Preparation method of folic acid modified Pluronic P85 copolymer and application of folic acid modified Pluronic P85 copolymer in 5-fluorouracil nano drug

A technology of fluorouracil and P85-NH2, which is applied in the field of pharmaceutical applications, can solve the problems of inconvenient clinical use, toxic and side effects, and restrictions on wide application, and achieve the effects of low toxic and side effects, growth inhibition, and good therapeutic effect

Active Publication Date: 2014-12-17
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004]5-fluorouracil (5-Fu) is the preferred chemotherapy drug for colorectal cancer, but 5-Fu has severe bone marrow suppression and gastrointestinal toxicity reaction, which largely limits its wide application in clinical
In clinical use, it is necessary to give folic acid (folic acid, FA) preparations in advance to enhance the effect of 5-FU and reduce the toxic and side effects of 5-FU, which is inconvenient for clinical use

Method used

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  • Preparation method of folic acid modified Pluronic P85 copolymer and application of folic acid modified Pluronic P85 copolymer in 5-fluorouracil nano drug
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  • Preparation method of folic acid modified Pluronic P85 copolymer and application of folic acid modified Pluronic P85 copolymer in 5-fluorouracil nano drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1. Synthesis of Folate-modified Pluronic P85 (P85-FA)

[0030]

[0031] (1) Synthesis of N,N'-carbonyldiimidazole (CDI)-activated Pluronic P85 (P85-CDI)

[0032]The synthesis of P85-CDI adopted the method in the literature ([1] W. Zhang, Y. Shi, Y. Chen, J. Ye, X. Sha, X. Fang, Multifunctional Pluronic P123 / F127 mixed polymeric micelles loaded with paclitaxel for the treatment of multidrug resistant tumors, Biomaterials, 32 (2011) 2894-2906.). Dissolve 1.0 g of Pluronic P85 (0.22 mmol) in 7 mL of dry acetonitrile, and slowly add dropwise to 7 mL of dry acetonitrile solution containing CDI (0.35 g, 2.15 mmol). Under the protection of nitrogen, the reaction was stirred overnight at room temperature. After the reaction was complete, the solution was concentrated under reduced pressure and poured into excess diethyl ether. Excess CDI was removed by centrifugation at a speed of 10,000 rpm, and the ether layer was collected. This step was repeated three times...

Embodiment 2

[0037] Example 2. Preparation of P85-FA / 5-Fu

[0038] Preparation of P85-FA / 5-Fu micelles: Using thin film hydration method, take 300 mg of P85-FA and a certain amount of 5-Fu in a 50 mL round-bottomed flask, dissolve them with an appropriate amount of acetonitrile, and heat them at 60 °C under 100 r / min rotary evaporation for 1 h to evaporate the organic solvent to dryness, and vacuum-dry for 5 h to remove the residual organic solvent to obtain a dry film. Heated in a water bath to dissolve the solid skeleton to obtain a transparent gel-like sample. Add 10 mL of isothermal purified water, stir at a constant speed for 30 min (700 r / min), and filter with a 0.22 μm membrane to obtain the P85-FA / 5-Fu micellar solution.

Embodiment 3

[0039] Example 3. Determination of P85-FA / 5-Fu Particle Size

[0040] The particle size of P85-FA / 5-Fu was measured with a Malvern particle size analyzer. The particle size measurement parameters were as follows: He-Ne laser (wavelength 635 nm), refractive index and viscosity were n=1.330 and η=0.888 cp, and the measurement temperature at 25°C. The sample concentration was 0.4 mg / ml. The particle size of the constructed P85-FA / 5-Fu is between 10-100 nm. (see attached figure 2 )

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Abstract

The invention relates to the technical field of biological medicines, firstly provides a folic acid modified Pluronic P85 copolymer and also relates to a preparation method of a 5-fluorouracil anti-cancer nano drug. Experiments show that the 5-fluorouracil nano drug prepared by adopting the folic acid modified Pluronic P85 copolymer can be used for obviously inhibiting tumour cell growth; meanwhile, in a mouse colonic carcinoma hepatic metastasis model, formation of colonic carcinoma liver metastases can be obviously reduced, and lifetime of a mouse can be obviously prolonged, so that the folic acid modified Pluronic P85 copolymer has a good effect on resisting colonic carcinoma hepatic metastasis, and the 5-fluorouracil anti-cancer nano drug is hopeful to be an anti-tumour drug with a clinical application prospect.

Description

technical field [0001] The present invention relates to the technical field of pharmaceutical application, in particular to the preparation of folic acid-modified Pluronic P85 copolymer (P85-FA). The present invention also relates to the preparation of 5-fluorouracil anticancer nanomedicine, especially in the Use in liver metastases from rectal cancer. Background technique [0002] Colorectal cancer is one of the common malignant tumors, which can occur in any part of the colorectum. Its incidence is increasing year by year worldwide, and it has become one of the three major cancers that cause patient death. Colorectal cancer metastases mostly occur in the liver, and it is reported that 30-40% of patients have liver metastases in the early stage of the disease; while in the late stage of the disease, 95% of the patients have liver metastases, and the death of colorectal cancer patients is more common for the development of liver metastases. Although there are a variety of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/34A61K47/22A61K9/51A61K31/513A61P35/00A61P35/04
Inventor 张黎侯静范婷婷朱鹏熹盛丹丹马建丽赵娜萍宋云龙张姗姗韩志鹏卫立辛芮耀诚辛海量刘厚佳
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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