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Redox-sensitive hyaluronic acid-docetaxel conjugate and preparation method thereof

A technology of docetaxel and hyaluronic acid, which is applied in the field of hyaluronic acid-docetaxel conjugates and its preparation, can solve problems such as occurrence, and achieve the effects of improving solubility, simple preparation method, and low cost

Inactive Publication Date: 2015-01-28
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, hypersensitivity and some side effects associated with Tween-80-based formulations may occur in clinical use

Method used

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  • Redox-sensitive hyaluronic acid-docetaxel conjugate and preparation method thereof
  • Redox-sensitive hyaluronic acid-docetaxel conjugate and preparation method thereof
  • Redox-sensitive hyaluronic acid-docetaxel conjugate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1: Preparation of redox-sensitive hyaluronic acid-docetaxel conjugates

[0042] Proceed as follows:

[0043] Weigh 300 mg of docetaxel, mix it with 2 mg of succinic anhydride, dissolve it in 4 mL of dichloromethane, add 60 μL of pyridine, stir at room temperature for 72 h, and vacuum rotary evaporate (remove dichloromethane). Purified to obtain 200 mg of docetaxel succinic anhydride derivative. Dissolve 120 mg of docetaxel succinic anhydride derivative in 4 mL of N,N-dimethylformamide, add 45 mg of N-hydroxysuccinimide and 824 mg of 1-ethyl-(3-dimethylaminopropyl) carbon The imide hydrochloride was activated at room temperature to obtain 130 mg of succinic anhydride activated ester of docetaxel.

[0044]Dissolve 3 g of hyaluronic acid in 1 mL of PBS buffer (pH 7.4), add 18 mg of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and 300 mg of thiolated N-hydroxybutyl The diimide is activated by stirring. After activation, 10 g of cystamine hydrochlor...

Embodiment 2

[0046] Example 2: Preparation of redox-sensitive hyaluronic acid-docetaxel conjugates

[0047] Proceed as follows:

[0048] Weigh 270 mg of docetaxel, mix it with 14 mg of succinic anhydride, dissolve it in 3 mL of dichloromethane, add 124 μL of pyridine, stir at room temperature for three days, and vacuum rotary evaporate (remove dichloromethane). Purified to obtain 250 mg of docetaxel succinic anhydride derivative. Dissolve 200 mg of docetaxel succinic anhydride derivative in 5 mL of N,N-dimethylformamide, add 68 mg of N-hydroxysuccinimide and 24 mg of 1-ethyl-(3-dimethylaminopropyl) carbon The imide hydrochloride was activated at room temperature to give 230 mg of the succinic anhydride activated ester of docetaxel.

[0049] Dissolve 3.2 g of hyaluronic acid in 4 mL of MES buffer (pH 4.75), add 48 mg of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and 27 mg of thiolated N-hydroxy Succinimide is activated by stirring. After activation, add 10 g of cystamine...

Embodiment 3

[0050] Example 3: Preparation of redox-sensitive hyaluronic acid-docetaxel conjugates

[0051] Proceed as follows:

[0052] Weigh 34 mg of docetaxel, mix with 12.5 mg of succinic anhydride, dissolve in 2 mL of dimethyl sulfoxide, add 0.565 mL of pyridine, stir at room temperature for 72 h, and vacuum rotary evaporate (remove dimethyl sulfoxide). Purified to obtain 30mg of docetaxel succinic anhydride derivative. Dissolve 20 mg of docetaxel succinic anhydride derivative in 5 mL of N,N-dimethylformamide, add 23 mg of N-hydroxysuccinimide and 76 mg of 1-ethyl-(3-dimethylaminopropyl) carbon The imide hydrochloride was activated at room temperature to give 25 mg of the succinic anhydride activated ester of docetaxel.

[0053] Dissolve 500mg of hyaluronic acid in 10mL of MES buffer (pH 4.75), add 48mg of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 27mg of thiolated N-hydroxybutyl The diimide is activated by stirring. After activation, adjust the pH to 7.4 with ...

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Abstract

The invention discloses a redox-sensitive hyaluronic acid-docetaxel conjugate and a preparation method thereof. The redox-sensitive hyaluronic acid-docetaxel conjugate is prepared by the following steps: mixing a raw material medicine with a connection body, dissolving the mixture into an organic solvent, adding an acid-binding agent, stirring under room temperature, and performing vacuum spinning steaming to remove the organic solvent; after purification is executed, dissolving a product into a proper amount of the solvent, adding an activating agent and a dewatering agent for activation under room temperature to generate anhydride activation ester serving as the raw material medicine; dissolving a carrier into a solution, and adding the activating agent and the dewatering agent for stirring activation; after activation is executed, adding a disulfide bond crosslinking agent, performing dialysis, dry-freezing to obtain a product; dissolving a carrier crosslinking product into the organic solvent; dripping the anhydride activation ester serving as the raw material medicine into a carrier solution, incubating for certain time, performing dialysis, and dry-freezing to obtain the target product. The conjugate prepared by the invention can effectively improve the solubility of docetaxel; the redox-sensitive hyaluronic acid-docetaxel conjugate is higher in targeting property and has the advantages of simple preparation method, low cost and the like.

Description

technical field [0001] The invention relates to a redox-sensitive hyaluronic acid-docetaxel conjugate and a preparation method. Background technique [0002] Hyaluronic acid (Hyaluronic acid, HA molecular weight: 9.7kDa) is a mucopolysaccharide with important biological functional properties, such as stabilizing the extracellular matrix, regulating cell adhesion and fluidity, and intervening in cell proliferation and differentiation. Hyaluronic acid and its derivatives have been matured as advanced materials for research in the fields of pharmaceuticals and biomedicine. The hyaluronic acid-bonded receptors CD44 and RHAMM are overexpressed on the cell surface of several hypermetabolic malignancies, making them targeted for drug delivery. Due to their high hydrophilicity and multiple modifiable functional groups, hyaluronic acid-drug conjugates have been used as biomaterials for active targeting of biologics. [0003] Docetaxel (DTX) is a very effective clinical chemotherapy...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K31/337A61K9/107A61P35/00C08B37/08
Inventor 翟光喜张海群杨小叶
Owner SHANDONG UNIV
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