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Preparation method and application of nano delivery system for combined administration of adriamycin and methotrexate

A methotrexate and delivery system technology, which can be applied to pharmaceutical formulations, medical preparations with inactive ingredients, and medical preparations containing active ingredients, etc., can solve problems such as chemical resistance mutation, tumor recurrence, etc. Side effects, simple preparation process, improved passive targeting effect

Active Publication Date: 2020-03-27
WUHAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Insufficient monotherapy, its one-dimensional mechanism of action can easily lead to the emergence of chemoresistant mutations and tumor recurrence, which can no longer meet the clinical needs, especially in patients with advanced cancer

Method used

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  • Preparation method and application of nano delivery system for combined administration of adriamycin and methotrexate
  • Preparation method and application of nano delivery system for combined administration of adriamycin and methotrexate
  • Preparation method and application of nano delivery system for combined administration of adriamycin and methotrexate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] (1) Dissolve 882mg (4mmol) of 2,2-dithiobipyridine in methanol (4.16mL) containing 160μL of glacial acetic acid, inject it into an eggplant-shaped bottle filled with nitrogen, and then add 228mg (2mmol) of mercaptoethylamine hydrochloride The salt was dissolved in 1.75mL of methanol and slowly added dropwise to the above solution, and stirred at 35°C for 48h. Concentrate under reduced pressure after the completion of the reaction to obtain 3-5 mL of yellow oil, add 20 mL of cold ether to obtain a precipitate, then dissolve in 5 mL of methanol, continue to precipitate with 20 mL of cold ether until no oily matter, and dry in vacuo to obtain a white powder, namely is PDA·HCl.

[0048] (2) Dissolve 100mg (0.263mmol) of hyaluronic acid (HA, MW=5300Da) in 5mL of formamide, then add 100mg (0.526mmol) of EDC·HCl to the above solution while stirring, and add 60.53mg after 1h (0.526mmol) NHS, activated at room temperature for 1h, another 318.59mg (2.63mmol) p-hydroxybenzaldehyd...

Embodiment 2

[0059](1) Dissolve 882mg (4mmol) of 2,2-dithiobipyridine in methanol (4.16mL) containing 160μL of glacial acetic acid, inject it into an eggplant-shaped bottle filled with nitrogen, and then add 228mg (2mmol) of mercaptoethylamine hydrochloride The salt was dissolved in 1.75mL of methanol and slowly added dropwise to the above solution, and stirred at 35°C for 48h. Concentrate under reduced pressure after the completion of the reaction to obtain 3-5 mL of yellow oil, add 20 mL of cold ether to obtain a precipitate, then dissolve in 5 mL of methanol, continue to precipitate with 20 mL of cold ether until no oily matter, and dry in vacuo to obtain a white powder, namely is PDA·HCl.

[0060] (2) Dissolve 100mg (0.263mmol) of hyaluronic acid (HA, MW=5300Da) in 5mL of formamide, then add 100mg (0.526mmol) of EDC·HCl to the above solution while stirring, and add 60.53mg after 1h (0.526mmol) NHS, activated at room temperature for 1h, another 318.59mg (2.63mmol) p-hydroxybenzaldehyde...

Embodiment 3

[0066] (1) Dissolve 882mg (4mmol) of 2,2-dithiobipyridine in methanol (4.16mL) containing 160μL of glacial acetic acid, inject it into an eggplant-shaped bottle filled with nitrogen, and then add 228mg (2mmol) of mercaptoethylamine hydrochloride The salt was dissolved in 1.75mL of methanol and slowly added dropwise to the above solution, and stirred at 35°C for 48h. Concentrate under reduced pressure after the completion of the reaction to obtain 3-5 mL of yellow oil, add 20 mL of cold ether to obtain a precipitate, then dissolve in 5 mL of methanol, continue to precipitate with 20 mL of cold ether until no oily matter, and dry in vacuo to obtain a white powder, namely is PDA·HCl.

[0067] (2) Dissolve 100mg (0.263mmol) of hyaluronic acid (HA, MW=9800Da) in 5mL of formamide, then add 100mg (0.526mmol) of EDC·HCl to the above solution while stirring, and add 60.53mg after 1h (0.526mmol) NHS, activated at room temperature for 1h, another 318.59mg (2.63mmol) p-hydroxybenzaldehyd...

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Abstract

The invention relates to a preparation method and application of a nano delivery system for combined administration of adriamycin and methotrexate. The preparation method comprises the following steps: synthesizing 2-(pyridyl dithio)-ethylamine hydrochloride; grafting p-hydroxybenzaldehyde onto carboxyl in hyaluronic acid; then grafting 2-(pyridyl dithio)-ethylamine hydrochloride onto carboxyl ofthe hyaluronic acid; then performing reacting with amino of adriamycin to form an imine bond; dissolving the obtained substance in formamide together with methotrexate; dropwise adding the mixed solution into distilled water to wrap the methotrexate; and finally performing crosslinking under catalysis of dithiothreitol to obtain the nano delivery system for combined administration of adriamycin and methotrexate. The preparation process is relatively simple and is easy to control, combined administration of adriamycin and methotrexate is realized, and the nano delivery system has a pH / GSH double-sensitive characteristic, improves a passive targeting property of drugs, reduces toxic and side effects of drugs on normal tissues and cells, and has a wide application prospect in the field of controlled release of anti-tumor drugs.

Description

technical field [0001] The invention relates to the technical field of nano-biomedicine, in particular to a preparation method and application of a nano-delivery system for combined administration of doxorubicin and methotrexate. Background technique [0002] Breast cancer is the second most deadly type of cancer among women in the world. There are no typical symptoms in the early stage, and it is easy to be ignored. Coupled with the fast pace of modern life, high work pressure, and irregular diet, the disease will come uninvited. When there is a lump in the breast, non-menstrual pain, nipple discharge, and "orange peel" on the skin, you should check with a professional medical institution. However, in most cases of breast cancer, surgical resection of the cancerous tissue is necessary, but there is a high risk of recurrence and metastasis due to residual malignant cells. Accordingly, the need for new treatment modalities for breast cancer is expanding. [0003] Doxorubici...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/69A61K31/519A61K31/704A61P35/00
CPCA61K31/519A61K31/704A61K47/61A61K47/6939A61P35/00A61K2300/00
Inventor 郑化刘灿李单宋亚静陈钢
Owner WUHAN UNIV OF TECH
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