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Adriamycin polyprodrug nano-micelle with reducibility response and preparation method and application thereof

A technology of nano-micelle and doxorubicin, which is applied in medical preparations with non-active ingredients, medical preparations containing active ingredients, and pharmaceutical formulas, etc. It can solve the problems of high toxic side effects, poor water solubility, and short half-life of doxorubicin, etc. problem, achieve the effect of reducing drug toxicity, improving water solubility and stability

Active Publication Date: 2020-06-12
SOUTH CHINA NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the shortcomings of doxorubicin, such as short half-life, poor targeting, poor water solubility, and large toxic and side effects, its further application is limited.
In order to improve the water solubility of doxorubicin, the common drug form in clinical practice is doxorubicin hydrochloride, but after turning into hydrochloride, the pharmacodynamic function of doxorubicin is greatly reduced, which brings great difficulties to clinical application

Method used

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  • Adriamycin polyprodrug nano-micelle with reducibility response and preparation method and application thereof
  • Adriamycin polyprodrug nano-micelle with reducibility response and preparation method and application thereof
  • Adriamycin polyprodrug nano-micelle with reducibility response and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1: Single-ended modification of 4,4'-dithiodibutyric acid

[0048] In a 250mL double-necked round bottom flask, weigh 4,4'-dithiodibutyric acid (5g, 20.98mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride Salt EDC (8.04g, 41.96mmol), DMAP (5.13g, 41.96mmol) and 100mL of dry dichloromethane were cooled in an ice-water bath and stirred with a magnet until completely dissolved. Return to room temperature and continue stirring for 4 h to fully dissolve the mixture, then add 2-hydroxyethyl methacrylate HEMA (2.49 g, 19.11 mmol), and stir overnight at room temperature. After 24 h, the reaction was stopped, and the solvent was removed by rotary evaporation. The crude product was separated and purified by silica gel column chromatography, and eluted with petroleum ether:dichloromethane=1:1 and dichloromethane to obtain a yellow oily liquid (4.19g, yield: 56%).

Embodiment 2

[0049] Example 2: Preparation of reductively responsive doxorubicin prodrug monomer DOXM

[0050] Doxorubicin hydrochloride is first desalted. In a 250 mL round bottom flask, weigh doxorubicin hydrochloride (40 mg, 6.9 mmol) and disperse it in 150 mL of dry dichloromethane, and add 200 mL of triethylamine (1 mg DOX·HCl is added to 5 mL of triethylamine). Stir at room temperature until doxorubicin hydrochloride is completely dissolved, concentrate the liquid to 30mL by rotary evaporation, collect the filtrate after filtration for use, weigh the product in Example 1 (24.18mg, 6.9mmol), 1-ethyl-(3-di Methylaminopropyl)carbodiimide hydrochloride EDC (2.65 mg, 13.8 mmol), N-hydroxysuccinimide NHS (1.59 mg, 13.8 mmol) were dissolved in 10 mL of dry dichloromethane. After stirring overnight at room temperature for 24 hours, the desalted DOX solution was added to continue the reaction for 24 hours. After the reaction, extract three times with deionized water and saturated NaCl aqueo...

Embodiment 3

[0051] Embodiment 3: the preparation of poly(N,N-dimethylacrylamide) PDMA macromolecular chain transfer agent

[0052] The chain transfer agent 4-cyano-4-(phenylthioformylthio)valeric acid (compound 4) (15 mg, 0.054 mmol), N,N-dimethylacrylamide (compound 5) (DMA, 319.4 mg, 3.222 mmol) and azobisisobutyronitrile (AIBN, 1.77 mg, 0.011 mmol) were dissolved in 1 mL of 1,4-dioxane in an ampoule. Freeze the ampoule bottle in liquid nitrogen and use an oil pump to pump air, then seal the ampoule bottle, return to room temperature to melt the reaction mixture, and then freeze and pump air again. Repeat the freeze-thaw cycle three times to make the reaction environment as free as possible. Air, in a state of vacuum. Then seal again, stir and react at 70°C for 13 hours, then stop the polymerization reaction with liquid nitrogen, open the reaction bottle, precipitate the reaction mixture in glacial ether, centrifuge, redissolve in dichloromethane and precipitate with a large amount of ...

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Abstract

The invention belongs to the field of degradable medical polymer synthesis and design and preparation of anti-cancer drug conjugates, and discloses adriamycin polyprodrug nano-micelle with reducibility response and a preparation method and application thereof. Hydroxyethyl methacrylate and 4, 4'-dithiodibutyric acid are adopted as basic raw materials, amino of adriamycin is modified, disulfide bond primitives are introduced, an adriamycin prodrug monomer DOXM with disulfide bond reducibility response is prepared, and polyprodrug amphiphilic molecules PDMA-b-PDOXM are prepared through RAFT. ThePDMA-b-PDOXM has very high drug loading capacity, and the water solubility and the stability of the drug are improved. The disulfide bonds enable the drug carrier to respond to a tumor cell reductivemicroenvironment after reaching a tumor targeting site to release a small molecular raw drug adriamycin, so that the drug toxicity is reduced and an anti-cancer drug can be intelligently released intumor cells.

Description

technical field [0001] The invention belongs to the fields of synthesis of degradable medical polymers and design and preparation of anticancer drug conjugates, and in particular relates to a doxorubicin polyprodrug nano-micelle with reductive response and its preparation method and application. Background technique [0002] Adriamycin (Adriamycin, DOX), also known as 1,4-hydroxydaunorubicin, 1,4-hydroxydaunomycin, doxorubicin, hydroxyerythromycin, is an anthracycline antitumor antibiotic , which is a cycle non-specific drug, has broad-spectrum anti-tumor activity, and has a killing effect on tumor cells in various growth cycles. Doxorubicin can successfully inhibit a variety of malignant tumors, including solid tumors such as breast cancer, liver cancer, gastric cancer, lung cancer, thyroid cancer, ovarian cancer, and bladder cancer. It is commonly used as a second-line drug in clinical practice, that is, it can be considered when the first-line drug is resistant. Its mol...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/107A61K31/704A61K47/58A61P35/00
CPCA61K9/1075A61K31/704A61K47/58A61P35/00
Inventor 胡祥龙张文佳
Owner SOUTH CHINA NORMAL UNIVERSITY
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