Anti-tumor medicine coupler decorated with saturated fatty acid and self-assembling nanometer system and preparation method of anti-tumor medicine coupler

Abstract

The invention relates to an anti-tumor medicine coupler decorated with saturated fatty acid and a self-assembling nanometer system and preparation method of the coupler. Firstly, the coupler obtained by decorating the structure of the anti-tumor medicine with different types of saturated fatty acid can be self-assembled into spherical nanoparticles uniform in granularity and high in stability in water; secondly, after any amphiphilic polymer material such as DSPE-PEG is added in the preparation process, the granularity of the self-assembled nanoparticles can be decreased, and the stability of the nanoparticles can be improved. By means of the method, the anti-tumor medicine where nanoparticles can hardly be self-assembled can be endowed with the self-assembling capacity, only one step of reaction is needed during synthesis, and the method is easy and convenient to implement; meanwhile, compared with a traditional carrier dependence type nanometer system and an amphiphilic prodrug micelle system, the self-assembling system has higher medicine loading capacity and higher stability; the preparation method is easier to implement and beneficial to industrial production and provides a new concept for design and establishment of nanometer medicines.

Description

technical field

[0001] The invention relates to the technical field of nano drug preparations, in particular to an antitumor drug conjugate based on saturated fatty acid modification, a self-assembled nano system and a preparation method. Background technique

[0002] The nano-drug delivery system of poorly soluble antitumor drugs has always been a research hotspot for pharmaceutical workers. In order to solubilize poorly soluble drugs, researchers usually use a large number of solubilizing carriers or excipients. For example, in order to solubilize paclitaxel, Taxol added A large amount of polyoxyethylene castor oil, and this excipient can cause significant adverse reactions. In addition, poorly soluble drugs are usually limited by the drug loading capacity of the carrier system, and insufficient drug loading affects the use and development of drugs. Contents of the invention

[0003] The present invention makes up for the deficiencies in the prior art and provides an an...

Examples

Embodiment 1

[0106] Embodiment 1: the synthesis of stearic acid-SN38

[0107] Under nitrogen protection, 7-ethyl-10-hydroxycamptothecin (40mg, 0.1mmol) was dissolved in an appropriate amount of anhydrous N,N-dimethylformamide, and dimethylaminopyridine (14.4mg, 0.1mmol ) and dicyclohexylcarbodiimide (24.6mg, 0.2mmol), stearic acid (29mg, 0.1mmol) was added under stirring conditions, and the stirring reaction at room temperature was continued for 12 hours. Remove the precipitate by filtration, mix the filtrate with an appropriate amount of silica gel, dry under reduced pressure and vacuum, separate and purify the sample by silica gel column chromatography, use petroleum ether: acetone (6:1) as the eluent, collect the eluate containing the sample, and blow it with nitrogen at room temperature drying or vacuum drying under reduced pressure to obtain a stearic acid-SN38 conjugate (yield 65%).

Embodiment 2

[0108] Embodiment 2: the synthesis of palmitic acid-doxorubicin

[0109] Under nitrogen protection, dissolve doxorubicin (55mg, 0.1mmol) in an appropriate amount of anhydrous dichloromethane, add O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU, 115mg, 0.15mmol) And N,N-diisopropylethylamine (100mg, 0.77mmol), then add palmitic acid (26mg, 0.1mmol), and continue stirring at room temperature for 12 hours. Remove the precipitate by filtration, mix the filtrate with an appropriate amount of silica gel, dry under reduced pressure and vacuum, separate and purify the sample by silica gel column chromatography, use petroleum ether: acetone (6:1) as the eluent, collect the eluate containing the sample, and blow it with nitrogen at room temperature Drying or vacuum drying under reduced pressure to obtain the palmitic acid-doxorubicin conjugate (yield 60%).

