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Preparation and application of alpha-polyglutamic acid-cisplatin compound

A technology of polyglutamic acid and complexes, which is applied in the field of preparation of anticancer drugs, can solve the problems of neurotoxicity and gastrointestinal adverse reactions, high liver and kidney toxicity, poor selectivity, etc., and achieve good antitumor effect and drug loading The effect of high dosage and high utilization rate of cisplatin

Inactive Publication Date: 2018-06-22
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, cisplatin has poor selectivity, short half-life, high liver and kidney toxicity, severe neurotoxicity and gastrointestinal adverse reactions, etc. Therefore, it is urgent to develop new platinum-based drugs

Method used

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  • Preparation and application of alpha-polyglutamic acid-cisplatin compound
  • Preparation and application of alpha-polyglutamic acid-cisplatin compound
  • Preparation and application of alpha-polyglutamic acid-cisplatin compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Preparation method and characterization of α-polyglutamic acid-cisplatin complex

[0034] Preparation method: Dissolve γ-benzyl-L-glutamic acid-N-carboxylic acid anhydride in dioxane, add dropwise triethylamine, N 2 After reacting at room temperature for four days, the reaction solution was added dropwise to an appropriate amount of ice ethanol, the precipitate was centrifuged and washed with ethanol three times, and finally the precipitate was vacuum dried at 45° C. to obtain white block polybenzyl glutamate. The polybenzyl glutamate was dissolved in dichloroacetic acid, and an appropriate amount of 33% HBr / acetic acid solution was added to react at room temperature for 4 hours. The reaction solution was dropped into ice ether, the precipitate was centrifuged, and washed with ether three times. The precipitate was dried in vacuum, then dissolved with an appropriate amount of saturated sodium bicarbonate, and lyophilized after dialysis to obtain α-polyglutamic acid. Disso...

Embodiment 2

[0039] Determination of cisplatin in α-polyglutamic acid-cisplatin complex

[0040] A graphite furnace atomic absorption spectrometer was used to determine the content of cisplatin in the composite. Detection conditions: wavelength 265.9nm, lamp current 6mA; slit width 0.2mm; sample volume 20μl; protective gas is high purity argon (Ar, 0.2L / min). Take the concentration as 10 6 The ng / ml platinum standard solution is the mother solution. The mother solution is diluted into a standard solution with a concentration of 40, 80, 120, 160, 200 μg / ml. The concentration is the abscissa and the absorption value is the ordinate to calculate the standard curve. The absorption value of the complex aqueous solution was determined after digestion and dilution with nitric acid. The content of cisplatin can be calculated from Biaoqu. It was determined that the utilization rate of cisplatin in Example 1 was greater than 80%, and the drug loading was greater than 28%. The calculation formula for ...

Embodiment 3

[0044] Study on the release of α-polyglutamic acid-cisplatin compound in vitro

[0045] Put 5ml of α-polyglutamic acid-cisplatin complex solution (0.2mg / ml) in a dialysis bag (with a molecular weight cut-off of 3.5kDa), and add 25ml of a PBS solution with a chloride ion concentration of 150mmol / L (pH 7.4). ) Mix and place in a constant temperature shaking box at 37°C. Take 1ml samples at different time periods (1, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144h) and save them for later use. At the same time, add 1ml of new PBS solution and use graphite furnace atom The absorption meter detects the amount of free cisplatin released and calculates its cumulative release rate. The results are shown in Figure 4 .

[0046] Figure 4 The results show that the α-polyglutamic acid-cisplatin complex has no burst release under physiological pH conditions and can be released slowly, and the cumulative release rate of 144h reaches 75%.

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Abstract

The invention relates to preparation and an application of an alpha-polyglutamic acid-cisplatin compound. Alpha-polyglutamic acid is obtained after ring opening polymerization of gamma-benzyl-L-glutamic acid-N-carboxylic acid anhydride and removal of a protecting group. Alpha-polyglutamic acid has good water solubility, has multiple free carboxyl groups and can be combined with multiple antitumordrugs to form polymer drug compounds, and cisplatin and alpha-polyglutamic acid form the alpha-polyglutamic acid-cisplatin compound with high drug loading capacity through ligand exchange coordination. In-vivo and in-vitro activity study indicates that the compound has high cisplatin utilization rate, has a slow release characteristic, can effectively inhibit tumor growth of mice with tumor and significantly prolong the lifetime of the mice with tumor and has high safety and great application prospects.

Description

Technical field [0001] The invention relates to an α-polyglutamic acid-cisplatin complex, and provides a preparation method and application of the complex, and belongs to the field of preparation of anticancer drugs. Background technique [0002] Due to the strong ability of tumor cells to invade and metastasize, malignant tumors are becoming the second leading cause of human mortality. Currently, chemotherapeutic drugs for the treatment of tumors mainly include cisplatin, paclitaxel, docetaxel, gemcitabine and so on. Although these drugs have good anti-tumor effects, their toxic and side effects are also very obvious. Therefore, the clinical use of drugs has great limitations and patients have poor compliance. [0003] Cisplatin (CDDP) is cytotoxic, is a non-specific cell cycle drug, and is one of the broad-spectrum anticancer drugs widely used in clinical practice. The principle of cisplatin killing tumor cells is: cisplatin enters the nucleus and cross-links with DNA bases to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K33/24A61K47/64A61P35/00
Inventor 涂家生王慧敏熊晔蓉
Owner CHINA PHARM UNIV
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