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Temozolomide polymer prodrug and preparation method and application thereof

A technology of temozolomide and polymers, which is applied in the field of temozolomide polymer prodrugs and its preparation, can solve the problems of entrapped drug leakage, sudden release, and high specificity of the carrier, and solve the problems of easy degradation, difficult dissociation, and overcoming easily leaked effect

Inactive Publication Date: 2019-11-01
XUZHOU NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Traditional nano-drug carriers can greatly enhance the water solubility of hydrophobic drugs, effectively reduce the side effects of drugs, and prolong the circulation time of drugs in the body, but they also have many disadvantages: 1) The carrier itself has a large specificity and the amount of drug contained is low; 2) When the drug carrier enters the body, the stability becomes poor due to a large amount of dilution, and the contained drug is easy to leak in advance, causing toxic and side effects to normal tissues; 3) burst release is prone to occur in tumor cells
At present, there are relatively few reports on the combination of temozolomide and polymers, so the work of developing new polymer prodrugs of temozolomide needs to be paid more attention

Method used

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  • Temozolomide polymer prodrug and preparation method and application thereof
  • Temozolomide polymer prodrug and preparation method and application thereof
  • Temozolomide polymer prodrug and preparation method and application thereof

Examples

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Effect test

Embodiment 1

[0021] Embodiment 1 synthetic target molecular weight is poly(2-ethyl-2-oxazoline) (PEtOz-OH) of 5000Da

[0022] Poly(2-ethyl-2-oxazoline) (PEtOz-OH) was synthesized by ring-opening polymerization of EtOz as monomer under the initiation of methyl p-toluenesulfonate (MeOTs). First, under nitrogen protection, EtOz (10.0g, 0.101mol), acetonitrile (33.3ml) and methyl p-toluenesulfonate (0.34g, 1.83×10 -3 mol) into the reaction flask. Then react at 100°C for 24h. Then it was cooled to room temperature and 18 ml of 0.1M potassium hydroxide methanol solution was added, the reaction was terminated after stirring for 4 hours, and then settled with glacial ether, the solid was collected and dried in vacuum for 24 hours. The actual molecular weight was measured to be 4700 Da.

Embodiment 2

[0023] Embodiment 2 Synthesis target molecular weight is poly(2-ethyl-2-oxazoline) (PEtOz-OH) of 7500Da

[0024] First, under nitrogen protection, EtOz (10.0g, 0.101mol), acetonitrile (33.3ml) and methyl p-toluenesulfonate (0.24g, 1.32×10 -3 mol) into the reaction flask. Then react at 100°C for 24h. Then it was cooled to room temperature and methanol solution of potassium hydroxide (0.1M, 33ml) was added, the reaction was terminated after stirring for 4h, and then settled with glacial ether, the solid was collected and dried in vacuum for 24h. The actual molecular weight was measured to be 8800 Da.

Embodiment 3

[0025] Example 3 Synthesis of carboxy-terminal temozolomide derivatives (TMZ-COOH)

[0026] Such as figure 1 As shown in a, 5 mg of TMZ was dissolved in 47 ml of concentrated sulfuric acid, the resulting yellow solution was cooled to 0°C under nitrogen, and 47 ml of an aqueous solution of sodium nitrite (4.02 g, 72.8 mmol) was added dropwise. After warming the mixture to room temperature while stirring in the dark for 24 h, the mixture was cooled to 0 °C and quenched with 122 g of ice. Further stirring at 0 °C resulted in the precipitation of a white solid, which was isolated by vacuum filtration. Washed with cold water and dried under vacuum to give TMZ-COOH.

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Abstract

The present invention discloses a temozolomide polymer prodrug and a preparation method and an application thereof. The temozolomide polymer prodrug comprises a hydrophilic polymer having a synthesizing terminal of a hydroxyl group and a temozolomide derivative having a synthesizing terminal of a carboxyl group; and the hydroxyl group of the terminal of the hydrophilic polymer reacts with the carboxyl group of the temozolomide derivative, the temozolomide is bonded to the terminal end of the hydrophilic polymer to obtain the temozolomide polymer prodrug. The temozolomide polymer prodrug is prepared by a covalent bond connection of the temozolomide and the polymer and can maintain stability in a body cycle; the temozolomide and the polymer are covalently bonded to form nanomicelles in water, the nanomicelles are not liable to dissociate extracellularly and in blood, and the temozolomide polymer prodrug solves problems that the temozolomide is liable to degrade under physiological conditions of the temozolomide, and drugs are easily leaked in body and short in cycle time, etc.

Description

technical field [0001] The invention relates to chemical synthesis and biomedicine, in particular to a temozolomide polymer prodrug and its preparation method and application. Background technique [0002] Traditional nano-drug carriers can greatly enhance the water solubility of hydrophobic drugs, effectively reduce the side effects of drugs, and prolong the circulation time of drugs in the body, but they also have many disadvantages: 1) The carrier itself has a large specificity and the amount of drug contained is low; 2) When the drug carrier enters the body, the stability becomes poor due to a large amount of dilution, and the contained drug is easy to leak in advance, causing toxic and side effects to normal tissues; 3) burst release is prone to occur in tumor cells. Because polymer prodrugs can effectively improve the stability, drug loading and pharmacokinetics of anticancer drugs, they have now developed into a nano-drug technology platform that is widely recognized ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/69A61K31/4188A61K47/59A61P35/00
CPCA61K31/4188A61K47/6907A61K47/59A61P35/00
Inventor 李玉玲许康张诃娜杜百祥
Owner XUZHOU NORMAL UNIVERSITY
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