Anti-tumor predrug by taking novel amphipathic dendritic macromolecules as carriers based on glycerol as branching unit and preparation method thereof

A branching unit and dendritic technology, applied in the field of anti-tumor prodrugs and preparation, to achieve the effect of improving hydrophilicity, improving degradability, and good reproducibility

Inactive Publication Date: 2010-01-06
XIANGTAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The prodrug is amphiphilic and can be made into a water-based preparation, which overcomes the shortcomings of the existing paclitaxel preparations such as poor water solubility and severe allergic reactions

Method used

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  • Anti-tumor predrug by taking novel amphipathic dendritic macromolecules as carriers based on glycerol as branching unit and preparation method thereof
  • Anti-tumor predrug by taking novel amphipathic dendritic macromolecules as carriers based on glycerol as branching unit and preparation method thereof
  • Anti-tumor predrug by taking novel amphipathic dendritic macromolecules as carriers based on glycerol as branching unit and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1: Preparation of an amphiphilic dendrimer paclitaxel prodrug containing a glycolic acid oligomer.

[0032] a) Add 9g of glycolic acid and 350mL of anhydrous ether into a 500ml single-necked round bottom flask with magnetic stirring. After the glycolic acid is completely dissolved, add 5.69mL of benzyl bromide and 12g of catalyst, and react for 24 hours. After the reaction was completed, it was filtered, and the filtrate was concentrated with a rotary evaporator. After extraction, 8.5 g of the product was obtained, with a yield of 80.7%.

[0033] b) Add 136g of benzaldehyde, 102g of glycerol, 20ml of cyclohexane and a catalyst into a 500ml single-necked flask with magnetic stirring and water separator, react at 100°C for 4.5h, pour off the upper layer of cyclohexane, and add 150ml of dihydrogen to the system. Chloromethane was extracted three times with alkaline aqueous solution, saturated NaCl solution and water respectively. Dry over anhydrous magnesium sulfa...

Embodiment 2

[0040] Example 2: Preparation of an amphiphilic dendrimer paclitaxel prodrug containing alternating oligomers of glycolic acid and lactic acid.

[0041] a) 2g 2-benzyloxypropanediol, 6g tert-butyl bromopropionate, 50ml dichloromethane, and 1.6g base were added in a 250ml single-mouthed round-bottomed flask with a magnetic stirring device, and after 24 hours of reaction, the precipitate was filtered off, Concentrate the solvent by rotary evaporation, use petroleum ether: ethyl acetate as the developing solvent, and separate through the column. A monomer in which the benzyl group protects the hydroxyl group and the tert-butyl group protects the carboxyl group is obtained.

[0042] b) Add 5g of lactic acid and 3.8g of alkali into a 250ml single-necked flask with magnetic stirring and condensing reflux device. After 4 hours of salt formation reaction, add 5.6g of tert-butyl bromoacetate. After 24 hours of reflux reaction, filter the precipitate generated by the reaction . Concen...

Embodiment 3

[0045] Example 3: Preparation of an amphiphilic dendrimer paclitaxel prodrug containing alternating oligomers of glycolic acid and glycine.

[0046] a) Preparation of glycolic acid glycine oligomer (taking tetramerization as an example): add an equivalent amount of fluorenylmethoxycarbonyl (Fmoc)-protected glycine and tert-butyl bromoacetate, 100ml anhydrous tetrahydrofuran in a 250ml single-necked flask, After completely dissolving, add an equimolar amount of alkali to form a salt, and a catalyst, and reflux the reaction. After the reaction was completed, it was separated by column chromatography to obtain a white solid (glycolic acid glycine dimer with tert-butyl-protected carboxyl group, Fmoc-protected amino group). Take 5g of each of these dimers, and use 100m piperidine / DMF solution to remove the Fmoc group and glycolic acid glycine dimer respectively.

[0047] b) The same amount of glycolic acid glycolic acid glycine dimer and bromoacetic acid described in a are dissolv...

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Abstract

The invention provides an anti-tumor predrug by taking novel amphipathic dendritic macromolecules as carriers based on glycerol as a branching unit and a preparation method thereof. The novel amphipathic dendritic macromolecules that are biodegradable are constructed based on glycerol and glycolic acid oligomer, lactic acid oligomer, glycolic acid and lactic acid alternative oligomer, glycolic acid, lactic acid and amino acid alternative oligomer, and copolymerization oligomer of all as well as polyethylene glycol or polyethylene glycol monomethyl ether; and the novel amphipathic dendritic macromolecules are in bonding reaction with anti-tumor medicines under the existence of a condensing agent, thereby obtaining the predrug of the anti-tumor medicines. The anti-tumor predrug improves the biocompatibility of medicinal carrier materials better, regulates and controls the degradation speed of the medicinal carrier materials in the human body by regulating the polymerization degree and the chemical compositions of oligomer simultaneously, realizes the regulation and control functions to release speed of medicines, has better medicinal slowly-controlled release function and avoids causing toxic and side effects to normal cells due to burst release of anti-tumor medicines.

Description

Technical field: [0001] The invention relates to an anti-tumor prodrug based on a novel amphiphilic degradable dendritic macromolecule with glycerol as a branch unit as a carrier and a preparation method thereof. technical background: [0002] In recent years, the development of pharmaceutical dosage forms is inseparable from polymers. Polymer materials play two important roles in it: serving as drug carriers and imparting controlled release functions. At present, the polymer materials used as drug controlled release carriers combine with drug molecules to form many polymer drug controlled release systems, that is, the use of natural or synthetic polymer compounds to embed drugs or other bioactive agents to enable long-term release of drugs, or To prolong the time that drugs circulate in the body, or to release drugs in response to stimuli. An ideal drug carrier should include the following characteristics: good biocompatibility, precise and controllable structure, narrow ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61P35/00A61K47/59A61K47/60
Inventor 张雪飞付军张力钟冠群张海良
Owner XIANGTAN UNIV
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