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A small molecule modified targeted paclitaxel prodrug and its preparation method and application

A prodrug, paclitaxel technology, applied in the field of biomedicine, can solve problems such as inability to overcome immunotoxicity, and achieve the effects of avoiding the toxicity of the body's immunogen, improving the therapeutic effect, and requiring less production environment

Inactive Publication Date: 2016-08-31
宿州学院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This invention also uses folic acid as the "directing group" of the drug, and uses the polypeptide-resin as the drug macromolecular carrier to synthesize the folic acid-polypeptide complex, which cannot overcome the problem of immunotoxicity caused by the macromolecular drug carrier

Method used

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  • A small molecule modified targeted paclitaxel prodrug and its preparation method and application
  • A small molecule modified targeted paclitaxel prodrug and its preparation method and application
  • A small molecule modified targeted paclitaxel prodrug and its preparation method and application

Examples

Experimental program
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Effect test

Embodiment 1

[0027] This embodiment is a preparation method of a targeted paclitaxel prodrug modified by a small molecule, comprising the following steps:

[0028] (1) Dissolve paclitaxel (100mg, 0.117mmol) in 15ml of dichloromethane (dissolve completely with a rotor), then add arginine (75.82mg, 0.117mmol) and stir (with turbidity), add a small amount of DMAP (0.117mmol), When it becomes turbid and clear, change the ice bath and stir, and add 10ml of dichloromethane dissolved in EDC·HCl (44.85mg, 0.234mmol) dropwise with a syringe. After adding dropwise for 20 minutes, stir at room temperature for 22 hours. TLC spot plate tracking once, after the reaction, the amino acid-paclitaxel reaction solution was obtained;

[0029] (2) Add the same volume of dichloromethane (15ml) to the reaction solution of step (1) to dilute, and wash twice with the same volume of water (40ml), then wash twice with the same volume of saturated saline (40ml), and use a separate The dichloromethane solution in whi...

Embodiment 2

[0039] In step (1) of this example, paclitaxel (100mg, 0.117mmol) was dissolved in 15ml of dichloromethane, and glutamic acid (49.78mg, 0.117mmol) was added to stir the reaction. In step (6), aminofluorescein Instead of FITC, other steps are the same as in Example 1 to obtain folic acid-glutamic acid-paclitaxel prodrugs and folic acid-glutamic acid-paclitaxel-aminofluorescein prodrugs, wherein the LC of the intermediate product glutamic acid-paclitaxel conjugate - MS chromatogram as Figure 4 As shown, the yield was 92%.

[0040] Folic acid-amino acid-paclitaxel-fluorescent dye prodrug water solubility determination of embodiment 1 and 2:

[0041] Accurately weigh 100 mg of the paclitaxel prodrug of Examples 1 and 2, add 50 μL of water each time with a micro-syringe, observe the dissolution situation by direct observation, until it is too much, count the amount of water required to dissolve 100 mg of the paclitaxel prodrug, and calculate the solubility. Wherein, the solubili...

Embodiment 3

[0043] In this example, the amino acid is methionine, and the fluorescent dye is a near-infrared fluorescent dye. Other steps are the same as in Example 1 to obtain folic acid-methionine-paclitaxel prodrugs and folic acid-methionine-paclitaxel-near-infrared fluorescent dye prodrugs.

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Abstract

The invention discloses a small-molecule modified target paclitaxel precursor medicament, as well as a preparation method and application thereof. The molecular structure of the precursor medicament comprises folic acid, amino acid and paclitaxel, wherein the folic acid is used as a targeting ligand, and the amino acid is used as a connexon. The precursor medicament also comprises a fluorescent dye. Compared with the prior art, the precursor medicament has the advantages that the problem of water solubility and targeting of paclitaxel can be solved, the toxicity of the paclitaxel medicament can be reduced, the treatment effect of the paclitaxel medicament can be improved, body immunogen toxin caused by macro-molecular protein can be avoided, and the defects of poor encapsulation rate, unstable structure and the like caused by using lipidosome as an insoluble medicinal carrier can be overcome.

Description

technical field [0001] The invention relates to a paclitaxel prodrug, which belongs to the field of biomedicine, and in particular to a small molecule modified targeted paclitaxel prodrug and its preparation method and application. Background technique [0002] Paclitaxel is an anti-cancer active substance extracted from the bark of the yew plant. Since 1992, the US FDA has successively approved paclitaxel for the treatment of advanced ovarian cancer, metastatic breast cancer, non-small cell lung cancer, and AIDS-related Kaposis. Malignant tumors. In 1998, the FDA approved the combined use of semi-synthetic paclitaxel and cisplatin for the treatment of advanced ovarian cancer. In 2001, the sales of paclitaxel reached 2 billion US dollars. [0003] Paclitaxel is a natural tricyclic diterpene substance with a very complex structure. It has a complex ring structure and many hydrophobic substituents. Its solubility in water is very poor, which restricts the wide application of p...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/48A61K31/337A61P35/00
Inventor 单玲玲单昕高贵珍曹稳根
Owner 宿州学院
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