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Anticancer hydroxyethyl starch-doxorubicin conjugate and preparation method thereof

A technology of hydroxyethyl starch and doxorubicin, which is applied in the field of biomedicine, can solve the problems of complex preparation process, dangerous operation, toxic and side effects of doxorubicin conjugates, etc., to prolong cycle time, facilitate operation and control, Improve the effect of treatment

Inactive Publication Date: 2017-01-18
HUAZHONG UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] In view of the above defects or improvement needs of the prior art, the present invention provides an anticancer drug hydroxyethyl starch-doxorubicin conjugate and a preparation method thereof. Propionic acid is used as a connecting arm to couple hydroxyethyl starch and doxorubicin through ester bonds and amide bonds, respectively, to obtain a reduction-responsive hydroxyethyl starch-doxorubicin conjugate, thereby solving the problems of the prior art. Doxorubicin conjugates have technical problems such as toxic and side effects in vivo, complicated preparation process, and dangerous operation

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  • Anticancer hydroxyethyl starch-doxorubicin conjugate and preparation method thereof
  • Anticancer hydroxyethyl starch-doxorubicin conjugate and preparation method thereof
  • Anticancer hydroxyethyl starch-doxorubicin conjugate and preparation method thereof

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preparation example Construction

[0060] The preparation method of hydroxyethyl starch-doxorubicin conjugate of the present invention comprises the following steps:

[0061] (1) react hydroxyethyl starch with 3,3'-dithiodipropionic acid in the presence of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) to generate formula (II ) of hydroxyethyl starch-3,3'-dithiodipropionic acid monoester, wherein R 1 and R 2 for H or CH 2 CH 2 OH;

[0062]

[0063] (2) The hydroxyethyl starch-3,3'-dithiodipropionic acid monoester obtained in step (1) was mixed with doxorubicin in 1-(3-dimethylaminopropyl) under the condition of avoiding light. Under the condition that -3-ethylcarbodiimide hydrochloride (EDCI), N-hydroxysuccinimide (NHS) and triethylamine exist, react the hydroxyethyl starch-doxorubicin shown in formula (I) prime conjugates.

[0064] The preparation method of described hydroxyethyl starch-doxorubicin conjugate specifically comprises the steps:

[0065] (1) Dissolve 3,3'-dithiodipropi...

Embodiment 1

[0079] Prepare the anticancer drug hydroxyethyl starch-doxorubicin conjugate according to the following steps:

[0080] (1) Dissolve 2.96g (14.10mmol) of 3,3'-dithiodipropionic acid in 20mL of dimethylsulfoxide, then add 0.58g (2.82mmol) of dicyclohexylcarbodiimide (DCC), 4- Dimethylaminopyridine (DMAP) 0.17g (1.41mmol), stirred at room temperature for 0.5h to obtain a brown reaction solution A, then added 1.04g of hydroxyethyl starch (sugar ring is 5.65mmol) to the brown reaction solution A, and continued at room temperature Stirring and reacting for 48 hours to obtain reaction solution B, wherein the molecular weight of hydroxyethyl starch is 200kDa, and the degree of substitution of hydroxyethyl is 0.5;

[0081] (2) Filter the reaction solution B to remove the dicyclohexyl urea generated in the reaction, pour the filtrate into 200 mL of ethanol / ether mixed solvent (1:1, V / V), and stir to obtain a suspension C;

[0082] (3) Suspension C was filtered to obtain a brown precip...

Embodiment 2

[0088] (1) Dissolve 2.96g (14.10mmol) of 3,3'-dithiodipropionic acid in 20mL of dimethylsulfoxide, then add 0.58g (2.82mmol) of dicyclohexylcarbodiimide (DCC), 4- Dimethylaminopyridine (DMAP) 0.17g (1.41mmol), stirred at room temperature for 0.5h to obtain a brown reaction solution A, then added 1.04g of hydroxyethyl starch (sugar ring is 5.65mmol) to the brown reaction solution A, and continued at room temperature Stirring and reacting for 48 hours to obtain reaction solution B, wherein the molecular weight of hydroxyethyl starch is 70kDa, and the degree of substitution of hydroxyethyl is 0.5;

[0089] (2) Filter the reaction solution B to remove the dicyclohexyl urea generated in the reaction, pour the filtrate into 200 mL of ethanol / ether mixed solvent (1:1, V / V), and stir to obtain a suspension C;

[0090] (3) Suspension C was filtered to obtain a brown precipitate, which was washed three times with 150 mL of ethanol / ether mixed solvent (1:1, V / V), 50 mL each time, and the...

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Abstract

The invention discloses a hydroxyethyl starch-doxorubicin conjugate and preparation method and application thereof. The preparation method comprises the following steps: with hydroxyethyl starch as a medicine carrier, coupling 3,3'-dithiobispropionic acid onto hydroxyethyl of the hydroxyethyl starch through monoester, and coupling doxorubicin onto carboxyl of hydroxyethyl starch-3,3'-dithiobispropionic acid monoester through an amido bond in a dark condition to obtain the hydroxyethyl starch-doxorubicin conjugate with reducing responsiveness. The hydroxyethyl starch-doxorubicin conjugate prepared by the preparation method provided by the invention can prolong the cycle time of the doxorubicin in blood, enhance enrichment of the doxorubicin on a tumor site and improve the therapeutic effect of doxorubicin on a tumor; meanwhile, the hydroxyethyl starch-doxorubicin conjugate can be reduced by glutathione to release the doxorubicin in a tumor cell, and after release of the doxorubicin, the medicine carrier does not contain potentially toxic groups and can be metabolized, so that the hydroxyethyl starch-doxorubicin conjugate is high in safety; the preparation method provided by the invention is short in process, simple in operation and mild in condition.

Description

technical field [0001] The invention belongs to the field of biomedicine, and more specifically relates to an anticancer drug hydroxyethyl starch-doxorubicin conjugate and a preparation method thereof. Background technique [0002] Doxorubicin is an anthracycline antibiotic. The mechanism of action of the drug is to intercalate into the DNA chain, thereby blocking the replication of DNA and arresting cells in S phase. Doxorubicin has been approved by the FDA for the clinical treatment of leukemia, breast cancer, bladder cancer, soft tissue sarcoma, etc. Since doxorubicin disappears in the blood soon after intravenous injection, it is widely distributed in normal tissues and organs, which seriously affects the efficacy of doxorubicin and can cause serious side effects, such as severe cardiotoxicity and nephrotoxicity. Therefore, prolonging the blood circulation time of doxorubicin, improving its targeting, and reducing its toxic and side effects have important clinical val...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K31/704C08B31/00A61P35/00
CPCA61K31/704C08B31/00
Inventor 杨祥良李子福万影徐辉碧胡航
Owner HUAZHONG UNIV OF SCI & TECH
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