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Preparation method and application of doxorubicin-methotrexate combined drug delivery nano-delivery system

A technology of methotrexate and delivery system, which is applied in the direction of medical formula, medical preparations with non-active ingredients, medical preparations containing active ingredients, etc., can solve the problems of chemical resistance mutation, tumor recurrence, etc., and achieve the goal of reducing toxicity. Side effects, broad application prospects, and the effect of improving passive targeting

Active Publication Date: 2021-04-27
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 doxorubicin-methotrexate combined drug delivery nano-delivery system
  • Preparation method and application of doxorubicin-methotrexate combined drug delivery nano-delivery system
  • Preparation method and application of doxorubicin-methotrexate combined drug delivery nano-delivery system

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 doxorubicin and methotrexate combined administration nano delivery system. It is prepared as follows: first synthesize 2-(pyridyl dithio)-ethylamine hydrochloride; then graft p-hydroxybenzaldehyde to the carboxyl group in hyaluronic acid; then 2-(pyridyl dithio) )-Ethylamine hydrochloride continues to be grafted to the carboxyl group of hyaluronic acid; then reacts with the amino group of doxorubicin to form an imine bond; then dissolves in formamide together with methotrexate, and adds it dropwise to distilled water to coat Methotrexate is finally cross-linked under the catalysis of dithiothreitol to obtain a combined drug delivery system of doxorubicin-methotrexate. The preparation process is relatively simple and easy to control, realizes the combined administration of doxorubicin and methotrexate, has pH / GSH dual sensitivity, improves the passive targeting of the drug, and reduces the toxic and side effects of the drug on normal tissues and cells. It has broad application prospects in the field of controlled release of antitumor 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 Patents(China)
IPC IPC(8): A61K47/69A61K47/61A61K31/519A61K31/704A61P35/00
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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