In-situ self-assembled tetravalent platinum drug, preparation method and application thereof

A tetravalent platinum and self-assembly technology, applied in the field of nano-biomedical materials, can solve the problems of limited toxic and side effects, drug resistance and toxic and side effects not completely overcome, and high drug tolerance, so as to increase intake, prolong residence time, The effect of increasing intake

Pending Publication Date: 2020-08-07
INST OF RADIATION MEDICINE CHINESE ACADEMY OF MEDICAL SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, problems such as drug resistance and high side effects of cisplatin during clinical use have greatly limited its application range.
In order to solve the above problems, scientists have introduced the second-generation and third-generation bivalent platinum drugs represented by carboplatin and oxaliplatin respectively on the basis of cisplatin. Although some disadvantages of cisplatin have been improved to a certain extent, However, problems such as drug resistance and toxic side effects have not been completely overcome

Method used

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  • In-situ self-assembled tetravalent platinum drug, preparation method and application thereof
  • In-situ self-assembled tetravalent platinum drug, preparation method and application thereof
  • In-situ self-assembled tetravalent platinum drug, preparation method and application thereof

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Experimental program
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Embodiment 1

[0045] For the preparation method of in-situ self-assembled tetravalent platinum drug, see the appendix figure 1 , mainly including the following steps:

[0046] 1) Platinum bisuccinate (Pt(OOCCH 2 CH 2 COOH) 2 , 26.7 mg, 0.05 mmol), N-hydroxysuccinimide (NHS, 12.1 mg, 0.105 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC HCl, 20.2 mg, 0.105 mmol) was placed in a round bottom flask, dissolved in 3 mL of anhydrous dimethyl sulfoxide (DMSO), and stirred at room temperature for 12 hours.

[0047] 2) Naproxen-capped short peptide Npx-ffky p (89.6 mg, 0.1 mmol) was added to the above mixture, and the pH of the mixture was adjusted to 8-9 using N,N-diisopropylethylamine (DIEA), and stirring was continued at room temperature for 24 hours. Finally, the product was purified by high performance liquid chromatography using water-methanol solution containing 0.1% trifluoroacetic acid as mobile phase. The product solution separated from the liquid phase is free...

Embodiment 2

[0051] The preparation method of platinum bis-succinate described in embodiment 1 comprises the steps:

[0052] 1) Put cisplatin (500 mg, 1.67 mmol), hydrogen peroxide (30 w / v, 4 mL) and 10 mL of distilled water in a round-bottomed flask, stir at 50 °C for 3 hours, then place the round-bottomed flask in Store overnight at 4°C;

[0053] 2) The filter cake was collected by vacuum filtration, washed three times with cold water, cold ethanol, and cold ether, and finally dried in vacuum to obtain the product cisplatin oxide;

[0054] 3) Disperse cisplatin oxide (200 mg, 0.6 mmol) in 5 mL of anhydrous N,N-dimethylformamide, add succinic anhydride (240 mg, 2.4 mmol), and stir at 70°C for 24 hours;

[0055] 4) The mixture was concentrated under reduced pressure to obtain a light yellow liquid, which was recrystallized by adding acetone at -20°C; the filter cake was collected by vacuum filtration, and washed repeatedly with cold ether to obtain platinum bisuccinate.

[0056] See atta...

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Abstract

The invention discloses an in-situ self-assembled tetravalent platinum drug, a preparation method and application thereof. Cis-platinum is subjected to chemical reaction to generate cis-platinum oxide, and the cis-platinum oxide is further subjected to reaction with lysine residue to covalently modify tyrosine phosphorylated self-assembled short peptide to construct the tetravalent platinum drug.The tetravalent platinum drug can be self-assembled in situ to form supramolecular hydrogel with a nanofiber microstructure under the action of high-expression phosphatase on the surface of a tumor cell. Under the action of glutathione highly expressed in tumor cells, the platinum-containing nanofibers taken by the cells release a bivalent platinum drug to play a role in treatment. The formation of the hydrogel promotes the uptake of platinum drugs by tumor cells and increases the residence time of the platinum drugs in the tumor cells. Compared with traditional cis-platinum, the killing effect of the tetravalent platinum drug on tumor cells is not influenced by cell drug resistance, and the systematic toxicity is obviously reduced.

Description

technical field [0001] The invention belongs to the field of nano-biological medical materials, and relates to an in-situ self-assembled tetravalent platinum drug, a preparation method thereof and an application in reversing tumor cisplatin resistance. Background technique [0002] Cisplatin, as the first divalent platinum drug used in clinical practice, has broad-spectrum anticancer effects and has good therapeutic effects on ovarian cancer, non-small cell lung cancer, gastric cancer, breast cancer and other cancers. However, problems such as drug resistance and high side effects of cisplatin during clinical use greatly limit its application range. In order to solve the above problems, scientists have introduced the second-generation and third-generation bivalent platinum drugs represented by carboplatin and oxaliplatin respectively on the basis of cisplatin. Although some disadvantages of cisplatin have been improved to a certain extent, However, problems such as drug res...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K33/243A61K47/64A61K9/19A61P35/00B82Y5/00
CPCA61K33/243A61K47/64A61K9/19A61P35/00B82Y5/00
Inventor 刘鉴峰王倩杨翠红杨丽军黄帆刘金剑任春华张玉民
Owner INST OF RADIATION MEDICINE CHINESE ACADEMY OF MEDICAL SCI
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