Mitoxantrone estrogen targeting PEG-modified liposome and applications thereof

An anthraquinone estrogen, mitoxantrone technology, applied in the directions of liposome delivery, antitumor drugs, drug combination, etc., can solve the problems of short metabolism time, low drug concentration, expensive raw materials, etc., and achieve high curative effect and distribution. Uniform and stable effect

Inactive Publication Date: 2015-10-14
JILIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Mitoxantrone liposomes are currently reported as conventional liposome preparations, with expensive raw materials, short metabolism time in the body, and low drug concentration at the tumor site

Method used

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  • Mitoxantrone estrogen targeting PEG-modified liposome and applications thereof
  • Mitoxantrone estrogen targeting PEG-modified liposome and applications thereof
  • Mitoxantrone estrogen targeting PEG-modified liposome and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Embodiment 1: Synthesis of estrone-pegylated distearoylphosphatidylethanolamine

[0062] 1. Preparation of activated estrone ester: Weigh 108.00 mg of estrone, 50.00 mg of succinic anhydride, 48.80 mg of 4-dimethylaminopyridine and 40.48 mg of triethylamine and dissolve them in dioxane. Stir overnight at room temperature. Dioxane was evaporated to dryness under vacuum, the residue was dissolved in dichloromethane and filtered. The filtrate was further concentrated, precipitated with ether, and dried to obtain the activated ester of estrone.

[0063] 2. Synthesis of estrone-pegylated distearoylphosphatidylethanolamine: 92.50 mg of estrone activated ester obtained above was dissolved in methylene chloride and 6.75 mg of hydroxybenzotriazole. Under ice cooling, 51.55 mg of dicyclohexylcarbodiimide and 137.50 mg of aminopegylated distearoylphosphatidylethanolamine were added. The resulting solution was stirred continuously for 18 hours until a precipitate formed. The pr...

Embodiment 2

[0064] Example 2: Synthesis of fulvestrant-pegylated dipalmitoylphosphatidylethanolamine

[0065] 1. Preparation of fulvestrant activated ester: Weigh 1122.50 mg of fulvestrant, 370.00 mg of succinic anhydride, 561.00 mg of triethylamine and 122.00 mg of 4-dimethylaminopyridine, dissolve them in 4 ml of dioxane, place React in a 10ml round-bottomed flask at 25°C for 48h under magnetic stirring, evaporate to dryness under reduced pressure, add 10mL of water in an ice-water bath and adjust the pH to 1 with 5mol / L HCl solution, after standing still, a precipitate precipitates, and filter under reduced pressure to obtain the product Fulvestre Group activated esters.

[0066] 2. Synthesis of fulvestrant-pegylated dipalmitoylphosphatidylethanolamine: dissolve 95.40 mg of the above fulvestrant activated ester in 4 ml of dichloromethane, add 18.24 mg of hydroxybenzotriazole and dicyclohexyl carbon Diimine 21.90 mg, reacted at room temperature for 1 hour, then added aminopegylated dip...

Embodiment 3

[0067] Example 3: Mitoxantrone estrogen-targeted PEG-modified liposome 1

[0068] Using the ammonium sulfate gradient method: take 200 mg of soybean lecithin, 50 mg of cholesterol, and 100 mg of polyethylene glycol-distearoylphosphatidylethanolamine and dissolve them in 30 ml of methanol, remove the organic solvent by rotary evaporation, and then add 10 ml of 250 mM ammonium sulfate aqueous solution to 60 ° C water for 0.5h. After sonicating for 5 min with a probe sonicator, it was dialyzed 4 times in 5% glucose solution. Add 20 mg of mitoxantrone and incubate for 1 hour, then dialyze, then add 10 mg of estrone-polyethylene glycol-distearoylphosphatidylethanolamine for incubation, and use an extruder to extrude through a 0.22 μm polycarbonate film for 10 times to obtain rice Toxantrone estrogen-targeted PEG-modified liposome formulation.

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Abstract

The present invention discloses a preparation method and uses of an anti-cancer drug estrogen targeting PEG-modified liposome. The liposome preparation method comprises: synthesizing estrone-pegylated phospholipid from activated estrone, taking 40-80 parts by weight of phospholipid, 5-45 parts by weight of cholesterol, and 5-40 parts by weight of pegylated phospholipid, dissolving in methanol, carrying out rotary evaporation, adding an ammonium sulfate aqueous solution, carrying out dialysis, adding 0.5-10 parts by weight of mitoxantrone, carrying out incubation, carrying out dialysis, adding 0.1-20 parts by weight of the estrone-pegylated phospholipid, carrying out incubation, and filtering with a membrane to obtain the liposome preparation. Compared with the liposome in the prior art, the obtained estrogen targeting PEG-modified liposome has characteristics of high encapsulation efficiency, uniform particle size, pharmacokinetics improving, anti-tumor efficacy enhancing, toxicity reducing, simple preparation process and easy scale-up production, and is expected to become the novel pharmaceutical preparation for cancer therapy. The uses are targeted treatments of breast cancer, leukemia and other cancers.

Description

technical field [0001] The invention relates to the field of drug liposomes, in particular to a mitoxantrone estrogen-targeted PEG-modified liposome and an application thereof. Background technique [0002] Mitoxantrone is a classic chemotherapy drug in clinical practice. Its chemical structure belongs to anthraquinone compounds. It has anti-tumor effects on breast cancer, leukemia, lymphoma, prostate cancer, etc., especially for refractory and refractory breast cancer. Cancer and leukemia have significant curative effect, and recently it has been used as an immunosuppressant for the treatment of multiple sclerosis. Due to its severe side effects such as myelosuppression, dose-limiting cardiotoxicity, gastrointestinal toxicity and hair loss during its clinical application, its clinical application and therapeutic effect are limited. [0003] As a drug carrier, liposomes are becoming more and more mature in the chemotherapy of tumors. As a drug carrier, liposomes have the fo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/127A61K31/136A61K47/34A61P35/00
Inventor 裴瑾徐国兴郝强高海成杨越王曾孙雨馨张正丛登立段明华
Owner JILIN UNIV
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