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Reduction sensitive type polyethylene glycol-medicament conjugate and preparation method thereof

A technology of drug conjugates and polyethylene glycol, applied in the field of biomedicine, can solve problems such as affecting the transfer speed of drugs, affecting biological activity, destruction or shielding, etc., to improve the efficacy of drugs, facilitate mass production, and prolong the half-life in vivo. Effect

Inactive Publication Date: 2014-11-05
XI AN JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, once the drug delivery system enters the tumor cells, if the "invisible" polyethylene glycol is not removed in time, it will affect the transfer speed of the drug from the endosome to the cytoplasm, and it will be easily degraded by the lysosome, which will affect the curative effect. one of the key factors
In addition, PEG modification of drugs will inevitably destroy or cover the active site of the drug to a certain extent, affecting its biological activity in vivo.

Method used

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  • Reduction sensitive type polyethylene glycol-medicament conjugate and preparation method thereof
  • Reduction sensitive type polyethylene glycol-medicament conjugate and preparation method thereof
  • Reduction sensitive type polyethylene glycol-medicament conjugate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] 1) Synthesis of 3,3'-dithiodipropionylhydrazide:

[0046] Add 3,3'-dithiodipropionic acid and ethanol to the reactor containing toluene and p-toluenesulfonic acid, reflux for 8 hours, then remove the solvent in vacuum, and then add mass concentration to the residue in the reactor 50% hydrazine hydrate aqueous solution, reflux reaction for 4 hours, and then recrystallized with a solvent mixed with water and ethanol at a volume ratio of 5:95 to obtain 3,3'-dithiodipropionyl hydrazide; wherein, The molar ratio of 3,3'-dithiodipropionic acid to ethanol added is 1:15, and the molar ratio of 3,3'-dithiodipropionic acid to hydrazine hydrate in the hydrazine hydrate aqueous solution is 1:20 , the molar ratio of 3,3'-dithiodipropionic acid to p-toluenesulfonic acid is 1:0.01, and 0.5mol of 3,3'-dithiodipropionic acid is added to every liter of toluene;

[0047] 2) Synthesis of 2,2'-dithiodiethylisocyanate:

[0048] Dissolve 3,3'-dithiodipropionylhydrazide in 2mol / L hydrochlori...

Embodiment 2

[0055] 1) Synthesis of 2,2'-dithiodiacetylhydrazide:

[0056] Add 2,2'-dithiodiacetic acid and methanol into a reactor filled with toluene and p-toluenesulfonic acid, reflux for 6 hours, then remove the solvent in a vacuum, and then add a mass concentration of 85% hydrazine hydrate aqueous solution, reflux reaction for 5 hours, and then recrystallized with a solvent mixed with water and ethanol at a volume ratio of 2:8 to obtain 2,2'-dithiodiacetylhydrazide; wherein, the added The molar ratio of 2,2'-dithiodiacetic acid to methanol is 1:30, the molar ratio of 2,2'-dithiodiacetic acid to hydrazine hydrate in aqueous solution is 1:25, 2,2' - The molar ratio of dithiodiacetic acid to p-toluenesulfonic acid is 1:0.01, and 1mol of 2,2'-dithiodiacetic acid is added to every liter of toluene;

[0057] 2) Synthesis of 1,1'-dithiodimethylisocyanate:

[0058] Dissolve 2,2'-dithiodiacetylhydrazide in 0.5mol / L hydrochloric acid, add dropwise an aqueous solution of sodium nitrite with a ...

Embodiment 3

[0065] 1) Synthesis of 3,3'-dithiodipropionylhydrazide:

[0066] Add 3,3'-dithiodipropionic acid and methanol to a reactor containing toluene and p-toluenesulfonic acid, reflux for 9 hours, then remove the solvent in a vacuum, and then add mass concentration to the residue in the reactor 70% hydrazine hydrate aqueous solution, reflux reaction for 3 hours, and then recrystallized with a solvent mixed with water and ethanol at a volume ratio of 1:9 to obtain 3,3'-dithiodipropionyl hydrazide; wherein, The molar ratio of 3,3'-dithiodipropionic acid to methanol added is 1:18, and the molar ratio of 3,3'-dithiodipropionic acid to hydrazine hydrate in the hydrazine hydrate aqueous solution is 1:24 , add 1.5mol of 3,3'-dithiodipropionic acid per liter of toluene;

[0067] 2) Synthesis of 2,2'-dithiodiethylisocyanate:

[0068] Dissolve 3,3'-dithiodipropionylhydrazide in 3mol / L hydrochloric acid, add dropwise an aqueous solution of sodium nitrite with a mass concentration of 30% under...

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Abstract

The invention discloses a reduction sensitive type polyethylene glycol-medicament conjugate and a preparation method thereof. Methoxy polyethylene glycol is modified by using a disulfide-bond-containing diisocyanate, then a cytotoxic anticancer medicament is bonded to the obtained isocyanate-terminated polyethylene glycol, and the reduction sensitive type polyethylene glycol-medicament conjugate is obtained through dialysis and freeze-drying. The preparation method has the advantages of being multiple in applicable medicament kinds, easily available in raw materials, low in cost and the like; and the disulfide bonds exist in connecting arms between polyethylene glycol and the medicament in the prepared conjugate. According to the polyethylene glycol-medicament conjugate, not only the medicament can be released quickly in a tumor-cell reductibility microenvironment, but also nanoparticles can be formed via self assembly in an aqueous medium; and the polyethylene glycol-medicament conjugate is hopeful to have a long circulation life and accumulate in a tumor, thereby the purpose of improvement of anticancer medicament curative effect and reduction of toxic and side effect is realized.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to a reduction-sensitive polyethylene glycol-drug conjugate and a preparation method thereof. Background technique [0002] Chemotherapy is a basic tumor treatment method, which uses cytotoxic drugs to kill tumor cells to achieve the purpose of treating tumors. Cytotoxic anticancer drugs commonly used in clinic include doxorubicin, epirubicin, paclitaxel, docetaxel, camptothecin, 10-hydroxycamptothecin, vinblastine and vincristine, etc. These cytotoxic drugs not only have a short half-life in vivo, are poorly soluble in water, and have poor selectivity, resulting in low bioavailability, but also have serious side effects on normal tissues / cells, and the curative effect and side effects are positively related to the dosage. Therefore, improving curative effect and reducing toxic and side effects have always been the goals pursued by the basic research and clinical ap...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/48A61K45/00A61P35/00A61K47/60
Inventor 锁爱莉钱军民柳雪峰胥伟军刘茸茸
Owner XI AN JIAOTONG UNIV
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