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Albumin binding type anti-tumor drug-maleimide molecule prodrug

A technology of albumin-binding and maleimide, which is applied in the direction of anti-tumor drugs, drug combinations, and pharmaceutical formulations, can solve the problems of lack of tumor targeting, low solubility of anti-tumor drugs, adverse reactions, etc., and achieve Prolonged residence time, increased stability, and good selectivity

Active Publication Date: 2018-06-22
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] At present, chemotherapy is still the main way to treat tumors, but most anticancer drugs are easily degraded and metabolized in the blood due to their low solubility, lack of tumor targeting and serious adverse reactions, etc., which greatly limit their clinical use.

Method used

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  • Albumin binding type anti-tumor drug-maleimide molecule prodrug
  • Albumin binding type anti-tumor drug-maleimide molecule prodrug
  • Albumin binding type anti-tumor drug-maleimide molecule prodrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Synthesis of docetaxel-maleimide prodrugs linked by three different linkages.

[0042] (a) Synthesis of non-sensitive bond ester bond-linked prodrugs (abbreviated as DM): Take 405mg docetaxel (DTX), 116mg maleimidohexanoic acid (EMC) dissolved in dichloromethane, add 210mg Bicyclohexylcarbimide (DCC), 12mg 4-dimethylaminopyridine (DMAP), N 2 The reaction was carried out at room temperature under protection for 12 hours, and the white powder compound DM was obtained by column chromatography.

[0043] (b) Synthesis of reduction-sensitive disulfide bond-linked prodrugs (abbreviated as DSSM): First, the key intermediate N-(2-hydroxyethyl)maleimide (compound 4) is synthesized according to the following synthetic route. Dissolve 30g of maleic anhydride in toluene, add furan, stir at room temperature for 24h to stop the reaction. A white solid precipitated in the solution, collected by filtration, washed with toluene three times, and dried to obtain furan ring-protected maleic anhy...

Embodiment 2

[0056] In vitro binding experiment of three docetaxel-maleimide prodrugs with bovine serum albumin and plasma

[0057] Weigh appropriate amounts of DM, DSSM and DSM and add them to the pH7.4 phosphate buffer of bovine serum albumin so that the prodrug and bovine serum albumin concentrations are 300 μM and 700 μM, respectively. Then the mixed solution was incubated in a constant temperature shaker at 37°C, and samples were taken into the high-performance liquid phase at a specific time point to investigate the binding situation.

[0058] In addition, the above-mentioned bovine serum albumin solution was replaced with rat plasma, and the above operation was repeated to investigate the binding of the three prodrugs to plasma albumin in vitro. And use excess maleimidohexanoic acid to conduct a competitive binding experiment: first add excess maleimidohexanoic acid to the plasma and incubate for 1h, then add each prodrug, take the point into the liquid phase, and investigate the plasma ...

Embodiment 3

[0061] In vitro release experiment of three albumin-prodrug complexes under different redox conditions

[0062] Using the conditions of the above-mentioned binding experiment, the three prodrugs and bovine serum albumin solution were incubated for 2h, and no free prodrug remained after sample injection, that is, the binding was complete. Then the solution was lyophilized to obtain three albumin-prodrug complexes (BSA-DM, BSA-DSSM and BSA-DSM). Then use 30% ethanol in pH 7.4 phosphate buffer as the release medium to investigate the release of the three albumin-prodrug complexes: the albumin-prodrug complex obtained by freeze-drying (the content of docetaxel is 500mg) was added to 1mL of pH 7.4 phosphate buffer, and transferred to a dialysis bag, placed in 30mL release medium, at 37 ℃, sampling at a set time point, the release was determined by high performance liquid chromatography The concentration of docetaxel. Add a certain concentration of hydrogen peroxide (H 2 O 2 ) Or dit...

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Abstract

The invention belongs to the technical field of medicines, and relates to a redox sensitive albumin binding prodrug with a series of tumor tissue specific responses. The albumin binding prodrug is ananti-tumor drug-maleimide molecule prodrug particularly including three docetaxel-maleimide small molecule prodrugs; by utilizing a maleimide ring in a prodrug structure as a target head of plasma albumin 34-bit free sulfydryl in a binding body, so that after a drug enters into a body through intravenous injection, the drug is quickly and specifically bound with albumin to form an albumin-drug composition; therefore, the drug stability is enhanced, the circulation time of the drug in the boy is obviously prolonged, and accumulation of the drug on tumor tissues is realized by utilizing an EPR (Enhanced Permeability and Retention) effect. In addition, in the prodrug structure, by using a redox sensitive key as a binding key, quick release of the drug in tumor cells is promoted, a toxic effect of the drug on normal cells also can be alleviated, the prodrug has high selectivity, the aims of increasing an effect and reducing the toxicity of docetaxel are fulfilled, and a greater market application prospect is achieved.

Description

Technical field [0001] The invention belongs to the field of drug preparation prodrug design, and relates to the design and synthesis of redox sensitive prodrugs specifically responding to tumor tissue with endogenous plasma albumin as a carrier, and its application in anti-tumor. Background technique [0002] At present, chemotherapy is still the main way to treat tumors, but most anti-tumor drugs have low solubility, easy degradation and metabolism in the blood, lack of tumor targeting, and serious adverse reactions, which greatly limit their clinical use. In order to develop an efficient and safe drug delivery system, we have modified the structure of anti-tumor drugs and designed prodrugs that can bind to plasma albumin in the body. After intravenous administration, the prodrugs can quickly bind to albumin in the systemic circulation. Realize drug delivery for the carrier. Albumin is the most abundant protein in plasma, and its half-life in the body is 19 days. At present, i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/64A61K47/54A61K45/00A61P35/00A61K31/337C07D405/12
CPCA61K31/337A61K45/00C07D405/12
Inventor 孙进何仲贵魏巍
Owner SHENYANG PHARMA UNIVERSITY
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