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Tripterine-dendritic macromolecular conjugate, preparation method thereof and application

A technology for triptolide and dendrimer, which is applied in the field of triptolide-dendrimer conjugate and its preparation, and can solve the problems of prolonging the systemic circulation time and not having specific targeting to tumor cells, etc. , to reduce toxic side effects, solve poor water solubility, and prolong circulation time

Active Publication Date: 2018-11-27
XIAMEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are many nano-preparations for improving the bioavailability of tripteryne at present, such as tripteryne flexible liposome (CN107149593A), tripteryne nanosuspension (CN106309364A), tripteryne immune nanoparticles (CN104800164A) etc., but these agents often do not have the ability to specifically target tumor cells and prolong the time in systemic circulation

Method used

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  • Tripterine-dendritic macromolecular conjugate, preparation method thereof and application
  • Tripterine-dendritic macromolecular conjugate, preparation method thereof and application
  • Tripterine-dendritic macromolecular conjugate, preparation method thereof and application

Examples

Experimental program
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Effect test

Embodiment 1

[0055] Example 1: Preparation of tripterine-fifth generation dendrimer conjugate modified by targeting EpCAM aptamer

[0056] (1) Take 20ml of the fifth generation PAMAM (G5-NH 2 ) (5mg / ml) methanol solution, rotate to remove methanol, completely dissolve in N,N-dimethylformamide, add 44.4mg of succinic anhydride in the dark, and stir at room temperature overnight for 24 hours, after the reaction, use a dialyzer with a molecular weight of 3500 ddH 2 Dialyzed against O for two days and then freeze-dried to obtain the G5-COOH polymer.

[0057] (2) Weigh 4.5 mg of G5-COOH polymer and dissolve it in phosphate buffered saline (PBS, pH6.8), add 4.8 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC ), after stirring at room temperature for 15 minutes in the dark, then add 1.4 mg of N-hydroxysuccinimide (NHS), continue stirring at room temperature for 45 minutes, and then add 40.5 mg of NHS 2 -PEG-COOH, stirred at room temperature overnight in the dark, after the reaction, p...

Embodiment 2

[0064] Example 2: Preparation of tripterine-fifth generation dendrimer conjugate modified by targeting EpCAM antibody

[0065] (1) Take 60ml of the fifth generation PAMAM (G5-NH 2 ) (5mg / ml) methanol solution on a rotary evaporator to remove methanol, then completely dissolved in N,N-dimethylformamide, added 133.2mg succinic anhydride in the dark and stirred at room temperature overnight, after the reaction was completed, use Dialysis bag placed in ddH 2 Dialyzed against O for two days and then freeze-dried to obtain the G5-COOH polymer.

[0066] (2) Weigh 3 mg of G5-COOH polymer and dissolve it in phosphate buffered saline (PBS) at pH 6.8, add 14.4 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide ( EDC), after stirring at room temperature for 15min in the dark, then add 4.2mg N-hydroxysuccinimide (NHS), continue stirring at room temperature for 45min, then add 121.5mg NH 2 -PEG-COOH, stirred at room temperature overnight in the dark, after the reaction, put a dialysis b...

Embodiment 3

[0069] Example 3: Preparation of tripterine-sixth generation dendrimer conjugate targeting EpCAM aptamer / antibody modification (1) Take 20ml of the sixth generation PAMAM (G6-NH 2 ) (5mg / ml) methanol solution on a rotary evaporator to remove methanol, then completely dissolved in N,N-dimethylformamide, added 44mg succinic anhydride in the dark and stirred at room temperature overnight, after the reaction was completed, dialyzed with a molecular weight of 3500 ddH 2 Dialyzed against O for two days and then freeze-dried to obtain the G6-COOH polymer. Other steps are the same as above (2), (3), (4).

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Abstract

The invention discloses a tripterine-dendritic macromolecular conjugate, a preparation method thereof and an application, and relates to a tripterine. The tripterine-dendritic macromolecular conjugatecomprises a center dendritic polyamide-organic polyamidoaminedendrimer nano-carrier, polyethylene glycol, surface targeting ligands and the tripterine. The preparation method of the conjugate includes the steps: performing partial carboxylation on amidogen on the surface of PAMAM (polyamidoaminedendrimers) by butanedioic anhydride; dialyzing and freeze-drying a partial carboxylation object to obtain a PAMAM-COOH derivative; activating the PAMAM-COOH derivative by EDC / NHS, and modifying the activated derivative by the polyethylene glycol; dialyzing the modified derivative to obtain the PAMAM-PEG-COOH derivative; activating the PAMAM-PEG-COOH derivative by EDC / NHS; connecting the activated PAMAM-PEG-COOH derivative with EpCAM targeting aptamers; removing unreacted aptamers in an ultra-filtering manner to obtain a multifunctional PAMAM derivative; dissolving the tripterine by solvents; activating the dissolved tripterine by EDC / NHS; covalently complexing the activated tripterine on the surface of the PAMAM derivative; dialyzing a complexed object to obtain the conjugate.

Description

technical field [0001] The invention relates to tripterine, in particular to a tripterine-dendrimer conjugate and a preparation method and application thereof. Background technique [0002] Cancer has become the number one killer threatening human health worldwide, and the morbidity and mortality of colon cancer rank among the top five among all cancers. In addition to surgical resection, chemotherapy is still one of the most important adjuvant treatments for colon cancer. However, due to the limited content of chemical drugs reaching the tumor site, it is usually difficult to bring effective therapeutic effects, and the toxic and side effects are strong. The lack of efficacy and safety greatly limits the approval progress and clinical application of new chemical drugs. [0003] Celastrol, also known as celastrol and celastrol, is a natural triterpenoid compound. Its chemical name is: 3-hydroxy-24-nor-2-oxo-1(10), 3,5,7-phthalate-29-oleic acid, and its molecular formula i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/59A61K47/68A61K31/56A61P35/00A61P35/02
CPCA61K31/56A61K47/595A61K47/68A61P35/00A61P35/02
Inventor 谢静静葛鹏金牛博宁张晓坤
Owner XIAMEN UNIV
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