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Water-soluble polyglutamic acid-cisplatin compound and preparation method and application thereof

A technology of polyglutamic acid and water-soluble poly, which is used in the field of preparation of anticancer drugs, can solve the problems of incomplete removal of small molecules, serious solution volume expansion, and difficulty in large-scale production, and achieves low production costs and high blood pressure. The effect of low therapeutic concentration and equipment requirements

Inactive Publication Date: 2015-08-05
FANTAI INST OF CHEM MEDICINES NANJING
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] (5) In the process of preparing γ-polyglutamic acid derivatives and drug-loaded micelles, the purification step adopts the dialysis bag method. This method cannot completely remove unreacted small molecules, and the purification time is relatively long. The volume expansion of the solution is serious, it is difficult to freeze-dry, and it is difficult to produce on a large scale

Method used

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  • Water-soluble polyglutamic acid-cisplatin compound and preparation method and application thereof
  • Water-soluble polyglutamic acid-cisplatin compound and preparation method and application thereof
  • Water-soluble polyglutamic acid-cisplatin compound and preparation method and application thereof

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Embodiment 1

[0054] Synthesis and structure characterization of γ-polyglutamic acid-citrate

[0055] Take about 3.04g of γ-polyglutamic acid, weigh it accurately, add 100mL of water, stir for 30min to dissolve, add EDC·HCl3.84g, DMAP1.22g, and stir in ice bath for 60min. Take 3.84g of anhydrous citric acid, accurately weighed, add to the above solution, stir to dissolve. Adjust its pH to about 7.5 with NaOH solution, and react at room temperature for 18 hours. Afterwards, the reaction solution was placed in an ultrafilter (the molecular weight of the filter bag was 10 kDa), and concentrated by ultrafiltration until the concentrated solution was colorless and transparent, and the pH of the filtrate was neutral. The concentrated solution is taken out and freeze-dried to obtain gamma-polyglutamic acid-citrate.

[0056] Structural characterization Take an appropriate amount of dry pure product of γ-polyglutamic acid-citrate, expressed as D 2 O is the solvent, the test temperature is 25°C, t...

Embodiment 2

[0058] Preparation of γ-polyglutamic acid-citric acid-cisplatin complex

[0059] Take an appropriate amount of γ-polyglutamic acid-citrate, accurately weigh it, and add it to 100mL of water to dissolve. Take an appropriate amount of cisplatin, weigh it accurately, add it to the above reaction solution, dissolve the cisplatin fully in a 37°C water bath, adjust its pH to 7.0-7.5 with NaOH, react in the dark for 48 hours at room temperature, and then freeze-dry to obtain γ-polymer Glutamate-cisplatin polymer drug complex.

Embodiment 3

[0061] Determination of molecular weight of γ-polyglutamic acid-citrate and γ-polyglutamic acid-citric acid-cisplatin complex

[0062] GPC determination conditions: the mobile phase is 0.2mol / L sodium sulfate solution with pH 4.0 (acetic acid is used as a pH regulator); the flow rate is 1mL min -1 ;Column temperature is 35°C; Injection volume 20μL; Detector: RID-10A; Chromatographic column model: OHpak SB-806MHQ, 300mm, Shodex.

[0063] Dextran standards with different molecular weights were used to make calibration curves, and the calculated molecular weights of the γ-polyglutamic acid-citrate and γ-polyglutamic acid-citric acid-cisplatin complexes were 9-12 kDa and 24-26 kDa, respectively.

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Abstract

The invention is a continuation of the patent CN102499986A ''a macromolecule-cisplatin compound and its preparation method and application'', the content and claim of which are both suitable for the invention. The invention relates to a water-soluble polyglutamic acid-cisplatin compound and provides a preparation method and an application of the compound. The invention belongs to the field of a bio-medical technology. According to the invention, gamma-polyglutamic acid prepared by biological fermentation is used as a raw material, and a small molecular modifier and an active group at the side chain of the gamma-polyglutamic acid react to prepare a gamma-polyglutamic acid derivative; and then, cisplatin reacts with a modified carrier to prepare a drug-loaded compound containing free cisplatin as well as combined cisplatin. Water solubility of the water-soluble polyglutamic acid-cisplatin compound is remarkably enhanced than water solubility of existing cisplatin compounds, and utilization rate of cisplatin is raised. The water-soluble polyglutamic acid-cisplatin compound has a more excellent anti-tumor effect than cisplatin, and toxicity in vivo of the water-soluble polyglutamic acid-cisplatin compound is obviously reduced.

Description

Technical field: [0001] The invention relates to a water-soluble polyglutamic acid-cisplatin complex, and provides a preparation method, an evaluation method and an application of the complex for treating tumors and cancers, and belongs to the field of preparation of anticancer drugs. Background technique: [0002] Cisplatin [cis-dichlorodiammineplatinum (Ⅱ), CDDP] is a heavy metal complex, which is widely used in the treatment of various malignant tumors clinically, and has a broad anticancer spectrum. The principle of cisplatin's anti-tumor effect is: Pt after cisplatin hydrolysis 2+ It can cross-link with the bases in the double-strand of DNA to form a stable complex, thereby causing DNA damage, affecting DNA replication and transcription, further inhibiting the synthesis of cellular DNA, leading to cell death or apoptosis. In practical application, cisplatin often produces serious side effects after administration, which is unacceptable to patients, and while achieving ...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K33/24A61P35/00
Inventor 涂家生吴建梅蒋薇薇
Owner FANTAI INST OF CHEM MEDICINES NANJING
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