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Redox dual-sensitive-bond bridged small-molecular prodrug and its self-assembled nanoparticles

A self-assembled nanoparticle and small molecule technology, applied in the direction of drug combination, active ingredients of hydroxyl compounds, anti-tumor drugs, etc., to achieve high-efficiency entrapment, simple synthesis method, and good stability

Active Publication Date: 2019-02-19
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The selenium bond (single-selenium bond and diselenide bond) of the same group as sulfur also has a certain redox sensitivity, but there are no reports on smart responsive prodrugs and self-assembled nano-drug delivery systems based on selenium bonds.

Method used

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  • Redox dual-sensitive-bond bridged small-molecular prodrug and its self-assembled nanoparticles
  • Redox dual-sensitive-bond bridged small-molecular prodrug and its self-assembled nanoparticles
  • Redox dual-sensitive-bond bridged small-molecular prodrug and its self-assembled nanoparticles

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Embodiment 1: the synthesis of monoselenium bridged paclitaxel-citronellol small molecule prodrug (PTX-Se-CIT)

[0054] Add an appropriate amount of selenodipropionic acid into a 50mL round-bottomed flask, and dissolve it with 3mL of acetic anhydride, stir at room temperature for 2 hours, monitor the reaction process by thin-layer chromatography, and then add 20mL of toluene to the system three times, and reduce Distilled to dryness. The obtained product was dissolved in 30 mL of dichloromethane, and an appropriate amount of citronellol and DMAP were added, stirred at room temperature for 1 hour, the reaction process was monitored by thin-layer chromatography, and an intermediate product was obtained by purification by silica gel column chromatography. Finally, the intermediate product, EDCI, HOBt and DMAP were dissolved in 50 mL of anhydrous dichloromethane, ice-bathed for 1 hour, then an appropriate amount of paclitaxel was added, stirred at room temperature for anoth...

Embodiment 2

[0057] Example 2: Synthesis of diselenide bridged paclitaxel-citronellol small molecule prodrug (PTX-SeSe-CIT)

[0058] Add an appropriate amount of 3,3'-diselenodipropionic acid into a 50mL round bottom flask, dissolve it with 3mL of acetic anhydride, stir at room temperature for 2 hours, monitor the reaction process by thin-layer chromatography, and then add 20mL of toluene three times system, and evaporated to dryness under reduced pressure. The obtained product was dissolved in 30 mL of dichloromethane, and an appropriate amount of citronellol and DMAP were added, stirred at room temperature for 1 hour, the reaction process was monitored by thin-layer chromatography, and an intermediate product was obtained by purification by silica gel column chromatography. Finally, the intermediate product, EDCI, HOBt and DMAP were dissolved in 50 mL of anhydrous dichloromethane, ice-bathed for 1 hour, then an appropriate amount of paclitaxel was added, stirred at room temperature for a...

Embodiment 3

[0061] Embodiment 3: Synthesis of monosulfide bridged paclitaxel-citronellol small molecule prodrug (PTX-S-CIT)

[0062] Add an appropriate amount of thiodipropionic acid into a 50mL round-bottomed flask, dissolve it with 3mL of acetic anhydride, stir at room temperature for 2 hours, monitor the reaction process by thin-layer chromatography, then add 20mL of toluene to the system three times, and reduce Distilled to dryness. The obtained product was dissolved in 30 mL of dichloromethane, and an appropriate amount of citronellol and DMAP were added, stirred at room temperature for 1 hour, the reaction process was monitored by thin-layer chromatography, and an intermediate product was obtained by purification by silica gel column chromatography. Finally, the intermediate product, EDCI, HOBt and DMAP were dissolved in 50 mL of anhydrous dichloromethane, ice-bathed for 1 hour, then an appropriate amount of paclitaxel was added, stirred at room temperature for another 24 hours, and...

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Abstract

The invention belongs to the technical field of medicine and relates to a redox dual-sensitive-bond bridged small-molecular prodrug and its self-assembled nanoparticles. The redox dual-sensitive-bondbridged small-molecular prodrug is made by connecting an antitumor drug with a carbon chain containing an unsaturated bond and active hydroxyl group through a selenium bond or a sulfur bond. The antitumor drug is an anticancer drug containing active hydroxyl group or amino group, selected from taxane groups, nucleoside compounds, anthracycline compounds or camptothecin compounds; the carbon chaincontaining the unsaturated bond and active hydroxyl group is vitamin E, ethylene glycol dioleate, citronellol, oleyl alcohol, linoleny alcohol or linoleic alcohol. The selenium bond is a mono-seleniumbond or di-selenium bond; the sulfur bond is mono-sulfur bond or di-sulfur bond. The redox dual-sensitive-bond bridged small-molecular prodrug can be self-assembled into nanoparticles, arriving at high drug-loading capacity, good stability, low toxic and side effect, specific quick drug release to tumor sites, and improving antitumor activity.

Description

technical field [0001] The invention belongs to the field of new excipients and new dosage forms of pharmaceutical preparations, and relates to the construction of self-assembled nanoparticles bridged by redox double-sensitive bonds, in particular to redox double-sensitive small molecule prodrugs bridged by multiple selenium bonds and sulfur bonds. Construction of small molecule prodrug self-assembled nanoparticles and their application in drug delivery. Background technique [0002] Cancer seriously threatens the health of all human beings. According to the statistics of the World Health Organization (WHO), more than 8 million people die of cancer every year in the world. Chemotherapy is one of the most commonly used and effective strategies in cancer treatment, especially for those tumors that cannot be removed by surgery and metastatic spread. However, most chemotherapeutic drugs are cytotoxic drugs, and have disadvantages such as low solubility, poor stability, narrow t...

Claims

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Application Information

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IPC IPC(8): A61K47/54A61K47/69A61K31/337A61K31/045A61P35/00
CPCA61K31/045A61K31/337A61K47/542A61K47/6929A61P35/00A61K2300/00
Inventor 孙进何仲贵孙丙军罗聪张轩博左诗意
Owner SHENYANG PHARMA UNIVERSITY
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