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Preparation method and application of acid sensitive doxorubicin prodrug based on polyethylene glycol

A polyethylene glycol and sensitive technology, which is applied in the direction of pharmaceutical formulations, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc. Side effects and other issues, to achieve good water solubility and storage stability, improve blood circulation time, easy to decompose effect

Inactive Publication Date: 2014-06-04
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In addition, they can quickly spread to healthy tissues in the body and distribute evenly throughout the body, resulting in only a small amount of drugs reaching the target site, resulting in uncertainty in the efficacy of the treatment process and large toxic and side effects, thus greatly limiting the effectiveness of these antineoplastic drugs. Applications
[0004] Many excellent hydrophobic drugs, such as paclitaxel, doxorubicin, etc., are extremely difficult to dissolve in water and have high toxicity, which limits their clinical application

Method used

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  • Preparation method and application of acid sensitive doxorubicin prodrug based on polyethylene glycol
  • Preparation method and application of acid sensitive doxorubicin prodrug based on polyethylene glycol
  • Preparation method and application of acid sensitive doxorubicin prodrug based on polyethylene glycol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1: Polyethylene glycol (NC- a -PEG 45 - a -NC) synthesis

[0051] First, polyethylene glycol (N 3 - a -PEG 45 - a -N 3 ), p-nitrophenyl propargyl carbonate, under the action of "click" chemical reaction catalyst and ligand, a click chemical reaction occurs to prepare polyethylene glycol with a p-nitrophenyl end (NC- a -PEG 45 - a -NC). The specific synthesis method is as follows:

[0052] Dry the branched round-bottomed flask with a stirrer in an oven at 120°C for at least 24 hours, then plug it with a glass stopper, connect it to an oil pump through a latex tube, and pump it to room temperature, then introduce high-purity argon gas, and vacuumize, repeat this process After filling with argon three times, quickly add polyethylene glycol N containing diazide ethyl diacetal group at the end. 3 - a -PEG 45 - a -N 3 (489 mg, 0.22 mmol), p-nitrophenyl propargyl carbonate (255 mg, 1.16 mmol), cuprous bromide (0.014 g, 0.10 mmol) and pentamethyldiethyle...

Embodiment 2

[0054] Example 2: Acid-sensitive doxorubicin prodrug based on polyethylene glycol (DOX- a -PEG 45 - a -DOX) synthesis

[0055] Dry the 50 mL round-bottomed flask and glass stopper with a stirring bar in an oven at 120 °C for at least 24 h, then cool to room temperature, add NC- a -PEG 45 - a -NC (123 mg, 0.05 mmol), doxorubicin hydrochloride (0.119 g, 0.2 mmol), triethylamine (0.1 mL, 0.6 mmol) and 10 mL dimethylformamide (DMF); After the reaction was completed, the DMF was pumped out with a vacuum oil pump at 50°C, dissolved by adding 2 mL of anhydrous methanol, dialyzed against anhydrous methanol for 24 h, followed by ultrapure water for 48 h, and freeze-dried to Constant weight, to obtain dark red solid product (DOX- a -PEG 45 - a -DOX, 78 mg), yield 60%.

[0056] Using H NMR spectroscopy ( 1 H NMR) and infrared spectroscopy (FT-IR) verified the structure of the obtained polymer as well as the polyethylene glycol-based acid-sensitive doxorubicin prodrug. attached...

Embodiment 3

[0057] Example three: Polyethylene glycol (NC- a -PEG 90 - a -NC) synthesis

[0058] Dry the branched round-bottomed flask with a stirrer in an oven at 120°C for at least 24 hours, then plug it with a glass stopper, connect it to an oil pump through a latex tube, and pump it to room temperature, then introduce high-purity argon gas, and vacuumize, repeat this process After filling with argon three times, quickly add polyethylene glycol N containing diazide ethyl diacetal group at the end. 3 - a -PEG 90 - a -N 3 (439 mg, 0.1 mmol), p-nitrophenyl propargyl carbonate (81 mg, 0.36 mmol), cuprous bromide (0.014 g, 0.10 mmol) and pentamethyldiethylenetriamine (21 μL , 0.10 mmol), pumped with an oil pump and filled with argon three times to remove the air in the bottle, then added 20 mL of solvent tetrahydrofuran (THF) with a dry syringe, and stirred until the mixture was completely dissolved and the solution turned blue. Then the round bottom flask was moved to an oil bath at ...

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Abstract

The present invention provides an acid sensitive doxorubicin prodrug based on polyethylene glycol, and a method and an application of the acid sensitive doxorubicin prodrug based on polyethylene glycol. The preparation method comprises: preparing a polyethylene glycol whose end contains an acid sensitive acetal group and a p-nitrophenyl ester azide group by a reaction of a polyethylene glycol whose double ends contain diazido ethyl diacetal groups with a p-nitro phenyl propargyl carbonate; preparing the acid sensitive doxorubicin prodrug based on the polyethylene glycol by the reaction of the prepared polyethylene glycol with doxorubicin hydrochloride. The acid sensitive and water soluble doxorubicin prodrug has good biocompatibility and acid sensitivity, thereby being used as a stimulation sensitive antineoplastic prodrug.

Description

technical field [0001] The invention belongs to the field of biomedical polymer materials, in particular to a polyethylene glycol-based acid-sensitive doxorubicin prodrug, its preparation method and its application as the prodrug. Background technique [0002] Globally, more than 7 million people die from cancer every year, and this number is increasing year by year. The treatment of cancer is the biggest test and problem facing mankind in the 21st century. According to the survey report released by the World Health Organization in February 2013, the number of people who died of cancer in the world in 2008 reached 7.6 million, and there were about 13 million new cancer patients every year, of which two-thirds of the new cancer patients and cancer deaths Patients are from developing countries. [0003] With the continuous progress and development of science and technology, many effective anti-tumor drugs have been used clinically, but most of the drugs used in clinical prac...

Claims

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Application Information

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IPC IPC(8): C08G65/00C08G65/48A61K47/48A61K31/704A61P35/00
Inventor 倪沛红王海蓉何金林张明祖李飞陶云锋
Owner SUZHOU UNIV
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