Preparation method and application of pH-sensitive hyaluronic acid-doxorubicin nanometer prodrug

A technology of hyaluronic acid and doxorubicin, which can be used in pharmaceutical formulations, medical preparations with non-active ingredients, and medical preparations containing active ingredients, etc. problems, to achieve the effect of convenient directional drug delivery, easy storage, and high stability

Inactive Publication Date: 2017-08-29
WUHAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although doxorubicin has a broad anti-tumor spectrum and good curative effect, the side effects of doxorubicin after intravenous injection, mainly including nau...

Method used

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  • Preparation method and application of pH-sensitive hyaluronic acid-doxorubicin nanometer prodrug
  • Preparation method and application of pH-sensitive hyaluronic acid-doxorubicin nanometer prodrug
  • Preparation method and application of pH-sensitive hyaluronic acid-doxorubicin nanometer prodrug

Examples

Experimental program
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Effect test

Embodiment 1

[0034] Dissolve 400mg of hyaluronic acid (HA, molecular weight 5300Da) in 30mL of formamide, and add 256mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) while magnetic stirring HCl), after reacting at room temperature for 30 min, 146 mg of N-hydroxysuccinimide (NHS) was added, and the reaction was continued for 2 h. At the same time, 255 mg of methyl 4-aminomethylbenzoate was dissolved in 15 mL of formamide, and after dissolution, it was added dropwise into the hyaluronic acid activation system, and reacted with magnetic stirring for 24 hours. After the reaction, the reaction mixture was dialyzed with distilled water (MWCO, 3500) for 3 days, and freeze-dried to obtain the product HA-Ester.

[0035] Weigh 300 mg of lyophilized HA-Ester and dissolve it in 15 mL of formamide, then add 1.5 mL of hydrazine hydrate (NH 2 -NH 2 ·H 2 O, mass fraction 85%), reflux reaction at 60° C. for 16 h under nitrogen protection condition. After removing most of the solv...

Embodiment 2

[0039] Dissolve 400mg of hyaluronic acid (HA, molecular weight: 9800Da) in 30mL of formamide, and add 256mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) while magnetically stirring HCl), after reacting at room temperature for 30 min, 146 mg of N-hydroxysuccinimide (NHS) was added, and the reaction was continued for 2 h. At the same time, 255 mg of methyl 4-aminomethylbenzoate was dissolved in 15 mL of formamide, and after dissolution, it was added dropwise into the hyaluronic acid activation system, and reacted with magnetic stirring for 24 hours. After the reaction, the reaction mixture was dialyzed with distilled water (MWCO, 3500) for 3 days, and freeze-dried to obtain the product HA-Ester.

[0040] Weigh 300 mg of lyophilized HA-Ester and dissolve it in 15 mL of formamide, then add 1.5 mL of hydrazine hydrate (NH 2 -NH 2 ·H 2 O, mass fraction 85%), reflux reaction at 60° C. for 16 h under nitrogen protection condition. After removing most of the...

Embodiment 3

[0044] Dissolve 400mg of hyaluronic acid (HA, molecular weight 37000Da) in 30mL of formamide, and add 256mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) while magnetically stirring HCl), after reacting at room temperature for 30 min, 146 mg of N-hydroxysuccinimide (NHS) was added, and the reaction was continued for 2 h. At the same time, 255 mg of methyl 4-aminomethylbenzoate was dissolved in 15 mL of formamide, and after dissolution, it was added dropwise into the hyaluronic acid activation system, and reacted with magnetic stirring for 24 hours. After the reaction, the reaction mixture was dialyzed with distilled water (MWCO, 3500) for 3 days, and freeze-dried to obtain the product HA-Ester.

[0045] Weigh 300 mg of lyophilized HA-Ester and dissolve it in 15 mL of formamide, then add 1.5 mL of hydrazine hydrate (NH 2 -NH 2 ·H 2 O, mass fraction 85%), reflux reaction at 60° C. for 16 h under nitrogen protection condition. After removing most of the...

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Abstract

The invention discloses a preparation method and application of a pH-sensitive hyaluronic acid-doxorubicin nanometer prodrug. The nanometer prodrug is prepared through the following preparation steps of firstly reacting amino in 4-aminomethyl methyl benzoate with carboxyl of hyaluronic acid to form an amido bond; forming hydrazine by using methoxy in a reactant in the previous step and hydrazine hydrate, and further forming a hydrazone bond by using a product and carbonyl of doxorubicin; and finally preparing nanometer prodrug particles through an ultrasonic assisted self-assembly method. The microstructure and the in vitro release property of the nanometer particles are researched, cellular uptake and a cytotoxicity test can be further carried out to prove that the macromolecular prodrug nanometer particles have obvious pH sensitivity and ideal in vitro anti-tumor activity, the problem of large toxic and side effects of the micromolecular drug doxorubicin can be solved and a basis can be provided for clinical application.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to a preparation method and application of a pH-sensitive hyaluronic acid-doxorubicin nanometer prodrug. Background technique [0002] Malignant tumor is a major disease that seriously threatens human life, and liver cancer is one of the common digestive system tumors. Doxorubicin, also commonly known as doxorubicin and daunorubicin, is an anthracycline broad-spectrum antitumor antibiotic, cycle non-specific drug, and has killing effects on tumor cells of various growth cycles. Doxorubicin can successfully inhibit a variety of malignancies, including acute leukemia, lymphoma, soft tissue and osteosarcoma, childhood malignancies, and adult solid tumors. Although doxorubicin has a broad anti-tumor spectrum and good curative effect, the side effects of doxorubicin after intravenous injection, mainly including nausea, vomiting, bone marrow suppression, gastrointestinal adverse reac...

Claims

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Application Information

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IPC IPC(8): A61K47/61A61K31/704A61P35/00A61K9/51
CPCA61K9/5161A61K31/704
Inventor 郑化费增明廖健洪曹俊王宝龙危培魏璇
Owner WUHAN UNIV OF TECH
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