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Phospholipase A2 sensitive glycerin skeleton anti-tumor prodrug and high-dispersing preparation thereof

An anti-tumor drug and anti-tumor technology, applied in the field of biomedicine, can solve the problems of low encapsulation rate, leakage of drugs into external water, etc., and achieve high-efficiency anti-tumor effect

Inactive Publication Date: 2014-12-17
ACADEMY OF MILITARY MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These factors determine that the encapsulation rate of most water-soluble drugs is low (<50%), sometimes very low (5%), and the encapsulation of the drug has the possibility of leakage into the outer water phase

Method used

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  • Phospholipase A2 sensitive glycerin skeleton anti-tumor prodrug and high-dispersing preparation thereof
  • Phospholipase A2 sensitive glycerin skeleton anti-tumor prodrug and high-dispersing preparation thereof
  • Phospholipase A2 sensitive glycerin skeleton anti-tumor prodrug and high-dispersing preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 11- 18

[0035] Example 1.1-octadecyl-2-conjugated linoleoyl-3-phosphoryl gemcitabine glyceride (OLGPG)

[0036] 1. Synthesis of N-benzoyl-3'-O-acetyl gemcitabine (BAG)

[0037] Dissolve gemcitabine (0.2638g, 1mmol) in 50ml of ethanol, reflux at 80°C, add benzoic anhydride (0.2728g, 1.2mmol) to continue the reaction for 1 hour, then add 1 part of benzoic anhydride (1.2mmol) per hour, and continue to add 3 time, a total of 3 hours, after the last 1 portion of benzoic anhydride was added, the reflux reaction was continued for 1 hour, and the solvent was removed under reduced pressure to obtain a colorless transparent viscous liquid. Dissolved in chloroform containing 4% methanol, separated on a silica gel column, collected dichloromethane: methanol = 15: 1 the corresponding components washed out from the eluent, and removed the solvent under reduced pressure to obtain white powdery N-benzoyl gemcitabine (BG).

[0038] Dissolve BG (0.3683g, 1.00mmol) and imidazole (0.2238g, 3.29mmol) in...

Embodiment 21- 18

[0053] Example 2. Preparation of sodium salt of 1-octadecyl-2-conjugated linoleoyl-3-phosphoryl gemcitabine glyceride

[0054] Molecular formula C 57 h 89 f 2 N 3 o 12 PNa. Take 1.078 g of 1-octadecyl-2-conjugated linoleoyl-3-phosphoryl gemcitabine glyceride, dissolve it in 10 ml of chloroform relative to 0.001 mol, add methanol solution containing 0.001 mol of NaOH, shake and sonicate, reduce The solvent was evaporated under pressure, and recrystallized from methanol to obtain white crystals of sodium salt of 1-octadecyl-2-conjugated linoleoyl-3-phosphoryl gemcitabine glyceride. Thin layer chromatography showed a spot. Other alkali salts such as potassium salts, calcium salts, magnesium salts, ammonia salts, and organic amine salts have similar preparation methods.

Embodiment 3

[0055] Example 3. Preparation of 1-stearyl ether-2-conjugated linoleoyl-3-phosphoryl fluoride darabine glyceride liposomes

[0056] Take 25 mg of 1-octadecyl ether-2-conjugated linoleoyl-3-phosphoryl fluoride darabine glyceride and 0.1 g of soybean lecithin in a 250 ml flask, dissolve in 20 ml of dichloromethane, and evaporate under reduced pressure. To obtain a layer of organic fat-soluble film, add 10ml of phosphate buffer solution with pH 7.4, oscillate, most of the film falls off, and sonicate at 50°C until a uniform suspension is obtained. Observe under a microscope, most of the particles are less than 1 micron in diameter. It is 1-stearyl ether-2-conjugated linoleoyl-3-phosphoryl fluoride darabine glyceride liposome.

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Abstract

The invention discloses a phospholipase A2 sensitive glycerin skeleton anti-tumor prodrug of which a molecular structure is a glycerin skeleton including a long-chain alkyl ether at a 1st position, a conjugated linoleoyl at a 2nd position and a phosphoryl nucleoside at a 3rd position. Because that a tumor tissue can highly express phospholipase A2, the glycerin skeleton anti-tumor prodrug has a tumor environmental specificity and can release a plurality of components which have activities on tumor cells at the position of the tumor. The components work in combination so that a high-efficient anti-tumor effect is achieved. An active compound of a nucleoside-type anti-tumor drug is selected from cytosine arabinoside, gemcitabine, capecitabine, fludarabine and derivatives thereof. The glycerin skeleton anti-tumor prodrug can be prepared into following high-dispersing preparations: a liposome, a nonionic surfactant vesicle, nano particles, a nano emulsion or a self-assembling transmission system.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a phospholipase A2-sensitive glycerol skeleton anti-tumor prodrug and a highly dispersed preparation thereof. Background technique [0002] Drug delivery systems (DDS) is a new concept in modern pharmacy, mainly including oral sustained and controlled release systems, transdermal drug delivery systems and targeted drug delivery systems. Targeted drug delivery systems are generally administered through blood vessels to deliver drugs to a specific tissue or site, and can be targeted to the liver, brain, tumors, etc. Among them, the tumor-targeted drug delivery system is the most studied. The microenvironment of tumor tissue is unique, including low pH (weakly acidic, pH about 6.5), overexpressed enzymes around, hypoxia in the core microenvironment, and specific expression of receptors on the cell surface. Secreted phospholipase A2 (sPLA2) is overexpressed in many tumors, and sPLA2 can s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P35/00A61K9/10A61K31/6615
Inventor 金义光杜丽娜李淼左靖
Owner ACADEMY OF MILITARY MEDICAL SCI
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