles in the blood and encapsulate the paclitaxel molecules, thereby affecting the diffusion of drug molecules to tissues and affecting the anti-tumor effect. In order to reduce adverse reactions and improve efficac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D305/14A61K31/337A61K9/107A61P35/00
CPCA61K9/1075A61K47/24C07D305/14
Inventor 辛洪亮王秀珍徐群为江艳吕玲燕吕伟
Owner NANJING MEDICAL UNIV
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