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Water-soluble paclitaxel derivative with cell targeting effect and preparation thereof

A paclitaxel derivative and cell-targeting technology, which is applied to medical preparations with non-active ingredients, medical preparations containing active ingredients, organic active ingredients, etc., can solve complex preparation processes, changes in drug structure, and affect drug efficacy, etc. problems, to achieve the effect of simple synthesis steps, controlled drug release, and improved water solubility

Active Publication Date: 2012-07-11
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In the above-mentioned documents, the methods reported in (1) and (2) all use other molecules to bond paclitaxel to the hydrophilic polymer through a relatively cumbersome and inefficient esterification reaction.
The introduction of more other compounds, on the one hand, changes the structure of the drug, which may affect the efficacy of the drug; on the other hand, the preparation process is more complicated and does not involve targeting in the drug structure
Although the methods reported in literature (3) and (4) involve the targeting of drug delivery, they do not involve folic acid and biodegradable water-soluble polyphosphates that mediate various tumors.

Method used

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  • Water-soluble paclitaxel derivative with cell targeting effect and preparation thereof
  • Water-soluble paclitaxel derivative with cell targeting effect and preparation thereof
  • Water-soluble paclitaxel derivative with cell targeting effect and preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1: Preparation method of paclitaxel-bonded polyphosphate drug

[0053] Put the glass syringe, needle, glass stopper, and branch bottle equipped with a stirrer in an oven at 120°C for 12 hours to dry, then take out the syringe and needle and put it in a desiccator to cool, put a stopper on the branch bottle and connect it to the double-row tube Use an oil pump to cool to room temperature, then fill with high-purity argon, and take a breath for three times, and finally fill with argon, and add paclitaxel white powder (0.30g, 0.35 mmol) and stannous octoate (0.07 g, 0.18 mmol) distilled under reduced pressure as a viscous liquid. Exhaust the gas twice, use a dry syringe to extract the solvent o-dichlorobenzene 2mL and tetrahydrofuran 4mL (volume ratio 1:2) into the branch vial, stir and dissolve until the system is clear and transparent. Add phosphate ester monomer 2-ethoxy-2-oxo-1,3,2-dioxaphospholane (EOP) with a molecular weight of 151 g / mol through a syringe, ...

Embodiment 2

[0056] Example 2: Preparation method of paclitaxel-polyphosphate-folate polymer drug (PTX-PEEP-FA)

[0057] Dry the vial with a stirrer, stopper and syringe with a 120°C oven, take it out and put it in a desiccator to cool, add folic acid (0.024g, 0.054mmol) with a molecular weight of 441g / mol to the vial filled with argon, and use Extract 5 mL of distilled and purified dimethyl sulfoxide and 0.5 mL of triethylamine (volume ratio 10:1) into a dry syringe, stir well and dissolve to a transparent yellow solution, add dicyclohexylcarbodiimide (0.014 g, 0.070 mmol ) and N-hydroxysuccinimine (0.008g, 0.070mmol), and the molar ratio of folic acid is 1:1.3, first stirred at room temperature for 12 to 24 hours in the dark. Then the drug macromolecule PTX-PEEP25 (0.20g, 0.043mmol) of polyphosphate-bonded paclitaxel with a number average molecular weight of about 4600g / mol was added to the folic acid reaction system, and the stirring reaction was continued for 24~ 48h.

[0058] After ...

Embodiment 3

[0060] Example 3: Preparation of polymer micelles containing anticancer drugs by dialysis

[0061] Take a 5mg sample of PTX-PEEP in a round bottom flask 25-FA was fully dissolved in 3mL of tetrahydrofuran with stirring, and then 8mL of phosphate buffer solution with a pH value of 7.4 was added dropwise at a rate of 0.5mL / min with a micro-sampling pump under stirring, and then 8 mL of a phosphate buffer solution with a pH value of 7.4 The solution was dialyzed for 24-30 hours to remove tetrahydrofuran, and then the phosphate buffer solution with a pH value of 7.4 was used to dilute to volume in a 25mL volumetric flask, and fully stirred for 48-72 hours. Using a transmission electron microscope to observe the morphology and size of micelles, it can be seen that the polymer drugs bonded by paclitaxel-polyphosphate-folate self-assemble into micelles with a particle size of 80-100nm under simulated physiological conditions. See Figure 4 .

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Abstract

The invention belongs to the field of high molecular medicaments, and discloses an anticancer medicament which has targeting properties on multiple cancer cells and contributes to bonding of polyphosphate ester with paclitaxel, and a preparation method thereof. The invention specifically discloses a paclitaxel-polyphosphate ester-folic acid bonded high molecular medicament which is self-assembledin a phosphoric acid buffer solution, so that a micelle in which folic acid is distributed on an outer layer is formed. On one hand, the high hydrophobic property of a paclitaxel medicament can be improved, so that the transplant reactions of a medicament in an in-vivo conveying process are avoided; and on the other hand, the accumulation of the medicament on cancer cells is enhanced, damages of the medicament to other normal cells of tissue organs are avoided, the degrading speed of a polymer in under an in-vivo circulating condition (the pH value is about 7.4) is slow, polyphosphate ester is degraded at a higher speed due to the falling of the pH value in the presence of in-vivo bio-enzymes after the medicament reaches the cancer cells, the medicament is released, and the effect of treating tumors is achieved.

Description

technical field [0001] The invention belongs to the field of drug controlled release, and relates to a drug and a synthesis method thereof, which has folic acid-mediated targeting of cancer cells, good water solubility, good biocompatibility, and biodegradable polyphosphate-bonded anticancer drug paclitaxel . Background technique [0002] Paclitaxel (trade name Taxol), a tricyclic diterpene substance extracted from Taxus genus, has unique anticancer activity. Since the United States Food and Drug Administration (FDA) approved paclitaxel for the treatment of advanced ovarian cancer in December 1992, it has gradually been found that it has a high curative effect on breast cancer, ovarian cancer and lung cancer. [0003] However, since paclitaxel consists of a bulky ring structure and numerous hydrophobic groups, its solubility in water is poor. In order to improve its water solubility, reduce its excretion by P-glycoprotein, and enhance its anticancer ability against colon c...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K31/337A61P35/00C08G79/04
Inventor 倪沛红张国艺张明祖
Owner SUZHOU UNIV
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