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Preparation method and application of cytarabine-modified methotrexate-loaded liposome

A technology of carrying methotrexate lipids and carrying methotrexate, which is applied in the field of biomedicine and can solve the problems of high disease recurrence rate, low specificity of methotrexate, and serious side effects

Active Publication Date: 2020-09-04
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The purpose of the present invention is to provide a cytarabine-modified methotrexate-loaded liposome in order to address the shortcomings of methotrexate in the treatment of trophoblastic tumors, such as low specificity, serious side effects, and high disease recurrence rate. Preparation,

Method used

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  • Preparation method and application of cytarabine-modified methotrexate-loaded liposome
  • Preparation method and application of cytarabine-modified methotrexate-loaded liposome
  • Preparation method and application of cytarabine-modified methotrexate-loaded liposome

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] 1. Cytarabine-PEG 2k -DSPE synthesis:

[0030] (1) Precisely weigh 140.00mg DSPE-PEG 2k -COOH (MW: 2800), dissolve in 10ml of dimethylformamide and shake well. Then accurately weighed 14.60mg cytarabine (MW: 243.22), 22.80mg 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate ( HATU), triethylamine, and 1-hydroxybenzotriazole (HOBt) were sequentially added to the above dimethylformamide solution system, and stirred in an ice bath for 3 hours, where DSPE-PEG 2k The molar ratio of COOH, cytarabine, HATU, HOBt and triethylamine is 1:1.2:1.2:1.2:2.

[0031] (2) After (1) the reaction is completed, the reaction system is moved to a dialysis bag with a molecular weight cut-off of 3500 Da, and dialyzed in 1000 ml of deionized water for 72 hours, changing the deionized water every 6 hours.

[0032] (3) After the dialysis, the liquid in the dialysis bag is cooled by program and freeze-dried for 48 hours to obtain Cytarabine-PEG 2k -DSPE.

[0033] 2. Preparation of c...

Embodiment 2

[0043] 1. Cytarabine-PEG 2k -DSPE synthesis:

[0044] (1) Precisely weigh 140.00mg DSPE-PEG 2k -COOH (MW: 2800), dissolve in 10ml of dimethylformamide and shake well. Then accurately weighed 14.60mg cytarabine (MW: 243.22), 22.80mg 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate ( HATU), triethylamine, and 1-hydroxybenzotriazole (HOBt) were sequentially added to the above dimethylformamide solution system, and stirred in an ice bath for 3 hours, where DSPE-PEG 2k The molar ratio of COOH, cytarabine, HATU, HOBt and triethylamine is 1:2:1.2:1.2:2.

[0045] (2) After (1) the reaction is completed, the reaction system is moved to a dialysis bag with a molecular weight cut-off of 3500 Da, and dialyzed in 1000 ml of deionized water for 72 hours, changing the deionized water every 6 hours.

[0046] (3) After the dialysis, the liquid in the dialysis bag is cooled by program and freeze-dried for 48 hours to obtain Cytarabine-PEG 2k -DSPE.

[0047] 2. Preparation of cyt...

Embodiment 3

[0055] 1. Cytarabine-PEG 2k -DSPE synthesis:

[0056] (1) Precisely weigh 140.00mg DSPE-PEG 2k -COOH (MW: 2800), dissolve in 10ml of dimethylformamide and shake well. Then accurately weigh 14.60mg cytarabine (MW: 243.22), 22.80mg 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate ( HATU), triethylamine, and 1-hydroxybenzotriazole (HOBt) were added to the above dimethylformamide solution system in sequence, and stirred in an ice bath for 5 hours, where DSPE-PEG 2k The molar ratio of COOH, cytarabine, HATU, HOBt and triethylamine is 1:1.2:1.2:1.2:2.

[0057] (2) After (1) the reaction is completed, the reaction system is moved to a dialysis bag with a molecular weight cut-off of 3500 Da, and dialyzed in 1000 ml of deionized water for 72 hours, changing the deionized water every 6 hours.

[0058] (3) After the dialysis, the liquid in the dialysis bag is cooled by program and freeze-dried for 48 hours to obtain Cytarabine-PEG 2k -DSPE.

[0059] 2. Preparation of cyta...

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Abstract

The invention provides preparation and application of a cytarabine-modified methotrexate-loaded liposome. The liposome is prepared by taking phospholipid, cholesterol, cytarabine-PEG2k-DSPE and methotrexate as raw materials and adopting a membrane dispersion method combined with an ultrasonic and high-pressure homogenization method through dissolution, membrane formation, hydration, ultrasonic andhigh-pressure homogenization and freeze-drying. The liposome prepared by the method has a particle diameter of about 125 nanometers, a dispersion coefficient of 0.218, a drug loading capacity of themethotrexate of about 10.37% and an entrapment ratio of about 85.26%. Nucleoside transporters 1 on the surfaces of choriocarcinoma cells can specifically recognize cytarabine and mediate the cytarabine-modified methotrexate-loaded liposome into the cells, thereby increasing the cytotoxicity of the drug. The cytarabine-modified methotrexate-loaded liposome has a simple preparation process, is easyto produce on a large scale, and provides a novel pharmaceutical preparation for the treatment of choriocarcinoma.

Description

Technical field [0001] The invention belongs to the field of biomedicine, and specifically relates to a preparation method of a methotrexate-loaded liposome modified with cytarabine and its application in the treatment of trophoblastic tumors. Background technique [0002] With the promulgation of my country's comprehensive two-child policy, women's demand for reproductive growth has increased sharply, and the incidence of gestational trophoblastic tumors (including choriocarcinoma) has further increased significantly. If not diagnosed early or treated improperly, gestational trophoblastic tumors may cause severe bleeding, rupture of the uterus, removal of the uterus, etc., seriously threatening women's reproductive health and even life. Methotrexate is the first-line drug for the treatment of gestational trophoblastic tumors. However, when methotrexate is administered systemically, it has poor specific distribution ability. It is prone to liver damage, abdominal pain, gastrointe...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/127A61K47/26A61K31/519A61P35/00
CPCA61K9/127A61K31/519A61K47/26A61P35/00
Inventor 费伟东郑彩虹秦佳乐孙东黎赵云春郑晓玲陈玥吴晓东
Owner ZHEJIANG UNIV
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