PH-responsive polyethylene glycol-anticarcinogen conjugate, and synthetic method and application thereof

A polyethylene glycol and responsive technology, applied in the field of biomedicine, can solve the problems of normal human cell damage, limited clinical effect, poor stability, etc.

Inactive Publication Date: 2012-05-30
INST OF CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, less than 10% of tumor patients can undergo preoperative chemotherapy and complete resection after radiotherapy, although about 90% of patients can receive radiotherapy, including radiofrequency or alcohol ablation, and administration of doxorubicin, 5-fluorouracil, etc. for systemic or arterial infusion. Injection, embolization and other chemotherapy treatments, these methods or drugs can indeed have a certain inhibitory or killing effect on tumor tissues or cells. However, when using traditional preparations to treat tumors, the drug-loading system cannot distinguish between normal tissues and tumors. Tissues, normal cells and tumor cells, so that the drug kills th

Method used

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  • PH-responsive polyethylene glycol-anticarcinogen conjugate, and synthetic method and application thereof
  • PH-responsive polyethylene glycol-anticarcinogen conjugate, and synthetic method and application thereof
  • PH-responsive polyethylene glycol-anticarcinogen conjugate, and synthetic method and application thereof

Examples

Experimental program
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Example Embodiment

[0066] Example 1 Synthesis of pH-responsive polyethylene glycol-anticancer drug conjugate based on methoxy polyethylene glycol benzaldehyde monoester

[0067] The synthetic route of the reaction is as follows:

[0068]

[0069]

[0070] (1) 4g (0.002mol) monomethoxy polyethylene glycol, 2.4g (0.016mol) p-aldehyde benzoic acid, 0.1222g (0.001mol) 4-dimethylaminopyridine (DMAP) were added to 100ml of In a round bottom flask, 60 ml of dry dichloromethane was added to mix the reaction well. In a water bath at 37°C with stirring, 10 ml of a dichloromethane solution in which 3.3 g (0.016 mol) of N,N'-dicyclohexylcarbodiimide (DCC) was dissolved was added dropwise to a round bottom flask to remove the reaction produced water. After constant temperature stirring for 24 hours, the reaction solution was filtered to remove the reaction by-product N,N'-dicyclohexylurea (DCU); the filtrate was concentrated and recrystallized with isopropanol, and the obtained crude product was succes...

Example Embodiment

[0072] Example 2 Synthesis of pH-responsive targeted polyethylene glycol-anticancer drug conjugate based on folic acid-terminated polyethylene glycol benzaldehyde

[0073] (1) 3.4g (0.001mol) polyethylene glycol with one end amino group and one end folic acid group and 0.99g (0.004mol, the molar ratio of one end amino group and one end folic acid group polyethylene glycol is 1:4) N-succinyl Imino-p-formylbenzoate (SFB) was dissolved in 60 ml of dry dichloromethane, reacted in a water bath at 50°C and stirred for 24 hours. After the completion of the reaction, the reaction solution was filtered to remove unreacted SFB; the filtrate was concentrated and then recrystallized with isopropanol, and the obtained crude product was washed three times with isopropanol and glacial ether successively, and was dried in vacuo to remove the solvent to obtain pale yellow. Powdered product - folic acid terminated polyethylene glycol benzaldehyde amide.

[0074] (2) Weigh 77.8 mg (0.138 mmol) ...

Example Embodiment

[0075] Example 3 Synthesis of pH-responsive polyethylene glycol-anticancer drug conjugate based on benzaldehyde-terminated polyethylene glycol

[0076] (1) Dissolve 4.6g (0.001mol) polyethylene glycol with a molecular weight of 4600 and 1.236g (0.008mol) p-aldehyde benzyl chloride in 60ml dry chloroform, add 0.6g K 2 CO 3 , after refluxing for 8 hours at a temperature of 80 ° C, the reaction solution was filtered, the filtrate was concentrated and recrystallized with isopropanol, and the obtained crude product was washed three times with isopropanol and glacial ether successively; after vacuum drying, a white powder was obtained The product in the form of a benzaldehyde-terminated polyethylene glycol (polyethylene glycol with benzaldehyde groups at both ends connected by ether bonds).

[0077] (2) Weigh 214 mg (0.4 mmol) of demethoxy daunorubicin, 242 mg (0.05 mmol, 1:8 molar ratio to demethoxy daunorubicin) of the end-benzaldehyde synthesized in step (1) Polyethylene glycol...

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Abstract

The invention discloses a pH-responsive polyethylene glycol-anticarcinogen conjugate, and a synthetic method and application thereof. After anticarcinogen molecules and polyethylene glycol are covalently linked through pH-sensitive phenylimide linkage, the conjugate is formed, wherein, anticarcinogen can be doxorubicin, epirubicin, daunorubicin, demethoxydaunorubicin or hydrochlorides of the above-mentioned anticarcinogens. The phenylimide linkage is stable under the condition of a normal physiological pH value but undergoes hydrolysis under the condition of a slightly acidic pH value, e.g., a solid tumor cell external pH value and a cell endosome and lysosome pH value; that is, the phenylimide linkage is sensitive to changes of pH values in a range of 7.4 to 4.5 or to below 4.5. The polyethylene glycol-anticarcinogen conjugate has amphiphilic nature and can form nanometer-scale micelle in a saline solution through self-assembly; the micelle can be used as a drug carrier to carry hydrophobic drugs and form a nanometer micelle preparation cladded with drugs, thereby realizing synergy therapy of a plurality of drugs.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to a pH-responsive polyethylene glycol-anticancer drug bond based on a phenylimine bond and a synthesis method thereof, and the polyethylene glycol-anticancer drug The application of the bond as a drug carrier. Background technique [0002] Cancer seriously endangers human life and health. According to the statistics of the World Health Organization, 7.6 million people died of cancer in the world in 2005, and it is estimated that the number will reach 9 million in 2015 and 11.5 million in 2030. Cancer has been listed as the "No. 2 killer" (after cardiovascular disease) facing mankind (China Cancer, 2009, 18, 88-89). Due to the difficulty of early detection, its treatment has always been a difficult point in the medical field. At present, less than 10% of tumor patients can undergo preoperative chemotherapy and complete resection after radiotherapy, although about ...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K31/704A61K31/4745A61K31/337A61K31/519A61K31/12A61K31/4375A61K31/216A61P35/00A61K47/34
Inventor 杨振忠朱丽君屈小中刘继广张成亮李焦丽王倩
Owner INST OF CHEM CHINESE ACAD OF SCI
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