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Preparation method of targeted small molecular prodrug for pH response and collaborative treatment

A technology of small molecules and prodrugs, which is applied in the field of preparation of targeted amphiphilic small molecule prodrugs, can solve the problems of uncontrollable drug release, high content of anti-tumor drug carriers, and low drug loading capacity, so as to improve the dual-drug synergistic effect

Active Publication Date: 2017-07-07
SOUTHWEST UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The present invention aims at the defects of high content of anti-tumor drug carrier, low drug loading and uncontrollable drug release, etc., and provides a pH-responsive and synergistic therapy targeting amphiphilic small molecule prodrug preparation and application

Method used

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  • Preparation method of targeted small molecular prodrug for pH response and collaborative treatment
  • Preparation method of targeted small molecular prodrug for pH response and collaborative treatment
  • Preparation method of targeted small molecular prodrug for pH response and collaborative treatment

Examples

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Embodiment 1

[0027] Example 1 Preparation of MTX-DOX Amphiphilic Small Molecule Prodrugs Responsive to pH Stimulation

[0028] (1) Under the condition of ice bath and argon (Ar) atmosphere, first dissolve 1.034 g MTX in 25 mL anhydrous N,N-dimethylformamide (DMF), then add 260.5 mg N-hydroxybutyrate Diimide (NHS) and 447.0 mg 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC·HCl); after stirring in an ice-water bath for 30 min, 325.3 mg Butyl carbazate (BH) was dissolved in 5 mL of anhydrous DMF solution, added to the above reaction solution, and stirred at room temperature in the dark for 24 h; precipitated in deionized water, filtered with suction and washed with acetone to obtain a stable product pH response The precursor of methotrexate (MTX-BH) was 308.0 mg, and the yield was 23.82%.

[0029] (2) First, the de-tert-butoxycarbonyl protection reaction of the amino group in MTX-BH, 85.4 mg of MTX-BH, a partial product of the reaction in step (1), was added to 1.5 mL of a m...

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Abstract

The invention relates to the field of synthesis of medicinal chemistry, and particularly relates to a preparation method of a targeted amphiphilic small molecular prodrug for pH response and collaborative treatment, which is a preparation method and application of an adriamycin-based amphiphilic small molecular prodrug for acid response. The preparation method of the amphiphilic small molecular prodrug comprises the following steps of (1) carrying out hydrophilic drug molecule methotrexate (MTX)-based chemical modification, introducing a tert-butyl oxygen carbonyl-protected pH responsive hydrazine bond to a hydroxyl part with low steric hindrance in methotrexate; and (2) introducing an adriamycin (DOX) hydrophobic drug molecule after hydrazide tert-butyl carbonyl protection and obtaining the amphiphilic small molecular prodrug for pH response. The obtained amphiphilic small molecular prodrug can be self-assembled into a drug nano-micelle, the drug can be selectively released, and the amphiphilic small molecular prodrug has the advantages of targeted delivery, high drug loading capacity, stimulus-response-controlled drug release and high micelle stability. The problems of the water solubility of the hydrophobic drug molecule and combined nanodrug delivery can be effectively solved.

Description

technical field [0001] The invention relates to the field of chemical medicines, in particular to the preparation and use of a targeted amphiphilic small molecule prodrug for pH response and synergistic therapy. Background technique [0002] Methotrexate (Methotrexate, MTX, alias: (+)-methotrexate, methyl amino folic acid, molecular formula: C 20 h 22 N 8 o 5 , CAS No.: 60388-53-6), is a folic acid antagonist, and the only difference from folic acid is that the hydrogen on NH on N10 is changed to methyl (CH 3 ), and the C4 keto group on the ring is changed to amino (NH 2 ), so it can compete with folic acid for the same enzyme, and inhibit the synthesis of tumor cell DNA by inhibiting dihydrofolate reductase, thereby inhibiting the growth and reproduction of tumor cells. It is an anti-cancer drug for antimetabolism therapy. At the same time, due to its similar structure to folic acid, methotrexate can specifically bind to folic acid receptors on the cell surface, so tha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/54A61K31/704A61K31/519A61K9/107A61K49/00A61P35/00
CPCA61K9/1075A61K31/519A61K31/704A61K49/0052A61K49/0082A61K2300/00
Inventor 许志刚侯美丽高永娥马晓倩康跃军汪敏
Owner SOUTHWEST UNIVERSITY
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