Embodiment 3

[0110] Embodiment 3: the synthesis of stearic acid-vinblastine

[0111] Under nitrogen protection, vinblastine (91 mg, 0.1 mmol) was dissolved in an appropriate amount of anhydrous dichloromethane, and dimethylaminopyridine (14.4 mg, 0.1 mmol) and dicyclohexylcarbodiimide (24.6 mg, 0.2 mmol), stearic acid (29mg, 0.1mmol) was added under stirring conditions, and the stirring reaction at room temperature was continued for 12 hours. Remove the precipitate by filtration, mix the filtrate with an appropriate amount of silica gel, dry under reduced pressure and vacuum, separate and purify the sample by silica gel column chromatography, use petroleum ether: acetone (6:1) as the eluent, collect the eluate containing the sample, and blow it with nitrogen at room temperature Drying or vacuum drying under reduced pressure, the palmitic acid-doxorubicin conjugate (yield 63%) was obtained.

technical field

[0001] The invention relates to the technical field of nano drug preparations, in particular to an antitumor drug conjugate based on saturated fatty acid modification, a self-assembled nano system and a preparation method. Background technique

[0002] The nano-drug delivery system of poorly soluble antitumor drugs has always been a research hotspot for pharmaceutical workers. In order to solubilize poorly soluble drugs, researchers usually use a large number of solubilizing carriers or excipients. For example, in order to solubilize paclitaxel, Taxol added A large amount of polyoxyethylene castor oil, and this excipient can cause significant adverse reactions. In addition, poorly soluble drugs are usually limited by the drug loading capacity of the carrier system, and insufficient drug loading affects the use and development of drugs. Contents of the invention

[0003] The present invention makes up for the deficiencies in the prior art and provides an an...

Examples

Embodiment 1

[0106] Embodiment 1: the synthesis of stearic acid-SN38

[0107] Under nitrogen protection, 7-ethyl-10-hydroxycamptothecin (40mg, 0.1mmol) was dissolved in an appropriate amount of anhydrous N,N-dimethylformamide, and dimethylaminopyridine (14.4mg, 0.1mmol ) and dicyclohexylcarbodiimide (24.6mg, 0.2mmol), stearic acid (29mg, 0.1mmol) was added under stirring conditions, and the stirring reaction at room temperature was continued for 12 hours. Remove the precipitate by filtration, mix the filtrate with an appropriate amount of silica gel, dry under reduced pressure and vacuum, separate and purify the sample by silica gel column chromatography, use petroleum ether: acetone (6:1) as the eluent, collect the eluate containing the sample, and blow it with nitrogen at room temperature drying or vacuum drying under reduced pressure to obtain a stearic acid-SN38 conjugate (yield 65%).

Embodiment 2

[0108] Embodiment 2: the synthesis of palmitic acid-doxorubicin

[0109] Under nitrogen protection, dissolve doxorubicin (55mg, 0.1mmol) in an appropriate amount of anhydrous dichloromethane, add O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU, 115mg, 0.15mmol) And N,N-diisopropylethylamine (100mg, 0.77mmol), then add palmitic acid (26mg, 0.1mmol), and continue stirring at room temperature for 12 hours. Remove the precipitate by filtration, mix the filtrate with an appropriate amount of silica gel, dry under reduced pressure and vacuum, separate and purify the sample by silica gel column chromatography, use petroleum ether: acetone (6:1) as the eluent, collect the eluate containing the sample, and blow it with nitrogen at room temperature Drying or vacuum drying under reduced pressure to obtain the palmitic acid-doxorubicin conjugate (yield 60%).

Embodiment 3

[0110] Embodiment 3: the synthesis of stearic acid-vinblastine

[0111] Under nitrogen protection, vinblastine (91 mg, 0.1 mmol) was dissolved in an appropriate amount of anhydrous dichloromethane, and dimethylaminopyridine (14.4 mg, 0.1 mmol) and dicyclohexylcarbodiimide (24.6 mg, 0.2 mmol), stearic acid (29mg, 0.1mmol) was added under stirring conditions, and the stirring reaction at room temperature was continued for 12 hours. Remove the precipitate by filtration, mix the filtrate with an appropriate amount of silica gel, dry under reduced pressure and vacuum, separate and purify the sample by silica gel column chromatography, use petroleum ether: acetone (6:1) as the eluent, collect the eluate containing the sample, and blow it with nitrogen at room temperature Drying or vacuum drying under reduced pressure, the palmitic acid-doxorubicin conjugate (yield 63%) was obtained.

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