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Bifunctional polyethylene glycol and adriamycin conjugate and preparation method thereof

A technology of polyethylene glycol and aldehyde-terminated polyethylene glycol, applied in the field of biomedicine, can solve the problems of difficult control of drug release rate and large uncertainty of enzyme degradation, so as to reduce renal clearance rate and overcome drug resistance , the effect of plasma stability and long-circulation properties

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

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Problems solved by technology

For example, the Chinese patent application number 201110343633.9 discloses a conjugate of poly(L-lysine) or chitosan and doxorubicin linked by an amide bond. Simple, but there are problems such as large uncertainty in enzymatic degradation and difficult control of drug release rate

Method used

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  • Bifunctional polyethylene glycol and adriamycin conjugate and preparation method thereof
  • Bifunctional polyethylene glycol and adriamycin conjugate and preparation method thereof
  • Bifunctional polyethylene glycol and adriamycin conjugate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] 1) Synthesis of aldehyde-terminated polyethylene glycol:

[0046] The methoxypolyethylene glycol that molecular weight is 2000 Daltons is dissolved in the mixed solvent of anhydrous dimethyl sulfoxide and anhydrous chloroform, is mixed with the methoxypolyethylene glycol solution that mass concentration is 10%, Then within 1 hour, dropwise add acetic anhydride in the amount of 5 times the number of moles of hydroxyl groups in methoxypolyethylene glycol to the methoxypolyethylene glycol solution, stir at room temperature for 12 hours, and use the reaction solution obtained after vacuum concentration Cold ether precipitation at 20°C to obtain aldehyde-terminated polyethylene glycol; wherein, the volume ratio of anhydrous dimethyl sulfoxide and anhydrous chloroform in the mixed solvent is 75:25;

[0047] 2) Synthesis of 3,3'-dithiodipropionylhydrazide:

[0048] Add 3,3'-dithiodipropionic acid and ethanol to the reactor containing toluene and p-toluenesulfonic acid, reflux...

Embodiment 2

[0055] 1) Synthesis of aldehyde-terminated polyethylene glycol:

[0056] The methoxypolyethylene glycol that molecular weight is 1500 daltons is dissolved in the mixed solvent of anhydrous dimethyl sulfoxide and anhydrous chloroform, is formulated as the methoxypolyethylene glycol solution that mass concentration is 1%, Then within 2 hours, dropwise add acetic anhydride of 2 times the number of moles of hydroxyl groups in methoxypolyethylene glycol to the methoxypolyethylene glycol solution, and stir at room temperature for 24 hours. Cold ether precipitation at 20°C to obtain aldehyde-terminated polyethylene glycol; wherein, the volume ratio of anhydrous dimethyl sulfoxide and anhydrous chloroform in the mixed solvent is 95:5;

[0057] 2) Synthesis of 2,2'-dithiodiacetylhydrazide:

[0058] Add 2,2'-dithiodiacetic acid and methanol into a reactor filled with toluene and p-toluenesulfonic acid, reflux for 12 hours, then remove the solvent in a vacuum, and then add a mass concen...

Embodiment 3

[0065] 1) Synthesis of aldehyde-terminated polyethylene glycol:

[0066] The methoxypolyethylene glycol that molecular weight is 1200 daltons is dissolved in the mixed solvent of anhydrous dimethyl sulfoxide and anhydrous chloroform, is mixed with the methoxypolyethylene glycol solution that mass concentration is 3%, Then within 0.5 hours, dropwise add acetic anhydride of 2 times the number of moles of hydroxyl groups in methoxypolyethylene glycol to the methoxypolyethylene glycol solution, stir at room temperature for 8 hours, and use subzero Cold ether precipitation at 20°C to obtain aldehyde-terminated polyethylene glycol; wherein, the volume ratio of anhydrous dimethyl sulfoxide and anhydrous chloroform in the mixed solvent is 8:1;

[0067] 2) Synthesis of 4,4'-dithiodibutyrhydrazide:

[0068] Add 4,4'-dithiodibutyric acid and methanol into a reactor containing toluene and p-toluenesulfonic acid, reflux for 12 hours, then remove the solvent in a vacuum, and then add mass ...

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Abstract

The invention relates to a bifunctional polyethylene glycol and adriamycin conjugate and a preparation method thereof. The bifunctional polyethylene glycol and adriamycin conjugate is prepared in the following steps: modifying methoxy polyethylene glycol which serves as a raw material through hydroformylation, carrying out a reductive amination reaction on the modified methoxy polyethylene glycol and disulfide-bond containing dihydrazide to generate terminal-hydrazide polyethylene glycol, and carrying out a reaction on the terminal hydrazide of the terminal-hydrazide polyethylene glycol and the ketone carbonyl of the adriamycin to generate a hydrazone bond to obtain the bifunctional polyethylene glycol and adriamycin conjugate. The bifunctional polyethylene glycol and adriamycin conjugate provided by the invention can adapt to the reductive acidic environment in a cancer cell to release drugs rapidly to improve the cancer treatment effect and reduce the drug resisting possibility of the cancer cell, and in addition, the bifunctional polyethylene glycol and adriamycin conjugate can be self-assembled into a nano particle in a water phase to be able to circulate for a long time in blood to improve the pharmacokinetics of the doxorubicin. The method for preparing the bifunctional polyethylene glycol and adriamycin conjugate has the advantages of simple process, mild reaction conditions, high drug carrying rate and low cost, and the raw materials are easy to obtain. The bifunctional polyethylene glycol and adriamycin conjugate has potential application values in the aspects of targeted delivery of drugs, controlled release of drugs and improvement of clinical cancer resisting and treating effects.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to a bifunctional polyethylene glycol-doxorubicin conjugate and a preparation method thereof. Background technique [0002] The use of cytotoxic drugs to treat tumors, namely chemotherapy, is a basic tumor treatment strategy. However, the clinical efficacy of chemotherapy drugs is often limited by the serious side effects of chemotherapy drugs on normal tissues / cells. The curative effect and toxic and side effects are positively correlated with the dosage. Therefore, improving the efficacy of chemotherapy while reducing the side effects has always been the goal pursued by the basic research and clinical application of cancer chemotherapy. To achieve this goal, drug delivery systems based on biomaterials, especially biopolymer materials, have been developed rapidly. Biopolymer materials have the advantages of flexible molecular design, diverse synthesis methods, co...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/48A61K31/704A61P35/00C08G65/48
Inventor 钱军民徐明辉胥伟军柳雪峰
Owner XI AN JIAOTONG UNIV
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