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Establishment of self-assembly nanoparticles of redox hypersensitive disulfide bond bridged prodrug

A technology of self-assembled nanoparticles and disulfide bridges, which is applied in drug combinations, pharmaceutical formulations, anti-tumor drugs, etc., can solve problems such as poor stability, low solubility, and large toxic and side effects, and achieve good stability and simple preparation process , Easy surface modification effect

Inactive Publication Date: 2018-09-04
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Prodrug strategies can improve the undesirable properties of chemotherapeutic drugs, including low solubility, poor stability, and large toxic and side effects, through ingenious structural modifications.

Method used

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  • Establishment of self-assembly nanoparticles of redox hypersensitive disulfide bond bridged prodrug
  • Establishment of self-assembly nanoparticles of redox hypersensitive disulfide bond bridged prodrug
  • Establishment of self-assembly nanoparticles of redox hypersensitive disulfide bond bridged prodrug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1: Synthesis of a small-molecule prodrug of paclitaxel-citronellol (α-PTX-SS-CIT) with a disulfide bond at the α position of the carbonyl group

[0042] Add an appropriate amount of 2,2'-dithiodiacetic acid to a 50mL round bottom flask and 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 into the system in three portions In and dry under reduced pressure distillation. The obtained product was dissolved in 30 mL of dichloromethane, and an appropriate amount of citronellol and DMAP was added, and stirred at room temperature for 1 hour. The reaction process was monitored by thin layer chromatography, and the intermediate product was purified 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 ad...

Embodiment 2

[0045] Example 2: Synthesis of a small-molecule prodrug of paclitaxel-citronellol (β-PTX-SS-CIT) with a disulfide bond at the β position of the carbonyl group

[0046] Add an appropriate amount of 3,3'-dithiodipropionic acid to a 50mL round bottom 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 in three portions In the system, and carry out vacuum distillation and drying. The obtained product was dissolved in 30 mL of dichloromethane, and an appropriate amount of citronellol and DMAP was added, and stirred at room temperature for 1 hour. The reaction process was monitored by thin layer chromatography, and the intermediate product was purified 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 w...

Embodiment 3

[0049] Example 3: Synthesis of a small-molecule prodrug of paclitaxel-citronellol (γ-PTX-SS-CIT) with a disulfide bond at the γ position of the carbonyl group

[0050] Add an appropriate amount of 4,4'-dithiodibutyric acid to a 50mL round bottom flask and dissolve it with 3mL of acetic anhydride. Stir for 2 hours at room temperature. Monitor the reaction process by thin layer chromatography. Then add 20mL of toluene in three portions In the system, and carry out vacuum distillation and drying. The obtained product was dissolved in 30 mL of dichloromethane, and an appropriate amount of citronellol and DMAP was added, and stirred at room temperature for 1 hour. The reaction process was monitored by thin layer chromatography, and the intermediate product was purified 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 adde...

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Abstract

The invention belongs to the technical field of medicine, and designs and synthesizes a series of disulfide bond-containing micromolecular prodrugs in which carbon chains in different lengths are linked (sulfur atoms in the disulfide bond are respectively located alpha, beta and gamma sites of an ester bond). PTX (Paclitaxel)-CIT (Citronellol) is used as a sample, and a synthesis method is simpleand easy. On the basis, a micromolecular prodrug self-assembly nano-drug delivery system is prepared. The preparation method is simple and convenient, the stability is high, and efficient encapsulation and delivery of drugs are realized. The invention discovers that the disulfide bond has redox dual sensitivity, can be fractured under the action of high-expression ROS (Reactive Oxygen Species) andGSH (Glutathione) of tumor cells, and PTX can be released; particularly, redox dual hypersensitivity is shown by PTX-CIT prodrugs (alpha-PTX-SS-CIT), which are located in the alpha site of a carbonylgroup, of the disulfide bond, the alpha-PTX-SS-CIT prodrugs can be quickly fractured to release the PTX and take effects, an anti-tumor effect of the PTX is remarkably improved, and a wide development prospect is obtained.

Description

Technical field [0001] The invention belongs to the field of new excipients and new dosage forms for pharmaceutical preparations, including the synthesis of redox super-sensitive disulfide bond bridged paclitaxel-citronellol prodrugs and the construction of prodrug self-assembled nanoparticles, and its application in drug delivery. Background technique [0002] Cancer is a serious threat to the health of all human beings. According to statistics from the World Health Organization (WHO), more than 8 million people die of cancer each year worldwide. Chemotherapy is one of the most commonly used and effective strategies in cancer treatment, especially for tumors that cannot be removed by surgery and metastasis. However, most chemotherapeutics are cytotoxic drugs, and have the disadvantages of low solubility, poor stability, narrow therapeutic window and poor pharmacokinetic properties. However, the existing formulation strategies have low delivery efficiency and poor tumor targetin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/55A61K47/60A61K47/69A61K31/337A61K31/045A61P35/00
CPCA61K47/55A61K31/045A61K31/337A61K47/60A61K47/6931A61P35/00A61K2300/00
Inventor 孙进何仲贵孙丙军罗聪于涵张轩博
Owner SHENYANG PHARMA UNIVERSITY
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